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Clinical Trial Results:
A Phase I/II study of LDE225 in pediatric patients with recurrent or refractory medulloblastoma or other tumors potentially dependent on the Hedgehog-signaling pathway and adult patients with recurrent or refractory medulloblastoma

Summary
EudraCT number	2010-019348-37
Trial protocol	FR GB IT
Global end of trial date	03 Oct 2014

Results information
Results version number	v1(current)
This version publication date	13 Jul 2016
First version publication date	06 Aug 2015
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

CLDE225X2104

ISRCTN number

US NCT number

NCT01125800

WHO universal trial number (UTN)

Sponsor organisation name

Novartis Pharma AG

Sponsor organisation address

CH-4002, Basel, Switzerland,

Public contact

Clinical Disclosure Office, Novartis Pharma AG, +41 613241111,

Scientific contact

Clinical Disclosure Office, Novartis Pharma AG, +41 613241111,

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

Yes

EMA paediatric investigation plan number(s)

EMEA-000880-PIP02-11

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

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

Yes

Analysis stage

Final

Date of interim/final analysis

03 Oct 2014

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

03 Oct 2014

Was the trial ended prematurely?

Main objective of the trial

Determine the maximum tolerated dose (MTD) and/or recommended Phase II dose (RP2D) of sonidegib in children with advanced solid tumors (recurrent or refractory medulloblastoma, rhabdomyosarcoma, neuroblastoma, hepatoblastoma, high-grade glioma, or osteosarcoma) when administered on a continuous daily dosing schedule. (Phase I) Assess preliminary efficacy of sonidegib, as determined by objective response rate (ORR) in recurrent or refractory medulloblastoma (MB) patients (adult and pediatric combined) regardless of Hedgehog (Hh) pathway status (activated or non-activated) (Phase II)

Protection of trial subjects

The study was in compliance with the ethical principles derived from the Declaration of Helsinki and in compliance with all International Conference on Harmonization (ICH) Good Clinical Practice (GCP) Guidelines. All the local regulatory requirements pertinent to safety of trial subjects were followed. Rescue medication was not allowed during the course of the study. The investigator provided follow-up medical care for all subjects who were prematurely withdrawn from the study, or referred them for appropriate ongoing care.

Background therapy

Evidence for comparator

Actual start date of recruitment

09 Feb 2011

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Number of subjects enrolled per country

Country: Number of subjects enrolled

United Kingdom: 11

Country: Number of subjects enrolled

France: 16

Country: Number of subjects enrolled

Italy: 17

Country: Number of subjects enrolled

Australia: 4

Country: Number of subjects enrolled

Canada: 6

Country: Number of subjects enrolled

United States: 22

Worldwide total number of subjects

EEA total number of subjects

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

Adolescents (12-17 years)

Adults (18-64 years)

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

The study was conducted at 14 centres in 6 countries.

Screening details

A total of 60 pediatric subjects and 16 adult subjects were enrolled in this study, of which 59 pediatric subjects received sonidegib during the dose-escalation and expansion part (Phase I); 17 subjects (1 child and 16 adults) received sonidegib in the Phase II.

Period 1 title

Overall study (overall period)

Is this the baseline period?

Yes

Allocation method

Not applicable

Blinding used

Not blinded

Blinding implementation details

As the study was an open-label study, this section was not applicable.

Are arms mutually exclusive

Yes

Pediatric subjects, LDE225 233 mg/m^2

Arm description

Pediatric subjects received LDE225 233 mg/m^2 once daily through oral route.

Arm type

Experimental

Investigational medicinal product name

Sonidegib

Investigational medicinal product code

LDE225

Other name

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

LDE225 capsules were administered once daily through oral route in pediatric subjects to provide a dose of 233 mg/m^2.

Pediatric subjects, LDE225 372 mg/m^2

Arm description

Pediatric subjects received LDE225 372 mg/m^2 once daily through oral route.

Arm type

Experimental

Investigational medicinal product name

Sonidegib

Investigational medicinal product code

LDE225

Other name

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

LDE225 capsules were administered once daily through oral route in pediatric subjects to provide a dose of 372 mg/m^2.

Pediatric subjects, LDE225 425 mg/m^2

Arm description

Pediatric subjects received LDE225 425 mg/m^2 once daily through oral route.

Arm type

Experimental

Investigational medicinal product name

Sonidegib

Investigational medicinal product code

LDE225

Other name

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

LDE225 capsules were administered once daily through oral route in pediatric subjects to provide a dose of 425 mg/m^2.

Pediatric subjects, LDE225 680 mg/m^2

Arm description

Pediatric subjects received LDE225 680 mg/m^2 once daily through oral route.

Arm type

Experimental

Investigational medicinal product name

Sonidegib

Investigational medicinal product code

LDE225

Other name

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

LDE225 capsules were administered once daily through oral route in pediatric subjects to provide a dose of 680 mg/m^2.

Adult subjects, LDE225 800 mg

Arm description

Adult subjects were treated with LDE225 800 mg capsule once daily.

Arm type

Experimental

Investigational medicinal product name

Sonidegib

Investigational medicinal product code

LDE225

Other name

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

LDE225 capsules of 800 mg strength was administered once daily.

Number of subjects in period 1	Pediatric subjects, LDE225 233 mg/m^2	Pediatric subjects, LDE225 372 mg/m^2	Pediatric subjects, LDE225 425 mg/m^2	Pediatric subjects, LDE225 680 mg/m^2	Adult subjects, LDE225 800 mg
Started	11	16	11	22	16
Completed	0	0	0	0	0
Not completed	11	16	11	22	16
Adverse event, non-fatal	1	1	1	1	2
Death	-	-	-	-	2
Disease Progression	10	15	10	21	12

Baseline characteristics

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Reporting group title

Pediatric subjects, LDE225 233 mg/m^2

Reporting group description

Pediatric subjects received LDE225 233 mg/m^2 once daily through oral route.

Reporting group title

Pediatric subjects, LDE225 372 mg/m^2

Reporting group description

Pediatric subjects received LDE225 372 mg/m^2 once daily through oral route.

Reporting group title

Pediatric subjects, LDE225 425 mg/m^2

Reporting group description

Pediatric subjects received LDE225 425 mg/m^2 once daily through oral route.

Reporting group title

Pediatric subjects, LDE225 680 mg/m^2

Reporting group description

Pediatric subjects received LDE225 680 mg/m^2 once daily through oral route.

Reporting group title

Adult subjects, LDE225 800 mg

Reporting group description

Adult subjects were treated with LDE225 800 mg capsule once daily.

Reporting group values	Pediatric subjects, LDE225 233 mg/m^2	Pediatric subjects, LDE225 372 mg/m^2	Pediatric subjects, LDE225 425 mg/m^2	Pediatric subjects, LDE225 680 mg/m^2	Adult subjects, LDE225 800 mg	Total
Number of subjects	11	16	11	22	16	76
Age categorical
Units: Subjects
≤ 10 years	4	3	5	11	0	23
>10 years to 17 years	7	13	6	11	0	37
18-65 years	0	0	0	0	16	16
Age continuous
Units: years
arithmetic mean (standard deviation)	12.36 ± 3.202	12.88 ± 3.519	10.27 ± 4.88	9.68 ± 4.932	35.13 ± 14.118	-
Gender categorical
Units: Subjects
Female	4	6	3	10	7	30
Male	7	10	8	12	9	46

End points

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Reporting group title

Pediatric subjects, LDE225 233 mg/m^2

Reporting group description

Pediatric subjects received LDE225 233 mg/m^2 once daily through oral route.

Reporting group title

Pediatric subjects, LDE225 372 mg/m^2

Reporting group description

Pediatric subjects received LDE225 372 mg/m^2 once daily through oral route.

Reporting group title

Pediatric subjects, LDE225 425 mg/m^2

Reporting group description

Pediatric subjects received LDE225 425 mg/m^2 once daily through oral route.

Reporting group title

Pediatric subjects, LDE225 680 mg/m^2

Reporting group description

Pediatric subjects received LDE225 680 mg/m^2 once daily through oral route.

Reporting group title

Adult subjects, LDE225 800 mg

Reporting group description

Adult subjects were treated with LDE225 800 mg capsule once daily.

Subject analysis set title

Pediatric subjects

Subject analysis set type

Sub-group analysis

Subject analysis set description

All the pediatric subjects were treated with LDE225 dose determined in the Phase I (233, 372, 425 and 680 mg/m^2).

Subject analysis set title

Adult subjects

Subject analysis set type

Sub-group analysis

Subject analysis set description

All adult subjects were treated with sonidegib 800 mg once daily in phase II portion of the study. Pediatric patients were also enrolled in phase II portion of the study at the recommended phase II pediatric dose - 680 mg/m^2

Primary: Maximum tolerated dose (MTD) of sonidegib in Phase 1

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End point title

Maximum tolerated dose (MTD) of sonidegib in Phase 1 ^[1] ^[2]

End point description

MTD was defined as highest dose level for which for is unlikely to have more than 33% of patients experienced dose-limiting toxicity (DLT) during the first 6 weeks of treatment,no more than 1 subject in a dose cohort experienced dose-limiting toxicity (DLT), based on a Bayesian logistic regression model (BLRM) employing the escalation with overdose control (EWOC) principle. DLT was defined as an adverse event (AE) or abnormal laboratory value assessed as unrelated to disease, disease progression, intercurrent illness, or concomitant medications. MTD was not achieved since no more than 1 DLT was observed in any cohort. One DLT was observed at 372 mg/m^2 dose. The posterior probability of true DLT rate lies in excessive toxicity interval [0.33, 1] even at 680 mg/m2 was still very small (0.7%);The RP2D was established using the BLRM and joint clinical review of the safety data by the Investigators and Novartis personnel, including the Novartis medical monitor,at a dose escalation meeting

End point type

Primary

End point timeframe

Baseline, End of dose escalation part

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: Only descriptive summary statistics was planned for this primary outcome measure.
[2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The end point summary statistics was planned only for treatment arms in Part 1 of the study.

End point values	Pediatric subjects, LDE225 233 mg/m^2	Pediatric subjects, LDE225 372 mg/m^2	Pediatric subjects, LDE225 425 mg/m^2	Pediatric subjects, LDE225 680 mg/m^2
Number of subjects analysed	11 ^[3]	16 ^[4]	11 ^[5]	22 ^[6]
Units: mg/m^2
arithmetic mean (standard deviation)	0 ± 0	0 ± 0	0 ± 0	0 ± 0

Notes
[3] - The MTD for the pediatric population was not established in this study.
[4] - The MTD for the pediatric population was not established in this study.
[5] - The MTD for the pediatric population was not established in this study.
[6] - The MTD for the pediatric population was not established in this study.

No statistical analyses for this end point

Primary: Percentage of subjects with objective response rate (ORR) by treatment

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End point title

Percentage of subjects with objective response rate (ORR) by treatment ^[7]

End point description

The tumour response to the sonidegib treatment was measured by ORR. The ORR was defined as the proportion of subjects with partial response or complete response as their best overall response. Subjects with stable disease, progressive disease tumour assessment were considered as non-responders. The analysis was performed in full analysis set (FAS), defined as all the subjects who received at least one dose of sonidegib.

End point type

Primary

End point timeframe

Baseline to End of treatment

Notes
[7] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Only descriptive summary statistics was planned for this primary outcome measure.

End point values	Pediatric subjects	Adult subjects
Number of subjects analysed	60	16
Units: percentage of tumor response
number (not applicable)
Complete response	3.3	13.5
Partial response	0	6.3
Stable disease	8.3	37.5
Progressive disease	76.7	37.5
Objective response rate	3.3	18.3

No statistical analyses for this end point

Secondary: Number of subjects with adverse events (AEs), serious adverse events (SAEs), treatment related AEs and death during the study

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End point title

Number of subjects with adverse events (AEs), serious adverse events (SAEs), treatment related AEs and death during the study

End point description

An AE was defined as any unfavorable and unintended sign, symptom, or disease temporally associated with the use of study drug, whether or not related to study drug. A SAE was defined as an event which was fatal or life threatening, required or prolonged hospitalization, was significantly or permanently disabling or incapacitating, constituted a congenital anomaly or a birth defect, or encompassed any other clinically significant event that could jeopardize the subject or require medical or surgical intervention to prevent one of the aforementioned outcomes. Treatment related AEs were defined as AEs that were suspected to be related to study treatment as per investigator. On-treatment deaths were deaths which occurred up to 30 days after last date of study treatment. The analysis was performed in safety set (SS), defined as all the subjects who received at least 1 dose of sonidegib.

End point type

Secondary

End point timeframe

Baseline (start of study treatment) up to End of treatment + 30 days

End point values	Pediatric subjects, LDE225 233 mg/m^2	Pediatric subjects, LDE225 372 mg/m^2	Pediatric subjects, LDE225 425 mg/m^2	Pediatric subjects, LDE225 680 mg/m^2	Adult subjects, LDE225 800 mg
Number of subjects analysed	11	16	11	22	16
Units: Number of subjects
AEs	11	16	11	22	16
AEs suspected to be drug related	8	13	9	14	13
AEs leading to discontinuation	1	1	1	1	3
On-treatment deaths	2	2	1	8	2
SAEs	5	8	4	14	5

No statistical analyses for this end point

Secondary: Area under the drug concentration time curve from time zero to 24 hours after dosing (AUC0-24h) of sonidegib in Phase 1

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End point title

Area under the drug concentration time curve from time zero to 24 hours after dosing (AUC0-24h) of sonidegib in Phase 1 ^[8]

End point description

AUC(0-24h) was defined as the area under the drug concentration time curve calculated using linear trapezoidal summation from time zero to 24 hours after dosing. The analysis was performed in pharmacokinetic analysis set (PAS), defined as all the subjects who received at least one (full or partial) dose of sonidegib and provided at least one evaluable pharmacokinetic (PK) blood sample. The 'n' signifies those subjects evaluable for this measure at specified time points for each group, respectively.

End point type

Secondary

End point timeframe

Day 1 and Day 22 of Cycle 1

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: The end point summary statistics was planned only for treatment arms in Part 1 of the study.

End point values	Pediatric subjects, LDE225 233 mg/m^2	Pediatric subjects, LDE225 372 mg/m^2	Pediatric subjects, LDE225 425 mg/m^2	Pediatric subjects, LDE225 680 mg/m^2
Number of subjects analysed	11	16	11	22
Units: nanogramshours/millilitres (nghr/mL)
arithmetic mean (standard deviation)
Cycle 1/Day 1 (n=11, 15, 11, 19)	1981.56 ± 736.928	2194.29 ± 1592.396	5309.44 ± 3247.088	5117.61 ± 2658.133
Cycle 1/Day 22 (n=9, 14, 9, 15)	10589.53 ± 4163.192	15431.43 ± 10433.35	17753.32 ± 11551.57	32622.67 ± 11670.63

No statistical analyses for this end point

Secondary: Time to reach maximum observed plasma concentration (Tmax) of sonidegib in Phase 1

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End point title

Time to reach maximum observed plasma concentration (Tmax) of sonidegib in Phase 1 ^[9]

End point description

Tmax was defined as the time required to reach maximum observed plasma concentration. Tmax was directly determined from the raw plasma concentration time data. The analysis was performed in PAS population. The 'n' signifies those subjects evaluable for this measure at specified time points for each group, respectively.

End point type

Secondary

End point timeframe

Day 1 and Day 22 of Cycle 1

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: The end point summary statistics was planned only for treatment arms in Part 1 of the study.

End point values	Pediatric subjects, LDE225 233 mg/m^2	Pediatric subjects, LDE225 372 mg/m^2	Pediatric subjects, LDE225 425 mg/m^2	Pediatric subjects, LDE225 680 mg/m^2
Number of subjects analysed	11	16	11	22
Units: Hours
median (full range (min-max))
Cycle 1/Day 1 (n=11, 15, 10, 17)	3.98 (1.07 to 6.75)	2.03 (1 to 7)	2.92 (0.5 to 7)	2.08 (1 to 4.08)
Cycle 1/Day 22 (n=9, 12, 9, 15)	1.98 (1 to 7)	2.06 (0.95 to 4.25)	2 (0.67 to 7)	2 (0 to 7.05)

No statistical analyses for this end point

Secondary: Maximum observed plasma concentration (Cmax) of sonidegib in Phase 1

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End point title

Maximum observed plasma concentration (Cmax) of sonidegib in Phase 1 ^[10]

End point description

Maximum observed plasma concentration following drug administration was calculated from the raw plasma concentration time data. The analysis was performed in PAS population. The 'n' signifies those subjects evaluable for this measure at specified time points for each group, respectively.

End point type

Secondary

End point timeframe

Day 1 and Day 22 of Cycle 1

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: The end point summary statistics was planned only for treatment arms in Part 1 of the study.

End point values	Pediatric subjects, LDE225 233 mg/m^2	Pediatric subjects, LDE225 372 mg/m^2	Pediatric subjects, LDE225 425 mg/m^2	Pediatric subjects, LDE225 680 mg/m^2
Number of subjects analysed	11	16	11	22
Units: nanograms/millitres(ng/mL)
arithmetic mean (standard deviation)
Cycle 1/Day 1 (n=11, 15, 10, 17)	191.18 ± 82.464	246.39 ± 211.034	642.5 ± 486.709	618.88 ± 403.466
Cycle 1/Day 22 (n=9, 12, 9, 15)	769.22 ± 496.021	944.17 ± 553.395	1122 ± 736.862	1930 ± 677.949

No statistical analyses for this end point

Secondary: Percentage of pediatric subjects with objective response rate (ORR) by Hedgehog (Hh) signaling pathway status

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End point title

Percentage of pediatric subjects with objective response rate (ORR) by Hedgehog (Hh) signaling pathway status

End point description

ORR was determined in the subjects with mutations on Hh gene (Hh positive) and the subjects without mutations on Hh gene (Hh negative). The analysis was performed in full analysis set (FAS). 'n' signifies those subjects evaluable for this measure at specified time points for each group, respectively. 60 patients were screened, 10 were Hh positive, of the 10, 3 were pediatric.

End point type

Secondary

End point timeframe

Baseline to End of treatment

End point values	Pediatric subjects
Number of subjects analysed	3 ^[11]
Units: Percentage of subjects
number (not applicable)
Objective response rate	66.7

Notes
[11] - Number Hh positive pediatric subjects

No statistical analyses for this end point

Secondary: Duration of response by treatment

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End point title

Duration of response by treatment

End point description

Duration of overall response (complete response (CR) or partial response (PR)) was calculated for those subjects whose best overall response was CR or PR. The start date was the date of the first documented tumor response (CR or PR) and the end date was the date of the event defined as the first documented progression or death due to underlying cancer or after the same treatment line. If a subject did not have a progression or death, the duration of response was censored at the date of last adequate tumor assessment in that treatment line. The analysis was performed in FAS population.

End point type

Secondary

End point timeframe

Baseline to End of treatment

End point values	Pediatric subjects, LDE225 233 mg/m^2	Pediatric subjects, LDE225 372 mg/m^2	Pediatric subjects, LDE225 425 mg/m^2	Pediatric subjects, LDE225 680 mg/m^2	Adult subjects, LDE225 800 mg
Number of subjects analysed	0 ^[12]	1 ^[13]	1 ^[14]	0 ^[15]	3 ^[16]
Units: Months
median (full range (min-max))	( to )	7.03 (7 to 7.03)	8.08 (8 to 8.1)	( to )	4.86 (1.6 to 8.7)

Notes
[12] - none of the subjects in this group acheived the endpoint
[13] - only one responder in this group
[14] - only one responder in this group
[15] - none of the subjects in this group achieved the endpoint
[16] - 3 responders in this group

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

Serious Adverse Events are monitored from date of First Subject First Visit (FSFV) until Last Subject Last Visit (LSLV). All other adverse events are monitored from First Subject First Treatment (FSFT) until Last Subject Last Visit (LSLV).

Adverse event reporting additional description

Consistent with EudraCT disclosure specifications, Novartis has reported under the Serious adverse events field “number of deaths resulting from adverse events” all those deaths, resulting from serious adverse events that are deemed to be causally related to treatment by the investigator.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

17.0

Reporting group title

Pediatric subjects, LDE225 233 mg/m^2

Reporting group description

Pediatric subjects received LDE225 233 mg/m^2 once daily through oral route.

Reporting group title

Pediatric subjects, LDE225 372 mg/m^2

Reporting group description

Pediatric subjects received LDE225 372 mg/m^2 once daily through oral route.

Reporting group title

Pediatric subjects, LDE225 425 mg/m^2

Reporting group description

Pediatric subjects received LDE225 425 mg/m^2 once daily through oral route.

Reporting group title

Pediatric subjects, LDE225 680 mg/m^2

Reporting group description

Pediatric subjects received LDE225 680 mg/m^2 once daily through oral route.

Reporting group title

Adult subjects, LDE225 800 mg

Reporting group description

Adult subjects were treated with LDE225 800 mg capsule once daily.

Serious adverse events	Pediatric subjects, LDE225 233 mg/m^2	Pediatric subjects, LDE225 372 mg/m^2	Pediatric subjects, LDE225 425 mg/m^2	Pediatric subjects, LDE225 680 mg/m^2	Adult subjects, LDE225 800 mg
Total subjects affected by serious adverse events
subjects affected / exposed	5 / 11 (45.45%)	8 / 16 (50.00%)	4 / 11 (36.36%)	14 / 22 (63.64%)	5 / 16 (31.25%)
number of deaths (all causes)	2	2	1	8	2
number of deaths resulting from adverse events	0	0	0	0	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Tumour Haemorrhage
subjects affected / exposed	0 / 11 (0.00%)	1 / 16 (6.25%)	0 / 11 (0.00%)	0 / 22 (0.00%)	0 / 16 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Vascular disorders
Venous Insufficiency
subjects affected / exposed	0 / 11 (0.00%)	1 / 16 (6.25%)	0 / 11 (0.00%)	0 / 22 (0.00%)	0 / 16 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
General disorders and administration site conditions
Chest Pain
subjects affected / exposed	0 / 11 (0.00%)	1 / 16 (6.25%)	0 / 11 (0.00%)	0 / 22 (0.00%)	0 / 16 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
General Physical Health Deterioration
subjects affected / exposed	1 / 11 (9.09%)	2 / 16 (12.50%)	0 / 11 (0.00%)	0 / 22 (0.00%)	0 / 16 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 2	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pain
subjects affected / exposed	0 / 11 (0.00%)	0 / 16 (0.00%)	0 / 11 (0.00%)	2 / 22 (9.09%)	0 / 16 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pyrexia
subjects affected / exposed	0 / 11 (0.00%)	0 / 16 (0.00%)	1 / 11 (9.09%)	0 / 22 (0.00%)	0 / 16 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Immune system disorders
Hypersensitivity
subjects affected / exposed	0 / 11 (0.00%)	1 / 16 (6.25%)	0 / 11 (0.00%)	0 / 22 (0.00%)	0 / 16 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Dyspnoea
subjects affected / exposed	0 / 11 (0.00%)	1 / 16 (6.25%)	0 / 11 (0.00%)	0 / 22 (0.00%)	0 / 16 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pleural Effusion
subjects affected / exposed	0 / 11 (0.00%)	0 / 16 (0.00%)	0 / 11 (0.00%)	1 / 22 (4.55%)	0 / 16 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pneumonia Aspiration
subjects affected / exposed	0 / 11 (0.00%)	0 / 16 (0.00%)	0 / 11 (0.00%)	0 / 22 (0.00%)	1 / 16 (6.25%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory Distress
subjects affected / exposed	0 / 11 (0.00%)	1 / 16 (6.25%)	0 / 11 (0.00%)	0 / 22 (0.00%)	1 / 16 (6.25%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
Psychiatric disorders
Agitation
subjects affected / exposed	0 / 11 (0.00%)	0 / 16 (0.00%)	0 / 11 (0.00%)	1 / 22 (4.55%)	0 / 16 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Confusional State
subjects affected / exposed	0 / 11 (0.00%)	0 / 16 (0.00%)	0 / 11 (0.00%)	2 / 22 (9.09%)	0 / 16 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Disorientation
subjects affected / exposed	0 / 11 (0.00%)	1 / 16 (6.25%)	0 / 11 (0.00%)	0 / 22 (0.00%)	0 / 16 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Suicidal Ideation
subjects affected / exposed	0 / 11 (0.00%)	0 / 16 (0.00%)	1 / 11 (9.09%)	0 / 22 (0.00%)	0 / 16 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Investigations
Alanine Aminotransferase Increased
subjects affected / exposed	0 / 11 (0.00%)	0 / 16 (0.00%)	0 / 11 (0.00%)	0 / 22 (0.00%)	1 / 16 (6.25%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Aspartate Aminotransferase Increased
subjects affected / exposed	0 / 11 (0.00%)	0 / 16 (0.00%)	0 / 11 (0.00%)	0 / 22 (0.00%)	1 / 16 (6.25%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Blood Creatine Phosphokinase Increased
subjects affected / exposed	0 / 11 (0.00%)	0 / 16 (0.00%)	0 / 11 (0.00%)	0 / 22 (0.00%)	2 / 16 (12.50%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	2 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Myoglobin Blood Increased
subjects affected / exposed	0 / 11 (0.00%)	0 / 16 (0.00%)	0 / 11 (0.00%)	0 / 22 (0.00%)	1 / 16 (6.25%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Injury, poisoning and procedural complications
Femur Fracture
subjects affected / exposed	0 / 11 (0.00%)	0 / 16 (0.00%)	0 / 11 (0.00%)	0 / 22 (0.00%)	1 / 16 (6.25%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Procedural Complication
subjects affected / exposed	0 / 11 (0.00%)	0 / 16 (0.00%)	1 / 11 (9.09%)	0 / 22 (0.00%)	0 / 16 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Nervous system disorders
Altered State Of Consciousness
subjects affected / exposed	0 / 11 (0.00%)	1 / 16 (6.25%)	0 / 11 (0.00%)	0 / 22 (0.00%)	0 / 16 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Amnesia
subjects affected / exposed	1 / 11 (9.09%)	0 / 16 (0.00%)	0 / 11 (0.00%)	0 / 22 (0.00%)	0 / 16 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Aphasia
subjects affected / exposed	1 / 11 (9.09%)	0 / 16 (0.00%)	0 / 11 (0.00%)	0 / 22 (0.00%)	0 / 16 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Coma
subjects affected / exposed	0 / 11 (0.00%)	1 / 16 (6.25%)	0 / 11 (0.00%)	0 / 22 (0.00%)	0 / 16 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Convulsion
subjects affected / exposed	0 / 11 (0.00%)	1 / 16 (6.25%)	0 / 11 (0.00%)	3 / 22 (13.64%)	0 / 16 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 5	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Depressed Level Of Consciousness
subjects affected / exposed	0 / 11 (0.00%)	0 / 16 (0.00%)	0 / 11 (0.00%)	2 / 22 (9.09%)	0 / 16 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Dysaesthesia
subjects affected / exposed	1 / 11 (9.09%)	0 / 16 (0.00%)	0 / 11 (0.00%)	0 / 22 (0.00%)	0 / 16 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Dystonia
subjects affected / exposed	0 / 11 (0.00%)	0 / 16 (0.00%)	1 / 11 (9.09%)	0 / 22 (0.00%)	0 / 16 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Encephalopathy
subjects affected / exposed	0 / 11 (0.00%)	0 / 16 (0.00%)	1 / 11 (9.09%)	0 / 22 (0.00%)	0 / 16 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Headache
subjects affected / exposed	1 / 11 (9.09%)	2 / 16 (12.50%)	1 / 11 (9.09%)	4 / 22 (18.18%)	0 / 16 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 3	0 / 1	0 / 4	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hydrocephalus
subjects affected / exposed	1 / 11 (9.09%)	0 / 16 (0.00%)	0 / 11 (0.00%)	1 / 22 (4.55%)	0 / 16 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
Intracranial Pressure Increased
subjects affected / exposed	1 / 11 (9.09%)	0 / 16 (0.00%)	0 / 11 (0.00%)	0 / 22 (0.00%)	0 / 16 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Neuralgia
subjects affected / exposed	0 / 11 (0.00%)	1 / 16 (6.25%)	0 / 11 (0.00%)	1 / 22 (4.55%)	0 / 16 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Neurological Decompensation
subjects affected / exposed	0 / 11 (0.00%)	0 / 16 (0.00%)	1 / 11 (9.09%)	1 / 22 (4.55%)	0 / 16 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Quadriparesis
subjects affected / exposed	0 / 11 (0.00%)	0 / 16 (0.00%)	0 / 11 (0.00%)	1 / 22 (4.55%)	0 / 16 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Somnolence
subjects affected / exposed	0 / 11 (0.00%)	0 / 16 (0.00%)	0 / 11 (0.00%)	1 / 22 (4.55%)	0 / 16 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Tremor
subjects affected / exposed	0 / 11 (0.00%)	0 / 16 (0.00%)	1 / 11 (9.09%)	0 / 22 (0.00%)	0 / 16 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
VIIth nerve paralysis
subjects affected / exposed	0 / 11 (0.00%)	0 / 16 (0.00%)	1 / 11 (9.09%)	0 / 22 (0.00%)	0 / 16 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Eye disorders
Vision Blurred
subjects affected / exposed	1 / 11 (9.09%)	0 / 16 (0.00%)	0 / 11 (0.00%)	0 / 22 (0.00%)	0 / 16 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
Abdominal Pain
subjects affected / exposed	0 / 11 (0.00%)	0 / 16 (0.00%)	0 / 11 (0.00%)	1 / 22 (4.55%)	0 / 16 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Dysphagia
subjects affected / exposed	0 / 11 (0.00%)	0 / 16 (0.00%)	1 / 11 (9.09%)	0 / 22 (0.00%)	1 / 16 (6.25%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Vomiting
subjects affected / exposed	1 / 11 (9.09%)	0 / 16 (0.00%)	1 / 11 (9.09%)	4 / 22 (18.18%)	0 / 16 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	1 / 1	0 / 5	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Renal and urinary disorders
Urinary Incontinence
subjects affected / exposed	0 / 11 (0.00%)	0 / 16 (0.00%)	0 / 11 (0.00%)	1 / 22 (4.55%)	0 / 16 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Muscular Weakness
subjects affected / exposed	0 / 11 (0.00%)	0 / 16 (0.00%)	1 / 11 (9.09%)	0 / 22 (0.00%)	1 / 16 (6.25%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pain In Extremity
subjects affected / exposed	0 / 11 (0.00%)	0 / 16 (0.00%)	0 / 11 (0.00%)	1 / 22 (4.55%)	0 / 16 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Rhabdomyolysis
subjects affected / exposed	0 / 11 (0.00%)	1 / 16 (6.25%)	0 / 11 (0.00%)	0 / 22 (0.00%)	0 / 16 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Infections and infestations
Cellulitis
subjects affected / exposed	0 / 11 (0.00%)	1 / 16 (6.25%)	0 / 11 (0.00%)	0 / 22 (0.00%)	0 / 16 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cystitis
subjects affected / exposed	0 / 11 (0.00%)	0 / 16 (0.00%)	0 / 11 (0.00%)	0 / 22 (0.00%)	1 / 16 (6.25%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Mucosal Infection
subjects affected / exposed	0 / 11 (0.00%)	1 / 16 (6.25%)	0 / 11 (0.00%)	0 / 22 (0.00%)	0 / 16 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pneumonia
subjects affected / exposed	0 / 11 (0.00%)	0 / 16 (0.00%)	1 / 11 (9.09%)	0 / 22 (0.00%)	0 / 16 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Urinary Tract Infection
subjects affected / exposed	0 / 11 (0.00%)	0 / 16 (0.00%)	1 / 11 (9.09%)	0 / 22 (0.00%)	0 / 16 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Wound Infection
subjects affected / exposed	0 / 11 (0.00%)	0 / 16 (0.00%)	0 / 11 (0.00%)	1 / 22 (4.55%)	0 / 16 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Metabolism and nutrition disorders
Decreased Appetite
subjects affected / exposed	1 / 11 (9.09%)	1 / 16 (6.25%)	1 / 11 (9.09%)	0 / 22 (0.00%)	0 / 16 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Dehydration
subjects affected / exposed	0 / 11 (0.00%)	0 / 16 (0.00%)	1 / 11 (9.09%)	0 / 22 (0.00%)	0 / 16 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0

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

Non-serious adverse events	Pediatric subjects, LDE225 233 mg/m^2	Pediatric subjects, LDE225 372 mg/m^2	Pediatric subjects, LDE225 425 mg/m^2	Pediatric subjects, LDE225 680 mg/m^2	Adult subjects, LDE225 800 mg
Total subjects affected by non serious adverse events
subjects affected / exposed	11 / 11 (100.00%)	16 / 16 (100.00%)	11 / 11 (100.00%)	21 / 22 (95.45%)	16 / 16 (100.00%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Skin Papilloma
subjects affected / exposed	1 / 11 (9.09%)	1 / 16 (6.25%)	0 / 11 (0.00%)	0 / 22 (0.00%)	0 / 16 (0.00%)
occurrences all number	2	1	0	0	0
Vascular disorders
Haematoma
subjects affected / exposed	0 / 11 (0.00%)	1 / 16 (6.25%)	0 / 11 (0.00%)	0 / 22 (0.00%)	0 / 16 (0.00%)
occurrences all number	0	1	0	0	0
Hypotension
subjects affected / exposed	1 / 11 (9.09%)	2 / 16 (12.50%)	0 / 11 (0.00%)	1 / 22 (4.55%)	1 / 16 (6.25%)
occurrences all number	1	2	0	1	1
Pallor
subjects affected / exposed	0 / 11 (0.00%)	0 / 16 (0.00%)	1 / 11 (9.09%)	0 / 22 (0.00%)	0 / 16 (0.00%)
occurrences all number	0	0	1	0	0
General disorders and administration site conditions
Asthenia
subjects affected / exposed	2 / 11 (18.18%)	4 / 16 (25.00%)	1 / 11 (9.09%)	1 / 22 (4.55%)	3 / 16 (18.75%)
occurrences all number	2	5	2	1	3
Chest Pain
subjects affected / exposed	0 / 11 (0.00%)	2 / 16 (12.50%)	0 / 11 (0.00%)	1 / 22 (4.55%)	0 / 16 (0.00%)
occurrences all number	0	2	0	1	0
Chills
subjects affected / exposed	1 / 11 (9.09%)	0 / 16 (0.00%)	0 / 11 (0.00%)	0 / 22 (0.00%)	0 / 16 (0.00%)
occurrences all number	1	0	0	0	0
Face Oedema
subjects affected / exposed	0 / 11 (0.00%)	1 / 16 (6.25%)	0 / 11 (0.00%)	0 / 22 (0.00%)	0 / 16 (0.00%)
occurrences all number	0	1	0	0	0
Facial Pain
subjects affected / exposed	0 / 11 (0.00%)	1 / 16 (6.25%)	0 / 11 (0.00%)	0 / 22 (0.00%)	1 / 16 (6.25%)
occurrences all number	0	1	0	0	1
Fatigue
subjects affected / exposed	5 / 11 (45.45%)	7 / 16 (43.75%)	3 / 11 (27.27%)	6 / 22 (27.27%)	1 / 16 (6.25%)
occurrences all number	7	10	3	6	1
Gait Disturbance
subjects affected / exposed	1 / 11 (9.09%)	1 / 16 (6.25%)	1 / 11 (9.09%)	1 / 22 (4.55%)	2 / 16 (12.50%)
occurrences all number	1	1	1	1	2
General Physical Health Deterioration
subjects affected / exposed	0 / 11 (0.00%)	0 / 16 (0.00%)	0 / 11 (0.00%)	0 / 22 (0.00%)	1 / 16 (6.25%)
occurrences all number	0	0	0	0	1
Influenza Like Illness
subjects affected / exposed	0 / 11 (0.00%)	0 / 16 (0.00%)	0 / 11 (0.00%)	0 / 22 (0.00%)	1 / 16 (6.25%)
occurrences all number	0	0	0	0	1
Non-Cardiac Chest Pain
subjects affected / exposed	0 / 11 (0.00%)	0 / 16 (0.00%)	1 / 11 (9.09%)	0 / 22 (0.00%)	0 / 16 (0.00%)
occurrences all number	0	0	1	0	0
Oedema Peripheral
subjects affected / exposed	0 / 11 (0.00%)	2 / 16 (12.50%)	0 / 11 (0.00%)	0 / 22 (0.00%)	1 / 16 (6.25%)
occurrences all number	0	2	0	0	1
Pain
subjects affected / exposed	0 / 11 (0.00%)	0 / 16 (0.00%)	1 / 11 (9.09%)	1 / 22 (4.55%)	0 / 16 (0.00%)
occurrences all number	0	0	1	1	0
Performance Status Decreased
subjects affected / exposed	0 / 11 (0.00%)	1 / 16 (6.25%)	0 / 11 (0.00%)	0 / 22 (0.00%)	0 / 16 (0.00%)
occurrences all number	0	1	0	0	0
Pyrexia
subjects affected / exposed	0 / 11 (0.00%)	1 / 16 (6.25%)	0 / 11 (0.00%)	3 / 22 (13.64%)	0 / 16 (0.00%)
occurrences all number	0	1	0	3	0
Immune system disorders
Hypersensitivity
subjects affected / exposed	0 / 11 (0.00%)	1 / 16 (6.25%)	0 / 11 (0.00%)	0 / 22 (0.00%)	0 / 16 (0.00%)
occurrences all number	0	1	0	0	0
Reproductive system and breast disorders
Penile Pain
subjects affected / exposed	1 / 11 (9.09%)	0 / 16 (0.00%)	0 / 11 (0.00%)	0 / 22 (0.00%)	0 / 16 (0.00%)
occurrences all number	1	0	0	0	0
Vaginal Discharge
subjects affected / exposed	0 / 11 (0.00%)	1 / 16 (6.25%)	0 / 11 (0.00%)	0 / 22 (0.00%)	0 / 16 (0.00%)
occurrences all number	0	1	0	0	0
Respiratory, thoracic and mediastinal disorders
Apnoea
subjects affected / exposed	0 / 11 (0.00%)	0 / 16 (0.00%)	1 / 11 (9.09%)	0 / 22 (0.00%)	0 / 16 (0.00%)
occurrences all number	0	0	1	0	0
Cough
subjects affected / exposed	3 / 11 (27.27%)	1 / 16 (6.25%)	5 / 11 (45.45%)	1 / 22 (4.55%)	3 / 16 (18.75%)
occurrences all number	3	1	5	1	3
Dyspnoea
subjects affected / exposed	2 / 11 (18.18%)	0 / 16 (0.00%)	0 / 11 (0.00%)	0 / 22 (0.00%)	0 / 16 (0.00%)
occurrences all number	3	0	0	0	0
Epistaxis
subjects affected / exposed	1 / 11 (9.09%)	2 / 16 (12.50%)	0 / 11 (0.00%)	1 / 22 (4.55%)	0 / 16 (0.00%)
occurrences all number	1	2	0	1	0
Hiccups
subjects affected / exposed	1 / 11 (9.09%)	0 / 16 (0.00%)	0 / 11 (0.00%)	0 / 22 (0.00%)	3 / 16 (18.75%)
occurrences all number	1	0	0	0	3
Laryngeal Inflammation
subjects affected / exposed	1 / 11 (9.09%)	0 / 16 (0.00%)	0 / 11 (0.00%)	0 / 22 (0.00%)	0 / 16 (0.00%)
occurrences all number	1	0	0	0	0
Nasal Congestion
subjects affected / exposed	1 / 11 (9.09%)	0 / 16 (0.00%)	0 / 11 (0.00%)	0 / 22 (0.00%)	0 / 16 (0.00%)
occurrences all number	1	0	0	0	0
Pleural Effusion
subjects affected / exposed	0 / 11 (0.00%)	1 / 16 (6.25%)	0 / 11 (0.00%)	0 / 22 (0.00%)	0 / 16 (0.00%)
occurrences all number	0	1	0	0	0
Rhinorrhoea
subjects affected / exposed	0 / 11 (0.00%)	1 / 16 (6.25%)	0 / 11 (0.00%)	0 / 22 (0.00%)	0 / 16 (0.00%)
occurrences all number	0	1	0	0	0
Stridor
subjects affected / exposed	0 / 11 (0.00%)	0 / 16 (0.00%)	1 / 11 (9.09%)	0 / 22 (0.00%)	0 / 16 (0.00%)
occurrences all number	0	0	1	0	0
Psychiatric disorders
Agitation
subjects affected / exposed	1 / 11 (9.09%)	0 / 16 (0.00%)	0 / 11 (0.00%)	1 / 22 (4.55%)	0 / 16 (0.00%)
occurrences all number	1	0	0	1	0
Anxiety
subjects affected / exposed	0 / 11 (0.00%)	2 / 16 (12.50%)	1 / 11 (9.09%)	1 / 22 (4.55%)	0 / 16 (0.00%)
occurrences all number	0	2	1	1	0
Bruxism
subjects affected / exposed	0 / 11 (0.00%)	0 / 16 (0.00%)	1 / 11 (9.09%)	0 / 22 (0.00%)	0 / 16 (0.00%)
occurrences all number	0	0	2	0	0
Confusional State
subjects affected / exposed	1 / 11 (9.09%)	2 / 16 (12.50%)	1 / 11 (9.09%)	0 / 22 (0.00%)	1 / 16 (6.25%)
occurrences all number	1	3	1	0	2
Disorientation
subjects affected / exposed	0 / 11 (0.00%)	1 / 16 (6.25%)	0 / 11 (0.00%)	0 / 22 (0.00%)	0 / 16 (0.00%)
occurrences all number	0	1	0	0	0
Euphoric Mood
subjects affected / exposed	0 / 11 (0.00%)	0 / 16 (0.00%)	1 / 11 (9.09%)	0 / 22 (0.00%)	0 / 16 (0.00%)
occurrences all number	0	0	1	0	0
Insomnia
subjects affected / exposed	2 / 11 (18.18%)	2 / 16 (12.50%)	1 / 11 (9.09%)	0 / 22 (0.00%)	0 / 16 (0.00%)
occurrences all number	2	2	1	0	0
Irritability
subjects affected / exposed	0 / 11 (0.00%)	1 / 16 (6.25%)	1 / 11 (9.09%)	0 / 22 (0.00%)	0 / 16 (0.00%)
occurrences all number	0	1	1	0	0
Mood Altered
subjects affected / exposed	0 / 11 (0.00%)	0 / 16 (0.00%)	1 / 11 (9.09%)	0 / 22 (0.00%)	0 / 16 (0.00%)
occurrences all number	0	0	1	0	0
Paranoia
subjects affected / exposed	1 / 11 (9.09%)	0 / 16 (0.00%)	0 / 11 (0.00%)	0 / 22 (0.00%)	0 / 16 (0.00%)
occurrences all number	1	0	0	0	0
Investigations
Activated Partial Thromboplastin Time Prolonged
subjects affected / exposed	0 / 11 (0.00%)	1 / 16 (6.25%)	0 / 11 (0.00%)	0 / 22 (0.00%)	0 / 16 (0.00%)
occurrences all number	0	1	0	0	0
Alanine Aminotransferase Increased
subjects affected / exposed	1 / 11 (9.09%)	2 / 16 (12.50%)	0 / 11 (0.00%)	2 / 22 (9.09%)	4 / 16 (25.00%)
occurrences all number	2	2	0	2	4
Aspartate Aminotransferase Increased
subjects affected / exposed	0 / 11 (0.00%)	2 / 16 (12.50%)	2 / 11 (18.18%)	2 / 22 (9.09%)	1 / 16 (6.25%)
occurrences all number	0	2	2	3	1
Blood Alkaline Phosphatase Increased
subjects affected / exposed	1 / 11 (9.09%)	1 / 16 (6.25%)	1 / 11 (9.09%)	0 / 22 (0.00%)	0 / 16 (0.00%)
occurrences all number	1	1	1	0	0
Blood Bilirubin Increased
subjects affected / exposed	0 / 11 (0.00%)	0 / 16 (0.00%)	0 / 11 (0.00%)	1 / 22 (4.55%)	1 / 16 (6.25%)
occurrences all number	0	0	0	1	1
Blood Creatine Phosphokinase Increased
subjects affected / exposed	1 / 11 (9.09%)	1 / 16 (6.25%)	2 / 11 (18.18%)	6 / 22 (27.27%)	8 / 16 (50.00%)
occurrences all number	1	3	4	6	15
Blood Creatinine Increased
subjects affected / exposed	0 / 11 (0.00%)	0 / 16 (0.00%)	1 / 11 (9.09%)	1 / 22 (4.55%)	0 / 16 (0.00%)
occurrences all number	0	0	2	1	0
Blood Fibrinogen Decreased
subjects affected / exposed	0 / 11 (0.00%)	1 / 16 (6.25%)	0 / 11 (0.00%)	0 / 22 (0.00%)	0 / 16 (0.00%)
occurrences all number	0	1	0	0	0
Blood Lactate Dehydrogenase Increased
subjects affected / exposed	2 / 11 (18.18%)	0 / 16 (0.00%)	0 / 11 (0.00%)	0 / 22 (0.00%)	0 / 16 (0.00%)
occurrences all number	2	0	0	0	0
Blood Magnesium Decreased
subjects affected / exposed	0 / 11 (0.00%)	0 / 16 (0.00%)	1 / 11 (9.09%)	0 / 22 (0.00%)	0 / 16 (0.00%)
occurrences all number	0	0	1	0	0
Blood Urea Increased
subjects affected / exposed	1 / 11 (9.09%)	0 / 16 (0.00%)	0 / 11 (0.00%)	0 / 22 (0.00%)	0 / 16 (0.00%)
occurrences all number	1	0	0	0	0
Cardiac Murmur
subjects affected / exposed	0 / 11 (0.00%)	1 / 16 (6.25%)	0 / 11 (0.00%)	0 / 22 (0.00%)	0 / 16 (0.00%)
occurrences all number	0	1	0	0	0
Haemoglobin Decreased
subjects affected / exposed	0 / 11 (0.00%)	1 / 16 (6.25%)	0 / 11 (0.00%)	0 / 22 (0.00%)	0 / 16 (0.00%)
occurrences all number	0	1	0	0	0
Lymphocyte Count Decreased
subjects affected / exposed	2 / 11 (18.18%)	1 / 16 (6.25%)	3 / 11 (27.27%)	3 / 22 (13.64%)	1 / 16 (6.25%)
occurrences all number	2	2	4	3	1
Neutrophil Count Decreased
subjects affected / exposed	0 / 11 (0.00%)	2 / 16 (12.50%)	2 / 11 (18.18%)	2 / 22 (9.09%)	0 / 16 (0.00%)
occurrences all number	0	2	2	5	0
Platelet Count Decreased
subjects affected / exposed	0 / 11 (0.00%)	2 / 16 (12.50%)	1 / 11 (9.09%)	0 / 22 (0.00%)	0 / 16 (0.00%)
occurrences all number	0	2	2	0	0
Weight Decreased
subjects affected / exposed	1 / 11 (9.09%)	2 / 16 (12.50%)	0 / 11 (0.00%)	2 / 22 (9.09%)	3 / 16 (18.75%)
occurrences all number	1	2	0	2	3
White Blood Cell Count Decreased
subjects affected / exposed	2 / 11 (18.18%)	2 / 16 (12.50%)	3 / 11 (27.27%)	3 / 22 (13.64%)	1 / 16 (6.25%)
occurrences all number	3	4	4	5	3
Injury, poisoning and procedural complications
Fall
subjects affected / exposed	0 / 11 (0.00%)	0 / 16 (0.00%)	0 / 11 (0.00%)	0 / 22 (0.00%)	1 / 16 (6.25%)
occurrences all number	0	0	0	0	1
Femur Fracture
subjects affected / exposed	0 / 11 (0.00%)	1 / 16 (6.25%)	0 / 11 (0.00%)	0 / 22 (0.00%)	0 / 16 (0.00%)
occurrences all number	0	1	0	0	0
Procedural Pain
subjects affected / exposed	1 / 11 (9.09%)	0 / 16 (0.00%)	0 / 11 (0.00%)	0 / 22 (0.00%)	0 / 16 (0.00%)
occurrences all number	1	0	0	0	0
Thermal Burn
subjects affected / exposed	0 / 11 (0.00%)	1 / 16 (6.25%)	0 / 11 (0.00%)	0 / 22 (0.00%)	0 / 16 (0.00%)
occurrences all number	0	1	0	0	0
Vascular Procedure Complication
subjects affected / exposed	0 / 11 (0.00%)	1 / 16 (6.25%)	0 / 11 (0.00%)	0 / 22 (0.00%)	0 / 16 (0.00%)
occurrences all number	0	1	0	0	0
Cardiac disorders
Left Ventricular Hypertrophy
subjects affected / exposed	0 / 11 (0.00%)	1 / 16 (6.25%)	0 / 11 (0.00%)	0 / 22 (0.00%)	0 / 16 (0.00%)
occurrences all number	0	1	0	0	0
Sinus Bradycardia
subjects affected / exposed	0 / 11 (0.00%)	0 / 16 (0.00%)	0 / 11 (0.00%)	0 / 22 (0.00%)	1 / 16 (6.25%)
occurrences all number	0	0	0	0	1
Nervous system disorders
Amnesia
subjects affected / exposed	0 / 11 (0.00%)	2 / 16 (12.50%)	0 / 11 (0.00%)	1 / 22 (4.55%)	0 / 16 (0.00%)
occurrences all number	0	3	0	1	0
Aphasia
subjects affected / exposed	0 / 11 (0.00%)	0 / 16 (0.00%)	1 / 11 (9.09%)	0 / 22 (0.00%)	0 / 16 (0.00%)
occurrences all number	0	0	1	0	0
Ataxia
subjects affected / exposed	2 / 11 (18.18%)	2 / 16 (12.50%)	2 / 11 (18.18%)	4 / 22 (18.18%)	0 / 16 (0.00%)
occurrences all number	2	2	2	4	0
Balance Disorder
subjects affected / exposed	1 / 11 (9.09%)	0 / 16 (0.00%)	1 / 11 (9.09%)	0 / 22 (0.00%)	1 / 16 (6.25%)
occurrences all number	1	0	2	0	1
Brain Oedema
subjects affected / exposed	1 / 11 (9.09%)	0 / 16 (0.00%)	0 / 11 (0.00%)	0 / 22 (0.00%)	0 / 16 (0.00%)
occurrences all number	1	0	0	0	0
Cerebellar Syndrome
subjects affected / exposed	0 / 11 (0.00%)	1 / 16 (6.25%)	0 / 11 (0.00%)	1 / 22 (4.55%)	1 / 16 (6.25%)
occurrences all number	0	2	0	1	1
Coma
subjects affected / exposed	1 / 11 (9.09%)	0 / 16 (0.00%)	0 / 11 (0.00%)	0 / 22 (0.00%)	0 / 16 (0.00%)
occurrences all number	1	0	0	0	0
Convulsion
subjects affected / exposed	0 / 11 (0.00%)	1 / 16 (6.25%)	2 / 11 (18.18%)	2 / 22 (9.09%)	1 / 16 (6.25%)
occurrences all number	0	1	7	2	1
Coordination Abnormal
subjects affected / exposed	0 / 11 (0.00%)	0 / 16 (0.00%)	1 / 11 (9.09%)	0 / 22 (0.00%)	0 / 16 (0.00%)
occurrences all number	0	0	2	0	0
Depressed Level Of Consciousness
subjects affected / exposed	0 / 11 (0.00%)	1 / 16 (6.25%)	0 / 11 (0.00%)	0 / 22 (0.00%)	0 / 16 (0.00%)
occurrences all number	0	1	0	0	0
Dizziness
subjects affected / exposed	1 / 11 (9.09%)	1 / 16 (6.25%)	1 / 11 (9.09%)	0 / 22 (0.00%)	0 / 16 (0.00%)
occurrences all number	1	2	1	0	0
Dysaesthesia
subjects affected / exposed	0 / 11 (0.00%)	0 / 16 (0.00%)	0 / 11 (0.00%)	0 / 22 (0.00%)	1 / 16 (6.25%)
occurrences all number	0	0	0	0	2
Dysarthria
subjects affected / exposed	0 / 11 (0.00%)	0 / 16 (0.00%)	1 / 11 (9.09%)	1 / 22 (4.55%)	0 / 16 (0.00%)
occurrences all number	0	0	1	1	0
Dysgeusia
subjects affected / exposed	1 / 11 (9.09%)	0 / 16 (0.00%)	0 / 11 (0.00%)	1 / 22 (4.55%)	0 / 16 (0.00%)
occurrences all number	2	0	0	1	0
Facial Nerve Disorder
subjects affected / exposed	1 / 11 (9.09%)	1 / 16 (6.25%)	0 / 11 (0.00%)	0 / 22 (0.00%)	0 / 16 (0.00%)
occurrences all number	1	1	0	0	0
Facial Paresis
subjects affected / exposed	1 / 11 (9.09%)	0 / 16 (0.00%)	0 / 11 (0.00%)	0 / 22 (0.00%)	0 / 16 (0.00%)
occurrences all number	2	0	0	0	0
Headache
subjects affected / exposed	6 / 11 (54.55%)	7 / 16 (43.75%)	4 / 11 (36.36%)	9 / 22 (40.91%)	2 / 16 (12.50%)
occurrences all number	7	17	13	10	2
Hemiparesis
subjects affected / exposed	0 / 11 (0.00%)	0 / 16 (0.00%)	1 / 11 (9.09%)	3 / 22 (13.64%)	0 / 16 (0.00%)
occurrences all number	0	0	1	3	0
Hemiplegia
subjects affected / exposed	0 / 11 (0.00%)	1 / 16 (6.25%)	0 / 11 (0.00%)	0 / 22 (0.00%)	0 / 16 (0.00%)
occurrences all number	0	1	0	0	0
Hyperaesthesia
subjects affected / exposed	0 / 11 (0.00%)	1 / 16 (6.25%)	0 / 11 (0.00%)	0 / 22 (0.00%)	0 / 16 (0.00%)
occurrences all number	0	2	0	0	0
Hypoaesthesia
subjects affected / exposed	0 / 11 (0.00%)	2 / 16 (12.50%)	0 / 11 (0.00%)	0 / 22 (0.00%)	0 / 16 (0.00%)
occurrences all number	0	2	0	0	0
IIIrd nerve paresis
subjects affected / exposed	1 / 11 (9.09%)	0 / 16 (0.00%)	0 / 11 (0.00%)	0 / 22 (0.00%)	0 / 16 (0.00%)
occurrences all number	1	0	0	0	0
Intracranial Pressure Increased
subjects affected / exposed	1 / 11 (9.09%)	1 / 16 (6.25%)	0 / 11 (0.00%)	0 / 22 (0.00%)	0 / 16 (0.00%)
occurrences all number	1	1	0	0	0
Lethargy
subjects affected / exposed	1 / 11 (9.09%)	0 / 16 (0.00%)	3 / 11 (27.27%)	0 / 22 (0.00%)	0 / 16 (0.00%)
occurrences all number	1	0	3	0	0
Meningism
subjects affected / exposed	2 / 11 (18.18%)	0 / 16 (0.00%)	0 / 11 (0.00%)	0 / 22 (0.00%)	0 / 16 (0.00%)
occurrences all number	2	0	0	0	0
Neuralgia
subjects affected / exposed	0 / 11 (0.00%)	1 / 16 (6.25%)	0 / 11 (0.00%)	1 / 22 (4.55%)	0 / 16 (0.00%)
occurrences all number	0	1	0	1	0
Neurological Decompensation
subjects affected / exposed	0 / 11 (0.00%)	0 / 16 (0.00%)	1 / 11 (9.09%)	0 / 22 (0.00%)	0 / 16 (0.00%)
occurrences all number	0	0	1	0	0
Neuropathy Peripheral
subjects affected / exposed	0 / 11 (0.00%)	1 / 16 (6.25%)	0 / 11 (0.00%)	0 / 22 (0.00%)	1 / 16 (6.25%)
occurrences all number	0	1	0	0	1
Paraesthesia
subjects affected / exposed	0 / 11 (0.00%)	1 / 16 (6.25%)	0 / 11 (0.00%)	0 / 22 (0.00%)	2 / 16 (12.50%)
occurrences all number	0	1	0	0	3
Paraparesis
subjects affected / exposed	0 / 11 (0.00%)	1 / 16 (6.25%)	0 / 11 (0.00%)	0 / 22 (0.00%)	0 / 16 (0.00%)
occurrences all number	0	2	0	0	0
Peripheral Sensory Neuropathy
subjects affected / exposed	1 / 11 (9.09%)	0 / 16 (0.00%)	0 / 11 (0.00%)	0 / 22 (0.00%)	0 / 16 (0.00%)
occurrences all number	1	0	0	0	0
Peroneal Nerve Palsy
subjects affected / exposed	0 / 11 (0.00%)	0 / 16 (0.00%)	0 / 11 (0.00%)	0 / 22 (0.00%)	1 / 16 (6.25%)
occurrences all number	0	0	0	0	1
Presyncope
subjects affected / exposed	0 / 11 (0.00%)	1 / 16 (6.25%)	0 / 11 (0.00%)	0 / 22 (0.00%)	0 / 16 (0.00%)
occurrences all number	0	1	0	0	0
Pyramidal Tract Syndrome
subjects affected / exposed	0 / 11 (0.00%)	1 / 16 (6.25%)	0 / 11 (0.00%)	0 / 22 (0.00%)	0 / 16 (0.00%)
occurrences all number	0	1	0	0	0
Somnolence
subjects affected / exposed	0 / 11 (0.00%)	3 / 16 (18.75%)	1 / 11 (9.09%)	1 / 22 (4.55%)	0 / 16 (0.00%)
occurrences all number	0	3	3	2	0
Speech Disorder
subjects affected / exposed	0 / 11 (0.00%)	0 / 16 (0.00%)	1 / 11 (9.09%)	0 / 22 (0.00%)	0 / 16 (0.00%)
occurrences all number	0	0	1	0	0
Tremor
subjects affected / exposed	0 / 11 (0.00%)	0 / 16 (0.00%)	1 / 11 (9.09%)	1 / 22 (4.55%)	0 / 16 (0.00%)
occurrences all number	0	0	2	1	0
VIIth nerve paralysis
subjects affected / exposed	0 / 11 (0.00%)	0 / 16 (0.00%)	1 / 11 (9.09%)	0 / 22 (0.00%)	0 / 16 (0.00%)
occurrences all number	0	0	1	0	0
VIth nerve disorder
subjects affected / exposed	0 / 11 (0.00%)	1 / 16 (6.25%)	0 / 11 (0.00%)	0 / 22 (0.00%)	0 / 16 (0.00%)
occurrences all number	0	1	0	0	0
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	0 / 11 (0.00%)	2 / 16 (12.50%)	4 / 11 (36.36%)	2 / 22 (9.09%)	0 / 16 (0.00%)
occurrences all number	0	2	4	2	0
Leukopenia
subjects affected / exposed	0 / 11 (0.00%)	0 / 16 (0.00%)	0 / 11 (0.00%)	0 / 22 (0.00%)	1 / 16 (6.25%)
occurrences all number	0	0	0	0	1
Lymphadenopathy
subjects affected / exposed	0 / 11 (0.00%)	0 / 16 (0.00%)	1 / 11 (9.09%)	0 / 22 (0.00%)	0 / 16 (0.00%)
occurrences all number	0	0	1	0	0
Lymphopenia
subjects affected / exposed	0 / 11 (0.00%)	1 / 16 (6.25%)	0 / 11 (0.00%)	2 / 22 (9.09%)	1 / 16 (6.25%)
occurrences all number	0	1	0	2	2
Thrombocytopenia
subjects affected / exposed	0 / 11 (0.00%)	0 / 16 (0.00%)	1 / 11 (9.09%)	0 / 22 (0.00%)	0 / 16 (0.00%)
occurrences all number	0	0	1	0	0
Ear and labyrinth disorders
Cerumen Impaction
subjects affected / exposed	2 / 11 (18.18%)	0 / 16 (0.00%)	0 / 11 (0.00%)	0 / 22 (0.00%)	0 / 16 (0.00%)
occurrences all number	2	0	0	0	0
Deafness
subjects affected / exposed	0 / 11 (0.00%)	1 / 16 (6.25%)	0 / 11 (0.00%)	0 / 22 (0.00%)	0 / 16 (0.00%)
occurrences all number	0	1	0	0	0
Ear Canal Stenosis
subjects affected / exposed	0 / 11 (0.00%)	1 / 16 (6.25%)	0 / 11 (0.00%)	0 / 22 (0.00%)	0 / 16 (0.00%)
occurrences all number	0	2	0	0	0
Ear Pain
subjects affected / exposed	0 / 11 (0.00%)	1 / 16 (6.25%)	0 / 11 (0.00%)	0 / 22 (0.00%)	0 / 16 (0.00%)
occurrences all number	0	1	0	0	0
Hypoacusis
subjects affected / exposed	0 / 11 (0.00%)	1 / 16 (6.25%)	0 / 11 (0.00%)	0 / 22 (0.00%)	0 / 16 (0.00%)
occurrences all number	0	1	0	0	0
Vertigo
subjects affected / exposed	0 / 11 (0.00%)	0 / 16 (0.00%)	0 / 11 (0.00%)	0 / 22 (0.00%)	1 / 16 (6.25%)
occurrences all number	0	0	0	0	1
Eye disorders
Blindness Unilateral
subjects affected / exposed	1 / 11 (9.09%)	0 / 16 (0.00%)	0 / 11 (0.00%)	0 / 22 (0.00%)	0 / 16 (0.00%)
occurrences all number	1	0	0	0	0
Conjunctivitis Allergic
subjects affected / exposed	0 / 11 (0.00%)	0 / 16 (0.00%)	1 / 11 (9.09%)	0 / 22 (0.00%)	0 / 16 (0.00%)
occurrences all number	0	0	1	0	0
Diplopia
subjects affected / exposed	0 / 11 (0.00%)	1 / 16 (6.25%)	0 / 11 (0.00%)	0 / 22 (0.00%)	0 / 16 (0.00%)
occurrences all number	0	1	0	0	0
Dry Eye
subjects affected / exposed	0 / 11 (0.00%)	0 / 16 (0.00%)	1 / 11 (9.09%)	1 / 22 (4.55%)	0 / 16 (0.00%)
occurrences all number	0	0	1	1	0
Eyelid Ptosis
subjects affected / exposed	0 / 11 (0.00%)	1 / 16 (6.25%)	0 / 11 (0.00%)	0 / 22 (0.00%)	0 / 16 (0.00%)
occurrences all number	0	1	0	0	0
Eye Irritation
subjects affected / exposed	0 / 11 (0.00%)	0 / 16 (0.00%)	1 / 11 (9.09%)	0 / 22 (0.00%)	0 / 16 (0.00%)
occurrences all number	0	0	1	0	0
Lacrimation Increased
subjects affected / exposed	0 / 11 (0.00%)	1 / 16 (6.25%)	0 / 11 (0.00%)	1 / 22 (4.55%)	0 / 16 (0.00%)
occurrences all number	0	1	0	1	0
Ocular Hyperaemia
subjects affected / exposed	0 / 11 (0.00%)	1 / 16 (6.25%)	0 / 11 (0.00%)	0 / 22 (0.00%)	0 / 16 (0.00%)
occurrences all number	0	1	0	0	0
Strabismus
subjects affected / exposed	0 / 11 (0.00%)	0 / 16 (0.00%)	1 / 11 (9.09%)	1 / 22 (4.55%)	0 / 16 (0.00%)
occurrences all number	0	0	2	1	0
Vision Blurred
subjects affected / exposed	0 / 11 (0.00%)	1 / 16 (6.25%)	2 / 11 (18.18%)	1 / 22 (4.55%)	0 / 16 (0.00%)
occurrences all number	0	1	2	1	0
Visual Acuity Reduced
subjects affected / exposed	0 / 11 (0.00%)	0 / 16 (0.00%)	1 / 11 (9.09%)	0 / 22 (0.00%)	0 / 16 (0.00%)
occurrences all number	0	0	1	0	0
Visual Impairment
subjects affected / exposed	1 / 11 (9.09%)	0 / 16 (0.00%)	1 / 11 (9.09%)	0 / 22 (0.00%)	0 / 16 (0.00%)
occurrences all number	1	0	1	0	0
Gastrointestinal disorders
Abdominal Pain
subjects affected / exposed	1 / 11 (9.09%)	3 / 16 (18.75%)	2 / 11 (18.18%)	5 / 22 (22.73%)	1 / 16 (6.25%)
occurrences all number	1	4	4	5	1
Abdominal Pain Lower
subjects affected / exposed	0 / 11 (0.00%)	1 / 16 (6.25%)	0 / 11 (0.00%)	0 / 22 (0.00%)	0 / 16 (0.00%)
occurrences all number	0	1	0	0	0
Anal Pruritus
subjects affected / exposed	0 / 11 (0.00%)	1 / 16 (6.25%)	0 / 11 (0.00%)	0 / 22 (0.00%)	0 / 16 (0.00%)
occurrences all number	0	1	0	0	0
Constipation
subjects affected / exposed	1 / 11 (9.09%)	6 / 16 (37.50%)	4 / 11 (36.36%)	3 / 22 (13.64%)	2 / 16 (12.50%)
occurrences all number	1	10	5	5	3
Dental Caries
subjects affected / exposed	0 / 11 (0.00%)	1 / 16 (6.25%)	0 / 11 (0.00%)	0 / 22 (0.00%)	0 / 16 (0.00%)
occurrences all number	0	1	0	0	0
Diarrhoea
subjects affected / exposed	2 / 11 (18.18%)	5 / 16 (31.25%)	2 / 11 (18.18%)	1 / 22 (4.55%)	4 / 16 (25.00%)
occurrences all number	2	7	2	1	5
Dysphagia
subjects affected / exposed	0 / 11 (0.00%)	2 / 16 (12.50%)	1 / 11 (9.09%)	0 / 22 (0.00%)	1 / 16 (6.25%)
occurrences all number	0	2	1	0	1
Faecal Incontinence
subjects affected / exposed	0 / 11 (0.00%)	0 / 16 (0.00%)	1 / 11 (9.09%)	0 / 22 (0.00%)	0 / 16 (0.00%)
occurrences all number	0	0	1	0	0
Faeces Hard
subjects affected / exposed	0 / 11 (0.00%)	0 / 16 (0.00%)	1 / 11 (9.09%)	0 / 22 (0.00%)	0 / 16 (0.00%)
occurrences all number	0	0	1	0	0
Gastritis
subjects affected / exposed	0 / 11 (0.00%)	0 / 16 (0.00%)	0 / 11 (0.00%)	0 / 22 (0.00%)	1 / 16 (6.25%)
occurrences all number	0	0	0	0	1
Gastrointestinal Pain
subjects affected / exposed	1 / 11 (9.09%)	0 / 16 (0.00%)	0 / 11 (0.00%)	0 / 22 (0.00%)	0 / 16 (0.00%)
occurrences all number	1	0	0	0	0
Gingival Pain
subjects affected / exposed	0 / 11 (0.00%)	0 / 16 (0.00%)	2 / 11 (18.18%)	0 / 22 (0.00%)	0 / 16 (0.00%)
occurrences all number	0	0	2	0	0
Mouth Ulceration
subjects affected / exposed	0 / 11 (0.00%)	0 / 16 (0.00%)	1 / 11 (9.09%)	0 / 22 (0.00%)	0 / 16 (0.00%)
occurrences all number	0	0	1	0	0
Nausea
subjects affected / exposed	5 / 11 (45.45%)	4 / 16 (25.00%)	3 / 11 (27.27%)	8 / 22 (36.36%)	4 / 16 (25.00%)
occurrences all number	5	5	8	10	5
Odynophagia
subjects affected / exposed	1 / 11 (9.09%)	0 / 16 (0.00%)	0 / 11 (0.00%)	0 / 22 (0.00%)	0 / 16 (0.00%)
occurrences all number	1	0	0	0	0
Oesophagitis
subjects affected / exposed	0 / 11 (0.00%)	1 / 16 (6.25%)	0 / 11 (0.00%)	0 / 22 (0.00%)	0 / 16 (0.00%)
occurrences all number	0	1	0	0	0
Oral Dysaesthesia
subjects affected / exposed	1 / 11 (9.09%)	0 / 16 (0.00%)	0 / 11 (0.00%)	0 / 22 (0.00%)	0 / 16 (0.00%)
occurrences all number	1	0	0	0	0
Oral Pain
subjects affected / exposed	0 / 11 (0.00%)	1 / 16 (6.25%)	0 / 11 (0.00%)	0 / 22 (0.00%)	0 / 16 (0.00%)
occurrences all number	0	1	0	0	0
Stomatitis
subjects affected / exposed	1 / 11 (9.09%)	1 / 16 (6.25%)	1 / 11 (9.09%)	0 / 22 (0.00%)	3 / 16 (18.75%)
occurrences all number	1	1	2	0	3
Tooth Disorder
subjects affected / exposed	1 / 11 (9.09%)	0 / 16 (0.00%)	0 / 11 (0.00%)	0 / 22 (0.00%)	0 / 16 (0.00%)
occurrences all number	1	0	0	0	0
Toothache
subjects affected / exposed	2 / 11 (18.18%)	1 / 16 (6.25%)	0 / 11 (0.00%)	0 / 22 (0.00%)	0 / 16 (0.00%)
occurrences all number	2	1	0	0	0
Vomiting
subjects affected / exposed	5 / 11 (45.45%)	9 / 16 (56.25%)	7 / 11 (63.64%)	15 / 22 (68.18%)	2 / 16 (12.50%)
occurrences all number	5	12	13	21	3
Hepatobiliary disorders
Hepatotoxicity
subjects affected / exposed	0 / 11 (0.00%)	0 / 16 (0.00%)	0 / 11 (0.00%)	0 / 22 (0.00%)	1 / 16 (6.25%)
occurrences all number	0	0	0	0	1
Skin and subcutaneous tissue disorders
Alopecia
subjects affected / exposed	0 / 11 (0.00%)	1 / 16 (6.25%)	3 / 11 (27.27%)	1 / 22 (4.55%)	0 / 16 (0.00%)
occurrences all number	0	1	3	1	0
Dermatitis
subjects affected / exposed	1 / 11 (9.09%)	0 / 16 (0.00%)	0 / 11 (0.00%)	0 / 22 (0.00%)	0 / 16 (0.00%)
occurrences all number	1	0	0	0	0
Dermatitis Acneiform
subjects affected / exposed	1 / 11 (9.09%)	0 / 16 (0.00%)	0 / 11 (0.00%)	0 / 22 (0.00%)	0 / 16 (0.00%)
occurrences all number	1	0	0	0	0
Dry Skin
subjects affected / exposed	0 / 11 (0.00%)	2 / 16 (12.50%)	3 / 11 (27.27%)	1 / 22 (4.55%)	1 / 16 (6.25%)
occurrences all number	0	2	3	1	1
Erythema
subjects affected / exposed	1 / 11 (9.09%)	0 / 16 (0.00%)	0 / 11 (0.00%)	0 / 22 (0.00%)	0 / 16 (0.00%)
occurrences all number	1	0	0	0	0
Fungating Wound
subjects affected / exposed	0 / 11 (0.00%)	0 / 16 (0.00%)	1 / 11 (9.09%)	0 / 22 (0.00%)	0 / 16 (0.00%)
occurrences all number	0	0	1	0	0
Hyperhidrosis
subjects affected / exposed	1 / 11 (9.09%)	0 / 16 (0.00%)	0 / 11 (0.00%)	0 / 22 (0.00%)	0 / 16 (0.00%)
occurrences all number	1	0	0	0	0
Madarosis
subjects affected / exposed	1 / 11 (9.09%)	1 / 16 (6.25%)	2 / 11 (18.18%)	0 / 22 (0.00%)	0 / 16 (0.00%)
occurrences all number	5	3	2	0	0
Nail Disorder
subjects affected / exposed	1 / 11 (9.09%)	0 / 16 (0.00%)	1 / 11 (9.09%)	0 / 22 (0.00%)	0 / 16 (0.00%)
occurrences all number	1	0	1	0	0
Pain Of Skin
subjects affected / exposed	0 / 11 (0.00%)	0 / 16 (0.00%)	0 / 11 (0.00%)	0 / 22 (0.00%)	1 / 16 (6.25%)
occurrences all number	0	0	0	0	1
Pruritus
subjects affected / exposed	2 / 11 (18.18%)	3 / 16 (18.75%)	1 / 11 (9.09%)	2 / 22 (9.09%)	0 / 16 (0.00%)
occurrences all number	2	4	1	3	0
Rash
subjects affected / exposed	1 / 11 (9.09%)	0 / 16 (0.00%)	0 / 11 (0.00%)	0 / 22 (0.00%)	1 / 16 (6.25%)
occurrences all number	1	0	0	0	1
Rash Maculo-Papular
subjects affected / exposed	0 / 11 (0.00%)	0 / 16 (0.00%)	1 / 11 (9.09%)	0 / 22 (0.00%)	0 / 16 (0.00%)
occurrences all number	0	0	1	0	0
Rash Papular
subjects affected / exposed	1 / 11 (9.09%)	0 / 16 (0.00%)	0 / 11 (0.00%)	0 / 22 (0.00%)	0 / 16 (0.00%)
occurrences all number	1	0	0	0	0
Skin Exfoliation
subjects affected / exposed	1 / 11 (9.09%)	0 / 16 (0.00%)	0 / 11 (0.00%)	0 / 22 (0.00%)	0 / 16 (0.00%)
occurrences all number	1	0	0	0	0
Solar Dermatitis
subjects affected / exposed	1 / 11 (9.09%)	0 / 16 (0.00%)	0 / 11 (0.00%)	0 / 22 (0.00%)	0 / 16 (0.00%)
occurrences all number	1	0	0	0	0
Renal and urinary disorders
Dysuria
subjects affected / exposed	0 / 11 (0.00%)	2 / 16 (12.50%)	0 / 11 (0.00%)	0 / 22 (0.00%)	0 / 16 (0.00%)
occurrences all number	0	2	0	0	0
Micturition Disorder
subjects affected / exposed	0 / 11 (0.00%)	1 / 16 (6.25%)	0 / 11 (0.00%)	0 / 22 (0.00%)	0 / 16 (0.00%)
occurrences all number	0	1	0	0	0
Micturition Urgency
subjects affected / exposed	1 / 11 (9.09%)	0 / 16 (0.00%)	0 / 11 (0.00%)	0 / 22 (0.00%)	0 / 16 (0.00%)
occurrences all number	1	0	0	0	0
Neurogenic Bladder
subjects affected / exposed	1 / 11 (9.09%)	1 / 16 (6.25%)	0 / 11 (0.00%)	0 / 22 (0.00%)	0 / 16 (0.00%)
occurrences all number	1	1	0	0	0
Pollakiuria
subjects affected / exposed	0 / 11 (0.00%)	1 / 16 (6.25%)	1 / 11 (9.09%)	1 / 22 (4.55%)	1 / 16 (6.25%)
occurrences all number	0	1	1	1	1
Polyuria
subjects affected / exposed	1 / 11 (9.09%)	0 / 16 (0.00%)	0 / 11 (0.00%)	0 / 22 (0.00%)	0 / 16 (0.00%)
occurrences all number	1	0	0	0	0
Urinary Incontinence
subjects affected / exposed	0 / 11 (0.00%)	0 / 16 (0.00%)	2 / 11 (18.18%)	0 / 22 (0.00%)	1 / 16 (6.25%)
occurrences all number	0	0	2	0	1
Urinary Retention
subjects affected / exposed	0 / 11 (0.00%)	0 / 16 (0.00%)	1 / 11 (9.09%)	1 / 22 (4.55%)	0 / 16 (0.00%)
occurrences all number	0	0	1	1	0
Urinary Tract Disorder
subjects affected / exposed	0 / 11 (0.00%)	0 / 16 (0.00%)	1 / 11 (9.09%)	0 / 22 (0.00%)	0 / 16 (0.00%)
occurrences all number	0	0	1	0	0
Endocrine disorders
Cushingoid
subjects affected / exposed	0 / 11 (0.00%)	1 / 16 (6.25%)	0 / 11 (0.00%)	0 / 22 (0.00%)	0 / 16 (0.00%)
occurrences all number	0	1	0	0	0
Musculoskeletal and connective tissue disorders
Arthralgia
subjects affected / exposed	2 / 11 (18.18%)	3 / 16 (18.75%)	3 / 11 (27.27%)	1 / 22 (4.55%)	0 / 16 (0.00%)
occurrences all number	3	5	5	2	0
Back Pain
subjects affected / exposed	0 / 11 (0.00%)	4 / 16 (25.00%)	0 / 11 (0.00%)	0 / 22 (0.00%)	1 / 16 (6.25%)
occurrences all number	0	4	0	0	1
Chondropathy
subjects affected / exposed	0 / 11 (0.00%)	1 / 16 (6.25%)	0 / 11 (0.00%)	0 / 22 (0.00%)	0 / 16 (0.00%)
occurrences all number	0	2	0	0	0
Epiphyseal Disorder
subjects affected / exposed	0 / 11 (0.00%)	0 / 16 (0.00%)	1 / 11 (9.09%)	0 / 22 (0.00%)	0 / 16 (0.00%)
occurrences all number	0	0	2	0	0
Muscle Spasms
subjects affected / exposed	2 / 11 (18.18%)	4 / 16 (25.00%)	5 / 11 (45.45%)	2 / 22 (9.09%)	4 / 16 (25.00%)
occurrences all number	5	9	9	2	5
Muscular Weakness
subjects affected / exposed	0 / 11 (0.00%)	1 / 16 (6.25%)	1 / 11 (9.09%)	0 / 22 (0.00%)	0 / 16 (0.00%)
occurrences all number	0	2	1	0	0
Musculoskeletal Pain
subjects affected / exposed	0 / 11 (0.00%)	1 / 16 (6.25%)	2 / 11 (18.18%)	0 / 22 (0.00%)	0 / 16 (0.00%)
occurrences all number	0	1	2	0	0
Musculoskeletal Stiffness
subjects affected / exposed	0 / 11 (0.00%)	1 / 16 (6.25%)	0 / 11 (0.00%)	0 / 22 (0.00%)	0 / 16 (0.00%)
occurrences all number	0	1	0	0	0
Myalgia
subjects affected / exposed	1 / 11 (9.09%)	2 / 16 (12.50%)	4 / 11 (36.36%)	5 / 22 (22.73%)	5 / 16 (31.25%)
occurrences all number	2	2	10	5	5
Neck Pain
subjects affected / exposed	0 / 11 (0.00%)	3 / 16 (18.75%)	2 / 11 (18.18%)	1 / 22 (4.55%)	2 / 16 (12.50%)
occurrences all number	0	5	2	1	2
Pain In Extremity
subjects affected / exposed	2 / 11 (18.18%)	6 / 16 (37.50%)	4 / 11 (36.36%)	0 / 22 (0.00%)	0 / 16 (0.00%)
occurrences all number	2	11	6	0	0
Pain In Jaw
subjects affected / exposed	1 / 11 (9.09%)	0 / 16 (0.00%)	2 / 11 (18.18%)	0 / 22 (0.00%)	1 / 16 (6.25%)
occurrences all number	1	0	3	0	1
Posture Abnormal
subjects affected / exposed	0 / 11 (0.00%)	0 / 16 (0.00%)	1 / 11 (9.09%)	0 / 22 (0.00%)	0 / 16 (0.00%)
occurrences all number	0	0	1	0	0
Rhabdomyolysis
subjects affected / exposed	0 / 11 (0.00%)	1 / 16 (6.25%)	0 / 11 (0.00%)	0 / 22 (0.00%)	0 / 16 (0.00%)
occurrences all number	0	1	0	0	0
Sensation Of Heaviness
subjects affected / exposed	1 / 11 (9.09%)	0 / 16 (0.00%)	0 / 11 (0.00%)	0 / 22 (0.00%)	0 / 16 (0.00%)
occurrences all number	1	0	0	0	0
Temporomandibular Joint Syndrome
subjects affected / exposed	0 / 11 (0.00%)	0 / 16 (0.00%)	1 / 11 (9.09%)	0 / 22 (0.00%)	0 / 16 (0.00%)
occurrences all number	0	0	1	0	0
Infections and infestations
Catheter Site Cellulitis
subjects affected / exposed	0 / 11 (0.00%)	1 / 16 (6.25%)	0 / 11 (0.00%)	0 / 22 (0.00%)	0 / 16 (0.00%)
occurrences all number	0	1	0	0	0
Cellulitis
subjects affected / exposed	0 / 11 (0.00%)	1 / 16 (6.25%)	0 / 11 (0.00%)	0 / 22 (0.00%)	0 / 16 (0.00%)
occurrences all number	0	1	0	0	0
Conjunctivitis
subjects affected / exposed	1 / 11 (9.09%)	1 / 16 (6.25%)	0 / 11 (0.00%)	1 / 22 (4.55%)	1 / 16 (6.25%)
occurrences all number	1	1	0	1	1
Ear Infection
subjects affected / exposed	0 / 11 (0.00%)	0 / 16 (0.00%)	0 / 11 (0.00%)	0 / 22 (0.00%)	1 / 16 (6.25%)
occurrences all number	0	0	0	0	2
Influenza
subjects affected / exposed	1 / 11 (9.09%)	0 / 16 (0.00%)	0 / 11 (0.00%)	0 / 22 (0.00%)	1 / 16 (6.25%)
occurrences all number	1	0	0	0	1
Nasopharyngitis
subjects affected / exposed	1 / 11 (9.09%)	0 / 16 (0.00%)	0 / 11 (0.00%)	0 / 22 (0.00%)	0 / 16 (0.00%)
occurrences all number	1	0	0	0	0
Pharyngitis
subjects affected / exposed	1 / 11 (9.09%)	0 / 16 (0.00%)	1 / 11 (9.09%)	0 / 22 (0.00%)	0 / 16 (0.00%)
occurrences all number	1	0	1	0	0
Skin Infection
subjects affected / exposed	1 / 11 (9.09%)	0 / 16 (0.00%)	0 / 11 (0.00%)	0 / 22 (0.00%)	1 / 16 (6.25%)
occurrences all number	1	0	0	0	1
Tooth Abscess
subjects affected / exposed	0 / 11 (0.00%)	1 / 16 (6.25%)	0 / 11 (0.00%)	0 / 22 (0.00%)	0 / 16 (0.00%)
occurrences all number	0	1	0	0	0
Upper Respiratory Tract Infection
subjects affected / exposed	0 / 11 (0.00%)	1 / 16 (6.25%)	0 / 11 (0.00%)	0 / 22 (0.00%)	2 / 16 (12.50%)
occurrences all number	0	1	0	0	2
Urinary Tract Infection
subjects affected / exposed	0 / 11 (0.00%)	1 / 16 (6.25%)	1 / 11 (9.09%)	1 / 22 (4.55%)	1 / 16 (6.25%)
occurrences all number	0	1	1	1	1
Vulvovaginal Mycotic Infection
subjects affected / exposed	1 / 11 (9.09%)	0 / 16 (0.00%)	0 / 11 (0.00%)	0 / 22 (0.00%)	0 / 16 (0.00%)
occurrences all number	1	0	0	0	0
Metabolism and nutrition disorders
Decreased Appetite
subjects affected / exposed	1 / 11 (9.09%)	1 / 16 (6.25%)	3 / 11 (27.27%)	4 / 22 (18.18%)	3 / 16 (18.75%)
occurrences all number	1	1	5	4	3
Dehydration
subjects affected / exposed	0 / 11 (0.00%)	0 / 16 (0.00%)	0 / 11 (0.00%)	3 / 22 (13.64%)	0 / 16 (0.00%)
occurrences all number	0	0	0	3	0
Hyperglycaemia
subjects affected / exposed	1 / 11 (9.09%)	1 / 16 (6.25%)	0 / 11 (0.00%)	0 / 22 (0.00%)	1 / 16 (6.25%)
occurrences all number	1	1	0	0	2
Hyperkalaemia
subjects affected / exposed	0 / 11 (0.00%)	0 / 16 (0.00%)	2 / 11 (18.18%)	2 / 22 (9.09%)	1 / 16 (6.25%)
occurrences all number	0	0	4	2	1
Hypermagnesaemia
subjects affected / exposed	0 / 11 (0.00%)	0 / 16 (0.00%)	1 / 11 (9.09%)	2 / 22 (9.09%)	0 / 16 (0.00%)
occurrences all number	0	0	1	2	0
Hypernatraemia
subjects affected / exposed	0 / 11 (0.00%)	0 / 16 (0.00%)	0 / 11 (0.00%)	0 / 22 (0.00%)	1 / 16 (6.25%)
occurrences all number	0	0	0	0	1
Hyperphagia
subjects affected / exposed	0 / 11 (0.00%)	1 / 16 (6.25%)	0 / 11 (0.00%)	0 / 22 (0.00%)	0 / 16 (0.00%)
occurrences all number	0	1	0	0	0
Hyperphosphataemia
subjects affected / exposed	1 / 11 (9.09%)	0 / 16 (0.00%)	0 / 11 (0.00%)	0 / 22 (0.00%)	0 / 16 (0.00%)
occurrences all number	1	0	0	0	0
Hypocalcaemia
subjects affected / exposed	0 / 11 (0.00%)	1 / 16 (6.25%)	1 / 11 (9.09%)	0 / 22 (0.00%)	0 / 16 (0.00%)
occurrences all number	0	1	1	0	0
Hypoglycaemia
subjects affected / exposed	0 / 11 (0.00%)	0 / 16 (0.00%)	0 / 11 (0.00%)	0 / 22 (0.00%)	1 / 16 (6.25%)
occurrences all number	0	0	0	0	1
Hypokalaemia
subjects affected / exposed	1 / 11 (9.09%)	0 / 16 (0.00%)	0 / 11 (0.00%)	1 / 22 (4.55%)	0 / 16 (0.00%)
occurrences all number	1	0	0	1	0
Hypomagnesaemia
subjects affected / exposed	0 / 11 (0.00%)	0 / 16 (0.00%)	1 / 11 (9.09%)	0 / 22 (0.00%)	0 / 16 (0.00%)
occurrences all number	0	0	1	0	0
Hyponatraemia
subjects affected / exposed	1 / 11 (9.09%)	3 / 16 (18.75%)	1 / 11 (9.09%)	3 / 22 (13.64%)	0 / 16 (0.00%)
occurrences all number	1	4	4	4	0
Hypophosphataemia
subjects affected / exposed	0 / 11 (0.00%)	1 / 16 (6.25%)	1 / 11 (9.09%)	1 / 22 (4.55%)	0 / 16 (0.00%)
occurrences all number	0	1	1	2	0
Vitamin D Deficiency
subjects affected / exposed	0 / 11 (0.00%)	0 / 16 (0.00%)	1 / 11 (9.09%)	0 / 22 (0.00%)	0 / 16 (0.00%)
occurrences all number	0	0	2	0	0

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Were there any global substantial amendments to the protocol? Yes

11 Jul 2011

List of breast cancer resistance protein (BCRP) substrates was added as non-authorized drugs in the study to avoid potential adverse drug-drug interactions.

11 Nov 2011

1. The second part of the study (Phase II) was incorporated to enroll approximately 55 adults and children with recurrent or refractory MB. 2. The plasma PK parameters to be analyzed was updated based on the emerging PK data. 3. The definition of MTD and RP2D was added and, clarified the BLRM considerations for specific DLTs with potentially more serious medical implications. 4. Hypersensitivity or signs of allergic reaction were not considered a DLT.

23 Jul 2014

Inclusion criteria for female subjects was modified. The language states that woman of child bearing potential must not become pregnant during the study and for 20 months after taking the last dose of study drug. This was changed from 6 to 20 months.

Were there any global interruptions to the trial? No

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

None reported

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Clinical trials

Clinical Trial Results:
A Phase I/II study of LDE225 in pediatric patients with recurrent or refractory medulloblastoma or other tumors potentially dependent on the Hedgehog-signaling pathway and adult patients with recurrent or refractory medulloblastoma

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Maximum tolerated dose (MTD) of sonidegib in Phase 1

Primary: Maximum tolerated dose (MTD) of sonidegib in Phase 1

Primary: Percentage of subjects with objective response rate (ORR) by treatment

Primary: Percentage of subjects with objective response rate (ORR) by treatment

Secondary: Number of subjects with adverse events (AEs), serious adverse events (SAEs), treatment related AEs and death during the study

Secondary: Number of subjects with adverse events (AEs), serious adverse events (SAEs), treatment related AEs and death during the study

Secondary: Area under the drug concentration time curve from time zero to 24 hours after dosing (AUC0-24h) of sonidegib in Phase 1

Secondary: Area under the drug concentration time curve from time zero to 24 hours after dosing (AUC0-24h) of sonidegib in Phase 1

Secondary: Time to reach maximum observed plasma concentration (Tmax) of sonidegib in Phase 1

Secondary: Time to reach maximum observed plasma concentration (Tmax) of sonidegib in Phase 1

Secondary: Maximum observed plasma concentration (Cmax) of sonidegib in Phase 1

Secondary: Maximum observed plasma concentration (Cmax) of sonidegib in Phase 1

Secondary: Percentage of pediatric subjects with objective response rate (ORR) by Hedgehog (Hh) signaling pathway status

Secondary: Percentage of pediatric subjects with objective response rate (ORR) by Hedgehog (Hh) signaling pathway status

Secondary: Duration of response by treatment

Secondary: Duration of response by treatment

Adverse events

Adverse events

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Substantial protocol amendments (globally)

Interruptions (globally)

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Clinical trials

Clinical Trial Results: A Phase I/II study of LDE225 in pediatric patients with recurrent or refractory medulloblastoma or other tumors potentially dependent on the Hedgehog-signaling pathway and adult patients with recurrent or refractory medulloblastoma

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Maximum tolerated dose (MTD) of sonidegib in Phase 1

Primary: Maximum tolerated dose (MTD) of sonidegib in Phase 1

Primary: Percentage of subjects with objective response rate (ORR) by treatment

Primary: Percentage of subjects with objective response rate (ORR) by treatment

Secondary: Number of subjects with adverse events (AEs), serious adverse events (SAEs), treatment related AEs and death during the study

Secondary: Number of subjects with adverse events (AEs), serious adverse events (SAEs), treatment related AEs and death during the study

Secondary: Area under the drug concentration time curve from time zero to 24 hours after dosing (AUC0-24h) of sonidegib in Phase 1

Secondary: Area under the drug concentration time curve from time zero to 24 hours after dosing (AUC0-24h) of sonidegib in Phase 1

Secondary: Time to reach maximum observed plasma concentration (Tmax) of sonidegib in Phase 1

Secondary: Time to reach maximum observed plasma concentration (Tmax) of sonidegib in Phase 1

Secondary: Maximum observed plasma concentration (Cmax) of sonidegib in Phase 1

Secondary: Maximum observed plasma concentration (Cmax) of sonidegib in Phase 1

Secondary: Percentage of pediatric subjects with objective response rate (ORR) by Hedgehog (Hh) signaling pathway status

Secondary: Percentage of pediatric subjects with objective response rate (ORR) by Hedgehog (Hh) signaling pathway status

Secondary: Duration of response by treatment

Secondary: Duration of response by treatment

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information

Clinical Trial Results:
A Phase I/II study of LDE225 in pediatric patients with recurrent or refractory medulloblastoma or other tumors potentially dependent on the Hedgehog-signaling pathway and adult patients with recurrent or refractory medulloblastoma