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Clinical Trial Results:
An Open-label Phase 1/2a Study of Oral BAL101553 in Adult Patients With Advanced Solid Tumors and in Adult Patients With Recurrent or Progressive Glioblastoma or High-grade Glioma

Summary
EudraCT number	2014-003371-34
Trial protocol	GB DE BE
Global end of trial date	24 Nov 2022

Results information
Results version number	v1(current)
This version publication date	16 Nov 2023
First version publication date	16 Nov 2023
Other versions

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

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Trial information

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Sponsor protocol code

CDI-CS-002

ISRCTN number

US NCT number

NCT02490800

WHO universal trial number (UTN)

Sponsor organisation name

Basilea Pharmaceutica International Ltd, Allschwil

Sponsor organisation address

Hegenheimermattweg 167b, Allschwil, Switzerland, 4123

Public contact

Thomas Kaindl, MD, Basilea Pharmaceutica International Ltd, Allschwil, +41 61 567 15 24, thomas.kaindl@basilea.com

Scientific contact

Thomas Kaindl, MD, Basilea Pharmaceutica International Ltd, Allschwil, +41 61 567 15 24, thomas.kaindl@basilea.com

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

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

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

Analysis stage

Final

Date of interim/final analysis

16 Dec 2022

Is this the analysis of the primary completion data?

Yes

Primary completion date

30 Sep 2022

Global end of trial reached?

Yes

Global end of trial date

24 Nov 2022

Was the trial ended prematurely?

Main objective of the trial

To determine the maximum tolerated dose (MTD) and to characterize dose-limiting toxicities (DLTs) of daily oral lisavanbulin, administered to adults with advanced or recurrent solid tumors who have failed standard therapy, or for whom no effective standard therapy is available, and to patients with recurrent or progressive glioblastoma (GBM) or high-grade glioma (HGG).

Protection of trial subjects

The study was conducted according to the ethical principles that have their origins in the World Medical Association’s Declaration of Helsinki, the International Council for Harmonisation (ICH) E6 Good Clinical Practice, and all applicable national and local laws and regulations for the conduct of clinical research and the protection of personal data. If conflicts between local laws and regulations arose, the more stringent requirements were adopted.

Background therapy

Evidence for comparator

Actual start date of recruitment

20 May 2015

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

United Kingdom: 63

Country: Number of subjects enrolled

Belgium: 2

Country: Number of subjects enrolled

Switzerland: 4

Country: Number of subjects enrolled

Germany: 3

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

Screening details

In the Phase 1 study, a total of 29 screening-failures occurred. Thus, a total of 72 patients with advanced solid tumors, recurrent or progressive glioblastoma (GBM) or high-grade glioma (HGG) were enrolled in this Phase 1 and Phase 2a study.

Period 1 title

Overall trial (overall period)

Is this the baseline period?

Yes

Allocation method

Not applicable

Blinding used

Not blinded

Are arms mutually exclusive

Yes

Phase 1 patients with solid tumors: Lisavanbulin 2 mg

Arm description

Solid tumor patients treated with lisavanbulin 2 mg/day in the dose escalation portion of the study

Arm type

Experimental

Investigational medicinal product name

Lisavanbulin

Investigational medicinal product code

BAL101553

Other name

Pharmaceutical forms

Capsule, hard

Routes of administration

Oral use

Dosage and administration details

Lisavanbulin 2 mg was given orally once daily to fasted patients until disease progression, unacceptable toxicity, or other discontinuation criteria were met.

Phase 1 patients with solid tumors: Lisavanbulin 4 mg

Arm description

Solid tumor patients treated with lisavanbulin 4 mg/day in the dose escalation portion of the study

Arm type

Experimental

Investigational medicinal product name

Lisavanbulin

Investigational medicinal product code

BAL101553

Other name

Pharmaceutical forms

Capsule, hard

Routes of administration

Oral use

Dosage and administration details

Lisavanbulin 4 mg was given orally once daily to fasted patients until disease progression, unacceptable toxicity, or other discontinuation criteria were met.

Phase 1 patients with solid tumors: Lisavanbulin 8 mg

Arm description

Solid tumor patients treated with lisavanbulin 8 mg/day in the dose escalation portion of the study

Arm type

Experimental

Investigational medicinal product name

Lisavanbulin

Investigational medicinal product code

BAL101553

Other name

Pharmaceutical forms

Capsule, hard

Routes of administration

Oral use

Dosage and administration details

Lisavanbulin 8 mg was given orally once daily to fasted patients until disease progression, unacceptable toxicity, or other discontinuation criteria were met.

Phase 1 patients with solid tumors: Lisavanbulin 16 mg

Arm description

Solid tumor patients treated with lisavanbulin 16 mg/day in the dose escalation portion of the study

Arm type

Experimental

Investigational medicinal product name

Lisavanbulin

Investigational medicinal product code

BAL101553

Other name

Pharmaceutical forms

Capsule, hard

Routes of administration

Oral use

Dosage and administration details

Lisavanbulin 16 mg was given orally once daily to fasted patients until disease progression, unacceptable toxicity, or other discontinuation criteria were met.

Phase 1 patients with solid tumors: Lisavanbulin 20 mg

Arm description

Solid tumor patients treated with lisavanbulin 20 mg/day in the dose escalation portion of the study

Arm type

Experimental

Investigational medicinal product name

Lisavanbulin

Investigational medicinal product code

BAL101553

Other name

Pharmaceutical forms

Capsule, hard

Routes of administration

Oral use

Dosage and administration details

Lisavanbulin 20 mg was given orally once daily to fasted patients until disease progression, unacceptable toxicity, or other discontinuation criteria were met.

Phase 1 patients with solid tumors: Lisavanbulin 30 mg

Arm description

Solid tumor patients treated with lisavanbulin 30 mg/day in the dose escalation portion of the study

Arm type

Experimental

Investigational medicinal product name

Lisavanbulin

Investigational medicinal product code

BAL101553

Other name

Pharmaceutical forms

Capsule, hard

Routes of administration

Oral use

Dosage and administration details

Lisavanbulin 30 mg was given orally once daily to fasted patients until disease progression, unacceptable toxicity, or other discontinuation criteria were met.

Phase 1 patients with GBM / HGG: Lisavanbulin 8 mg

Arm description

HGG and GBM patients treated with lisavanbulin 8 mg/day in the dose escalation portion of the study

Arm type

Experimental

Investigational medicinal product name

Lisavanbulin

Investigational medicinal product code

BAL101553

Other name

Pharmaceutical forms

Capsule, hard

Routes of administration

Oral use

Dosage and administration details

Lisavanbulin 8 mg was given orally once daily to fasted patients until disease progression, unacceptable toxicity, or other discontinuation criteria were met.

Phase 1 patients with GBM / HGG: Lisavanbulin 15 mg

Arm description

HGG and GBM patients treated with lisavanbulin 15 mg/day in the dose escalation portion of the study

Arm type

Experimental

Investigational medicinal product name

Lisavanbulin

Investigational medicinal product code

BAL101553

Other name

Pharmaceutical forms

Capsule, hard

Routes of administration

Oral use

Dosage and administration details

Lisavanbulin 15 mg was given orally once daily to fasted patients until disease progression, unacceptable toxicity, or other discontinuation criteria were met.

Phase 1 patients with GBM / HGG: Lisavanbulin 20 mg

Arm description

HGG and GBM patients treated with lisavanbulin 20 mg/day in the dose escalation portion of the study

Arm type

Experimental

Investigational medicinal product name

Lisavanbulin

Investigational medicinal product code

BAL101553

Other name

Pharmaceutical forms

Capsule, hard

Routes of administration

Oral use

Dosage and administration details

Lisavanbulin 20 mg was given orally once daily to fasted patients until disease progression, unacceptable toxicity, or other discontinuation criteria were met.

Phase 1 patients with GBM / HGG: Lisavanbulin 25 mg

Arm description

HGG and GBM patients treated with lisavanbulin 25 mg/day in the dose escalation portion of the study

Arm type

Experimental

Investigational medicinal product name

Lisavanbulin

Investigational medicinal product code

BAL101553

Other name

Pharmaceutical forms

Capsule, hard

Routes of administration

Oral use

Dosage and administration details

Lisavanbulin 25 mg was given orally once daily to fasted patients until disease progression, unacceptable toxicity, or other discontinuation criteria were met.

Phase 1 patients with GBM / HGG: Lisavanbulin 30 mg

Arm description

HGG and GBM patients treated with lisavanbulin 30 mg/day in the dose escalation portion of the study

Arm type

Experimental

Investigational medicinal product name

Lisavanbulin

Investigational medicinal product code

BAL101553

Other name

Pharmaceutical forms

Capsule, hard

Routes of administration

Oral use

Dosage and administration details

Lisavanbulin 30 mg was given orally once daily to fasted patients until disease progression, unacceptable toxicity, or other discontinuation criteria were met.

Phase 1 patients with GBM / HGG: Lisavanbulin 35 mg

Arm description

HGG and GBM patients treated with lisavanbulin 35 mg/day in the dose escalation portion of the study

Arm type

Experimental

Investigational medicinal product name

Lisavanbulin

Investigational medicinal product code

BAL101553

Other name

Pharmaceutical forms

Capsule, hard

Routes of administration

Oral use

Dosage and administration details

Lisavanbulin 35 mg was given orally once daily to fasted patients until disease progression, unacceptable toxicity, or other discontinuation criteria were met.

Phase 2a patients with GBM: Lisavanbulin 25 mg

Arm description

GBM patients treated with lisavanbulin 25 mg/day in the dose expansion portion of the study

Arm type

Experimental

Investigational medicinal product name

Lisavanbulin

Investigational medicinal product code

BAL101553

Other name

Pharmaceutical forms

Capsule, hard

Routes of administration

Oral use

Dosage and administration details

Lisavanbulin 25 mg was given orally once daily to fasted patients until disease progression, unacceptable toxicity, or other discontinuation criteria were met.

Number of subjects in period 1	Phase 1 patients with solid tumors: Lisavanbulin 2 mg	Phase 1 patients with solid tumors: Lisavanbulin 4 mg	Phase 1 patients with solid tumors: Lisavanbulin 8 mg	Phase 1 patients with solid tumors: Lisavanbulin 16 mg	Phase 1 patients with solid tumors: Lisavanbulin 20 mg	Phase 1 patients with solid tumors: Lisavanbulin 30 mg	Phase 1 patients with GBM / HGG: Lisavanbulin 8 mg	Phase 1 patients with GBM / HGG: Lisavanbulin 15 mg	Phase 1 patients with GBM / HGG: Lisavanbulin 20 mg	Phase 1 patients with GBM / HGG: Lisavanbulin 25 mg	Phase 1 patients with GBM / HGG: Lisavanbulin 30 mg	Phase 1 patients with GBM / HGG: Lisavanbulin 35 mg	Phase 2a patients with GBM: Lisavanbulin 25 mg
Started	3	3	3	7	7	3	4	3	7	3	8	3	18
Completed	0	0	0	0	0	0	0	0	0	0	0	0	0
Not completed	3	3	3	7	7	3	4	3	7	3	8	3	18
Consent withdrawn by subject	-	-	-	1	-	-	-	-	1	-	-	-	-
Patient enrolled in post-trial access	-	-	-	-	-	-	-	-	-	1	1	-	6
Adverse event, non-fatal	-	-	-	2	3	2	-	-	-	-	-	2	2
Progressive disease	3	3	3	4	4	1	4	3	6	2	7	1	10

Baseline characteristics

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Reporting group title

Phase 1 patients with solid tumors: Lisavanbulin 2 mg

Reporting group description

Solid tumor patients treated with lisavanbulin 2 mg/day in the dose escalation portion of the study

Reporting group title

Phase 1 patients with solid tumors: Lisavanbulin 4 mg

Reporting group description

Solid tumor patients treated with lisavanbulin 4 mg/day in the dose escalation portion of the study

Reporting group title

Phase 1 patients with solid tumors: Lisavanbulin 8 mg

Reporting group description

Solid tumor patients treated with lisavanbulin 8 mg/day in the dose escalation portion of the study

Reporting group title

Phase 1 patients with solid tumors: Lisavanbulin 16 mg

Reporting group description

Solid tumor patients treated with lisavanbulin 16 mg/day in the dose escalation portion of the study

Reporting group title

Phase 1 patients with solid tumors: Lisavanbulin 20 mg

Reporting group description

Solid tumor patients treated with lisavanbulin 20 mg/day in the dose escalation portion of the study

Reporting group title

Phase 1 patients with solid tumors: Lisavanbulin 30 mg

Reporting group description

Solid tumor patients treated with lisavanbulin 30 mg/day in the dose escalation portion of the study

Reporting group title

Phase 1 patients with GBM / HGG: Lisavanbulin 8 mg

Reporting group description

HGG and GBM patients treated with lisavanbulin 8 mg/day in the dose escalation portion of the study

Reporting group title

Phase 1 patients with GBM / HGG: Lisavanbulin 15 mg

Reporting group description

HGG and GBM patients treated with lisavanbulin 15 mg/day in the dose escalation portion of the study

Reporting group title

Phase 1 patients with GBM / HGG: Lisavanbulin 20 mg

Reporting group description

HGG and GBM patients treated with lisavanbulin 20 mg/day in the dose escalation portion of the study

Reporting group title

Phase 1 patients with GBM / HGG: Lisavanbulin 25 mg

Reporting group description

HGG and GBM patients treated with lisavanbulin 25 mg/day in the dose escalation portion of the study

Reporting group title

Phase 1 patients with GBM / HGG: Lisavanbulin 30 mg

Reporting group description

HGG and GBM patients treated with lisavanbulin 30 mg/day in the dose escalation portion of the study

Reporting group title

Phase 1 patients with GBM / HGG: Lisavanbulin 35 mg

Reporting group description

HGG and GBM patients treated with lisavanbulin 35 mg/day in the dose escalation portion of the study

Reporting group title

Phase 2a patients with GBM: Lisavanbulin 25 mg

Reporting group description

GBM patients treated with lisavanbulin 25 mg/day in the dose expansion portion of the study

Reporting group values	Phase 1 patients with solid tumors: Lisavanbulin 2 mg	Phase 1 patients with solid tumors: Lisavanbulin 4 mg	Phase 1 patients with solid tumors: Lisavanbulin 8 mg	Phase 1 patients with solid tumors: Lisavanbulin 16 mg	Phase 1 patients with solid tumors: Lisavanbulin 20 mg	Phase 1 patients with solid tumors: Lisavanbulin 30 mg	Phase 1 patients with GBM / HGG: Lisavanbulin 8 mg	Phase 1 patients with GBM / HGG: Lisavanbulin 15 mg	Phase 1 patients with GBM / HGG: Lisavanbulin 20 mg	Phase 1 patients with GBM / HGG: Lisavanbulin 25 mg	Phase 1 patients with GBM / HGG: Lisavanbulin 30 mg	Phase 1 patients with GBM / HGG: Lisavanbulin 35 mg	Phase 2a patients with GBM: Lisavanbulin 25 mg	Total
Number of subjects	3	3	3	7	7	3	4	3	7	3	8	3	18	72
Age categorical
Units: Subjects
In utero														0
Preterm newborn infants (gestational age < 37 wks)														0
Newborns (0-27 days)														0
Infants and toddlers (28 days-23 months)														0
Children (2-11 years)														0
Adolescents (12-17 years)														0
Adults (18-64 years)														0
From 65-84 years														0
85 years and over														0
Age continuous
Units: years
arithmetic mean (standard deviation)	51.3 ( 21.94 )	66.7 ( 10.50 )	63.3 ( 6.51 )	61.0 ( 16.55 )	64.4 ( 7.00 )	65.7 ( 12.06 )	53.8 ( 9.95 )	53.7 ( 7.77 )	42.3 ( 9.62 )	45.3 ( 11.50 )	53.6 ( 9.78 )	51.3 ( 16.74 )	55.6 ( 10.43 )	-
Gender categorical
Units: Subjects
Female	2	2	1	5	6	0	2	2	3	2	2	1	3	31
Male	1	1	2	2	1	3	2	1	4	1	6	2	15	41
Race
Units: Subjects
Asian	0	0	0	0	0	0	0	0	0	0	1	1	0	2
Black or African American	0	0	0	0	0	0	1	0	0	0	0	0	0	1
White	3	3	3	7	7	3	3	3	7	3	7	2	18	69

End points

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Reporting group title

Phase 1 patients with solid tumors: Lisavanbulin 2 mg

Reporting group description

Solid tumor patients treated with lisavanbulin 2 mg/day in the dose escalation portion of the study

Reporting group title

Phase 1 patients with solid tumors: Lisavanbulin 4 mg

Reporting group description

Solid tumor patients treated with lisavanbulin 4 mg/day in the dose escalation portion of the study

Reporting group title

Phase 1 patients with solid tumors: Lisavanbulin 8 mg

Reporting group description

Solid tumor patients treated with lisavanbulin 8 mg/day in the dose escalation portion of the study

Reporting group title

Phase 1 patients with solid tumors: Lisavanbulin 16 mg

Reporting group description

Solid tumor patients treated with lisavanbulin 16 mg/day in the dose escalation portion of the study

Reporting group title

Phase 1 patients with solid tumors: Lisavanbulin 20 mg

Reporting group description

Solid tumor patients treated with lisavanbulin 20 mg/day in the dose escalation portion of the study

Reporting group title

Phase 1 patients with solid tumors: Lisavanbulin 30 mg

Reporting group description

Solid tumor patients treated with lisavanbulin 30 mg/day in the dose escalation portion of the study

Reporting group title

Phase 1 patients with GBM / HGG: Lisavanbulin 8 mg

Reporting group description

HGG and GBM patients treated with lisavanbulin 8 mg/day in the dose escalation portion of the study

Reporting group title

Phase 1 patients with GBM / HGG: Lisavanbulin 15 mg

Reporting group description

HGG and GBM patients treated with lisavanbulin 15 mg/day in the dose escalation portion of the study

Reporting group title

Phase 1 patients with GBM / HGG: Lisavanbulin 20 mg

Reporting group description

HGG and GBM patients treated with lisavanbulin 20 mg/day in the dose escalation portion of the study

Reporting group title

Phase 1 patients with GBM / HGG: Lisavanbulin 25 mg

Reporting group description

HGG and GBM patients treated with lisavanbulin 25 mg/day in the dose escalation portion of the study

Reporting group title

Phase 1 patients with GBM / HGG: Lisavanbulin 30 mg

Reporting group description

HGG and GBM patients treated with lisavanbulin 30 mg/day in the dose escalation portion of the study

Reporting group title

Phase 1 patients with GBM / HGG: Lisavanbulin 35 mg

Reporting group description

HGG and GBM patients treated with lisavanbulin 35 mg/day in the dose escalation portion of the study

Reporting group title

Phase 2a patients with GBM: Lisavanbulin 25 mg

Reporting group description

GBM patients treated with lisavanbulin 25 mg/day in the dose expansion portion of the study

Subject analysis set title

MTD-evaluable patients with solid tumors

Subject analysis set type

Sub-group analysis

Subject analysis set description

All patients who received at least one dose of lisavanbulin and experienced a DLT, or received at least 24 doses without experiencing a DLT during the first 28 days.

Subject analysis set title

MTD-evaluable patients with GBM or HGG

Subject analysis set type

Sub-group analysis

Subject analysis set description

All patients who received at least one dose of lisavanbulin and experienced a DLT, or received at least 24 doses without experiencing a DLT during the first 28 days.

Primary: Phase 1: Maximum tolerated dose (MTD) of daily oral lisavanbulin

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End point title

Phase 1: Maximum tolerated dose (MTD) of daily oral lisavanbulin ^[1]

End point description

MTD: highest dose level of lisavanbulin at which no more than 1 of 6 MTD-evaluable subjects experienced dose limiting toxicities (DLT).

End point type

Primary

End point timeframe

During first 28 day cycle

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: As the endpoint is descriptive in nature, no statistical analysis is provided.

End point values	MTD-evaluable patients with solid tumors	MTD-evaluable patients with GBM or HGG
Number of subjects analysed	23	24
Units: mg
number (not applicable)
MTD of daily oral lisavanbulin	16	30

No statistical analyses for this end point

Primary: Phase 2a: Objective Response Rate (ORR)

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End point title

Phase 2a: Objective Response Rate (ORR) ^[2] ^[3]

End point description

The ORR was calculated as the proportion of patients (rate) with complete or partial responses and its 95% Confidence Interval (CI) based on RANO criteria.

End point type

Primary

End point timeframe

Assessed every 8 weeks from time of first dose until disease progression.

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: As the endpoint is descriptive in nature, no statistical analysis is provided.
[3] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This primary endpoint only applies to Phase 2a.

End point values	Phase 2a patients with GBM: Lisavanbulin 25 mg
Number of subjects analysed	9
Units: proportion of patients (rate)
number (confidence interval 95%)	11.1 (0.3 to 48.2)

No statistical analyses for this end point

Primary: Phase 2a: Best objective response

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End point title

Phase 2a: Best objective response ^[4] ^[5]

End point description

The best objective response in patients with measurable disease at baseline and at least one "radiological assessment in neuro-oncology (RANO)" after 6 weeks of study treatment.

End point type

Primary

End point timeframe

Assessed every 8 weeks from time of first dose until disease progression.

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: As the endpoint is descriptive in nature, no statistical analysis is provided.
[5] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This primary endpoint only applies to Phase 2a.

End point values	Phase 2a patients with GBM: Lisavanbulin 25 mg
Number of subjects analysed	9
Units: Number of patients
Complete response	0
Partial response	1
Stable disease	4
Progressive disease	4

No statistical analyses for this end point

Secondary: Number of Patients With CTCAE Grade 3-4 TEAEs

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End point title

Number of Patients With CTCAE Grade 3-4 TEAEs

End point description

Number of patients experiencing treatment-emergent adverse events (TEAE) of CTCAE Grade 3 or 4.

End point type

Secondary

End point timeframe

TEAEs were defined as all events occurring after lisavanbulin treatment began and up to 28 days after last study drug administration.

End point values	Phase 1 patients with solid tumors: Lisavanbulin 2 mg	Phase 1 patients with solid tumors: Lisavanbulin 4 mg	Phase 1 patients with solid tumors: Lisavanbulin 8 mg	Phase 1 patients with solid tumors: Lisavanbulin 16 mg	Phase 1 patients with solid tumors: Lisavanbulin 20 mg	Phase 1 patients with solid tumors: Lisavanbulin 30 mg	Phase 1 patients with GBM / HGG: Lisavanbulin 8 mg	Phase 1 patients with GBM / HGG: Lisavanbulin 15 mg	Phase 1 patients with GBM / HGG: Lisavanbulin 20 mg	Phase 1 patients with GBM / HGG: Lisavanbulin 25 mg	Phase 1 patients with GBM / HGG: Lisavanbulin 30 mg	Phase 1 patients with GBM / HGG: Lisavanbulin 35 mg	Phase 2a patients with GBM: Lisavanbulin 25 mg
Number of subjects analysed	3	3	3	7	7	3	4	3	7	3	8	3	18
Units: Number of patients
Patients with unrelated TEAEs of Grade 3-4	0	1	0	3	1	0	1	0	1	1	4	0	5
Patients with related TEAEs of Grade 3-4	0	0	1	2	4	2	0	0	0	0	0	1	3
Patients without TEAEs of Grade 3-4	3	2	2	2	2	1	3	3	6	2	4	2	10

No statistical analyses for this end point

Secondary: Phase 1: Best Objective Response

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End point title

Phase 1: Best Objective Response ^[6]

End point description

The best objective response according to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 for patients with advanced or recurrent solid tumors and based on RANO criteria for patients with recurrent or progressive GBM / HGG.

End point type

Secondary

End point timeframe

Assessed every 8 weeks from time of first dose until disease progression.

Notes
[6] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This secondary endpoint only applies to Phase 1.

End point values	Phase 1 patients with solid tumors: Lisavanbulin 2 mg	Phase 1 patients with solid tumors: Lisavanbulin 4 mg	Phase 1 patients with solid tumors: Lisavanbulin 8 mg	Phase 1 patients with solid tumors: Lisavanbulin 16 mg	Phase 1 patients with solid tumors: Lisavanbulin 20 mg	Phase 1 patients with solid tumors: Lisavanbulin 30 mg	Phase 1 patients with GBM / HGG: Lisavanbulin 8 mg	Phase 1 patients with GBM / HGG: Lisavanbulin 15 mg	Phase 1 patients with GBM / HGG: Lisavanbulin 20 mg	Phase 1 patients with GBM / HGG: Lisavanbulin 25 mg	Phase 1 patients with GBM / HGG: Lisavanbulin 30 mg	Phase 1 patients with GBM / HGG: Lisavanbulin 35 mg
Number of subjects analysed	3	3	3	7	7	3	4	3	7	3	8	3
Units: Number of patients
Complete response	0	0	0	0	0	0	0	0	0	0	1	0
Partial response	0	0	0	0	0	0	0	0	0	1	0	0
Stable disease	1	0	1	4	3	1	0	1	2	1	1	2
Progressive disease	2	3	2	2	4	2	4	2	5	1	5	1
Missing	0	0	0	1	0	0	0	0	0	0	1	0

No statistical analyses for this end point

Secondary: Phase 1: Objective Response Rate (ORR)

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End point title

Phase 1: Objective Response Rate (ORR) ^[7]

End point description

The ORR was calculated as the proportion of patients (rate) with complete or partial responses and its 95% CI based on RECIST criteria v1.1 for patients with advanced or recurrent solid tumors; and based on RANO criteria for patients with recurrent or progressive GBM / HGG.

End point type

Secondary

End point timeframe

Assessed every 8 weeks from time of first dose until disease progression.

Notes
[7] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This secondary endpoint only applies to Phase 1.

Phase 1 patients with solid tumors: Lisavanbulin 2 mg

Phase 1 patients with solid tumors: Lisavanbulin 4 mg

Phase 1 patients with solid tumors: Lisavanbulin 8 mg

Phase 1 patients with solid tumors: Lisavanbulin 16 mg

Phase 1 patients with solid tumors: Lisavanbulin 20 mg

Phase 1 patients with solid tumors: Lisavanbulin 30 mg

Phase 1 patients with GBM / HGG: Lisavanbulin 8 mg

Phase 1 patients with GBM / HGG: Lisavanbulin 15 mg

Phase 1 patients with GBM / HGG: Lisavanbulin 20 mg

Phase 1 patients with GBM / HGG: Lisavanbulin 25 mg

Phase 1 patients with GBM / HGG: Lisavanbulin 30 mg

Phase 1 patients with GBM / HGG: Lisavanbulin 35 mg

Number of subjects analysed

Units: Proportion of patients (rate)

number (confidence interval 95%)

0 (0.0 to 70.8)

0 (0.0 to 41.0)

0 (0.0 to 70.8)

0 (0.0 to 60.2)

0 (0.0 to 70.8)

0 (0.0 to 41.0)

33.3 (0.8 to 90.6)

12.5 (0.3 to 52.7)

0 (0.0 to 70.8)

No statistical analyses for this end point

Secondary: Phase 2a: PFS at 6 Months

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End point title

Phase 2a: PFS at 6 Months ^[8]

End point description

The probability of being event free at 6 months

End point type

Secondary

End point timeframe

Six months

Notes
[8] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint only applies to Phase 2a.

End point values	Phase 2a patients with GBM: Lisavanbulin 25 mg
Number of subjects analysed	18
Units: percent
number (confidence interval 95%)	31.3 (11.8 to 53.1)

No statistical analyses for this end point

Secondary: Phase 2a: Progression-free survival (PFS)

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End point title

Phase 2a: Progression-free survival (PFS) ^[9]

End point description

PFS was defined as the interval between the date of first study drug administration and the earliest date of objective disease progression based on RANO criteria. Patients who have not progressed or died at the end of the study were censored at the time of their latest objective tumor assessment.

End point type

Secondary

End point timeframe

Assessed every 8 weeks from time of first dose until disease progression.

Notes
[9] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint only applies to Phase 2a.

End point values	Phase 2a patients with GBM: Lisavanbulin 25 mg
Number of subjects analysed	18
Units: Months
median (confidence interval 95%)	2.5 (1.4 to 7.5)

No statistical analyses for this end point

Secondary: Phase 2a: Overall survival (OS) at 12 months

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End point title

Phase 2a: Overall survival (OS) at 12 months ^[10]

End point description

The probability of surviving for twelve months

End point type

Secondary

End point timeframe

Twelve months

Notes
[10] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint only applies to Phase 2a.

End point values	Phase 2a patients with GBM: Lisavanbulin 25 mg
Number of subjects analysed	18
Units: percent
number (confidence interval 95%)	42.9 (15.9 to 67.8)

No statistical analyses for this end point

Secondary: AUC of avanbulin (BAL27862)

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End point title

AUC of avanbulin (BAL27862)

End point description

Area under the plasma concentration time curve from time point zero to the last quantifiable concentration

End point type

Secondary

End point timeframe

Day 1 of Cycle 1

End point values	Phase 1 patients with solid tumors: Lisavanbulin 2 mg	Phase 1 patients with solid tumors: Lisavanbulin 4 mg	Phase 1 patients with solid tumors: Lisavanbulin 8 mg	Phase 1 patients with solid tumors: Lisavanbulin 16 mg	Phase 1 patients with solid tumors: Lisavanbulin 20 mg	Phase 1 patients with solid tumors: Lisavanbulin 30 mg	Phase 1 patients with GBM / HGG: Lisavanbulin 8 mg	Phase 1 patients with GBM / HGG: Lisavanbulin 15 mg	Phase 1 patients with GBM / HGG: Lisavanbulin 20 mg	Phase 1 patients with GBM / HGG: Lisavanbulin 25 mg	Phase 1 patients with GBM / HGG: Lisavanbulin 30 mg	Phase 1 patients with GBM / HGG: Lisavanbulin 35 mg	Phase 2a patients with GBM: Lisavanbulin 25 mg
Number of subjects analysed	3	3	3	7	7	3	4	3	7	3	8	3	18
Units: h*ng/mL
geometric mean (geometric coefficient of variation)	34.040 ( 0.840 )	180.060 ( 0.150 )	258.460 ( 0.320 )	823.980 ( 0.350 )	1014.130 ( 0.650 )	1649.350 ( 0.250 )	230.800 ( 0.800 )	692.230 ( 0.160 )	344.540 ( 0.580 )	575.060 ( 0.440 )	1055.130 ( 0.250 )	1264.610 ( 0.320 )	713.710 ( 0.480 )

No statistical analyses for this end point

Secondary: Half-life of avanbulin (BAL27862)

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End point title

Half-life of avanbulin (BAL27862)

End point description

Terminal half-life

End point type

Secondary

End point timeframe

Day 1 of Cycle 1

Phase 1 patients with solid tumors: Lisavanbulin 2 mg

Phase 1 patients with solid tumors: Lisavanbulin 4 mg

Phase 1 patients with solid tumors: Lisavanbulin 8 mg

Phase 1 patients with solid tumors: Lisavanbulin 16 mg

Phase 1 patients with solid tumors: Lisavanbulin 20 mg

Phase 1 patients with solid tumors: Lisavanbulin 30 mg

Phase 1 patients with GBM / HGG: Lisavanbulin 8 mg

Phase 1 patients with GBM / HGG: Lisavanbulin 15 mg

Phase 1 patients with GBM / HGG: Lisavanbulin 20 mg

Phase 1 patients with GBM / HGG: Lisavanbulin 25 mg

Phase 1 patients with GBM / HGG: Lisavanbulin 30 mg

Phase 1 patients with GBM / HGG: Lisavanbulin 35 mg

Phase 2a patients with GBM: Lisavanbulin 25 mg

Number of subjects analysed

Units: hour

median (full range (min-max))

10.3 (5.2 to 20.2)

12.6 (12.3 to 15.7)

13.7 (11.2 to 19.7)

14.8 (9.6 to 21.4)

19.3 (10.7 to 30.6)

14.0 (13.4 to 32.4)

12.2 (10.7 to 21.9)

20.6 (18.7 to 20.6)

8.1 (3.9 to 21.3)

11.3 (10.2 to 12.3)

13.9 (9.5 to 35.4)

12.4 (11.5 to 21.3)

12.8 (5.7 to 43.4)

No statistical analyses for this end point

Secondary: Tmax of avanbulin (BAL27862)

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End point title

Tmax of avanbulin (BAL27862)

End point description

Time to maximum plasma concentration

End point type

Secondary

End point timeframe

Day 1 of Cycle 1

Phase 1 patients with solid tumors: Lisavanbulin 2 mg

Phase 1 patients with solid tumors: Lisavanbulin 4 mg

Phase 1 patients with solid tumors: Lisavanbulin 8 mg

Phase 1 patients with solid tumors: Lisavanbulin 16 mg

Phase 1 patients with solid tumors: Lisavanbulin 20 mg

Phase 1 patients with solid tumors: Lisavanbulin 30 mg

Phase 1 patients with GBM / HGG: Lisavanbulin 8 mg

Phase 1 patients with GBM / HGG: Lisavanbulin 15 mg

Phase 1 patients with GBM / HGG: Lisavanbulin 20 mg

Phase 1 patients with GBM / HGG: Lisavanbulin 25 mg

Phase 1 patients with GBM / HGG: Lisavanbulin 30 mg

Phase 1 patients with GBM / HGG: Lisavanbulin 35 mg

Phase 2a patients with GBM: Lisavanbulin 25 mg

Number of subjects analysed

Units: hour

median (full range (min-max))

2.0 (1.1 to 3.0)

1.1 (1.0 to 2.0)

3.0 (1.0 to 4.1)

1.1 (1.0 to 2.2)

1.0 (1.0 to 2.1)

2.0 (1.1 to 3.0)

1.5 (1.0 to 2.2)

1.1 (0.8 to 2.0)

1.2 (0.6 to 2.2)

1.0 (1.0 to 2.0)

2.0 (0.5 to 3.0)

2.2 (2.1 to 3.1)

2.0 (0.6 to 3.0)

No statistical analyses for this end point

Secondary: Cmax of avanbulin (BAL27862)

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End point title

Cmax of avanbulin (BAL27862)

End point description

Maximum drug concentration observed in plasma

End point type

Secondary

End point timeframe

Day 1 of Cycle 1

End point values	Phase 1 patients with solid tumors: Lisavanbulin 2 mg	Phase 1 patients with solid tumors: Lisavanbulin 4 mg	Phase 1 patients with solid tumors: Lisavanbulin 8 mg	Phase 1 patients with solid tumors: Lisavanbulin 16 mg	Phase 1 patients with solid tumors: Lisavanbulin 20 mg	Phase 1 patients with solid tumors: Lisavanbulin 30 mg	Phase 1 patients with GBM / HGG: Lisavanbulin 8 mg	Phase 1 patients with GBM / HGG: Lisavanbulin 15 mg	Phase 1 patients with GBM / HGG: Lisavanbulin 20 mg	Phase 1 patients with GBM / HGG: Lisavanbulin 25 mg	Phase 1 patients with GBM / HGG: Lisavanbulin 30 mg	Phase 1 patients with GBM / HGG: Lisavanbulin 35 mg	Phase 2a patients with GBM: Lisavanbulin 25 mg
Number of subjects analysed	3	3	3	7	7	3	4	3	7	3	8	3	18
Units: ng/mL
geometric mean (geometric coefficient of variation)	6.900 ( 0.580 )	23.400 ( 0.440 )	29.190 ( 0.490 )	120.260 ( 0.490 )	116.630 ( 0.580 )	159.020 ( 0.080 )	35.260 ( 0.560 )	75.130 ( 0.110 )	64.110 ( 0.460 )	103.950 ( 0.470 )	146.500 ( 0.580 )	159.100 ( 0.650 )	98.210 ( 0.410 )

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

From first administration of study medication up to 30 days after the last administration.

Adverse event reporting additional description

Treatment-emergent adverse events and serious adverse events

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

25.0

Reporting group title

Ph1STC2

Reporting group description

Ph1 ST - Cohort 2mg/day

Reporting group title

Ph1STC4

Reporting group description

Ph1 ST - Cohort 4mg/day

Reporting group title

Ph1STC8

Reporting group description

Ph1 ST - Cohort 8mg/day

Reporting group title

Ph1STC16

Reporting group description

Ph1 ST - Cohort 16mg/day

Reporting group title

Ph1STC20

Reporting group description

Ph1 ST - Cohort 20mg/day

Reporting group title

Ph1STC30

Reporting group description

Ph1 ST - Cohort 30mg/day

Reporting group title

Ph1GBC8

Reporting group description

Ph1 GBM - Cohort 8mg/day

Reporting group title

Ph1GBC15

Reporting group description

Ph1 GBM - Cohort 15mg/day

Reporting group title

Ph1GBC20

Reporting group description

Ph1 GBM - Cohort 20mg/day

Reporting group title

Ph1GBC25

Reporting group description

Ph1 GBM - Cohort 25mg/day

Reporting group title

Ph1GBC30

Reporting group description

Ph1 GBM - Cohort 30mg/day

Reporting group title

Ph1GBC35

Reporting group description

Ph1 GBM - Cohort 35mg/day

Reporting group title

Ph2aC25

Reporting group description

Ph2a - Cohort 25mg/day

Ph1STC2

Ph1STC4

Ph1STC8

Ph1STC16

Ph1STC20

Ph1STC30

Ph1GBC8

Ph1GBC15

Ph1GBC20

Ph1GBC25

Ph1GBC30

Ph1GBC35

Ph2aC25

Total subjects affected by serious adverse events

subjects affected / exposed

0 / 3 (0.00%)

2 / 3 (66.67%)

0 / 3 (0.00%)

4 / 7 (57.14%)

5 / 7 (71.43%)

1 / 3 (33.33%)

0 / 4 (0.00%)

0 / 3 (0.00%)

2 / 7 (28.57%)

1 / 3 (33.33%)

4 / 8 (50.00%)

2 / 3 (66.67%)

8 / 18 (44.44%)

number of deaths (all causes)

number of deaths resulting from adverse events

Neoplasms benign, malignant and unspecified (incl cysts and polyps)

Intracranial tumour haemorrhage

subjects affected / exposed

0 / 3 (0.00%)

0 / 7 (0.00%)

0 / 3 (0.00%)

0 / 4 (0.00%)

0 / 3 (0.00%)

0 / 7 (0.00%)

0 / 3 (0.00%)

1 / 8 (12.50%)

0 / 3 (0.00%)

0 / 18 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Cholangiocarcinoma

subjects affected / exposed

0 / 3 (0.00%)

1 / 7 (14.29%)

0 / 7 (0.00%)

0 / 3 (0.00%)

0 / 4 (0.00%)

0 / 3 (0.00%)

0 / 7 (0.00%)

0 / 3 (0.00%)

0 / 8 (0.00%)

0 / 3 (0.00%)

0 / 18 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

General disorders and administration site conditions

Fatigue

subjects affected / exposed

0 / 3 (0.00%)

0 / 7 (0.00%)

0 / 3 (0.00%)

0 / 4 (0.00%)

0 / 3 (0.00%)

0 / 7 (0.00%)

0 / 3 (0.00%)

0 / 8 (0.00%)

0 / 3 (0.00%)

1 / 18 (5.56%)

occurrences causally related to treatment / all

0 / 0

1 / 1

deaths causally related to treatment / all

0 / 0

Disease progression

subjects affected / exposed

0 / 3 (0.00%)

0 / 7 (0.00%)

0 / 3 (0.00%)

0 / 4 (0.00%)

0 / 3 (0.00%)

0 / 7 (0.00%)

0 / 3 (0.00%)

0 / 8 (0.00%)

0 / 3 (0.00%)

1 / 18 (5.56%)

occurrences causally related to treatment / all

0 / 0

0 / 1

deaths causally related to treatment / all

0 / 0

0 / 1

Peripheral swelling

subjects affected / exposed

0 / 3 (0.00%)

1 / 3 (33.33%)

0 / 3 (0.00%)

0 / 7 (0.00%)

0 / 3 (0.00%)

0 / 4 (0.00%)

0 / 3 (0.00%)

0 / 7 (0.00%)

0 / 3 (0.00%)

0 / 8 (0.00%)

0 / 3 (0.00%)

0 / 18 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Gait disturbance

subjects affected / exposed

0 / 3 (0.00%)

0 / 7 (0.00%)

0 / 3 (0.00%)

0 / 4 (0.00%)

0 / 3 (0.00%)

0 / 7 (0.00%)

0 / 3 (0.00%)

0 / 8 (0.00%)

2 / 3 (66.67%)

0 / 18 (0.00%)

occurrences causally related to treatment / all

0 / 0

2 / 2

0 / 0

deaths causally related to treatment / all

0 / 0

Pyrexia

subjects affected / exposed

0 / 3 (0.00%)

1 / 3 (33.33%)

0 / 3 (0.00%)

1 / 7 (14.29%)

0 / 7 (0.00%)

0 / 3 (0.00%)

0 / 4 (0.00%)

0 / 3 (0.00%)

0 / 7 (0.00%)

0 / 3 (0.00%)

1 / 8 (12.50%)

1 / 3 (33.33%)

0 / 18 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

General physical health deterioration

subjects affected / exposed

0 / 3 (0.00%)

0 / 7 (0.00%)

0 / 3 (0.00%)

0 / 4 (0.00%)

0 / 3 (0.00%)

0 / 7 (0.00%)

0 / 3 (0.00%)

0 / 8 (0.00%)

0 / 3 (0.00%)

1 / 18 (5.56%)

occurrences causally related to treatment / all

0 / 0

0 / 1

deaths causally related to treatment / all

0 / 0

Pain

subjects affected / exposed

0 / 3 (0.00%)

1 / 7 (14.29%)

0 / 7 (0.00%)

0 / 3 (0.00%)

0 / 4 (0.00%)

0 / 3 (0.00%)

0 / 7 (0.00%)

0 / 3 (0.00%)

0 / 8 (0.00%)

0 / 3 (0.00%)

0 / 18 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Respiratory, thoracic and mediastinal disorders

Dyspnoea

subjects affected / exposed

0 / 3 (0.00%)

1 / 3 (33.33%)

0 / 3 (0.00%)

0 / 7 (0.00%)

0 / 3 (0.00%)

0 / 4 (0.00%)

0 / 3 (0.00%)

0 / 7 (0.00%)

0 / 3 (0.00%)

0 / 8 (0.00%)

0 / 3 (0.00%)

0 / 18 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Aspiration

subjects affected / exposed

0 / 3 (0.00%)

0 / 7 (0.00%)

0 / 3 (0.00%)

0 / 4 (0.00%)

0 / 3 (0.00%)

0 / 7 (0.00%)

0 / 3 (0.00%)

0 / 8 (0.00%)

0 / 3 (0.00%)

1 / 18 (5.56%)

occurrences causally related to treatment / all

0 / 0

0 / 1

deaths causally related to treatment / all

0 / 0

Psychiatric disorders

Confusional state

subjects affected / exposed

0 / 3 (0.00%)

0 / 7 (0.00%)

0 / 3 (0.00%)

0 / 4 (0.00%)

0 / 3 (0.00%)

0 / 7 (0.00%)

0 / 3 (0.00%)

1 / 8 (12.50%)

2 / 3 (66.67%)

1 / 18 (5.56%)

occurrences causally related to treatment / all

0 / 0

0 / 1

2 / 2

1 / 1

deaths causally related to treatment / all

0 / 0

Delirium

subjects affected / exposed

0 / 3 (0.00%)

0 / 7 (0.00%)

0 / 3 (0.00%)

0 / 4 (0.00%)

0 / 3 (0.00%)

0 / 7 (0.00%)

0 / 3 (0.00%)

0 / 8 (0.00%)

0 / 3 (0.00%)

1 / 18 (5.56%)

occurrences causally related to treatment / all

0 / 0

0 / 1

deaths causally related to treatment / all

0 / 0

Hallucination, visual

subjects affected / exposed

0 / 3 (0.00%)

0 / 7 (0.00%)

1 / 7 (14.29%)

1 / 3 (33.33%)

0 / 4 (0.00%)

0 / 3 (0.00%)

0 / 7 (0.00%)

0 / 3 (0.00%)

0 / 8 (0.00%)

0 / 3 (0.00%)

0 / 18 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Hallucination

subjects affected / exposed

0 / 3 (0.00%)

0 / 7 (0.00%)

0 / 3 (0.00%)

0 / 4 (0.00%)

0 / 3 (0.00%)

0 / 7 (0.00%)

0 / 3 (0.00%)

0 / 8 (0.00%)

1 / 3 (33.33%)

0 / 18 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Investigations

Troponin I increased

subjects affected / exposed

0 / 3 (0.00%)

0 / 7 (0.00%)

1 / 7 (14.29%)

0 / 3 (0.00%)

0 / 4 (0.00%)

0 / 3 (0.00%)

0 / 7 (0.00%)

0 / 3 (0.00%)

0 / 8 (0.00%)

0 / 3 (0.00%)

0 / 18 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Alanine aminotransferase increased

subjects affected / exposed

0 / 3 (0.00%)

0 / 7 (0.00%)

0 / 3 (0.00%)

0 / 4 (0.00%)

0 / 3 (0.00%)

0 / 7 (0.00%)

0 / 3 (0.00%)

0 / 8 (0.00%)

0 / 3 (0.00%)

1 / 18 (5.56%)

occurrences causally related to treatment / all

0 / 0

1 / 1

deaths causally related to treatment / all

0 / 0

Aspartate aminotransferase increased

subjects affected / exposed

0 / 3 (0.00%)

0 / 7 (0.00%)

0 / 3 (0.00%)

0 / 4 (0.00%)

0 / 3 (0.00%)

0 / 7 (0.00%)

0 / 3 (0.00%)

0 / 8 (0.00%)

0 / 3 (0.00%)

1 / 18 (5.56%)

occurrences causally related to treatment / all

0 / 0

1 / 1

deaths causally related to treatment / all

0 / 0

Injury, poisoning and procedural complications

Accidental overdose

subjects affected / exposed

0 / 3 (0.00%)

0 / 7 (0.00%)

0 / 3 (0.00%)

0 / 4 (0.00%)

0 / 3 (0.00%)

0 / 7 (0.00%)

0 / 3 (0.00%)

1 / 8 (12.50%)

0 / 3 (0.00%)

0 / 18 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 2

0 / 0

deaths causally related to treatment / all

0 / 0

Femoral neck fracture

subjects affected / exposed

0 / 3 (0.00%)

0 / 7 (0.00%)

1 / 7 (14.29%)

0 / 3 (0.00%)

0 / 4 (0.00%)

0 / 3 (0.00%)

0 / 7 (0.00%)

0 / 3 (0.00%)

0 / 8 (0.00%)

0 / 3 (0.00%)

0 / 18 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Stoma prolapse

subjects affected / exposed

0 / 3 (0.00%)

0 / 7 (0.00%)

0 / 3 (0.00%)

0 / 4 (0.00%)

0 / 3 (0.00%)

0 / 7 (0.00%)

1 / 3 (33.33%)

0 / 8 (0.00%)

0 / 3 (0.00%)

0 / 18 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Fall

subjects affected / exposed

0 / 3 (0.00%)

0 / 7 (0.00%)

0 / 3 (0.00%)

0 / 4 (0.00%)

0 / 3 (0.00%)

0 / 7 (0.00%)

0 / 3 (0.00%)

0 / 8 (0.00%)

0 / 3 (0.00%)

1 / 18 (5.56%)

occurrences causally related to treatment / all

0 / 0

0 / 2

deaths causally related to treatment / all

0 / 0

Humerus fracture

subjects affected / exposed

0 / 3 (0.00%)

0 / 7 (0.00%)

0 / 3 (0.00%)

0 / 4 (0.00%)

0 / 3 (0.00%)

0 / 7 (0.00%)

0 / 3 (0.00%)

0 / 8 (0.00%)

0 / 3 (0.00%)

1 / 18 (5.56%)

occurrences causally related to treatment / all

0 / 0

0 / 1

deaths causally related to treatment / all

0 / 0

Fractured coccyx

subjects affected / exposed

0 / 3 (0.00%)

0 / 7 (0.00%)

0 / 3 (0.00%)

0 / 4 (0.00%)

0 / 3 (0.00%)

0 / 7 (0.00%)

1 / 3 (33.33%)

0 / 8 (0.00%)

0 / 3 (0.00%)

0 / 18 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Cardiac disorders

Atrial fibrillation

subjects affected / exposed

0 / 3 (0.00%)

0 / 7 (0.00%)

0 / 3 (0.00%)

0 / 4 (0.00%)

0 / 3 (0.00%)

0 / 7 (0.00%)

0 / 3 (0.00%)

1 / 8 (12.50%)

0 / 3 (0.00%)

0 / 18 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Nervous system disorders

Ataxia

subjects affected / exposed

0 / 3 (0.00%)

0 / 7 (0.00%)

0 / 3 (0.00%)

0 / 4 (0.00%)

0 / 3 (0.00%)

0 / 7 (0.00%)

1 / 3 (33.33%)

0 / 8 (0.00%)

0 / 3 (0.00%)

0 / 18 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Somnolence

subjects affected / exposed

0 / 3 (0.00%)

0 / 7 (0.00%)

0 / 3 (0.00%)

0 / 4 (0.00%)

0 / 3 (0.00%)

0 / 7 (0.00%)

0 / 3 (0.00%)

1 / 8 (12.50%)

0 / 3 (0.00%)

0 / 18 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Cognitive disorder

subjects affected / exposed

0 / 3 (0.00%)

0 / 7 (0.00%)

0 / 3 (0.00%)

0 / 4 (0.00%)

0 / 3 (0.00%)

0 / 7 (0.00%)

0 / 3 (0.00%)

0 / 8 (0.00%)

0 / 3 (0.00%)

1 / 18 (5.56%)

occurrences causally related to treatment / all

0 / 0

0 / 1

deaths causally related to treatment / all

0 / 0

Ischaemic stroke

subjects affected / exposed

0 / 3 (0.00%)

0 / 7 (0.00%)

0 / 3 (0.00%)

0 / 4 (0.00%)

0 / 3 (0.00%)

0 / 7 (0.00%)

0 / 3 (0.00%)

1 / 8 (12.50%)

0 / 3 (0.00%)

0 / 18 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Headache

subjects affected / exposed

0 / 3 (0.00%)

0 / 7 (0.00%)

0 / 3 (0.00%)

0 / 4 (0.00%)

0 / 3 (0.00%)

1 / 7 (14.29%)

0 / 3 (0.00%)

0 / 8 (0.00%)

0 / 3 (0.00%)

0 / 18 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Seizure

subjects affected / exposed

0 / 3 (0.00%)

0 / 7 (0.00%)

0 / 3 (0.00%)

0 / 4 (0.00%)

0 / 3 (0.00%)

0 / 7 (0.00%)

0 / 3 (0.00%)

1 / 8 (12.50%)

0 / 3 (0.00%)

2 / 18 (11.11%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 2

deaths causally related to treatment / all

0 / 0

Thalamic infarction

subjects affected / exposed

0 / 3 (0.00%)

0 / 7 (0.00%)

0 / 3 (0.00%)

0 / 4 (0.00%)

0 / 3 (0.00%)

0 / 7 (0.00%)

0 / 3 (0.00%)

1 / 8 (12.50%)

0 / 3 (0.00%)

0 / 18 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Dysarthria

subjects affected / exposed

0 / 3 (0.00%)

0 / 7 (0.00%)

0 / 3 (0.00%)

0 / 4 (0.00%)

0 / 3 (0.00%)

0 / 7 (0.00%)

0 / 3 (0.00%)

0 / 8 (0.00%)

1 / 3 (33.33%)

0 / 18 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Partial seizures

subjects affected / exposed

0 / 3 (0.00%)

0 / 7 (0.00%)

0 / 3 (0.00%)

0 / 4 (0.00%)

0 / 3 (0.00%)

0 / 7 (0.00%)

0 / 3 (0.00%)

0 / 8 (0.00%)

1 / 3 (33.33%)

0 / 18 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Gastrointestinal disorders

Intestinal obstruction

subjects affected / exposed

0 / 3 (0.00%)

1 / 7 (14.29%)

0 / 7 (0.00%)

0 / 3 (0.00%)

0 / 4 (0.00%)

0 / 3 (0.00%)

0 / 7 (0.00%)

0 / 3 (0.00%)

0 / 8 (0.00%)

0 / 3 (0.00%)

0 / 18 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Constipation

subjects affected / exposed

0 / 3 (0.00%)

1 / 7 (14.29%)

0 / 7 (0.00%)

0 / 3 (0.00%)

0 / 4 (0.00%)

0 / 3 (0.00%)

0 / 7 (0.00%)

0 / 3 (0.00%)

0 / 8 (0.00%)

0 / 3 (0.00%)

0 / 18 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Abdominal pain

subjects affected / exposed

0 / 3 (0.00%)

2 / 7 (28.57%)

1 / 7 (14.29%)

0 / 3 (0.00%)

0 / 4 (0.00%)

0 / 3 (0.00%)

0 / 7 (0.00%)

0 / 3 (0.00%)

0 / 8 (0.00%)

0 / 3 (0.00%)

0 / 18 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 2

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Haematemesis

subjects affected / exposed

0 / 3 (0.00%)

0 / 7 (0.00%)

1 / 7 (14.29%)

0 / 3 (0.00%)

0 / 4 (0.00%)

0 / 3 (0.00%)

0 / 7 (0.00%)

0 / 3 (0.00%)

0 / 8 (0.00%)

0 / 3 (0.00%)

0 / 18 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Nausea

subjects affected / exposed

0 / 3 (0.00%)

0 / 7 (0.00%)

1 / 7 (14.29%)

0 / 3 (0.00%)

0 / 4 (0.00%)

0 / 3 (0.00%)

0 / 7 (0.00%)

0 / 3 (0.00%)

0 / 8 (0.00%)

0 / 3 (0.00%)

0 / 18 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Vomiting

subjects affected / exposed

0 / 3 (0.00%)

0 / 7 (0.00%)

0 / 3 (0.00%)

0 / 4 (0.00%)

0 / 3 (0.00%)

0 / 7 (0.00%)

0 / 3 (0.00%)

0 / 8 (0.00%)

0 / 3 (0.00%)

2 / 18 (11.11%)

occurrences causally related to treatment / all

0 / 0

2 / 2

deaths causally related to treatment / all

0 / 0

Hepatobiliary disorders

Cholangitis

subjects affected / exposed

0 / 3 (0.00%)

1 / 7 (14.29%)

0 / 7 (0.00%)

0 / 3 (0.00%)

0 / 4 (0.00%)

0 / 3 (0.00%)

0 / 7 (0.00%)

0 / 3 (0.00%)

0 / 8 (0.00%)

0 / 3 (0.00%)

0 / 18 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Renal and urinary disorders

Urinary retention

subjects affected / exposed

0 / 3 (0.00%)

0 / 7 (0.00%)

0 / 3 (0.00%)

0 / 4 (0.00%)

0 / 3 (0.00%)

0 / 7 (0.00%)

0 / 3 (0.00%)

0 / 8 (0.00%)

1 / 3 (33.33%)

0 / 18 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Urinary incontinence

subjects affected / exposed

0 / 3 (0.00%)

0 / 7 (0.00%)

0 / 3 (0.00%)

0 / 4 (0.00%)

0 / 3 (0.00%)

0 / 7 (0.00%)

0 / 3 (0.00%)

0 / 8 (0.00%)

0 / 3 (0.00%)

1 / 18 (5.56%)

occurrences causally related to treatment / all

0 / 0

0 / 1

deaths causally related to treatment / all

0 / 0

Musculoskeletal and connective tissue disorders

Muscular weakness

subjects affected / exposed

0 / 3 (0.00%)

0 / 7 (0.00%)

0 / 3 (0.00%)

0 / 4 (0.00%)

0 / 3 (0.00%)

1 / 7 (14.29%)

0 / 3 (0.00%)

0 / 8 (0.00%)

0 / 3 (0.00%)

0 / 18 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Infections and infestations

Urinary tract infection

subjects affected / exposed

0 / 3 (0.00%)

0 / 7 (0.00%)

0 / 3 (0.00%)

0 / 4 (0.00%)

0 / 3 (0.00%)

0 / 7 (0.00%)

0 / 3 (0.00%)

0 / 8 (0.00%)

0 / 3 (0.00%)

1 / 18 (5.56%)

occurrences causally related to treatment / all

0 / 0

0 / 1

deaths causally related to treatment / all

0 / 0

Sepsis

subjects affected / exposed

0 / 3 (0.00%)

0 / 7 (0.00%)

0 / 3 (0.00%)

0 / 4 (0.00%)

0 / 3 (0.00%)

0 / 7 (0.00%)

0 / 3 (0.00%)

0 / 8 (0.00%)

1 / 3 (33.33%)

0 / 18 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Metabolism and nutrition disorders

Hyponatraemia

subjects affected / exposed

0 / 3 (0.00%)

0 / 7 (0.00%)

2 / 7 (28.57%)

0 / 3 (0.00%)

0 / 4 (0.00%)

0 / 3 (0.00%)

0 / 7 (0.00%)

0 / 3 (0.00%)

0 / 8 (0.00%)

0 / 3 (0.00%)

0 / 18 (0.00%)

occurrences causally related to treatment / all

0 / 0

2 / 3

0 / 0

deaths causally related to treatment / all

0 / 0

Frequency threshold for reporting non-serious adverse events: 0%

Non-serious adverse events	Ph1STC2	Ph1STC4	Ph1STC8	Ph1STC16	Ph1STC20	Ph1STC30	Ph1GBC8	Ph1GBC15	Ph1GBC20	Ph1GBC25	Ph1GBC30	Ph1GBC35	Ph2aC25
Total subjects affected by non serious adverse events
subjects affected / exposed	3 / 3 (100.00%)	3 / 3 (100.00%)	3 / 3 (100.00%)	6 / 7 (85.71%)	7 / 7 (100.00%)	3 / 3 (100.00%)	4 / 4 (100.00%)	3 / 3 (100.00%)	5 / 7 (71.43%)	3 / 3 (100.00%)	7 / 8 (87.50%)	3 / 3 (100.00%)	18 / 18 (100.00%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Benign neoplasm
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	1 / 3 (33.33%)	0 / 8 (0.00%)	0 / 3 (0.00%)	0 / 18 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	1	0	0	0
Metastases to meninges
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	1 / 18 (5.56%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	0	1
Haemangioma of liver
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	1 / 18 (5.56%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	0	1
Skin papilloma
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	1 / 8 (12.50%)	0 / 3 (0.00%)	0 / 18 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	1	0	0
Tumour pain
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	0 / 18 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0	0	0	0	0	0
Vascular disorders
Hypotension
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	1 / 4 (25.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	0 / 18 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0	0	0	0	0
Hot flush
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	1 / 8 (12.50%)	0 / 3 (0.00%)	0 / 18 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	1	0	0
Hypertension
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	1 / 7 (14.29%)	1 / 7 (14.29%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	2 / 18 (11.11%)
occurrences all number	0	0	1	2	2	0	0	0	0	0	0	0	3
General disorders and administration site conditions
Chills
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	1 / 7 (14.29%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	1 / 18 (5.56%)
occurrences all number	0	0	0	0	1	0	0	0	0	0	0	0	1
Fatigue
subjects affected / exposed	1 / 3 (33.33%)	1 / 3 (33.33%)	1 / 3 (33.33%)	3 / 7 (42.86%)	3 / 7 (42.86%)	0 / 3 (0.00%)	0 / 4 (0.00%)	2 / 3 (66.67%)	3 / 7 (42.86%)	2 / 3 (66.67%)	0 / 8 (0.00%)	0 / 3 (0.00%)	8 / 18 (44.44%)
occurrences all number	1	1	1	3	3	0	0	2	4	2	0	0	10
Pyrexia
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 7 (14.29%)	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	1 / 8 (12.50%)	0 / 3 (0.00%)	0 / 18 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0	0	0	1	0	0
Early satiety
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	1 / 7 (14.29%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	0 / 18 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0	0	0	0	0	0
Unevaluable event
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	1 / 7 (14.29%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	0 / 18 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0	0	0	0	0	0
Gait disturbance
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	1 / 8 (12.50%)	0 / 3 (0.00%)	3 / 18 (16.67%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	1	0	3
Oedema peripheral
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	1 / 7 (14.29%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	1 / 18 (5.56%)
occurrences all number	0	0	0	0	1	0	0	0	0	0	0	0	1
General physical health deterioration
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	1 / 18 (5.56%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	0	1
Localised oedema
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	0 / 18 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0	0	0	0	0	0
Reproductive system and breast disorders
Acquired phimosis
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	1 / 3 (33.33%)	0 / 18 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	1	0
Erectile dysfunction
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	1 / 8 (12.50%)	0 / 3 (0.00%)	0 / 18 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	1	0	0
Vaginal haemorrhage
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	1 / 7 (14.29%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	0 / 18 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0	0	0	0	0	0
Respiratory, thoracic and mediastinal disorders
Productive cough
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 7 (14.29%)	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	0 / 18 (0.00%)
occurrences all number	0	0	0	2	0	0	0	0	0	0	0	0	0
Rhinorrhoea
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	2 / 3 (66.67%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	0 / 18 (0.00%)
occurrences all number	0	0	2	0	0	0	0	0	0	0	0	0	0
Dyspnoea exertional
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	1 / 7 (14.29%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	0 / 18 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0	0	0	0	0	0
Oropharyngeal pain
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 7 (14.29%)	1 / 7 (14.29%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	1 / 7 (14.29%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	0 / 18 (0.00%)
occurrences all number	0	0	0	1	1	0	0	0	1	0	0	0	0
Epistaxis
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	0 / 18 (0.00%)
occurrences all number	1	0	1	0	0	0	0	0	0	0	0	0	0
Cough
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	1 / 7 (14.29%)	1 / 7 (14.29%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	1 / 3 (33.33%)	0 / 8 (0.00%)	0 / 3 (0.00%)	1 / 18 (5.56%)
occurrences all number	0	0	1	1	1	0	0	0	0	1	0	0	1
Pleuritic pain
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	1 / 3 (33.33%)	0 / 8 (0.00%)	0 / 3 (0.00%)	0 / 18 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	1	0	0	0
Dyspnoea
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 7 (14.29%)	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	0 / 18 (0.00%)
occurrences all number	1	0	0	1	0	0	0	0	0	0	0	0	0
Psychiatric disorders
Depressed mood
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	1 / 7 (14.29%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	0 / 18 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0	0	0	0	0	0
Hallucination
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	1 / 7 (14.29%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	1 / 3 (33.33%)	0 / 18 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0	0	0	0	1	0
Depression
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	1 / 7 (14.29%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	0 / 18 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	1	0	0	0	0
Disorientation
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	1 / 18 (5.56%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	0	1
Anxiety
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	1 / 18 (5.56%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	0	1
Psychomotor retardation
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	1 / 18 (5.56%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	0	1
Libido decreased
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	1 / 8 (12.50%)	0 / 3 (0.00%)	0 / 18 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	1	0	0
Insomnia
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 7 (0.00%)	1 / 7 (14.29%)	0 / 3 (0.00%)	1 / 4 (25.00%)	1 / 3 (33.33%)	0 / 7 (0.00%)	0 / 3 (0.00%)	2 / 8 (25.00%)	1 / 3 (33.33%)	6 / 18 (33.33%)
occurrences all number	0	0	1	0	1	0	1	1	0	0	2	1	6
Agitation
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	1 / 8 (12.50%)	1 / 3 (33.33%)	0 / 18 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	1	1	0
Somnambulism
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	1 / 18 (5.56%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	0	1
Confusional state
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 7 (0.00%)	1 / 3 (33.33%)	0 / 4 (0.00%)	0 / 3 (0.00%)	1 / 7 (14.29%)	0 / 3 (0.00%)	1 / 8 (12.50%)	0 / 3 (0.00%)	2 / 18 (11.11%)
occurrences all number	0	0	0	0	0	1	0	0	1	0	1	0	2
Hallucination, visual
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 7 (0.00%)	1 / 3 (33.33%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	0 / 18 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0	0	0	0	0	0
Investigations
Blood bilirubin increased
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 7 (14.29%)	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	0 / 18 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0	0	0	0	0	0
Gamma-glutamyltransferase increased
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 3 (33.33%)	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	1 / 18 (5.56%)
occurrences all number	0	0	0	0	0	0	0	1	0	0	0	0	1
Electrocardiogram abnormal
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 3 (33.33%)	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	0 / 18 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0	0	0	0	0
Alanine aminotransferase increased
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 7 (14.29%)	2 / 7 (28.57%)	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 3 (33.33%)	0 / 7 (0.00%)	1 / 3 (33.33%)	3 / 8 (37.50%)	0 / 3 (0.00%)	4 / 18 (22.22%)
occurrences all number	1	0	0	1	2	0	0	2	0	1	5	0	5
Aspartate aminotransferase increased
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	2 / 7 (28.57%)	3 / 7 (42.86%)	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 3 (33.33%)	0 / 7 (0.00%)	1 / 3 (33.33%)	2 / 8 (25.00%)	0 / 3 (0.00%)	3 / 18 (16.67%)
occurrences all number	0	0	0	2	3	0	0	2	0	1	2	0	3
Blood alkaline phosphatase increased
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	2 / 7 (28.57%)	3 / 7 (42.86%)	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 3 (33.33%)	0 / 7 (0.00%)	0 / 3 (0.00%)	1 / 8 (12.50%)	0 / 3 (0.00%)	0 / 18 (0.00%)
occurrences all number	0	0	0	2	3	0	0	1	0	0	2	0	0
Blood glucose increased
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	1 / 18 (5.56%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	0	1
Neutrophil count decreased
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	1 / 4 (25.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	0 / 18 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0	0	0	0	0
Lymphocyte count decreased
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	2 / 18 (11.11%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	0	2
Blood creatine phosphokinase decreased
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	1 / 18 (5.56%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	0	1
Blood creatine phosphokinase increased
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	1 / 7 (14.29%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	1 / 3 (33.33%)	1 / 8 (12.50%)	1 / 3 (33.33%)	2 / 18 (11.11%)
occurrences all number	0	0	0	0	1	0	0	0	0	2	1	1	2
Blood creatinine increased
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	1 / 18 (5.56%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	0	1
White blood cell count decreased
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 3 (33.33%)	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	0 / 18 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0	0	0	0	0
Neutrophil count increased
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	1 / 7 (14.29%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	0 / 18 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	1	0	0	0	0
Troponin increased
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	2 / 7 (28.57%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	1 / 8 (12.50%)	0 / 3 (0.00%)	0 / 18 (0.00%)
occurrences all number	0	0	0	0	2	0	0	0	0	0	1	0	0
Lipase increased
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	1 / 18 (5.56%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	0	2
Troponin T increased
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	1 / 18 (5.56%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	0	1
White blood cell count increased
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	1 / 18 (5.56%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	0	2
Weight decreased
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	1 / 7 (14.29%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	0 / 18 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0	0	0	0	0	0
Injury, poisoning and procedural complications
Fall
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	1 / 7 (14.29%)	0 / 3 (0.00%)	3 / 4 (75.00%)	1 / 3 (33.33%)	1 / 7 (14.29%)	0 / 3 (0.00%)	0 / 8 (0.00%)	1 / 3 (33.33%)	3 / 18 (16.67%)
occurrences all number	0	0	0	0	1	0	3	2	1	0	0	1	8
Procedural pain
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	0 / 18 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0	0	0	0	0	0
Skin laceration
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	1 / 18 (5.56%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	0	1
Contusion
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 3 (33.33%)	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	1 / 18 (5.56%)
occurrences all number	0	0	0	0	0	0	0	1	0	0	0	0	1
Cardiac disorders
Myocardial ischaemia
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	0 / 18 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0	0	0	0	0	0
Tachycardia
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 3 (33.33%)	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	0 / 18 (0.00%)
occurrences all number	0	0	1	0	0	0	0	1	0	0	0	0	0
Ventricular extrasystoles
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	1 / 7 (14.29%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	0 / 18 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0	0	0	0	0	0
Sinus tachycardia
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 3 (33.33%)	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	1 / 18 (5.56%)
occurrences all number	0	0	0	0	0	0	0	1	0	0	0	0	1
Palpitations
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	1 / 18 (5.56%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	0	2
Ventricular arrhythmia
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	1 / 7 (14.29%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	0 / 18 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0	0	0	0	0	0
Sinus bradycardia
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	1 / 8 (12.50%)	0 / 3 (0.00%)	0 / 18 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	1	0	0
Nervous system disorders
Amnesia
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 3 (33.33%)	0 / 7 (0.00%)	0 / 3 (0.00%)	1 / 8 (12.50%)	0 / 3 (0.00%)	1 / 18 (5.56%)
occurrences all number	0	0	0	0	0	0	0	2	0	0	1	0	1
Brain oedema
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	1 / 18 (5.56%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	0	1
Dysarthria
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	1 / 7 (14.29%)	0 / 3 (0.00%)	1 / 4 (25.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	1 / 3 (33.33%)	0 / 18 (0.00%)
occurrences all number	0	0	0	0	1	0	1	0	0	0	0	1	0
Aphasia
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	1 / 4 (25.00%)	0 / 3 (0.00%)	1 / 7 (14.29%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	3 / 18 (16.67%)
occurrences all number	0	0	0	0	0	0	1	0	1	0	0	0	4
Balance disorder
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	1 / 7 (14.29%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	2 / 18 (11.11%)
occurrences all number	0	0	0	0	0	0	0	0	1	0	0	0	2
Facial paralysis
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	1 / 18 (5.56%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	0	1
Hemianopia
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	2 / 18 (11.11%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	0	2
Lethargy
subjects affected / exposed	0 / 3 (0.00%)	2 / 3 (66.67%)	0 / 3 (0.00%)	1 / 7 (14.29%)	1 / 7 (14.29%)	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 3 (33.33%)	1 / 7 (14.29%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	2 / 18 (11.11%)
occurrences all number	0	2	0	1	1	0	0	1	1	0	0	0	3
Disturbance in attention
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	1 / 7 (14.29%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	1 / 18 (5.56%)
occurrences all number	0	0	0	0	1	0	0	0	0	0	0	0	1
Dizziness
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	1 / 8 (12.50%)	0 / 3 (0.00%)	1 / 18 (5.56%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	1	0	2
Coordination abnormal
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	1 / 7 (14.29%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	0 / 18 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	1	0	0	0	0
Migraine
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	0 / 18 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0	0	0	0	0	0
Meralgia paraesthetica
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	1 / 3 (33.33%)	0 / 8 (0.00%)	0 / 3 (0.00%)	0 / 18 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	1	0	0	0
Neuralgia
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	1 / 8 (12.50%)	0 / 3 (0.00%)	0 / 18 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0	0	0	1	0	0
Hyporesponsive to stimuli
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	1 / 18 (5.56%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	0	1
Memory impairment
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	1 / 8 (12.50%)	0 / 3 (0.00%)	0 / 18 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	1	0	0
Cognitive disorder
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	1 / 18 (5.56%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	0	1
Paraesthesia
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 7 (0.00%)	1 / 3 (33.33%)	0 / 4 (0.00%)	2 / 3 (66.67%)	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	1 / 18 (5.56%)
occurrences all number	0	0	0	0	0	1	0	2	0	0	0	0	1
Hemiparesis
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	1 / 4 (25.00%)	0 / 3 (0.00%)	1 / 7 (14.29%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	4 / 18 (22.22%)
occurrences all number	0	0	0	0	0	0	1	0	1	0	0	0	4
Sensory loss
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	1 / 18 (5.56%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	0	1
Seizure
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	1 / 4 (25.00%)	0 / 3 (0.00%)	2 / 7 (28.57%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	3 / 18 (16.67%)
occurrences all number	0	0	0	0	0	0	2	0	6	0	0	0	6
Partial seizures
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 3 (33.33%)	0 / 7 (0.00%)	0 / 3 (0.00%)	1 / 8 (12.50%)	0 / 3 (0.00%)	0 / 18 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0	0	1	0	0
Headache
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	2 / 3 (66.67%)	0 / 7 (0.00%)	1 / 7 (14.29%)	1 / 3 (33.33%)	1 / 4 (25.00%)	0 / 3 (0.00%)	1 / 7 (14.29%)	1 / 3 (33.33%)	1 / 8 (12.50%)	1 / 3 (33.33%)	3 / 18 (16.67%)
occurrences all number	0	0	2	0	1	1	1	0	1	1	1	1	4
Restless legs syndrome
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	1 / 8 (12.50%)	0 / 3 (0.00%)	0 / 18 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	1	0	0
Neurologic neglect syndrome
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	1 / 7 (14.29%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	1 / 18 (5.56%)
occurrences all number	0	0	0	0	0	0	0	0	1	0	0	0	1
Neuropathy peripheral
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	1 / 7 (14.29%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	1 / 8 (12.50%)	0 / 3 (0.00%)	0 / 18 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0	0	0	2	0	0
Tremor
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	1 / 4 (25.00%)	1 / 3 (33.33%)	0 / 7 (0.00%)	0 / 3 (0.00%)	2 / 8 (25.00%)	0 / 3 (0.00%)	1 / 18 (5.56%)
occurrences all number	0	0	0	0	0	0	1	1	0	0	2	0	1
Peroneal nerve palsy
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	1 / 8 (12.50%)	0 / 3 (0.00%)	0 / 18 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	1	0	0
Sciatica
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	1 / 3 (33.33%)	0 / 8 (0.00%)	0 / 3 (0.00%)	0 / 18 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	2	0	0	0
Blood and lymphatic system disorders
Neutropenia
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	1 / 8 (12.50%)	0 / 3 (0.00%)	0 / 18 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	3	0	0
Neutrophilia
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	1 / 18 (5.56%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	0	2
Anaemia
subjects affected / exposed	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 7 (0.00%)	2 / 7 (28.57%)	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 3 (33.33%)	1 / 7 (14.29%)	1 / 3 (33.33%)	0 / 8 (0.00%)	0 / 3 (0.00%)	1 / 18 (5.56%)
occurrences all number	0	1	0	0	2	0	0	1	1	1	0	0	1
Thrombocytopenia
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	2 / 18 (11.11%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	0	2
Ear and labyrinth disorders
Tinnitus
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	1 / 8 (12.50%)	0 / 3 (0.00%)	0 / 18 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	1	0	0
Vertigo
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	1 / 18 (5.56%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	0	1
Otorrhoea
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	1 / 3 (33.33%)	0 / 8 (0.00%)	0 / 3 (0.00%)	0 / 18 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	1	0	0	0
Ear pain
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	1 / 7 (14.29%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	1 / 3 (33.33%)	0 / 8 (0.00%)	0 / 3 (0.00%)	0 / 18 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0	0	1	0	0	0
Eye disorders
Visual impairment
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	1 / 18 (5.56%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	0	1
Vitreous floaters
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 7 (14.29%)	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	0 / 18 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0	0	0	0	0	0
Cataract
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	1 / 8 (12.50%)	0 / 3 (0.00%)	1 / 18 (5.56%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	2	0	1
Blepharitis
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	1 / 7 (14.29%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	0 / 18 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0	0	0	0	0	0
Eye pain
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	1 / 7 (14.29%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	0 / 18 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	1	0	0	0	0
Cataract subcapsular
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	1 / 3 (33.33%)	0 / 8 (0.00%)	0 / 3 (0.00%)	0 / 18 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	1	0	0	0
Gastrointestinal disorders
Abdominal discomfort
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	1 / 7 (14.29%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	0 / 18 (0.00%)
occurrences all number	0	0	0	0	2	0	0	0	0	0	0	0	0
Anal incontinence
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	1 / 18 (5.56%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	0	1
Abdominal pain upper
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	1 / 7 (14.29%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	0 / 18 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0	0	0	0	0	0
Abdominal pain lower
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	1 / 18 (5.56%)
occurrences all number	1	0	0	0	0	0	0	0	0	0	0	0	1
Abdominal pain
subjects affected / exposed	1 / 3 (33.33%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 7 (0.00%)	2 / 7 (28.57%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	2 / 3 (66.67%)	0 / 18 (0.00%)
occurrences all number	1	1	0	0	2	0	0	0	0	0	0	2	0
Mouth ulceration
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 7 (14.29%)	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	0 / 18 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0	0	0	0	0	0
Diarrhoea
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	2 / 3 (66.67%)	0 / 7 (0.00%)	3 / 7 (42.86%)	1 / 3 (33.33%)	1 / 4 (25.00%)	0 / 3 (0.00%)	2 / 7 (28.57%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	1 / 18 (5.56%)
occurrences all number	3	0	2	0	5	1	1	0	2	0	0	0	1
Constipation
subjects affected / exposed	0 / 3 (0.00%)	2 / 3 (66.67%)	1 / 3 (33.33%)	1 / 7 (14.29%)	3 / 7 (42.86%)	1 / 3 (33.33%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	1 / 3 (33.33%)	0 / 8 (0.00%)	1 / 3 (33.33%)	3 / 18 (16.67%)
occurrences all number	0	3	2	1	3	1	0	0	0	1	0	1	3
Intestinal fistula
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 7 (14.29%)	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	0 / 18 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0	0	0	0	0	0
Lip dry
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	0 / 18 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0	0	0	0	0	0
Dysphagia
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	1 / 18 (5.56%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	0	1
Dry mouth
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 7 (14.29%)	0 / 7 (0.00%)	0 / 3 (0.00%)	1 / 4 (25.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	1 / 18 (5.56%)
occurrences all number	0	0	0	1	0	0	1	0	0	0	0	0	1
Defaecation urgency
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	1 / 7 (14.29%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	0 / 18 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	1	0	0	0	0
Stomatitis
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 7 (14.29%)	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	0 / 18 (0.00%)
occurrences all number	0	0	0	2	0	0	0	0	0	0	0	0	0
Rectal perforation
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	1 / 3 (33.33%)	0 / 8 (0.00%)	0 / 3 (0.00%)	0 / 18 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	1	0	0	0
Vomiting
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 7 (14.29%)	1 / 7 (14.29%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	1 / 3 (33.33%)	1 / 8 (12.50%)	1 / 3 (33.33%)	0 / 18 (0.00%)
occurrences all number	1	0	0	1	1	0	0	0	0	1	1	1	0
Gastrooesophageal reflux disease
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	1 / 7 (14.29%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	2 / 18 (11.11%)
occurrences all number	0	0	0	0	1	0	0	0	0	0	0	0	2
Oral pain
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	1 / 8 (12.50%)	0 / 3 (0.00%)	1 / 18 (5.56%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	1	0	1
Epigastric discomfort
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	1 / 18 (5.56%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	0	1
Rectal haemorrhage
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	1 / 7 (14.29%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	1 / 18 (5.56%)
occurrences all number	0	0	0	0	1	0	0	0	0	0	0	0	1
Nausea
subjects affected / exposed	1 / 3 (33.33%)	1 / 3 (33.33%)	1 / 3 (33.33%)	2 / 7 (28.57%)	3 / 7 (42.86%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	1 / 7 (14.29%)	2 / 3 (66.67%)	1 / 8 (12.50%)	1 / 3 (33.33%)	1 / 18 (5.56%)
occurrences all number	1	1	1	2	4	0	0	0	1	2	1	1	1
Gastrointestinal haemorrhage
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	1 / 7 (14.29%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	0 / 18 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0	0	0	0	0	0
Hepatobiliary disorders
Hepatic cyst
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	1 / 18 (5.56%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	0	1
Hyperbilirubinaemia
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	0 / 18 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0	0	0	0	0	0
Skin and subcutaneous tissue disorders
Alopecia
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	2 / 3 (66.67%)	0 / 8 (0.00%)	0 / 3 (0.00%)	0 / 18 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	2	0	0	0
Palmar-plantar erythrodysaesthesia syndrome
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	0 / 18 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0	0	0	0	0	0
Hair growth abnormal
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	1 / 7 (14.29%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	0 / 18 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0	0	0	0	0	0
Cold sweat
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	1 / 7 (14.29%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	0 / 18 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0	0	0	0	0	0
Hair colour changes
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	2 / 7 (28.57%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	0 / 18 (0.00%)
occurrences all number	0	0	0	0	2	0	0	0	0	0	0	0	0
Dry skin
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	0 / 18 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0	0	0	0	0	0
Rash maculo-papular
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	1 / 4 (25.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	1 / 8 (12.50%)	1 / 3 (33.33%)	1 / 18 (5.56%)
occurrences all number	0	0	1	0	0	0	1	0	0	0	1	1	1
Pruritus
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	2 / 7 (28.57%)	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 3 (33.33%)	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	0 / 18 (0.00%)
occurrences all number	1	0	0	0	2	0	0	1	0	0	0	0	0
Night sweats
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	1 / 18 (5.56%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	0	1
Petechiae
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	1 / 18 (5.56%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	0	1
Skin disorder
subjects affected / exposed	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	0 / 18 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0	0	0	0	0
Skin ulcer
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	1 / 18 (5.56%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	0	1
Urticaria
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	1 / 18 (5.56%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	0	1
Rash
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	1 / 7 (14.29%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	1 / 18 (5.56%)
occurrences all number	0	0	0	0	2	0	0	0	0	0	0	0	1
Xeroderma
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	0 / 18 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0	0	0	0	0	0
Renal and urinary disorders
Bladder discomfort
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	1 / 3 (33.33%)	0 / 8 (0.00%)	0 / 3 (0.00%)	0 / 18 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	1	0	0	0
Renal colic
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	1 / 3 (33.33%)	0 / 8 (0.00%)	0 / 3 (0.00%)	0 / 18 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	1	0	0	0
Polyuria
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	1 / 18 (5.56%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	0	1
Calculus urinary
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	1 / 3 (33.33%)	0 / 8 (0.00%)	0 / 3 (0.00%)	0 / 18 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	1	0	0	0
Pollakiuria
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	1 / 7 (14.29%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	1 / 18 (5.56%)
occurrences all number	0	0	0	0	0	0	0	0	1	0	0	0	1
Haematuria
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	1 / 7 (14.29%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	1 / 3 (33.33%)	0 / 8 (0.00%)	0 / 3 (0.00%)	0 / 18 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0	0	1	0	0	0
Micturition urgency
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	2 / 3 (66.67%)	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	0 / 18 (0.00%)
occurrences all number	0	0	0	0	0	0	0	2	0	0	0	0	0
Urinary incontinence
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	1 / 8 (12.50%)	0 / 3 (0.00%)	2 / 18 (11.11%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	1	0	2
Nephrolithiasis
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	1 / 3 (33.33%)	0 / 8 (0.00%)	0 / 3 (0.00%)	0 / 18 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	2	0	0	0
Nocturia
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	1 / 7 (14.29%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	0 / 18 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0	0	0	0	0	0
Musculoskeletal and connective tissue disorders
Joint swelling
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	1 / 7 (14.29%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	0 / 18 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0	0	0	0	0	0
Arthralgia
subjects affected / exposed	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	1 / 7 (14.29%)	1 / 7 (14.29%)	0 / 3 (0.00%)	1 / 4 (25.00%)	0 / 3 (0.00%)	1 / 7 (14.29%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	1 / 18 (5.56%)
occurrences all number	0	2	0	1	1	0	1	0	1	0	0	0	1
Back pain
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	1 / 3 (33.33%)	1 / 7 (14.29%)	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	1 / 18 (5.56%)
occurrences all number	1	0	1	1	0	0	0	0	0	0	0	0	1
Sacral pain
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	0 / 18 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0	0	0	0	0	0
Limb discomfort
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	1 / 7 (14.29%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	1 / 18 (5.56%)
occurrences all number	0	0	0	0	1	0	0	0	0	0	0	0	1
Muscular weakness
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 7 (0.00%)	1 / 3 (33.33%)	0 / 4 (0.00%)	0 / 3 (0.00%)	1 / 7 (14.29%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	0 / 18 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0	1	0	0	0	0
Neck pain
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	1 / 7 (14.29%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	1 / 18 (5.56%)
occurrences all number	0	0	0	0	0	0	0	0	1	0	0	0	1
Pain in extremity
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	1 / 3 (33.33%)	0 / 8 (0.00%)	0 / 3 (0.00%)	1 / 18 (5.56%)
occurrences all number	0	0	0	0	0	0	0	0	0	1	0	0	1
Musculoskeletal discomfort
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	1 / 7 (14.29%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	0 / 18 (0.00%)
occurrences all number	0	0	0	0	2	0	0	0	0	0	0	0	0
Musculoskeletal chest pain
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	1 / 3 (33.33%)	1 / 18 (5.56%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	1	1
Muscle spasms
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	1 / 7 (14.29%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	2 / 18 (11.11%)
occurrences all number	0	0	0	0	1	0	0	0	0	0	0	0	3
Infections and infestations
COVID-19
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	1 / 3 (33.33%)	1 / 8 (12.50%)	0 / 3 (0.00%)	4 / 18 (22.22%)
occurrences all number	0	0	0	0	0	0	0	0	0	3	2	0	4
Escherichia urinary tract infection
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	0 / 18 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0	0	0	0	0	0
Gastroenteritis viral
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	1 / 3 (33.33%)	0 / 8 (0.00%)	0 / 3 (0.00%)	0 / 18 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	1	0	0	0
Lip infection
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	1 / 4 (25.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	0 / 18 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0	0	0	0	0
Fungal infection
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	1 / 3 (33.33%)	0 / 18 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	1	0
Cystitis
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	1 / 18 (5.56%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	0	4
Nasopharyngitis
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	1 / 7 (14.29%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	0 / 18 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	1	0	0	0	0
Oral herpes
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 7 (14.29%)	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	0 / 18 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0	0	0	0	0	0
Candida infection
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	1 / 3 (33.33%)	1 / 18 (5.56%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	1	1
Rhinitis
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	1 / 7 (14.29%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	1 / 3 (33.33%)	0 / 8 (0.00%)	0 / 3 (0.00%)	0 / 18 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0	0	1	0	0	0
Upper respiratory tract infection
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	1 / 3 (33.33%)	0 / 8 (0.00%)	0 / 3 (0.00%)	0 / 18 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	3	0	0	0
Hordeolum
subjects affected / exposed	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	0 / 18 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0	0	0	0	0
Lower respiratory tract infection
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	1 / 8 (12.50%)	0 / 3 (0.00%)	1 / 18 (5.56%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	1	0	1
Urinary tract infection
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	1 / 7 (14.29%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	1 / 3 (33.33%)	2 / 18 (11.11%)
occurrences all number	1	0	0	0	1	0	0	0	0	0	0	1	2
Viral infection
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	0 / 18 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0	0	0	0	0	0
Oral candidiasis
subjects affected / exposed	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	0 / 18 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0	0	0	0	0
Skin infection
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	1 / 18 (5.56%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	0	1
Metabolism and nutrition disorders
Dehydration
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	1 / 18 (5.56%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	0	1
Hypoglycaemia
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	1 / 18 (5.56%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	0	1
Decreased appetite
subjects affected / exposed	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	2 / 7 (28.57%)	3 / 7 (42.86%)	0 / 3 (0.00%)	1 / 4 (25.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	1 / 3 (33.33%)	0 / 8 (0.00%)	0 / 3 (0.00%)	2 / 18 (11.11%)
occurrences all number	0	2	0	3	3	0	1	0	0	1	0	0	2
Hypocalcaemia
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	1 / 18 (5.56%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	0	1
Hyponatraemia
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	1 / 7 (14.29%)	2 / 3 (66.67%)	0 / 4 (0.00%)	0 / 3 (0.00%)	1 / 7 (14.29%)	0 / 3 (0.00%)	1 / 8 (12.50%)	0 / 3 (0.00%)	3 / 18 (16.67%)
occurrences all number	0	0	0	0	2	2	0	0	1	0	1	0	6
Vitamin B12 deficiency
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	1 / 3 (33.33%)	0 / 8 (0.00%)	0 / 3 (0.00%)	0 / 18 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	1	0	0	0
Hypophagia
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	1 / 3 (33.33%)	1 / 18 (5.56%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	1	1
Hyperglycaemia
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	1 / 7 (14.29%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	0 / 18 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	1	0	0	0	0
Hypercalcaemia
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 7 (14.29%)	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	0 / 18 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0	0	0	0	0	0
Hypokalaemia
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 7 (14.29%)	0 / 7 (0.00%)	2 / 3 (66.67%)	1 / 4 (25.00%)	0 / 3 (0.00%)	1 / 7 (14.29%)	2 / 3 (66.67%)	1 / 8 (12.50%)	0 / 3 (0.00%)	2 / 18 (11.11%)
occurrences all number	0	0	0	1	0	2	2	0	1	2	1	0	2
Vitamin D deficiency
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	1 / 18 (5.56%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	0	1
Hyperphosphataemia
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	1 / 3 (33.33%)	0 / 8 (0.00%)	0 / 3 (0.00%)	0 / 18 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	1	0	0	0

More information

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Were there any global substantial amendments to the protocol? Yes

06 Jul 2016

Enrollment of patients with glioblastoma or high-grade glioma as separate dose cohorts. Option to implement a twice-daily dosing regimen. Changes in biomarker assessments.

14 Dec 2016

Packaging of future batches of lisavanbulin capsules (1 mg and 5 mg) in brown glass bottles or plastic (HDPE) bottles.

22 Jun 2017

Requirement for serum sodium to be documented to be institutional LLN at screening. Review of safety laboratory parameters at investigator and pharmacy levels prior to dispensing of new study medication.

28 May 2018

Update to the sponsor's pharmacovigilance service provider.

23 Mar 2020

Changes in response to the COVID-19 pandemic, consistent with the NHS Guidance COVID-19: Guidance for sponsors, sites and researchers (v2.1 20 March 2020).

30 Mar 2020

Modification of the Phase 2a design, and associated changes, following completion of the Phase 1 portion of the study. Phase 2a to continue in patients with recurrent GBM only whose GBM tumor tissue was positive for end-binding protein 1 (EB1).

09 Apr 2021

Addition of a cumulative safety evaluation. Introduction of a survival follow-up. Alignment of inclusion criterion 7 with the CTFG contraception guidance. Removal of references to patients not qualified or incapable of giving legal consent.

01 Jul 2021

Alignment of Protocol Section 6.3 with storage conditions outlined in the IMPD. Clarification of Protocol Inclusion criterion 7 consistent with Section 4.3 of the CTFG guidance Recommendations related to contraception and pregnancy testing in clinical trials Version 1.1 (CTFG 21/09/2020).

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: An Open-label Phase 1/2a Study of Oral BAL101553 in Adult Patients With Advanced Solid Tumors and in Adult Patients With Recurrent or Progressive Glioblastoma or High-grade Glioma

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Phase 1: Maximum tolerated dose (MTD) of daily oral lisavanbulin

Primary: Phase 1: Maximum tolerated dose (MTD) of daily oral lisavanbulin

Primary: Phase 2a: Objective Response Rate (ORR)

Primary: Phase 2a: Objective Response Rate (ORR)

Primary: Phase 2a: Best objective response

Primary: Phase 2a: Best objective response

Secondary: Number of Patients With CTCAE Grade 3-4 TEAEs

Secondary: Number of Patients With CTCAE Grade 3-4 TEAEs

Secondary: Phase 1: Best Objective Response

Secondary: Phase 1: Best Objective Response

Secondary: Phase 1: Objective Response Rate (ORR)

Secondary: Phase 1: Objective Response Rate (ORR)

Secondary: Phase 2a: PFS at 6 Months

Secondary: Phase 2a: PFS at 6 Months

Secondary: Phase 2a: Progression-free survival (PFS)

Secondary: Phase 2a: Progression-free survival (PFS)

Secondary: Phase 2a: Overall survival (OS) at 12 months

Secondary: Phase 2a: Overall survival (OS) at 12 months

Secondary: AUC of avanbulin (BAL27862)

Secondary: AUC of avanbulin (BAL27862)

Secondary: Half-life of avanbulin (BAL27862)

Secondary: Half-life of avanbulin (BAL27862)

Secondary: Tmax of avanbulin (BAL27862)

Secondary: Tmax of avanbulin (BAL27862)

Secondary: Cmax of avanbulin (BAL27862)

Secondary: Cmax of avanbulin (BAL27862)

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information

Clinical Trial Results:
An Open-label Phase 1/2a Study of Oral BAL101553 in Adult Patients With Advanced Solid Tumors and in Adult Patients With Recurrent or Progressive Glioblastoma or High-grade Glioma