Download PDF

Clinical Trial Results:
A Phase 1b/2 study to assess the safety, tolerability and efficacy of BGB-290 in combination with radiation therapy and/or temozolomide in subjects with first-line or recurrent/refractory glioblastoma

Summary
EudraCT number	2017-001554-33
Trial protocol	NL
Global end of trial date	17 Mar 2021

Results information
Results version number	v1
This version publication date	19 Mar 2022
First version publication date	19 Mar 2022
Other versions	v2

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

Collapse all Expand all

Trial information

Top of page

Sponsor protocol code

BGB-290-104

ISRCTN number

US NCT number

NCT03150862

WHO universal trial number (UTN)

Sponsor organisation name

BeiGene, Ltd

Sponsor organisation address

2955 Campus Drive, Suite 200, San Mateo, CA , United States, 94403

Public contact

Clinical Trial Information Email, BeiGene USA, Inc., +1 877-828-5568 , clinicaltrials@beigene.com

Scientific contact

Clinical Trial Information Email, BeiGene USA, Inc., +1 877-828-5568 , clinicaltrials@beigene.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

13 Apr 2021

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

17 Mar 2021

Was the trial ended prematurely?

Main objective of the trial

PHASE 1: 1) Arm A: • To assess safety and tolerability of BGB-290 combined with RT • To identify dose-limiting toxicity (DLT) and determine the maximum tolerated dose (MTD) or maximum administered dose (MAD) for BGB-290 combined with RT • To select the recommended Phase 2 schedule for full-dose BGB 290 combined with RT 2) Arm B: • To assess safety and tolerability of BGB-290 combined with RT and TMZ • To identify DLTs and determine the MTD or MAD for TMZ combined with RT and the MTD/MAD for BGB-290 of Arm A • To select the RP2D for TMZ combined with RT and the MTD/MAD for BGB-290 of Arm A 3) Arm C: • To assess safety and tolerability of BGB-290 combined with TMZ • To identify DLTs and determine the MTD or MAD for TMZ combined with full-dose BGB-290 • To select the RP2D for TMZ combined with full-dose BGB 290 PHASE 2: To assess the efficacy of BGB-290 combined with: 1) RT (Arm A) 2) RT and TMZ (Arm B) 3) TMZ (Arm C)

Protection of trial subjects

This study was conducted in accordance with Sponsor procedures, which comply with the principles of Good Clinical Practice, International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use Guidelines, the Declaration of Helsinki, and local regulatory requirements.

Background therapy

Evidence for comparator

Actual start date of recruitment

24 Jul 2017

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

United States: 111

Country: Number of subjects enrolled

Switzerland: 1

Country: Number of subjects enrolled

Netherlands: 4

Worldwide total number of subjects

116

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

Top of page

Recruitment details

This study was conducted in 20 centers and 116 participants were treated.

Screening details

This study consisted of a dose escalation phase and a dose expansion phase. A total of 116 participants were recruited in Netherlands, Switzerland and United States.

Period 1 title

Overall period

Is this the baseline period?

Yes

Allocation method

Non-randomised - controlled

Blinding used

Not blinded

Are arms mutually exclusive

Yes

Arm A: Dose Escalation (DE) - Pamiparib 2Wks + RT 6 Wks

Arm description

Participants with newly diagnosed unmethylated glioblastoma (GBM) received 60 milligrams (mg) pamiparib orally twice daily (BID) for 2 weeks in combination with up to 60 Gy radiation for 6 weeks

Arm type

Experimental

Investigational medicinal product name

Pamiparib

Investigational medicinal product code

BGB-290

Other name

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

60 mg pamiparib BID for 2 weeks in combination with up to 60 Gy radiation for 6 weeks

Arm A: DE-Pamiparib 4 Wks + RT 6 Wks

Arm description

Participants with newly diagnosed unmethylated GBM received 60 mg pamiparib orally for 4 weeks in combination with up to 60 Gy radiation for 6 weeks

Arm type

Experimental

Investigational medicinal product name

Pamiparib

Investigational medicinal product code

BGB-290

Other name

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

60 mg pamiparib BID for 4 weeks in combination with up to 60 Gy radiation for 6 weeks

Arm A: DE- Pamiparib 6Wks + RT 6 Wks

Arm description

Participants with newly diagnosed unmethylated GBM received 60 mg pamiparib orally for 6 weeks in combination with up to 60 Gy radiation for 6 weeks

Arm type

Experimental

Investigational medicinal product name

Pamiparib

Investigational medicinal product code

BGB-290

Other name

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

60 mg pamiparib BID for 6 weeks in combination with up to 60 Gy radiation for 6 weeks

Arm A: Dose Expansion (E) - Pamiparib 6 Wks + RT 6 Wks

Arm description

Participants with newly diagnosed unmethylated GBM received 60 mg pamiparib orally for 6 weeks in combination with up to 60 Gy radiation for 6 weeks

Arm type

Experimental

Investigational medicinal product name

Pamiparib

Investigational medicinal product code

BGB-290

Other name

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

60 mg pamiparib BID for 6 weeks in combination with up to 60 Gy radiation for 6 weeks

Arm B: DE-Pamiparib 6 Wks + RT 6 Wks + + Temozolomide

Arm description

Participants with newly diagnosed unmethylated GBM received 60 mg pamiparib orally for 6 weeks in combination with up to 60 Gy radiation for 6 weeks and 60 mg temozolomide Wks 1 and 5

Arm type

Experimental

Investigational medicinal product name

Pamiparib

Investigational medicinal product code

BGB-290

Other name

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

60 mg pamiparib BID for 6 weeks in combination with up to 60 Gy radiation for 6 weeks

Investigational medicinal product name

Temozolomide

Investigational medicinal product code

Other name

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

60 mg temozolomide wks 1 and 5

Arm C: DE – Pamiparib + Temozolomide 20 mg

Arm description

Participants with both methylated and unmethylated recurrent/refractory GBM received 60 mg pamiparib BID and 20 mg temozolomide once daily orally from Day 1 to Day 21

Arm type

Experimental

Investigational medicinal product name

Pamiparib

Investigational medicinal product code

BGB-290

Other name

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

60 mg pamiparib BID for 6weeks in combination with up to 60 Gy radiation for 6 weeks

Investigational medicinal product name

Temozolomide

Investigational medicinal product code

Other name

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

temozolomide 40 mg once daily from Day 1 to day 21

Arm C: DE – Pamiparib + Temozolomide 40 mg

Arm description

Participants with both methylated and unmethylated recurrent/refractory GBM received 60 mg pamiparib BID and 40 mg temozolomide once daily orally from Day 1 to Day 21

Arm type

Experimental

Investigational medicinal product name

Temozolomide

Investigational medicinal product code

Other name

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

temozolomide 40 mg once daily from Day 1 to day 21

Arm C: E- Pamiparib + Temozolomide 60 mg

Arm description

Participants with both methylated and unmethylated recurrent/refractory GBM received 60 mg pamiparib BID and 60 mg temozolomide once daily orally from Day 1 to Day 7

Arm type

Experimental

Investigational medicinal product name

Temozolomide

Investigational medicinal product code

Other name

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

temozolomide 60 mg once daily from Day 1 to day 21

Number of subjects in period 1	Arm A: Dose Escalation (DE) - Pamiparib 2Wks + RT 6 Wks	Arm A: DE-Pamiparib 4 Wks + RT 6 Wks	Arm A: DE- Pamiparib 6Wks + RT 6 Wks	Arm A: Dose Expansion (E) - Pamiparib 6 Wks + RT 6 Wks	Arm B: DE-Pamiparib 6 Wks + RT 6 Wks + + Temozolomide	Arm C: DE – Pamiparib + Temozolomide 20 mg	Arm C: DE – Pamiparib + Temozolomide 40 mg	Arm C: E- Pamiparib + Temozolomide 60 mg
Started	3	8	9	40	9	9	8	30
Completed	0	0	0	0	0	0	0	0
Not completed	3	8	9	40	9	9	8	30
Consent withdrawn by subject	1	1	-	3	1	1	1	3
Sponsor's Decision	-	-	-	10	3	-	1	1
Roll-Over to Long term	-	-	-	-	-	-	-	1
Death	2	7	8	27	4	8	6	21
Progressive Disease	-	-	-	-	-	-	-	2
Lost to follow-up	-	-	1	-	-	-	-	2
Change in Methylation status	-	-	-	-	1	-	-	-

Baseline characteristics

Top of page

Reporting group title

Arm A: Dose Escalation (DE) - Pamiparib 2Wks + RT 6 Wks

Reporting group description

Participants with newly diagnosed unmethylated glioblastoma (GBM) received 60 milligrams (mg) pamiparib orally twice daily (BID) for 2 weeks in combination with up to 60 Gy radiation for 6 weeks

Reporting group title

Arm A: DE-Pamiparib 4 Wks + RT 6 Wks

Reporting group description

Participants with newly diagnosed unmethylated GBM received 60 mg pamiparib orally for 4 weeks in combination with up to 60 Gy radiation for 6 weeks

Reporting group title

Arm A: DE- Pamiparib 6Wks + RT 6 Wks

Reporting group description

Participants with newly diagnosed unmethylated GBM received 60 mg pamiparib orally for 6 weeks in combination with up to 60 Gy radiation for 6 weeks

Reporting group title

Arm A: Dose Expansion (E) - Pamiparib 6 Wks + RT 6 Wks

Reporting group description

Participants with newly diagnosed unmethylated GBM received 60 mg pamiparib orally for 6 weeks in combination with up to 60 Gy radiation for 6 weeks

Reporting group title

Arm B: DE-Pamiparib 6 Wks + RT 6 Wks + + Temozolomide

Reporting group description

Participants with newly diagnosed unmethylated GBM received 60 mg pamiparib orally for 6 weeks in combination with up to 60 Gy radiation for 6 weeks and 60 mg temozolomide Wks 1 and 5

Reporting group title

Arm C: DE – Pamiparib + Temozolomide 20 mg

Reporting group description

Participants with both methylated and unmethylated recurrent/refractory GBM received 60 mg pamiparib BID and 20 mg temozolomide once daily orally from Day 1 to Day 21

Reporting group title

Arm C: DE – Pamiparib + Temozolomide 40 mg

Reporting group description

Participants with both methylated and unmethylated recurrent/refractory GBM received 60 mg pamiparib BID and 40 mg temozolomide once daily orally from Day 1 to Day 21

Reporting group title

Arm C: E- Pamiparib + Temozolomide 60 mg

Reporting group description

Participants with both methylated and unmethylated recurrent/refractory GBM received 60 mg pamiparib BID and 60 mg temozolomide once daily orally from Day 1 to Day 7

Reporting group values	Arm A: Dose Escalation (DE) - Pamiparib 2Wks + RT 6 Wks	Arm A: DE-Pamiparib 4 Wks + RT 6 Wks	Arm A: DE- Pamiparib 6Wks + RT 6 Wks	Arm A: Dose Expansion (E) - Pamiparib 6 Wks + RT 6 Wks	Arm B: DE-Pamiparib 6 Wks + RT 6 Wks + + Temozolomide	Arm C: DE – Pamiparib + Temozolomide 20 mg	Arm C: DE – Pamiparib + Temozolomide 40 mg	Arm C: E- Pamiparib + Temozolomide 60 mg	Total
Number of subjects	3	8	9	40	9	9	8	30	116
Age categorical
Units: Subjects
Age continuous
Units: years
arithmetic mean (standard deviation)	59.7 ( 8.39 )	63.4 ( 8.80 )	58.8 ( 7.66 )	56.7 ( 13.48 )	60.9 ( 9.94 )	49.2 ( 12.63 )	49.1 ( 15.51 )	58.6 ( 10.54 )	-
Gender categorical
Units: Subjects
Female	0	1	2	17	4	1	4	10	39
Male	3	7	7	23	5	8	4	20	77
Race/Ethnicity, Customized
Units: Subjects
Asian	0	0	1	0	0	0	0	1	2
Black or African American	0	1	1	0	0	1	0	0	3
White	3	7	7	38	9	7	8	27	106
Unknown/Not Reported	0	0	0	2	0	1	0	2	5

End points

Top of page

Reporting group title

Arm A: Dose Escalation (DE) - Pamiparib 2Wks + RT 6 Wks

Reporting group description

Participants with newly diagnosed unmethylated glioblastoma (GBM) received 60 milligrams (mg) pamiparib orally twice daily (BID) for 2 weeks in combination with up to 60 Gy radiation for 6 weeks

Reporting group title

Arm A: DE-Pamiparib 4 Wks + RT 6 Wks

Reporting group description

Participants with newly diagnosed unmethylated GBM received 60 mg pamiparib orally for 4 weeks in combination with up to 60 Gy radiation for 6 weeks

Reporting group title

Arm A: DE- Pamiparib 6Wks + RT 6 Wks

Reporting group description

Participants with newly diagnosed unmethylated GBM received 60 mg pamiparib orally for 6 weeks in combination with up to 60 Gy radiation for 6 weeks

Reporting group title

Arm A: Dose Expansion (E) - Pamiparib 6 Wks + RT 6 Wks

Reporting group description

Participants with newly diagnosed unmethylated GBM received 60 mg pamiparib orally for 6 weeks in combination with up to 60 Gy radiation for 6 weeks

Reporting group title

Arm B: DE-Pamiparib 6 Wks + RT 6 Wks + + Temozolomide

Reporting group description

Participants with newly diagnosed unmethylated GBM received 60 mg pamiparib orally for 6 weeks in combination with up to 60 Gy radiation for 6 weeks and 60 mg temozolomide Wks 1 and 5

Reporting group title

Arm C: DE – Pamiparib + Temozolomide 20 mg

Reporting group description

Participants with both methylated and unmethylated recurrent/refractory GBM received 60 mg pamiparib BID and 20 mg temozolomide once daily orally from Day 1 to Day 21

Reporting group title

Arm C: DE – Pamiparib + Temozolomide 40 mg

Reporting group description

Participants with both methylated and unmethylated recurrent/refractory GBM received 60 mg pamiparib BID and 40 mg temozolomide once daily orally from Day 1 to Day 21

Reporting group title

Arm C: E- Pamiparib + Temozolomide 60 mg

Reporting group description

Participants with both methylated and unmethylated recurrent/refractory GBM received 60 mg pamiparib BID and 60 mg temozolomide once daily orally from Day 1 to Day 7

Primary: Phase 1b Escalation Phase: Number of Participants with Dose-Limiting Toxicities (DLTs) as assessed by CTCAE

Top of page

End point title

Phase 1b Escalation Phase: Number of Participants with Dose-Limiting Toxicities (DLTs) as assessed by CTCAE ^[1] ^[2]

End point description

A DLT is defined as one of the following toxicities occurring during the DLT assessment window: Grade ≥3 non-hematologic, non-hepatic major organ adverse event (AE) Grade 4 neutropenia lasting >7 days Grade ≥3 febrile neutropenia Grade 3 thrombocytopenia with clinically significant bleeding Grade 4 thrombocytopenia lasting > 3 days and requiring transfusion, or any decreased platelet count <15,000/mm3/ <15.0 x 109/L Grade ≥4 anemia Grade ≥3 total bilirubin or hepatic transaminases (ALT [SGPT] or AST [SGOT])

End point type

Primary

End point timeframe

Arm A:Day 1 Pamiparib dose until 4 weeks after the last RT (up to 3 years and 7.5 months); Arm B: Day 1 of Pamiparib and Temozolomide until 4 weeks after the last RT (up to 3 years and 7.5 months); Arm C: 1st cycle of 28 days(up to 3 years and 7.5 months)

Notes
[1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Endpoint is descriptive and no statistical analyses were performed per protocol.
[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: DLTs were collected only for escalation phase per protocol.

End point values	Arm A: Dose Escalation (DE) - Pamiparib 2Wks + RT 6 Wks	Arm A: DE-Pamiparib 4 Wks + RT 6 Wks	Arm A: DE- Pamiparib 6Wks + RT 6 Wks	Arm B: DE-Pamiparib 6 Wks + RT 6 Wks + + Temozolomide	Arm C: DE – Pamiparib + Temozolomide 20 mg	Arm C: DE – Pamiparib + Temozolomide 40 mg
Number of subjects analysed	3	8	9	9	9	8
Units: Number of participants	0	0	2	1	0	3

No statistical analyses for this end point

Primary: Phase 1b Escalation Phase: Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) as Assessed by CTCAE

Top of page

End point title

Phase 1b Escalation Phase: Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) as Assessed by CTCAE ^[3] ^[4]

End point description

Safety analysis Set; A treatment-emergent adverse event (TEAE) is defined as an AE that had an onset date on or after first dose of study treatment or was worsening in severity from baseline (pretreatment) up to 30 days following permanent study treatment discontinuation or initiation of new anti-cancer therapy, whichever occurs first. An SAE is any untoward medical occurrence that, at any dose meets at least one of the following criteria: results in death, is life-threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, is a congenital anomaly/birth defect, is considered a significant medical AE based on medical judgment. SAEs were collected from the day the participant signs the Informed Consent Form (ICF). SAEs were collected from the day the participant signs the Informed Consent Form (ICF).

End point type

Primary

End point timeframe

From date of first dose up to 30 days after the last study treatment or initiation of new anticancer therapy, whichever occurs first (up to 3 years and 7.5 months)

Notes
[3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Endpoint is descriptive and no statistical analyses were performed per protocol.
[4] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Data from Phase 1b are reported per protocol.

End point values	Arm A: Dose Escalation (DE) - Pamiparib 2Wks + RT 6 Wks	Arm A: DE-Pamiparib 4 Wks + RT 6 Wks	Arm A: DE- Pamiparib 6Wks + RT 6 Wks	Arm B: DE-Pamiparib 6 Wks + RT 6 Wks + + Temozolomide	Arm C: DE – Pamiparib + Temozolomide 20 mg	Arm C: DE – Pamiparib + Temozolomide 40 mg
Number of subjects analysed	3	8	9	9	9	8
Units: Number of participants
Participants with At Least 1 TEAE	3	8	9	9	9	8
TEAE with Grade 3 or Higher	1	3	4	4	5	7
Treatment Emergent SAEs	0	2	2	2	4	3
TEAE Leading to Death	0	0	0	0	0	0

No statistical analyses for this end point

Primary: Phase 1b Escalation Phase Arm C: Number of Participants with Clinically Relevant Changes in Vital signs and Clinical Laboratory Measurements

Top of page

End point title

Phase 1b Escalation Phase Arm C: Number of Participants with Clinically Relevant Changes in Vital signs and Clinical Laboratory Measurements ^[5] ^[6]

End point description

End point type

Primary

End point timeframe

From the date of first dose up to EOS visit (3 years and 7.5 months)

Notes
[5] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Endpoint is descriptive and no statistical analyses were performed per protocol.
[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: Endpoint is descriptive and no statistical analyses were performed.

End point values	Arm C: DE – Pamiparib + Temozolomide 20 mg	Arm C: DE – Pamiparib + Temozolomide 40 mg
Number of subjects analysed	9	8
Units: Number of Participants	0	0

No statistical analyses for this end point

Primary: Phase 2 Arm A Expansion Phase: Modified Disease Control Rate as Assessed by Response Assessment in Neuro-Oncology (RANO) Criteria

Top of page

End point title

Phase 2 Arm A Expansion Phase: Modified Disease Control Rate as Assessed by Response Assessment in Neuro-Oncology (RANO) Criteria ^[7] ^[8]

End point description

Modified DCR is defined as the percentage of participants with complete response (CR), partial response (PR) or stable disease (SD) per RANO criteria as the response assessment at the end-of-treatment (EOT) visit. The Efficacy Analysis Set includes participants in the Safety Analysis Set who had a tumor assessment at baseline and at End of Treatment unless discontinued treatment or study early due to disease progression or death prior to tumor assessment.

End point type

Primary

End point timeframe

From the date of first dose up to EOS visit (3 years and 7.5 months)

Notes
[7] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Endpoint is descriptive and no statistical analyses were performed per protocol.
[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: Arms C data are reported per protocol.

End point values	Arm A: Dose Expansion (E) - Pamiparib 6 Wks + RT 6 Wks
Number of subjects analysed	32
Units: Percentage of participants
number (confidence interval 95%)	65.6 (46.8 to 81.4)

No statistical analyses for this end point

Primary: Phase 2 Arm C: Objective Response Rate (ORR) as Assessed Using RANO Criteria

Top of page

End point title

Phase 2 Arm C: Objective Response Rate (ORR) as Assessed Using RANO Criteria ^[9] ^[10]

End point description

ORR (objective response rate) is defined as percentage of participants with best overall response of CR or PR per RANO criteria (confirmed by a subsequent tumor assessment at least four weeks apart). The Efficacy Analysis Set includes participants in the Safety Analysis Set who had measurable disease at baseline and at least one postbaseline tumor assessment unless discontinued treatment or study early due to disease progression or death prior to tumor assessment.

End point type

Primary

End point timeframe

From the date of first dose up to first documentation of disease progression while participant is alive (3 years and 7.5 months)

Notes
[9] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: No statistical analysis were performed per protocol.
[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: Arms C data are reported per protocol.

End point values	Arm C: E- Pamiparib + Temozolomide 60 mg
Number of subjects analysed	28
Units: Percentage of participants
number (confidence interval 95%)	3 (2.3 to 28.2)

No statistical analyses for this end point

Primary: Phase 1b Arm C: Number of Cycles of Treatment Received by Participants

Top of page

End point title

Phase 1b Arm C: Number of Cycles of Treatment Received by Participants ^[11] ^[12]

End point description

Data shows the percentage of participants who received treatment for the given number of cycles.

End point type

Primary

End point timeframe

From the date of first dose up to EOS visit ( up to 3 years and 7.5 months)

Notes
[11] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Endpoint is descriptive and no statistical analyses were performed per protocol.
[12] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Endpoint is to report only Arm C values

End point values	Arm C: DE – Pamiparib + Temozolomide 20 mg	Arm C: DE – Pamiparib + Temozolomide 40 mg
Number of subjects analysed	9	8
Units: Percentage of participants
number (not applicable)
<1 cycle	22.2	37.5
1 cycle	44.4	0
2 cycles	11.1	25.0
3 cycles	0	12.5
4 cycles	11.1	0
5 cycles	11.1	0
6 cycles	0	0
7 cycles	0	0
>7 cycles	0	25.0

No statistical analyses for this end point

Primary: Phase 1b Arm C: Average Dose Intensity of Pamiparib And TMZ Received per Participant

Top of page

End point title

Phase 1b Arm C: Average Dose Intensity of Pamiparib And TMZ Received per Participant ^[13] ^[14]

End point description

End point type

Primary

End point timeframe

From the date of first dose until EOS visit (up to 3 years and 7.5 months)

Notes
[13] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: No statistical analysis were performed per protocol.
[14] - 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: Endpoint is to report only Arm C values

End point values	Arm C: DE – Pamiparib + Temozolomide 20 mg	Arm C: DE – Pamiparib + Temozolomide 40 mg
Number of subjects analysed	9	8
Units: Milligrams/Day
arithmetic mean (standard deviation)
Pamiparib	97.5 ( 25.41 )	107.6 ( 14.65 )
TMZ	13.6 ( 1.88 )	28.2 ( 10.80 )

No statistical analyses for this end point

Secondary: Phase 1B and Phase 2:Pharmacokinetics: Ctrough of Pamiparib

Top of page

End point title

Phase 1B and Phase 2:Pharmacokinetics: Ctrough of Pamiparib

End point description

The Pharmacokinetic Analysis Set includes all participants for whom valid pamiparib PK parameters can be estimated. Participants with available data were included in the analysis.

End point type

Secondary

End point timeframe

Pre-dose, 2 hours post dose on Days 1 and 15 of radiation Therapy

End point values	Arm A: Dose Escalation (DE) - Pamiparib 2Wks + RT 6 Wks	Arm A: DE-Pamiparib 4 Wks + RT 6 Wks	Arm A: DE- Pamiparib 6Wks + RT 6 Wks	Arm A: Dose Expansion (E) - Pamiparib 6 Wks + RT 6 Wks	Arm B: DE-Pamiparib 6 Wks + RT 6 Wks + + Temozolomide	Arm C: DE – Pamiparib + Temozolomide 20 mg	Arm C: DE – Pamiparib + Temozolomide 40 mg	Arm C: E- Pamiparib + Temozolomide 60 mg
Number of subjects analysed	3	5	6	35	7	6	6	25
Units: ng/mL
arithmetic mean (standard deviation)	891.3 ( 444.51 )	1817.0 ( 1226.53 )	1848.3 ( 784.38 )	2239.9 ( 1011.07 )	2134.3 ( 953.06 )	1893.3 ( 718.46 )	1550.8 ( 1422.55 )	1500.2 ( 943.35 )

No statistical analyses for this end point

Secondary: Phase 1b Arm A and Arm B Escalation Phase: Modified Disease Control Rate as Assessed by RANO Criteria

Top of page

End point title

Phase 1b Arm A and Arm B Escalation Phase: Modified Disease Control Rate as Assessed by RANO Criteria ^[15]

End point description

End point type

Secondary

End point timeframe

From the date of first dose up to first documentation of disease progression while participant is alive (3 years and 7.5 months)

Notes
[15] - 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: Arms A and B data are reported per protocol.

End point values	Arm A: Dose Escalation (DE) - Pamiparib 2Wks + RT 6 Wks	Arm A: DE-Pamiparib 4 Wks + RT 6 Wks	Arm A: DE- Pamiparib 6Wks + RT 6 Wks	Arm B: DE-Pamiparib 6 Wks + RT 6 Wks + + Temozolomide
Number of subjects analysed	3	6	7	5
Units: Percentage of participants
number (confidence interval 95%)	66.7 (9.4 to 99.2)	100.0 (54.1 to 100.0)	42.9 (9.9 to 81.6)	80.0 (28.4 to 99.5)

No statistical analyses for this end point

Secondary: Phase 1b Escalation Phase Arm C: Disease Control Rate as Assessed by RANO Criteria

Top of page

End point title

Phase 1b Escalation Phase Arm C: Disease Control Rate as Assessed by RANO Criteria ^[16]

End point description

DCR is defined as the percentage of participants with best overall response of CR, PR or SD per RANO criteria. CR or PR will be confirmed by a subsequent tumor assessment at least four weeks apart. Efficacy Analysis Set

End point type

Secondary

End point timeframe

From the date of first dose up to first documentation of disease progression while participant is alive (3 years and 7.5 months)

Notes
[16] - 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: Arms C data are reported per protocol.

End point values	Arm C: DE – Pamiparib + Temozolomide 20 mg	Arm C: DE – Pamiparib + Temozolomide 40 mg
Number of subjects analysed	9	7
Units: Percentage of participants
number (confidence interval 95%)	55.6 (21.2 to 86.3)	71.4 (29.0 to 96.3)

No statistical analyses for this end point

Secondary: Phase 1b and Phase 2 Arms A and B: ORR as Assessed Using RANO Criteria

Top of page

End point title

Phase 1b and Phase 2 Arms A and B: ORR as Assessed Using RANO Criteria ^[17]

End point description

ORR is defined as percentage of participants with best overall response of CR or PR per RANO criteria (confirmed by a subsequent tumor assessment at least four weeks apart). Efficacy Analysis Set

End point type

Secondary

End point timeframe

From the date of first dose up to first documentation of disease progression while participant is alive (3 years and 7.5 months)

Notes
[17] - 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: Data for Arms A and B are reported per protocol.

End point values	Arm A: Dose Escalation (DE) - Pamiparib 2Wks + RT 6 Wks	Arm A: DE-Pamiparib 4 Wks + RT 6 Wks	Arm A: DE- Pamiparib 6Wks + RT 6 Wks	Arm A: Dose Expansion (E) - Pamiparib 6 Wks + RT 6 Wks	Arm B: DE-Pamiparib 6 Wks + RT 6 Wks + + Temozolomide
Number of subjects analysed	3	6	7	32	5
Units: Percentage of participants
number (confidence interval 95%)	0 (0.0 to 70.8)	16.7 (0.4 to 64.1)	0 (0.0 to 41.0)	3.1 (0.1 to 16.2)	0 (0.0 to 52.2)

No statistical analyses for this end point

Secondary: Phase 1b and Phase2 Arms A, B and C: Clinical Benefit Rate as Assessed Using RANO Criteria

Top of page

End point title

Phase 1b and Phase2 Arms A, B and C: Clinical Benefit Rate as Assessed Using RANO Criteria

End point description

Clinical benefit rate (CBR) is defined as the percentage of participants with best overall response of CR, PR or SD ≥ 24 weeks per RANO criteria (confirmed by a subsequent tumor assessment at least four weeks apart). Efficacy Analysis Set

End point type

Secondary

End point timeframe

From the date of first dose up to first documentation of disease progression while participant is alive (3 years and 7.5 months)

End point values	Arm A: Dose Escalation (DE) - Pamiparib 2Wks + RT 6 Wks	Arm A: DE-Pamiparib 4 Wks + RT 6 Wks	Arm A: DE- Pamiparib 6Wks + RT 6 Wks	Arm A: Dose Expansion (E) - Pamiparib 6 Wks + RT 6 Wks	Arm B: DE-Pamiparib 6 Wks + RT 6 Wks + + Temozolomide	Arm C: DE – Pamiparib + Temozolomide 20 mg	Arm C: DE – Pamiparib + Temozolomide 40 mg	Arm C: E- Pamiparib + Temozolomide 60 mg
Number of subjects analysed	3	6	7	32	5	9	7	28
Units: Percentage of participants
number (confidence interval 95%)	0 (0.0 to 70.8)	33.3 (4.3 to 77.7)	0 (0.0 to 41.0)	37.6 (21.1 to 56.34)	40.0 (5.3 to 85.3)	0 (0.0 to 33.6)	28.6 (3.7 to 71.0)	17.9 (6.1 to 36.9)

No statistical analyses for this end point

Secondary: Phase 1b and Phase 2 Arms A, B and C: Duration of Response (DOR) as Assessed Using RANO Criteria

Top of page

End point title

Phase 1b and Phase 2 Arms A, B and C: Duration of Response (DOR) as Assessed Using RANO Criteria

End point description

DOR is defined as the time from the date of the earliest documented response to disease progression or death for any cause whichever occurs earlier. Efficacy Analysis Set; 9999 = Not estimable due to insufficient number of events

End point type

Secondary

End point timeframe

From first documentation of CR or PR to first documentation of disease progression or death ( up to 3 years and 7.5 months)

End point values	Arm A: Dose Escalation (DE) - Pamiparib 2Wks + RT 6 Wks	Arm A: DE-Pamiparib 4 Wks + RT 6 Wks	Arm A: DE- Pamiparib 6Wks + RT 6 Wks	Arm A: Dose Expansion (E) - Pamiparib 6 Wks + RT 6 Wks	Arm B: DE-Pamiparib 6 Wks + RT 6 Wks + + Temozolomide	Arm C: DE – Pamiparib + Temozolomide 20 mg	Arm C: DE – Pamiparib + Temozolomide 40 mg	Arm C: E- Pamiparib + Temozolomide 60 mg
Number of subjects analysed	0 ^[18]	1	0 ^[19]	1 ^[20]	0 ^[21]	0 ^[22]	1	3
Units: Months
median (confidence interval 95%)	( to )	6.44 (-9999 to 9999)	( to )	10.32 (-9999 to 9999)	( to )	( to )	11.7 (-9999 to 9999)	9999 (12.68 to 9999)

Notes
[18] - Only the participants with objective responses were included in DOR analysis.
[19] - Only the participants with objective responses were included in DOR analysis.
[20] - Only the participants with objective responses were included in DOR analysis.
[21] - Only the participants with objective responses were included in DOR analysis.
[22] - Only the participants with objective responses were included in DOR analysis.

No statistical analyses for this end point

Secondary: Phase 1b and Phase2 Arms A, B and C: Progression free survival (PFS) as Assessed Using RANO Criteria

Top of page

End point title

Phase 1b and Phase2 Arms A, B and C: Progression free survival (PFS) as Assessed Using RANO Criteria

End point description

PFS is defined as the time from the first dose date to disease progression per RANO criteria or death, whichever occurs first. 9999 = Not estimable to due to insufficient number of events

End point type

Secondary

End point timeframe

From the date of first dose up to first documentation of disease progression or death (up to 3 years and 7.5 months)

End point values	Arm A: Dose Escalation (DE) - Pamiparib 2Wks + RT 6 Wks	Arm A: DE-Pamiparib 4 Wks + RT 6 Wks	Arm A: DE- Pamiparib 6Wks + RT 6 Wks	Arm A: Dose Expansion (E) - Pamiparib 6 Wks + RT 6 Wks	Arm B: DE-Pamiparib 6 Wks + RT 6 Wks + + Temozolomide	Arm C: DE – Pamiparib + Temozolomide 20 mg	Arm C: DE – Pamiparib + Temozolomide 40 mg	Arm C: E- Pamiparib + Temozolomide 60 mg
Number of subjects analysed	3	8	9	40	8	9	8	30
Units: Months
median (confidence interval 95%)	3.12 (2.79 to 3.29)	8.94 (3.78 to 11.56)	2.56 (2.14 to 9999)	4.44 (3.29 to 6.24)	5.75 (2.37 to 6.47)	1.81 (0.82 to 3.48)	2.66 (0.66 to 7.39)	1.87 (1.48 to 1.91)

No statistical analyses for this end point

Secondary: Phase 1b and Phase2 Arms A, B and C: Overall survival (OS)

Top of page

End point title

Phase 1b and Phase2 Arms A, B and C: Overall survival (OS)

End point description

OS is defined as the time from the first dose date to date of death for any cause. 9999 = Not estimable due to insufficient number of events.

End point type

Secondary

End point timeframe

From the date of first dose up to EOS visit (3 years and 7.5 months)

End point values	Arm A: Dose Escalation (DE) - Pamiparib 2Wks + RT 6 Wks	Arm A: DE-Pamiparib 4 Wks + RT 6 Wks	Arm A: DE- Pamiparib 6Wks + RT 6 Wks	Arm A: Dose Expansion (E) - Pamiparib 6 Wks + RT 6 Wks	Arm B: DE-Pamiparib 6 Wks + RT 6 Wks + + Temozolomide	Arm C: DE – Pamiparib + Temozolomide 20 mg	Arm C: DE – Pamiparib + Temozolomide 40 mg	Arm C: E- Pamiparib + Temozolomide 60 mg
Number of subjects analysed	3	8	9	40	8	9	8	30
Units: Months
median (confidence interval 95%)	14.46 (13.93 to 14.98)	13.44 (4.14 to 20.24)	10.25 (4.44 to 19.84)	12.71 (9.79 to 14.46)	14.23 (7.98 to 9999)	6.00 (2.60 to 9.79)	8.62 (2.96 to 9999)	7.79 (6.21 to 10.68)

No statistical analyses for this end point

Secondary: Phase 2 Arms A and C Expansion Phase: Number of Participants with Treatment Emergent adverse events (TEAEs) and Serious adverse events (SAEs)

Top of page

End point title

Phase 2 Arms A and C Expansion Phase: Number of Participants with Treatment Emergent adverse events (TEAEs) and Serious adverse events (SAEs) ^[23]

End point description

A treatment-emergent adverse event (TEAE) is defined as an AE that had an onset date on or after first dose of study treatment or was worsening in severity from baseline (pretreatment) up to 30 days following permanent study treatment discontinuation or initiation of new anti-cancer therapy, whichever occurs first. An SAE is any untoward medical occurrence that, at any dose meets at least one of the following criteria: results in death, is life-threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, is a congenital anomaly/birth defect, is considered a significant medical AE based on medical judgment. SAEs were collected from the day the participant signs the Informed Consent Form (ICF).

End point type

Secondary

End point timeframe

From date of first dose up to 30 days after the last study treatment or initiation of new anticancer therapy, whichever occurs first (up to 3 years and 7.5 months

Notes
[23] - 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: Arms A and C data are reported per protocol.

End point values	Arm A: Dose Expansion (E) - Pamiparib 6 Wks + RT 6 Wks	Arm C: E- Pamiparib + Temozolomide 60 mg
Number of subjects analysed	40	30
Units: Number of participants
Participants with at Lease 1 TEAE	40	29
TEAE with Grade 3 or Higher	25	19
Treatment Emergent SAEs	18	11
TEAE Leading to Death	3	1

No statistical analyses for this end point

Secondary: Phase 2 Expansion Phase Arm A and C: Number of Participants with Clinically Relevant Changes in Vital signs and Clinical Laboratory Measurements

Top of page

End point title

Phase 2 Expansion Phase Arm A and C: Number of Participants with Clinically Relevant Changes in Vital signs and Clinical Laboratory Measurements ^[24]

End point description

End point type

Secondary

End point timeframe

From the date of first dose up to EOS visit (3 years and 7.5 months)

Notes
[24] - 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: Data from Arms A and C are reported per protocol.

End point values	Arm A: Dose Expansion (E) - Pamiparib 6 Wks + RT 6 Wks	Arm C: E- Pamiparib + Temozolomide 60 mg
Number of subjects analysed	40	30
Units: Number of participants	0	0

No statistical analyses for this end point

Secondary: Phase 2 Arms A and C Expansion Phase: Number of Cycles of Treatment Received by Participants

Top of page

End point title

Phase 2 Arms A and C Expansion Phase: Number of Cycles of Treatment Received by Participants ^[25]

End point description

Data shows the percentage of participants who received treatment for the given number of cycles.

End point type

Secondary

End point timeframe

From date of first dose up to EOS Visit (up to 3 years and 7.5 months)

Notes
[25] - 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: Arm B had no expansion phase

End point values	Arm A: Dose Expansion (E) - Pamiparib 6 Wks + RT 6 Wks	Arm C: E- Pamiparib + Temozolomide 60 mg
Number of subjects analysed	40	30
Units: Percentage of participants
number (not applicable)
<1 cycle	10.3	26.7
1 cycle	31.0	26.7
3 cycles	6.9	3.3
2 cycles	6.9	23.3
4 cycles	10.3	3.3
5 cycles	10.3	0.0
6 cycles	10.3	0.0
7 cycles	0.0	0.0
>7 cycles	13.8	16.7

No statistical analyses for this end point

Secondary: Phase 2 Arms A and C Expansion Phase: Average Dose Intensity of Pamiparib and TMZ Received per Participant

Top of page

End point title

Phase 2 Arms A and C Expansion Phase: Average Dose Intensity of Pamiparib and TMZ Received per Participant ^[26]

End point description

9999 = Not applicable since no TMZ was administered in this arm

End point type

Secondary

End point timeframe

From date of first dose up to EOS Visit (up to 3 years and 7.5 months)

Notes
[26] - 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: Arm B had no expansion phase

End point values	Arm A: Dose Expansion (E) - Pamiparib 6 Wks + RT 6 Wks	Arm C: E- Pamiparib + Temozolomide 60 mg
Number of subjects analysed	40	30
Units: Milligrams/Day
arithmetic mean (standard deviation)
Pamiparib	109.0 ( 22.07 )	109.5 ( 15.22 )
TMZ	9999 ( 9999 )	19.6 ( 11.60 )

No statistical analyses for this end point

Adverse events

Top of page

Timeframe for reporting adverse events

From date of first dose up to 30 days after the last study treatment or initiation of new anticancer therapy, whichever occurs first (up to 3 years and 7.5 months

Adverse event reporting additional description

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

23.0

Reporting group title

Arm 1Arm A: DE - Pamiparib 2 Wks + Radiation Therapy (RT) 6 Wk

Reporting group description

Participants with newly diagnosed unmethylated glioblastoma (GBM) received 60 mg pamiparib orally BID for 2 weeks in combination with up to 60 Gy radiation for 6 weeks

Reporting group title

Arm A: DE-Pamiparib 4 Wks + RT 6 Wks

Reporting group description

Participants with newly diagnosed unmethylated GBM received 60 mg pamiparib orally for 4 weeks in combination with up to 60 Gy radiation for 6 weeks

Reporting group title

Arm A: DE- Pamiparib 6Wks + RT 6 Wks

Reporting group description

Participants with newly diagnosed unmethylated GBM received 60 mg pamiparib orally for 6 weeks in combination with up to 60 Gy radiation for 6 weeks

Reporting group title

Arm A: Dose Expansion (E) - Pamiparib 6 Wks + RT 6 Wks

Reporting group description

Participants with newly diagnosed unmethylated GBM received 60 mg pamiparib orally for 6 weeks in combination with up to 60 Gy radiation for 6 weeks

Reporting group title

Arm B: DE-Pamiparib 6 Wks + RT 6 Wks + Temozolomide

Reporting group description

Participants with newly diagnosed unmethylated GBM received 60 mg pamiparib orally for 6 weeks in combination with up to 60 Gy radiation for 6 weeks and 60 mg temozolomide Wks 1 and 5

Reporting group title

Arm C: DE – Pamiparib + Temozolomide 20 mg

Reporting group description

Participants with both methylated and unmethylated recurrent/refractory GBM received 60 mg pamiparib BID and 20 mg temozolomide once daily orally from Day 1 to Day 21

Reporting group title

Arm C: DE – Pamiparib + Temozolomide 40 mg

Reporting group description

Participants with both methylated and unmethylated recurrent/refractory GBM received 60 mg pamiparib BID and 40 mg temozolomide once daily orally from Day 1 to Day 21

Reporting group title

Arm C: E- Pamiparib + Temozolomide 60 mg

Reporting group description

Participants with both methylated and unmethylated recurrent/refractory GBM received 60 mg pamiparib BID and 60 mg temozolomide once daily orally from Day 1 to Day 7

Serious adverse events	Arm 1Arm A: DE - Pamiparib 2 Wks + Radiation Therapy (RT) 6 Wk	Arm A: DE-Pamiparib 4 Wks + RT 6 Wks	Arm A: DE- Pamiparib 6Wks + RT 6 Wks	Arm A: Dose Expansion (E) - Pamiparib 6 Wks + RT 6 Wks	Arm B: DE-Pamiparib 6 Wks + RT 6 Wks + Temozolomide	Arm C: DE – Pamiparib + Temozolomide 20 mg	Arm C: DE – Pamiparib + Temozolomide 40 mg	Arm C: E- Pamiparib + Temozolomide 60 mg
Total subjects affected by serious adverse events
subjects affected / exposed	0 / 3 (0.00%)	2 / 8 (25.00%)	2 / 9 (22.22%)	18 / 40 (45.00%)	2 / 9 (22.22%)	4 / 9 (44.44%)	3 / 8 (37.50%)	11 / 30 (36.67%)
number of deaths (all causes)	2	7	8	27	4	8	6	21
number of deaths resulting from adverse events	0	0	0	3	0	0	0	1
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Malignant melanoma
subjects affected / exposed	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 9 (0.00%)	0 / 40 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 8 (0.00%)	1 / 30 (3.33%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Tumour flare
subjects affected / exposed	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 9 (0.00%)	0 / 40 (0.00%)	1 / 9 (11.11%)	0 / 9 (0.00%)	0 / 8 (0.00%)	1 / 30 (3.33%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	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 / 0	0 / 0	0 / 0	0 / 0
Vascular disorders
Deep vein thrombosis
subjects affected / exposed	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 9 (0.00%)	0 / 40 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	1 / 8 (12.50%)	0 / 30 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Embolism
subjects affected / exposed	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 9 (0.00%)	0 / 40 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 8 (0.00%)	2 / 30 (6.67%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Haematoma
subjects affected / exposed	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 9 (0.00%)	0 / 40 (0.00%)	0 / 9 (0.00%)	1 / 9 (11.11%)	0 / 8 (0.00%)	0 / 30 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hypotension
subjects affected / exposed	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 9 (0.00%)	0 / 40 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 8 (0.00%)	1 / 30 (3.33%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
General disorders and administration site conditions
Asthenia
subjects affected / exposed	0 / 3 (0.00%)	0 / 8 (0.00%)	1 / 9 (11.11%)	0 / 40 (0.00%)	0 / 9 (0.00%)	1 / 9 (11.11%)	0 / 8 (0.00%)	0 / 30 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Chills
subjects affected / exposed	0 / 3 (0.00%)	0 / 8 (0.00%)	1 / 9 (11.11%)	0 / 40 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 8 (0.00%)	0 / 30 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Fatigue
subjects affected / exposed	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 9 (0.00%)	2 / 40 (5.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	1 / 8 (12.50%)	0 / 30 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 2	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gait disturbance
subjects affected / exposed	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 9 (0.00%)	1 / 40 (2.50%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 8 (0.00%)	1 / 30 (3.33%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Impaired healing
subjects affected / exposed	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 9 (0.00%)	0 / 40 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 8 (0.00%)	1 / 30 (3.33%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pyrexia
subjects affected / exposed	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 9 (0.00%)	1 / 40 (2.50%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 8 (0.00%)	0 / 30 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 2	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Laryngeal haemorrhage
subjects affected / exposed	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 9 (0.00%)	0 / 40 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 8 (0.00%)	1 / 30 (3.33%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pulmonary embolism
subjects affected / exposed	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 9 (0.00%)	3 / 40 (7.50%)	0 / 9 (0.00%)	0 / 9 (0.00%)	1 / 8 (12.50%)	0 / 30 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 3	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Psychiatric disorders
Agitation
subjects affected / exposed	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 9 (0.00%)	1 / 40 (2.50%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 8 (0.00%)	0 / 30 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Confusional state
subjects affected / exposed	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 9 (0.00%)	0 / 40 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	1 / 8 (12.50%)	1 / 30 (3.33%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Mental status changes
subjects affected / exposed	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 9 (0.00%)	1 / 40 (2.50%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 8 (0.00%)	0 / 30 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Suicide attempt
subjects affected / exposed	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 9 (0.00%)	1 / 40 (2.50%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 8 (0.00%)	0 / 30 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
Injury, poisoning and procedural complications
Fall
subjects affected / exposed	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 9 (0.00%)	0 / 40 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 8 (0.00%)	1 / 30 (3.33%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Subarachnoid haematoma
subjects affected / exposed	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 9 (0.00%)	0 / 40 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 8 (0.00%)	1 / 30 (3.33%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cardiac disorders
Atrial fibrillation
subjects affected / exposed	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 9 (0.00%)	0 / 40 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 8 (0.00%)	1 / 30 (3.33%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Nervous system disorders
Aphasia
subjects affected / exposed	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 9 (0.00%)	1 / 40 (2.50%)	0 / 9 (0.00%)	1 / 9 (11.11%)	0 / 8 (0.00%)	1 / 30 (3.33%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Apraxia
subjects affected / exposed	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 9 (0.00%)	1 / 40 (2.50%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 8 (0.00%)	0 / 30 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Brain oedema
subjects affected / exposed	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 9 (0.00%)	1 / 40 (2.50%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 8 (0.00%)	0 / 30 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
Cerebral cyst
subjects affected / exposed	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 9 (0.00%)	1 / 40 (2.50%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 8 (0.00%)	0 / 30 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cerebrovascular accident
subjects affected / exposed	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 9 (0.00%)	0 / 40 (0.00%)	0 / 9 (0.00%)	1 / 9 (11.11%)	0 / 8 (0.00%)	0 / 30 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Depressed level of consciousness
subjects affected / exposed	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 9 (0.00%)	0 / 40 (0.00%)	1 / 9 (11.11%)	0 / 9 (0.00%)	0 / 8 (0.00%)	0 / 30 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	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	0 / 0	0 / 0	0 / 0
Dysaesthesia
subjects affected / exposed	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 9 (0.00%)	0 / 40 (0.00%)	0 / 9 (0.00%)	1 / 9 (11.11%)	0 / 8 (0.00%)	0 / 30 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Dysarthria
subjects affected / exposed	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 9 (0.00%)	1 / 40 (2.50%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 8 (0.00%)	0 / 30 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hemiparesis
subjects affected / exposed	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 9 (0.00%)	1 / 40 (2.50%)	0 / 9 (0.00%)	1 / 9 (11.11%)	0 / 8 (0.00%)	0 / 30 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hemiplegia
subjects affected / exposed	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 9 (0.00%)	1 / 40 (2.50%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 8 (0.00%)	0 / 30 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hydrocephalus
subjects affected / exposed	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 9 (0.00%)	1 / 40 (2.50%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 8 (0.00%)	0 / 30 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Nervous system disorder
subjects affected / exposed	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 9 (0.00%)	1 / 40 (2.50%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 8 (0.00%)	0 / 30 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Partial seizures
subjects affected / exposed	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 9 (0.00%)	1 / 40 (2.50%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 8 (0.00%)	1 / 30 (3.33%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Psychogenic seizure
subjects affected / exposed	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 9 (0.00%)	1 / 40 (2.50%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 8 (0.00%)	0 / 30 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Seizure
subjects affected / exposed	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 9 (0.00%)	2 / 40 (5.00%)	1 / 9 (11.11%)	1 / 9 (11.11%)	0 / 8 (0.00%)	0 / 30 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 2	0 / 1	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Syncope
subjects affected / exposed	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 9 (0.00%)	1 / 40 (2.50%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 8 (0.00%)	0 / 30 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Vasogenic cerebral oedema
subjects affected / exposed	0 / 3 (0.00%)	1 / 8 (12.50%)	0 / 9 (0.00%)	1 / 40 (2.50%)	0 / 9 (0.00%)	0 / 9 (0.00%)	1 / 8 (12.50%)	0 / 30 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 9 (0.00%)	2 / 40 (5.00%)	1 / 9 (11.11%)	0 / 9 (0.00%)	0 / 8 (0.00%)	0 / 30 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	2 / 2	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Febrile neutropenia
subjects affected / exposed	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 9 (0.00%)	0 / 40 (0.00%)	1 / 9 (11.11%)	0 / 9 (0.00%)	0 / 8 (0.00%)	0 / 30 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	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	0 / 0	0 / 0	0 / 0
Neutropenia
subjects affected / exposed	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 9 (0.00%)	1 / 40 (2.50%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 8 (0.00%)	0 / 30 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Ear and labyrinth disorders
Vertigo
subjects affected / exposed	0 / 3 (0.00%)	0 / 8 (0.00%)	1 / 9 (11.11%)	0 / 40 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 8 (0.00%)	0 / 30 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
Anal incontinence
subjects affected / exposed	0 / 3 (0.00%)	0 / 8 (0.00%)	1 / 9 (11.11%)	0 / 40 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 8 (0.00%)	0 / 30 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Constipation
subjects affected / exposed	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 9 (0.00%)	1 / 40 (2.50%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 8 (0.00%)	0 / 30 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal haemorrhage
subjects affected / exposed	0 / 3 (0.00%)	1 / 8 (12.50%)	0 / 9 (0.00%)	0 / 40 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 8 (0.00%)	0 / 30 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Nausea
subjects affected / exposed	0 / 3 (0.00%)	0 / 8 (0.00%)	1 / 9 (11.11%)	1 / 40 (2.50%)	0 / 9 (0.00%)	0 / 9 (0.00%)	1 / 8 (12.50%)	0 / 30 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	2 / 2	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Vomiting
subjects affected / exposed	0 / 3 (0.00%)	0 / 8 (0.00%)	1 / 9 (11.11%)	1 / 40 (2.50%)	0 / 9 (0.00%)	0 / 9 (0.00%)	1 / 8 (12.50%)	0 / 30 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	2 / 2	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Skin and subcutaneous tissue disorders
Rash
subjects affected / exposed	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 9 (0.00%)	1 / 40 (2.50%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 8 (0.00%)	0 / 30 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Renal and urinary disorders
Nephrolithiasis
subjects affected / exposed	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 9 (0.00%)	1 / 40 (2.50%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 8 (0.00%)	1 / 30 (3.33%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Muscular weakness
subjects affected / exposed	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 9 (0.00%)	0 / 40 (0.00%)	0 / 9 (0.00%)	1 / 9 (11.11%)	0 / 8 (0.00%)	2 / 30 (6.67%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Neck pain
subjects affected / exposed	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 9 (0.00%)	1 / 40 (2.50%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 8 (0.00%)	0 / 30 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Infections and infestations
Bronchitis
subjects affected / exposed	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 9 (0.00%)	1 / 40 (2.50%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 8 (0.00%)	0 / 30 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pneumonia
subjects affected / exposed	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 9 (0.00%)	0 / 40 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 8 (0.00%)	1 / 30 (3.33%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
Sepsis
subjects affected / exposed	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 9 (0.00%)	1 / 40 (2.50%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 8 (0.00%)	0 / 30 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
Wound infection
subjects affected / exposed	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 9 (0.00%)	1 / 40 (2.50%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 8 (0.00%)	1 / 30 (3.33%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0

Frequency threshold for reporting non-serious adverse events: 3%

Non-serious adverse events	Arm 1Arm A: DE - Pamiparib 2 Wks + Radiation Therapy (RT) 6 Wk	Arm A: DE-Pamiparib 4 Wks + RT 6 Wks	Arm A: DE- Pamiparib 6Wks + RT 6 Wks	Arm A: Dose Expansion (E) - Pamiparib 6 Wks + RT 6 Wks	Arm B: DE-Pamiparib 6 Wks + RT 6 Wks + Temozolomide	Arm C: DE – Pamiparib + Temozolomide 20 mg	Arm C: DE – Pamiparib + Temozolomide 40 mg	Arm C: E- Pamiparib + Temozolomide 60 mg
Total subjects affected by non serious adverse events
subjects affected / exposed	3 / 3 (100.00%)	8 / 8 (100.00%)	9 / 9 (100.00%)	40 / 40 (100.00%)	9 / 9 (100.00%)	9 / 9 (100.00%)	7 / 8 (87.50%)	29 / 30 (96.67%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Renal hamartoma
subjects affected / exposed	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 9 (0.00%)	0 / 40 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 8 (0.00%)	1 / 30 (3.33%)
occurrences all number	0	0	0	0	0	0	0	1
Vascular disorders
Deep vein thrombosis
subjects affected / exposed	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 9 (0.00%)	1 / 40 (2.50%)	1 / 9 (11.11%)	0 / 9 (0.00%)	0 / 8 (0.00%)	1 / 30 (3.33%)
occurrences all number	0	0	0	1	1	0	0	1
Hypertension
subjects affected / exposed	0 / 3 (0.00%)	0 / 8 (0.00%)	1 / 9 (11.11%)	1 / 40 (2.50%)	2 / 9 (22.22%)	0 / 9 (0.00%)	0 / 8 (0.00%)	0 / 30 (0.00%)
occurrences all number	0	0	1	1	2	0	0	0
Hypotension
subjects affected / exposed	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 9 (0.00%)	0 / 40 (0.00%)	1 / 9 (11.11%)	1 / 9 (11.11%)	0 / 8 (0.00%)	1 / 30 (3.33%)
occurrences all number	0	0	0	0	1	1	0	1
Pallor
subjects affected / exposed	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 9 (0.00%)	0 / 40 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 8 (0.00%)	1 / 30 (3.33%)
occurrences all number	0	0	0	0	0	0	0	1
General disorders and administration site conditions
Asthenia
subjects affected / exposed	0 / 3 (0.00%)	1 / 8 (12.50%)	0 / 9 (0.00%)	2 / 40 (5.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 8 (0.00%)	1 / 30 (3.33%)
occurrences all number	0	1	0	2	0	0	0	2
Chest pain
subjects affected / exposed	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 9 (0.00%)	1 / 40 (2.50%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 8 (0.00%)	1 / 30 (3.33%)
occurrences all number	0	0	0	1	0	0	0	1
Chills
subjects affected / exposed	0 / 3 (0.00%)	0 / 8 (0.00%)	1 / 9 (11.11%)	0 / 40 (0.00%)	1 / 9 (11.11%)	0 / 9 (0.00%)	0 / 8 (0.00%)	0 / 30 (0.00%)
occurrences all number	0	0	1	0	1	0	0	0
Early satiety
subjects affected / exposed	0 / 3 (0.00%)	0 / 8 (0.00%)	1 / 9 (11.11%)	0 / 40 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 8 (0.00%)	0 / 30 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0
Fatigue
subjects affected / exposed	3 / 3 (100.00%)	2 / 8 (25.00%)	6 / 9 (66.67%)	29 / 40 (72.50%)	6 / 9 (66.67%)	1 / 9 (11.11%)	4 / 8 (50.00%)	17 / 30 (56.67%)
occurrences all number	3	2	7	34	7	1	4	20
Feeling cold
subjects affected / exposed	0 / 3 (0.00%)	1 / 8 (12.50%)	0 / 9 (0.00%)	0 / 40 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 8 (0.00%)	1 / 30 (3.33%)
occurrences all number	0	1	0	0	0	0	0	1
Gait disturbance
subjects affected / exposed	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 9 (0.00%)	2 / 40 (5.00%)	2 / 9 (22.22%)	1 / 9 (11.11%)	1 / 8 (12.50%)	2 / 30 (6.67%)
occurrences all number	0	0	0	2	2	1	1	2
Influenza like illness
subjects affected / exposed	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 9 (0.00%)	0 / 40 (0.00%)	0 / 9 (0.00%)	1 / 9 (11.11%)	0 / 8 (0.00%)	1 / 30 (3.33%)
occurrences all number	0	0	0	0	0	1	0	1
Malaise
subjects affected / exposed	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 9 (0.00%)	3 / 40 (7.50%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 8 (0.00%)	1 / 30 (3.33%)
occurrences all number	0	0	0	3	0	0	0	2
Non-cardiac chest pain
subjects affected / exposed	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 9 (0.00%)	1 / 40 (2.50%)	0 / 9 (0.00%)	1 / 9 (11.11%)	0 / 8 (0.00%)	0 / 30 (0.00%)
occurrences all number	0	0	0	1	0	1	0	0
Oedema peripheral
subjects affected / exposed	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 9 (0.00%)	4 / 40 (10.00%)	2 / 9 (22.22%)	1 / 9 (11.11%)	0 / 8 (0.00%)	3 / 30 (10.00%)
occurrences all number	0	0	0	4	2	1	0	4
Pyrexia
subjects affected / exposed	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 9 (0.00%)	1 / 40 (2.50%)	0 / 9 (0.00%)	1 / 9 (11.11%)	0 / 8 (0.00%)	3 / 30 (10.00%)
occurrences all number	0	0	0	1	0	1	0	3
Swelling face
subjects affected / exposed	0 / 3 (0.00%)	1 / 8 (12.50%)	0 / 9 (0.00%)	0 / 40 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 8 (0.00%)	0 / 30 (0.00%)
occurrences all number	0	2	0	0	0	0	0	0
Vessel puncture site pain
subjects affected / exposed	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 9 (0.00%)	0 / 40 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 8 (0.00%)	1 / 30 (3.33%)
occurrences all number	0	0	0	0	0	0	0	1
Respiratory, thoracic and mediastinal disorders
Chronic obstructive pulmonary disease
subjects affected / exposed	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 9 (0.00%)	0 / 40 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 8 (0.00%)	1 / 30 (3.33%)
occurrences all number	0	0	0	0	0	0	0	1
Cough
subjects affected / exposed	0 / 3 (0.00%)	1 / 8 (12.50%)	0 / 9 (0.00%)	4 / 40 (10.00%)	0 / 9 (0.00%)	1 / 9 (11.11%)	0 / 8 (0.00%)	2 / 30 (6.67%)
occurrences all number	0	1	0	5	0	1	0	3
Dysphonia
subjects affected / exposed	0 / 3 (0.00%)	2 / 8 (25.00%)	0 / 9 (0.00%)	0 / 40 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 8 (0.00%)	0 / 30 (0.00%)
occurrences all number	0	2	0	0	0	0	0	0
Dyspnoea
subjects affected / exposed	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 9 (0.00%)	1 / 40 (2.50%)	1 / 9 (11.11%)	0 / 9 (0.00%)	0 / 8 (0.00%)	4 / 30 (13.33%)
occurrences all number	0	0	0	1	1	0	0	5
Dyspnoea exertional
subjects affected / exposed	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 9 (0.00%)	0 / 40 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 8 (0.00%)	1 / 30 (3.33%)
occurrences all number	0	0	0	0	0	0	0	1
Epistaxis
subjects affected / exposed	0 / 3 (0.00%)	0 / 8 (0.00%)	1 / 9 (11.11%)	0 / 40 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 8 (0.00%)	0 / 30 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0
Hiccups
subjects affected / exposed	0 / 3 (0.00%)	0 / 8 (0.00%)	1 / 9 (11.11%)	1 / 40 (2.50%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 8 (0.00%)	1 / 30 (3.33%)
occurrences all number	0	0	1	1	0	0	0	1
Hypoxia
subjects affected / exposed	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 9 (0.00%)	0 / 40 (0.00%)	0 / 9 (0.00%)	1 / 9 (11.11%)	0 / 8 (0.00%)	0 / 30 (0.00%)
occurrences all number	0	0	0	0	0	2	0	0
Laryngeal inflammation
subjects affected / exposed	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 9 (0.00%)	0 / 40 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 8 (0.00%)	1 / 30 (3.33%)
occurrences all number	0	0	0	0	0	0	0	1
Nasal congestion
subjects affected / exposed	0 / 3 (0.00%)	1 / 8 (12.50%)	1 / 9 (11.11%)	3 / 40 (7.50%)	1 / 9 (11.11%)	0 / 9 (0.00%)	1 / 8 (12.50%)	3 / 30 (10.00%)
occurrences all number	0	1	1	3	1	0	1	3
Nasal polyps
subjects affected / exposed	0 / 3 (0.00%)	1 / 8 (12.50%)	0 / 9 (0.00%)	0 / 40 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 8 (0.00%)	0 / 30 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0
Productive cough
subjects affected / exposed	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 9 (0.00%)	0 / 40 (0.00%)	1 / 9 (11.11%)	0 / 9 (0.00%)	0 / 8 (0.00%)	0 / 30 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0
Pulmonary embolism
subjects affected / exposed	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 9 (0.00%)	2 / 40 (5.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 8 (0.00%)	1 / 30 (3.33%)
occurrences all number	0	0	0	2	0	0	0	1
Rhinitis allergic
subjects affected / exposed	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 9 (0.00%)	1 / 40 (2.50%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 8 (0.00%)	1 / 30 (3.33%)
occurrences all number	0	0	0	1	0	0	0	1
Sinus congestion
subjects affected / exposed	0 / 3 (0.00%)	1 / 8 (12.50%)	0 / 9 (0.00%)	1 / 40 (2.50%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 8 (0.00%)	0 / 30 (0.00%)
occurrences all number	0	1	0	1	0	0	0	0
Upper-airway cough syndrome
subjects affected / exposed	0 / 3 (0.00%)	1 / 8 (12.50%)	0 / 9 (0.00%)	0 / 40 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 8 (0.00%)	0 / 30 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0
Wheezing
subjects affected / exposed	0 / 3 (0.00%)	1 / 8 (12.50%)	0 / 9 (0.00%)	0 / 40 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 8 (0.00%)	1 / 30 (3.33%)
occurrences all number	0	1	0	0	0	0	0	1
Psychiatric disorders
Agitation
subjects affected / exposed	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 9 (0.00%)	4 / 40 (10.00%)	1 / 9 (11.11%)	1 / 9 (11.11%)	0 / 8 (0.00%)	0 / 30 (0.00%)
occurrences all number	0	0	0	4	1	1	0	0
Alcohol abuse
subjects affected / exposed	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 9 (0.00%)	0 / 40 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 8 (0.00%)	1 / 30 (3.33%)
occurrences all number	0	0	0	0	0	0	0	1
Anxiety
subjects affected / exposed	0 / 3 (0.00%)	0 / 8 (0.00%)	1 / 9 (11.11%)	6 / 40 (15.00%)	2 / 9 (22.22%)	0 / 9 (0.00%)	0 / 8 (0.00%)	1 / 30 (3.33%)
occurrences all number	0	0	1	6	2	0	0	1
Confusional state
subjects affected / exposed	0 / 3 (0.00%)	2 / 8 (25.00%)	1 / 9 (11.11%)	4 / 40 (10.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 8 (0.00%)	3 / 30 (10.00%)
occurrences all number	0	2	1	5	0	0	0	3
Decreased interest
subjects affected / exposed	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 9 (0.00%)	0 / 40 (0.00%)	1 / 9 (11.11%)	0 / 9 (0.00%)	0 / 8 (0.00%)	0 / 30 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0
Depression
subjects affected / exposed	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 9 (0.00%)	1 / 40 (2.50%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 8 (0.00%)	3 / 30 (10.00%)
occurrences all number	0	0	0	1	0	0	0	3
Insomnia
subjects affected / exposed	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 9 (0.00%)	6 / 40 (15.00%)	2 / 9 (22.22%)	0 / 9 (0.00%)	1 / 8 (12.50%)	4 / 30 (13.33%)
occurrences all number	0	0	0	6	2	0	1	4
Irritability
subjects affected / exposed	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 9 (0.00%)	2 / 40 (5.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 8 (0.00%)	0 / 30 (0.00%)
occurrences all number	0	0	0	2	0	0	0	0
Persistent depressive disorder
subjects affected / exposed	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 9 (0.00%)	0 / 40 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 8 (0.00%)	1 / 30 (3.33%)
occurrences all number	0	0	0	0	0	0	0	1
Suicidal ideation
subjects affected / exposed	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 9 (0.00%)	0 / 40 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 8 (0.00%)	1 / 30 (3.33%)
occurrences all number	0	0	0	0	0	0	0	1
Investigations
Alanine aminotransferase increased
subjects affected / exposed	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 9 (0.00%)	3 / 40 (7.50%)	0 / 9 (0.00%)	1 / 9 (11.11%)	0 / 8 (0.00%)	1 / 30 (3.33%)
occurrences all number	0	0	0	3	0	1	0	1
Aspartate aminotransferase increased
subjects affected / exposed	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 9 (0.00%)	3 / 40 (7.50%)	0 / 9 (0.00%)	1 / 9 (11.11%)	0 / 8 (0.00%)	0 / 30 (0.00%)
occurrences all number	0	0	0	3	0	1	0	0
Blood bilirubin increased
subjects affected / exposed	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 9 (0.00%)	1 / 40 (2.50%)	1 / 9 (11.11%)	2 / 9 (22.22%)	1 / 8 (12.50%)	1 / 30 (3.33%)
occurrences all number	0	0	0	4	1	2	1	1
Blood bilirubin unconjugated increased
subjects affected / exposed	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 9 (0.00%)	0 / 40 (0.00%)	1 / 9 (11.11%)	0 / 9 (0.00%)	0 / 8 (0.00%)	0 / 30 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0
Blood creatinine increased
subjects affected / exposed	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 9 (0.00%)	4 / 40 (10.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	1 / 8 (12.50%)	2 / 30 (6.67%)
occurrences all number	0	0	0	5	0	0	1	3
Cortisol decreased
subjects affected / exposed	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 9 (0.00%)	0 / 40 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 8 (0.00%)	1 / 30 (3.33%)
occurrences all number	0	0	0	0	0	0	0	1
Electrocardiogram QT prolonged
subjects affected / exposed	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 9 (0.00%)	0 / 40 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 8 (0.00%)	1 / 30 (3.33%)
occurrences all number	0	0	0	0	0	0	0	1
Lymphocyte count decreased
subjects affected / exposed	0 / 3 (0.00%)	0 / 8 (0.00%)	1 / 9 (11.11%)	3 / 40 (7.50%)	2 / 9 (22.22%)	3 / 9 (33.33%)	1 / 8 (12.50%)	4 / 30 (13.33%)
occurrences all number	0	0	1	3	2	3	1	5
Neutrophil count decreased
subjects affected / exposed	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 9 (0.00%)	6 / 40 (15.00%)	3 / 9 (33.33%)	2 / 9 (22.22%)	2 / 8 (25.00%)	5 / 30 (16.67%)
occurrences all number	0	0	0	9	3	2	2	10
Platelet count decreased
subjects affected / exposed	0 / 3 (0.00%)	0 / 8 (0.00%)	1 / 9 (11.11%)	7 / 40 (17.50%)	1 / 9 (11.11%)	3 / 9 (33.33%)	1 / 8 (12.50%)	8 / 30 (26.67%)
occurrences all number	0	0	1	8	2	3	1	18
Weight decreased
subjects affected / exposed	0 / 3 (0.00%)	0 / 8 (0.00%)	1 / 9 (11.11%)	9 / 40 (22.50%)	0 / 9 (0.00%)	0 / 9 (0.00%)	1 / 8 (12.50%)	3 / 30 (10.00%)
occurrences all number	0	0	1	10	0	0	1	3
White blood cell count decreased
subjects affected / exposed	0 / 3 (0.00%)	0 / 8 (0.00%)	1 / 9 (11.11%)	6 / 40 (15.00%)	4 / 9 (44.44%)	2 / 9 (22.22%)	1 / 8 (12.50%)	6 / 30 (20.00%)
occurrences all number	0	0	1	8	7	2	1	10
Injury, poisoning and procedural complications
Contusion
subjects affected / exposed	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 9 (0.00%)	2 / 40 (5.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 8 (0.00%)	3 / 30 (10.00%)
occurrences all number	0	0	0	3	0	0	0	3
Eye contusion
subjects affected / exposed	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 9 (0.00%)	0 / 40 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 8 (0.00%)	1 / 30 (3.33%)
occurrences all number	0	0	0	0	0	0	0	1
Fall
subjects affected / exposed	0 / 3 (0.00%)	1 / 8 (12.50%)	0 / 9 (0.00%)	5 / 40 (12.50%)	1 / 9 (11.11%)	0 / 9 (0.00%)	3 / 8 (37.50%)	5 / 30 (16.67%)
occurrences all number	0	2	0	6	1	0	3	8
Ligament sprain
subjects affected / exposed	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 9 (0.00%)	0 / 40 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 8 (0.00%)	1 / 30 (3.33%)
occurrences all number	0	0	0	0	0	0	0	1
Pseudomeningocele
subjects affected / exposed	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 9 (0.00%)	0 / 40 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	1 / 8 (12.50%)	0 / 30 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0
Radiation injury
subjects affected / exposed	0 / 3 (0.00%)	1 / 8 (12.50%)	0 / 9 (0.00%)	1 / 40 (2.50%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 8 (0.00%)	0 / 30 (0.00%)
occurrences all number	0	2	0	1	0	0	0	0
Radiation skin injury
subjects affected / exposed	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 9 (0.00%)	2 / 40 (5.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 8 (0.00%)	0 / 30 (0.00%)
occurrences all number	0	0	0	2	0	0	0	0
Skin laceration
subjects affected / exposed	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 9 (0.00%)	0 / 40 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 8 (0.00%)	2 / 30 (6.67%)
occurrences all number	0	0	0	0	0	0	0	3
Subdural haematoma
subjects affected / exposed	0 / 3 (0.00%)	1 / 8 (12.50%)	0 / 9 (0.00%)	0 / 40 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 8 (0.00%)	0 / 30 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0
Traumatic haematoma
subjects affected / exposed	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 9 (0.00%)	0 / 40 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 8 (0.00%)	1 / 30 (3.33%)
occurrences all number	0	0	0	0	0	0	0	1
Cardiac disorders
Angina pectoris
subjects affected / exposed	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 9 (0.00%)	0 / 40 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 8 (0.00%)	1 / 30 (3.33%)
occurrences all number	0	0	0	0	0	0	0	1
Bradycardia
subjects affected / exposed	0 / 3 (0.00%)	1 / 8 (12.50%)	0 / 9 (0.00%)	0 / 40 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 8 (0.00%)	0 / 30 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0
Sinus tachycardia
subjects affected / exposed	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 9 (0.00%)	0 / 40 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 8 (0.00%)	1 / 30 (3.33%)
occurrences all number	0	0	0	0	0	0	0	1
Tachycardia
subjects affected / exposed	0 / 3 (0.00%)	1 / 8 (12.50%)	0 / 9 (0.00%)	0 / 40 (0.00%)	0 / 9 (0.00%)	1 / 9 (11.11%)	0 / 8 (0.00%)	1 / 30 (3.33%)
occurrences all number	0	1	0	0	0	1	0	1
Ventricular extrasystoles
subjects affected / exposed	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 9 (0.00%)	0 / 40 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 8 (0.00%)	1 / 30 (3.33%)
occurrences all number	0	0	0	0	0	0	0	1
Nervous system disorders
Ageusia
subjects affected / exposed	0 / 3 (0.00%)	0 / 8 (0.00%)	1 / 9 (11.11%)	0 / 40 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 8 (0.00%)	0 / 30 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0
Amnesia
subjects affected / exposed	1 / 3 (33.33%)	1 / 8 (12.50%)	0 / 9 (0.00%)	0 / 40 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 8 (0.00%)	2 / 30 (6.67%)
occurrences all number	1	1	0	0	0	0	0	2
Aphasia
subjects affected / exposed	0 / 3 (0.00%)	1 / 8 (12.50%)	3 / 9 (33.33%)	6 / 40 (15.00%)	1 / 9 (11.11%)	1 / 9 (11.11%)	0 / 8 (0.00%)	3 / 30 (10.00%)
occurrences all number	0	1	3	7	2	1	0	3
Ataxia
subjects affected / exposed	0 / 3 (0.00%)	0 / 8 (0.00%)	1 / 9 (11.11%)	0 / 40 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 8 (0.00%)	0 / 30 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0
Balance disorder
subjects affected / exposed	0 / 3 (0.00%)	0 / 8 (0.00%)	2 / 9 (22.22%)	0 / 40 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 8 (0.00%)	0 / 30 (0.00%)
occurrences all number	0	0	2	0	0	0	0	0
Brain oedema
subjects affected / exposed	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 9 (0.00%)	0 / 40 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	1 / 8 (12.50%)	0 / 30 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0
Carpal tunnel syndrome
subjects affected / exposed	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 9 (0.00%)	0 / 40 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 8 (0.00%)	1 / 30 (3.33%)
occurrences all number	0	0	0	0	0	0	0	1
Cerebrospinal fluid leakage
subjects affected / exposed	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 9 (0.00%)	0 / 40 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 8 (0.00%)	1 / 30 (3.33%)
occurrences all number	0	0	0	0	0	0	0	1
Cognitive disorder
subjects affected / exposed	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 9 (0.00%)	2 / 40 (5.00%)	0 / 9 (0.00%)	2 / 9 (22.22%)	0 / 8 (0.00%)	0 / 30 (0.00%)
occurrences all number	0	0	0	2	0	2	0	0
Disturbance in attention
subjects affected / exposed	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 9 (0.00%)	1 / 40 (2.50%)	0 / 9 (0.00%)	1 / 9 (11.11%)	0 / 8 (0.00%)	1 / 30 (3.33%)
occurrences all number	0	0	0	1	0	1	0	1
Dizziness
subjects affected / exposed	0 / 3 (0.00%)	1 / 8 (12.50%)	0 / 9 (0.00%)	11 / 40 (27.50%)	2 / 9 (22.22%)	1 / 9 (11.11%)	1 / 8 (12.50%)	8 / 30 (26.67%)
occurrences all number	0	1	0	12	2	1	1	8
Drooling
subjects affected / exposed	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 9 (0.00%)	0 / 40 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 8 (0.00%)	1 / 30 (3.33%)
occurrences all number	0	0	0	0	0	0	0	1
Dysaesthesia
subjects affected / exposed	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 9 (0.00%)	0 / 40 (0.00%)	0 / 9 (0.00%)	1 / 9 (11.11%)	0 / 8 (0.00%)	0 / 30 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0
Dysarthria
subjects affected / exposed	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 9 (0.00%)	0 / 40 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 8 (0.00%)	1 / 30 (3.33%)
occurrences all number	0	0	0	0	0	0	0	1
Dysgeusia
subjects affected / exposed	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 9 (0.00%)	10 / 40 (25.00%)	2 / 9 (22.22%)	1 / 9 (11.11%)	0 / 8 (0.00%)	2 / 30 (6.67%)
occurrences all number	0	0	0	11	2	1	0	3
Dyslexia
subjects affected / exposed	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 9 (0.00%)	0 / 40 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 8 (0.00%)	1 / 30 (3.33%)
occurrences all number	0	0	0	0	0	0	0	1
Encephalopathy
subjects affected / exposed	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 9 (0.00%)	0 / 40 (0.00%)	0 / 9 (0.00%)	1 / 9 (11.11%)	0 / 8 (0.00%)	0 / 30 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0
Epilepsy
subjects affected / exposed	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 9 (0.00%)	0 / 40 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 8 (0.00%)	1 / 30 (3.33%)
occurrences all number	0	0	0	0	0	0	0	3
Facial paralysis
subjects affected / exposed	0 / 3 (0.00%)	0 / 8 (0.00%)	1 / 9 (11.11%)	0 / 40 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 8 (0.00%)	0 / 30 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0
Facial paresis
subjects affected / exposed	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 9 (0.00%)	0 / 40 (0.00%)	0 / 9 (0.00%)	1 / 9 (11.11%)	0 / 8 (0.00%)	1 / 30 (3.33%)
occurrences all number	0	0	0	0	0	1	0	1
Headache
subjects affected / exposed	1 / 3 (33.33%)	1 / 8 (12.50%)	4 / 9 (44.44%)	18 / 40 (45.00%)	2 / 9 (22.22%)	1 / 9 (11.11%)	0 / 8 (0.00%)	8 / 30 (26.67%)
occurrences all number	1	1	4	24	3	1	0	11
Hemianopia homonymous
subjects affected / exposed	0 / 3 (0.00%)	0 / 8 (0.00%)	1 / 9 (11.11%)	0 / 40 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 8 (0.00%)	0 / 30 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0
Hemiparesis
subjects affected / exposed	0 / 3 (0.00%)	0 / 8 (0.00%)	1 / 9 (11.11%)	8 / 40 (20.00%)	3 / 9 (33.33%)	3 / 9 (33.33%)	1 / 8 (12.50%)	4 / 30 (13.33%)
occurrences all number	0	0	1	9	3	3	1	4
Hypersomnia
subjects affected / exposed	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 9 (0.00%)	1 / 40 (2.50%)	1 / 9 (11.11%)	0 / 9 (0.00%)	0 / 8 (0.00%)	2 / 30 (6.67%)
occurrences all number	0	0	0	1	1	0	0	2
Hypoaesthesia
subjects affected / exposed	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 9 (0.00%)	2 / 40 (5.00%)	1 / 9 (11.11%)	0 / 9 (0.00%)	0 / 8 (0.00%)	0 / 30 (0.00%)
occurrences all number	0	0	0	2	1	0	0	0
Memory impairment
subjects affected / exposed	0 / 3 (0.00%)	1 / 8 (12.50%)	0 / 9 (0.00%)	6 / 40 (15.00%)	1 / 9 (11.11%)	1 / 9 (11.11%)	0 / 8 (0.00%)	0 / 30 (0.00%)
occurrences all number	0	1	0	6	1	1	0	0
Muscle spasticity
subjects affected / exposed	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 9 (0.00%)	0 / 40 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 8 (0.00%)	1 / 30 (3.33%)
occurrences all number	0	0	0	0	0	0	0	2
Myoclonus
subjects affected / exposed	0 / 3 (0.00%)	0 / 8 (0.00%)	1 / 9 (11.11%)	0 / 40 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 8 (0.00%)	0 / 30 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0
Paraesthesia
subjects affected / exposed	0 / 3 (0.00%)	1 / 8 (12.50%)	1 / 9 (11.11%)	1 / 40 (2.50%)	1 / 9 (11.11%)	1 / 9 (11.11%)	0 / 8 (0.00%)	2 / 30 (6.67%)
occurrences all number	0	1	1	1	1	1	0	2
Partial seizures
subjects affected / exposed	0 / 3 (0.00%)	1 / 8 (12.50%)	1 / 9 (11.11%)	2 / 40 (5.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 8 (0.00%)	0 / 30 (0.00%)
occurrences all number	0	1	1	2	0	0	0	0
Peripheral motor neuropathy
subjects affected / exposed	0 / 3 (0.00%)	0 / 8 (0.00%)	1 / 9 (11.11%)	0 / 40 (0.00%)	0 / 9 (0.00%)	1 / 9 (11.11%)	0 / 8 (0.00%)	0 / 30 (0.00%)
occurrences all number	0	0	1	0	0	2	0	0
Peripheral sensory neuropathy
subjects affected / exposed	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 9 (0.00%)	0 / 40 (0.00%)	1 / 9 (11.11%)	0 / 9 (0.00%)	0 / 8 (0.00%)	0 / 30 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0
Seizure
subjects affected / exposed	0 / 3 (0.00%)	0 / 8 (0.00%)	1 / 9 (11.11%)	6 / 40 (15.00%)	0 / 9 (0.00%)	1 / 9 (11.11%)	0 / 8 (0.00%)	4 / 30 (13.33%)
occurrences all number	0	0	1	9	0	1	0	4
Somnolence
subjects affected / exposed	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 9 (0.00%)	0 / 40 (0.00%)	0 / 9 (0.00%)	1 / 9 (11.11%)	0 / 8 (0.00%)	0 / 30 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0
Taste disorder
subjects affected / exposed	0 / 3 (0.00%)	0 / 8 (0.00%)	1 / 9 (11.11%)	0 / 40 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 8 (0.00%)	0 / 30 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0
Tremor
subjects affected / exposed	0 / 3 (0.00%)	0 / 8 (0.00%)	1 / 9 (11.11%)	1 / 40 (2.50%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 8 (0.00%)	1 / 30 (3.33%)
occurrences all number	0	0	2	1	0	0	0	1
Visual field defect
subjects affected / exposed	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 9 (0.00%)	3 / 40 (7.50%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 8 (0.00%)	2 / 30 (6.67%)
occurrences all number	0	0	0	3	0	0	0	2
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	0 / 3 (0.00%)	1 / 8 (12.50%)	0 / 9 (0.00%)	13 / 40 (32.50%)	4 / 9 (44.44%)	3 / 9 (33.33%)	3 / 8 (37.50%)	6 / 30 (20.00%)
occurrences all number	0	1	0	19	7	3	6	15
Increased tendency to bruise
subjects affected / exposed	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 9 (0.00%)	0 / 40 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 8 (0.00%)	1 / 30 (3.33%)
occurrences all number	0	0	0	0	0	0	0	1
Leukopenia
subjects affected / exposed	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 9 (0.00%)	0 / 40 (0.00%)	1 / 9 (11.11%)	0 / 9 (0.00%)	0 / 8 (0.00%)	2 / 30 (6.67%)
occurrences all number	0	0	0	0	1	0	0	2
Lymphopenia
subjects affected / exposed	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 9 (0.00%)	2 / 40 (5.00%)	1 / 9 (11.11%)	0 / 9 (0.00%)	0 / 8 (0.00%)	4 / 30 (13.33%)
occurrences all number	0	0	0	2	1	0	0	4
Neutropenia
subjects affected / exposed	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 9 (0.00%)	2 / 40 (5.00%)	1 / 9 (11.11%)	0 / 9 (0.00%)	1 / 8 (12.50%)	3 / 30 (10.00%)
occurrences all number	0	0	0	3	2	0	1	3
Thrombocytopenia
subjects affected / exposed	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 9 (0.00%)	4 / 40 (10.00%)	1 / 9 (11.11%)	0 / 9 (0.00%)	1 / 8 (12.50%)	3 / 30 (10.00%)
occurrences all number	0	0	0	5	1	0	2	3
Ear and labyrinth disorders
Ear congestion
subjects affected / exposed	0 / 3 (0.00%)	1 / 8 (12.50%)	0 / 9 (0.00%)	0 / 40 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 8 (0.00%)	0 / 30 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0
Ear discomfort
subjects affected / exposed	0 / 3 (0.00%)	1 / 8 (12.50%)	0 / 9 (0.00%)	1 / 40 (2.50%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 8 (0.00%)	0 / 30 (0.00%)
occurrences all number	0	1	0	1	0	0	0	0
Ear pain
subjects affected / exposed	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 9 (0.00%)	2 / 40 (5.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 8 (0.00%)	0 / 30 (0.00%)
occurrences all number	0	0	0	2	0	0	0	0
Hypoacusis
subjects affected / exposed	0 / 3 (0.00%)	0 / 8 (0.00%)	1 / 9 (11.11%)	2 / 40 (5.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 8 (0.00%)	0 / 30 (0.00%)
occurrences all number	0	0	1	2	0	0	0	0
Tinnitus
subjects affected / exposed	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 9 (0.00%)	3 / 40 (7.50%)	1 / 9 (11.11%)	0 / 9 (0.00%)	1 / 8 (12.50%)	1 / 30 (3.33%)
occurrences all number	0	0	0	3	1	0	1	1
Vertigo
subjects affected / exposed	0 / 3 (0.00%)	0 / 8 (0.00%)	1 / 9 (11.11%)	0 / 40 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 8 (0.00%)	0 / 30 (0.00%)
occurrences all number	0	0	2	0	0	0	0	0
Eye disorders
Dry eye
subjects affected / exposed	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 9 (0.00%)	1 / 40 (2.50%)	0 / 9 (0.00%)	1 / 9 (11.11%)	0 / 8 (0.00%)	0 / 30 (0.00%)
occurrences all number	0	0	0	1	0	1	0	0
Erythema of eyelid
subjects affected / exposed	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 9 (0.00%)	0 / 40 (0.00%)	0 / 9 (0.00%)	1 / 9 (11.11%)	0 / 8 (0.00%)	0 / 30 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0
Lacrimation increased
subjects affected / exposed	0 / 3 (0.00%)	1 / 8 (12.50%)	1 / 9 (11.11%)	0 / 40 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 8 (0.00%)	0 / 30 (0.00%)
occurrences all number	0	1	1	0	0	0	0	0
Photophobia
subjects affected / exposed	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 9 (0.00%)	0 / 40 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 8 (0.00%)	1 / 30 (3.33%)
occurrences all number	0	0	0	0	0	0	0	1
Vision blurred
subjects affected / exposed	0 / 3 (0.00%)	1 / 8 (12.50%)	0 / 9 (0.00%)	3 / 40 (7.50%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 8 (0.00%)	0 / 30 (0.00%)
occurrences all number	0	1	0	3	0	0	0	0
Visual impairment
subjects affected / exposed	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 9 (0.00%)	0 / 40 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 8 (0.00%)	1 / 30 (3.33%)
occurrences all number	0	0	0	0	0	0	0	1
Gastrointestinal disorders
Abdominal discomfort
subjects affected / exposed	0 / 3 (0.00%)	0 / 8 (0.00%)	1 / 9 (11.11%)	0 / 40 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 8 (0.00%)	0 / 30 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0
Abdominal distension
subjects affected / exposed	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 9 (0.00%)	2 / 40 (5.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 8 (0.00%)	0 / 30 (0.00%)
occurrences all number	0	0	0	2	0	0	0	0
Abdominal pain
subjects affected / exposed	1 / 3 (33.33%)	1 / 8 (12.50%)	1 / 9 (11.11%)	5 / 40 (12.50%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 8 (0.00%)	1 / 30 (3.33%)
occurrences all number	1	1	1	8	0	0	0	1
Breath odour
subjects affected / exposed	0 / 3 (0.00%)	1 / 8 (12.50%)	0 / 9 (0.00%)	0 / 40 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 8 (0.00%)	0 / 30 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0
Colitis
subjects affected / exposed	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 9 (0.00%)	0 / 40 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 8 (0.00%)	1 / 30 (3.33%)
occurrences all number	0	0	0	0	0	0	0	1
Constipation
subjects affected / exposed	0 / 3 (0.00%)	1 / 8 (12.50%)	3 / 9 (33.33%)	14 / 40 (35.00%)	3 / 9 (33.33%)	2 / 9 (22.22%)	2 / 8 (25.00%)	12 / 30 (40.00%)
occurrences all number	0	1	3	16	3	2	2	17
Diarrhoea
subjects affected / exposed	0 / 3 (0.00%)	2 / 8 (25.00%)	0 / 9 (0.00%)	12 / 40 (30.00%)	2 / 9 (22.22%)	2 / 9 (22.22%)	1 / 8 (12.50%)	4 / 30 (13.33%)
occurrences all number	0	2	0	17	2	2	1	5
Dry mouth
subjects affected / exposed	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 9 (0.00%)	4 / 40 (10.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 8 (0.00%)	1 / 30 (3.33%)
occurrences all number	0	0	0	4	0	0	0	1
Dyspepsia
subjects affected / exposed	0 / 3 (0.00%)	1 / 8 (12.50%)	1 / 9 (11.11%)	2 / 40 (5.00%)	1 / 9 (11.11%)	0 / 9 (0.00%)	0 / 8 (0.00%)	2 / 30 (6.67%)
occurrences all number	0	1	1	2	1	0	0	2
Dysphagia
subjects affected / exposed	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 9 (0.00%)	1 / 40 (2.50%)	1 / 9 (11.11%)	0 / 9 (0.00%)	0 / 8 (0.00%)	1 / 30 (3.33%)
occurrences all number	0	0	0	1	1	0	0	1
Eructation
subjects affected / exposed	0 / 3 (0.00%)	0 / 8 (0.00%)	1 / 9 (11.11%)	1 / 40 (2.50%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 8 (0.00%)	0 / 30 (0.00%)
occurrences all number	0	0	1	1	0	0	0	0
Femoral hernia
subjects affected / exposed	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 9 (0.00%)	0 / 40 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 8 (0.00%)	1 / 30 (3.33%)
occurrences all number	0	0	0	0	0	0	0	1
Flatulence
subjects affected / exposed	0 / 3 (0.00%)	0 / 8 (0.00%)	1 / 9 (11.11%)	2 / 40 (5.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 8 (0.00%)	1 / 30 (3.33%)
occurrences all number	0	0	1	2	0	0	0	1
Gastrooesophageal reflux disease
subjects affected / exposed	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 9 (0.00%)	0 / 40 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	1 / 8 (12.50%)	1 / 30 (3.33%)
occurrences all number	0	0	0	0	0	0	1	1
Haematemesis
subjects affected / exposed	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 9 (0.00%)	0 / 40 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 8 (0.00%)	1 / 30 (3.33%)
occurrences all number	0	0	0	0	0	0	0	1
Hyperaesthesia teeth
subjects affected / exposed	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 9 (0.00%)	0 / 40 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 8 (0.00%)	1 / 30 (3.33%)
occurrences all number	0	0	0	0	0	0	0	1
Inguinal hernia
subjects affected / exposed	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 9 (0.00%)	0 / 40 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 8 (0.00%)	1 / 30 (3.33%)
occurrences all number	0	0	0	0	0	0	0	2
Melaena
subjects affected / exposed	0 / 3 (0.00%)	1 / 8 (12.50%)	0 / 9 (0.00%)	0 / 40 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 8 (0.00%)	0 / 30 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0
Nausea
subjects affected / exposed	1 / 3 (33.33%)	3 / 8 (37.50%)	5 / 9 (55.56%)	29 / 40 (72.50%)	7 / 9 (77.78%)	4 / 9 (44.44%)	4 / 8 (50.00%)	13 / 30 (43.33%)
occurrences all number	1	3	5	42	8	4	5	18
Oral dysaesthesia
subjects affected / exposed	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 9 (0.00%)	0 / 40 (0.00%)	1 / 9 (11.11%)	0 / 9 (0.00%)	0 / 8 (0.00%)	0 / 30 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0
Retching
subjects affected / exposed	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 9 (0.00%)	0 / 40 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 8 (0.00%)	1 / 30 (3.33%)
occurrences all number	0	0	0	0	0	0	0	1
Stomatitis
subjects affected / exposed	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 9 (0.00%)	2 / 40 (5.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 8 (0.00%)	0 / 30 (0.00%)
occurrences all number	0	0	0	2	0	0	0	0
Tooth discolouration
subjects affected / exposed	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 9 (0.00%)	0 / 40 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 8 (0.00%)	1 / 30 (3.33%)
occurrences all number	0	0	0	0	0	0	0	1
Umbilical hernia
subjects affected / exposed	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 9 (0.00%)	0 / 40 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 8 (0.00%)	1 / 30 (3.33%)
occurrences all number	0	0	0	0	0	0	0	1
Vomiting
subjects affected / exposed	1 / 3 (33.33%)	0 / 8 (0.00%)	2 / 9 (22.22%)	13 / 40 (32.50%)	2 / 9 (22.22%)	1 / 9 (11.11%)	4 / 8 (50.00%)	7 / 30 (23.33%)
occurrences all number	1	0	2	20	2	1	5	15
Vomiting projectile
subjects affected / exposed	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 9 (0.00%)	0 / 40 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 8 (0.00%)	1 / 30 (3.33%)
occurrences all number	0	0	0	0	0	0	0	1
Hepatobiliary disorders
Hepatic lesion
subjects affected / exposed	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 9 (0.00%)	0 / 40 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 8 (0.00%)	1 / 30 (3.33%)
occurrences all number	0	0	0	0	0	0	0	2
Skin and subcutaneous tissue disorders
Acne
subjects affected / exposed	0 / 3 (0.00%)	1 / 8 (12.50%)	0 / 9 (0.00%)	0 / 40 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 8 (0.00%)	0 / 30 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0
Alopecia
subjects affected / exposed	2 / 3 (66.67%)	2 / 8 (25.00%)	2 / 9 (22.22%)	14 / 40 (35.00%)	4 / 9 (44.44%)	0 / 9 (0.00%)	0 / 8 (0.00%)	0 / 30 (0.00%)
occurrences all number	2	2	2	16	4	0	0	0
Dermatitis
subjects affected / exposed	0 / 3 (0.00%)	0 / 8 (0.00%)	1 / 9 (11.11%)	1 / 40 (2.50%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 8 (0.00%)	0 / 30 (0.00%)
occurrences all number	0	0	1	1	0	0	0	0
Dermatitis acneiform
subjects affected / exposed	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 9 (0.00%)	2 / 40 (5.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 8 (0.00%)	0 / 30 (0.00%)
occurrences all number	0	0	0	2	0	0	0	0
Dermatitis contact
subjects affected / exposed	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 9 (0.00%)	1 / 40 (2.50%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 8 (0.00%)	1 / 30 (3.33%)
occurrences all number	0	0	0	1	0	0	0	1
Dry skin
subjects affected / exposed	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 9 (0.00%)	0 / 40 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 8 (0.00%)	1 / 30 (3.33%)
occurrences all number	0	0	0	0	0	0	0	1
Erythema
subjects affected / exposed	0 / 3 (0.00%)	1 / 8 (12.50%)	1 / 9 (11.11%)	0 / 40 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 8 (0.00%)	1 / 30 (3.33%)
occurrences all number	0	1	1	0	0	0	0	1
Night sweats
subjects affected / exposed	0 / 3 (0.00%)	1 / 8 (12.50%)	0 / 9 (0.00%)	1 / 40 (2.50%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 8 (0.00%)	0 / 30 (0.00%)
occurrences all number	0	1	0	1	0	0	0	0
Pain of skin
subjects affected / exposed	0 / 3 (0.00%)	2 / 8 (25.00%)	0 / 9 (0.00%)	0 / 40 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 8 (0.00%)	0 / 30 (0.00%)
occurrences all number	0	2	0	0	0	0	0	0
Petechiae
subjects affected / exposed	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 9 (0.00%)	0 / 40 (0.00%)	1 / 9 (11.11%)	0 / 9 (0.00%)	0 / 8 (0.00%)	0 / 30 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0
Pruritus
subjects affected / exposed	1 / 3 (33.33%)	1 / 8 (12.50%)	0 / 9 (0.00%)	1 / 40 (2.50%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 8 (0.00%)	1 / 30 (3.33%)
occurrences all number	1	1	0	1	0	0	0	1
Purpura
subjects affected / exposed	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 9 (0.00%)	0 / 40 (0.00%)	1 / 9 (11.11%)	0 / 9 (0.00%)	0 / 8 (0.00%)	0 / 30 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0
Rash maculo-papular
subjects affected / exposed	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 9 (0.00%)	1 / 40 (2.50%)	3 / 9 (33.33%)	2 / 9 (22.22%)	0 / 8 (0.00%)	2 / 30 (6.67%)
occurrences all number	0	0	0	1	3	2	0	2
Skin atrophy
subjects affected / exposed	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 9 (0.00%)	2 / 40 (5.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 8 (0.00%)	0 / 30 (0.00%)
occurrences all number	0	0	0	2	0	0	0	0
Renal and urinary disorders
Acute kidney injury
subjects affected / exposed	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 9 (0.00%)	0 / 40 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 8 (0.00%)	1 / 30 (3.33%)
occurrences all number	0	0	0	0	0	0	0	1
Haematuria
subjects affected / exposed	0 / 3 (0.00%)	0 / 8 (0.00%)	1 / 9 (11.11%)	2 / 40 (5.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 8 (0.00%)	1 / 30 (3.33%)
occurrences all number	0	0	1	2	0	0	0	1
Nephrolithiasis
subjects affected / exposed	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 9 (0.00%)	0 / 40 (0.00%)	1 / 9 (11.11%)	0 / 9 (0.00%)	0 / 8 (0.00%)	0 / 30 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0
Pollakiuria
subjects affected / exposed	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 9 (0.00%)	1 / 40 (2.50%)	0 / 9 (0.00%)	0 / 9 (0.00%)	1 / 8 (12.50%)	1 / 30 (3.33%)
occurrences all number	0	0	0	1	0	0	1	1
Polyuria
subjects affected / exposed	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 9 (0.00%)	0 / 40 (0.00%)	1 / 9 (11.11%)	0 / 9 (0.00%)	0 / 8 (0.00%)	0 / 30 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0
Urinary incontinence
subjects affected / exposed	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 9 (0.00%)	6 / 40 (15.00%)	2 / 9 (22.22%)	1 / 9 (11.11%)	0 / 8 (0.00%)	0 / 30 (0.00%)
occurrences all number	0	0	0	6	2	1	0	0
Musculoskeletal and connective tissue disorders
Arthralgia
subjects affected / exposed	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 9 (0.00%)	1 / 40 (2.50%)	2 / 9 (22.22%)	0 / 9 (0.00%)	0 / 8 (0.00%)	2 / 30 (6.67%)
occurrences all number	0	0	0	1	2	0	0	2
Back pain
subjects affected / exposed	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 9 (0.00%)	3 / 40 (7.50%)	1 / 9 (11.11%)	1 / 9 (11.11%)	0 / 8 (0.00%)	0 / 30 (0.00%)
occurrences all number	0	0	0	3	1	1	0	0
Flank pain
subjects affected / exposed	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 9 (0.00%)	0 / 40 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 8 (0.00%)	1 / 30 (3.33%)
occurrences all number	0	0	0	0	0	0	0	1
Groin pain
subjects affected / exposed	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 9 (0.00%)	1 / 40 (2.50%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 8 (0.00%)	1 / 30 (3.33%)
occurrences all number	0	0	0	1	0	0	0	1
Muscle spasms
subjects affected / exposed	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 9 (0.00%)	1 / 40 (2.50%)	1 / 9 (11.11%)	0 / 9 (0.00%)	0 / 8 (0.00%)	0 / 30 (0.00%)
occurrences all number	0	0	0	1	2	0	0	0
Muscular weakness
subjects affected / exposed	0 / 3 (0.00%)	1 / 8 (12.50%)	1 / 9 (11.11%)	1 / 40 (2.50%)	1 / 9 (11.11%)	1 / 9 (11.11%)	1 / 8 (12.50%)	3 / 30 (10.00%)
occurrences all number	0	1	1	1	1	1	1	3
Musculoskeletal pain
subjects affected / exposed	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 9 (0.00%)	0 / 40 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 8 (0.00%)	2 / 30 (6.67%)
occurrences all number	0	0	0	0	0	0	0	3
Myalgia
subjects affected / exposed	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 9 (0.00%)	1 / 40 (2.50%)	1 / 9 (11.11%)	0 / 9 (0.00%)	0 / 8 (0.00%)	3 / 30 (10.00%)
occurrences all number	0	0	0	1	1	0	0	3
Neck pain
subjects affected / exposed	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 9 (0.00%)	0 / 40 (0.00%)	1 / 9 (11.11%)	0 / 9 (0.00%)	0 / 8 (0.00%)	1 / 30 (3.33%)
occurrences all number	0	0	0	0	1	0	0	1
Pain in extremity
subjects affected / exposed	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 9 (0.00%)	1 / 40 (2.50%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 8 (0.00%)	1 / 30 (3.33%)
occurrences all number	0	0	0	1	0	0	0	1
Pain in jaw
subjects affected / exposed	0 / 3 (0.00%)	1 / 8 (12.50%)	0 / 9 (0.00%)	0 / 40 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 8 (0.00%)	0 / 30 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0
Tenosynovitis
subjects affected / exposed	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 9 (0.00%)	0 / 40 (0.00%)	1 / 9 (11.11%)	0 / 9 (0.00%)	0 / 8 (0.00%)	0 / 30 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0
Infections and infestations
Cellulitis
subjects affected / exposed	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 9 (0.00%)	0 / 40 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 8 (0.00%)	1 / 30 (3.33%)
occurrences all number	0	0	0	0	0	0	0	1
Eye infection
subjects affected / exposed	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 9 (0.00%)	0 / 40 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 8 (0.00%)	1 / 30 (3.33%)
occurrences all number	0	0	0	0	0	0	0	1
Hordeolum
subjects affected / exposed	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 9 (0.00%)	0 / 40 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 8 (0.00%)	1 / 30 (3.33%)
occurrences all number	0	0	0	0	0	0	0	1
Influenza
subjects affected / exposed	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 9 (0.00%)	0 / 40 (0.00%)	1 / 9 (11.11%)	0 / 9 (0.00%)	0 / 8 (0.00%)	0 / 30 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0
Oral candidiasis
subjects affected / exposed	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 9 (0.00%)	1 / 40 (2.50%)	2 / 9 (22.22%)	0 / 9 (0.00%)	0 / 8 (0.00%)	1 / 30 (3.33%)
occurrences all number	0	0	0	1	2	0	0	2
Oral herpes
subjects affected / exposed	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 9 (0.00%)	1 / 40 (2.50%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 8 (0.00%)	2 / 30 (6.67%)
occurrences all number	0	0	0	1	0	0	0	3
Osteomyelitis chronic
subjects affected / exposed	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 9 (0.00%)	0 / 40 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 8 (0.00%)	1 / 30 (3.33%)
occurrences all number	0	0	0	0	0	0	0	1
Otitis media
subjects affected / exposed	0 / 3 (0.00%)	1 / 8 (12.50%)	0 / 9 (0.00%)	2 / 40 (5.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 8 (0.00%)	0 / 30 (0.00%)
occurrences all number	0	1	0	2	0	0	0	0
Pneumonia
subjects affected / exposed	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 9 (0.00%)	0 / 40 (0.00%)	0 / 9 (0.00%)	1 / 9 (11.11%)	0 / 8 (0.00%)	0 / 30 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0
Postoperative wound infection
subjects affected / exposed	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 9 (0.00%)	1 / 40 (2.50%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 8 (0.00%)	1 / 30 (3.33%)
occurrences all number	0	0	0	1	0	0	0	1
Sinusitis
subjects affected / exposed	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 9 (0.00%)	1 / 40 (2.50%)	1 / 9 (11.11%)	0 / 9 (0.00%)	0 / 8 (0.00%)	0 / 30 (0.00%)
occurrences all number	0	0	0	1	1	0	0	0
Tooth infection
subjects affected / exposed	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 9 (0.00%)	0 / 40 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 8 (0.00%)	1 / 30 (3.33%)
occurrences all number	0	0	0	0	0	0	0	1
Upper respiratory tract infection
subjects affected / exposed	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 9 (0.00%)	2 / 40 (5.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 8 (0.00%)	1 / 30 (3.33%)
occurrences all number	0	0	0	3	0	0	0	1
Urinary tract infection
subjects affected / exposed	0 / 3 (0.00%)	1 / 8 (12.50%)	0 / 9 (0.00%)	1 / 40 (2.50%)	1 / 9 (11.11%)	0 / 9 (0.00%)	0 / 8 (0.00%)	1 / 30 (3.33%)
occurrences all number	0	1	0	2	1	0	0	1
Wound infection
subjects affected / exposed	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 9 (0.00%)	0 / 40 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 8 (0.00%)	2 / 30 (6.67%)
occurrences all number	0	0	0	0	0	0	0	2
Metabolism and nutrition disorders
Decreased appetite
subjects affected / exposed	1 / 3 (33.33%)	1 / 8 (12.50%)	3 / 9 (33.33%)	14 / 40 (35.00%)	4 / 9 (44.44%)	2 / 9 (22.22%)	1 / 8 (12.50%)	7 / 30 (23.33%)
occurrences all number	1	1	3	15	4	2	1	8
Dehydration
subjects affected / exposed	0 / 3 (0.00%)	1 / 8 (12.50%)	0 / 9 (0.00%)	1 / 40 (2.50%)	0 / 9 (0.00%)	0 / 9 (0.00%)	1 / 8 (12.50%)	0 / 30 (0.00%)
occurrences all number	0	1	0	2	0	0	1	0
Hyperglycaemia
subjects affected / exposed	1 / 3 (33.33%)	0 / 8 (0.00%)	1 / 9 (11.11%)	2 / 40 (5.00%)	1 / 9 (11.11%)	2 / 9 (22.22%)	0 / 8 (0.00%)	1 / 30 (3.33%)
occurrences all number	1	0	1	3	1	2	0	1
Hypernatraemia
subjects affected / exposed	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 9 (0.00%)	1 / 40 (2.50%)	1 / 9 (11.11%)	1 / 9 (11.11%)	0 / 8 (0.00%)	0 / 30 (0.00%)
occurrences all number	0	0	0	1	1	1	0	0
Hypoalbuminaemia
subjects affected / exposed	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 9 (0.00%)	1 / 40 (2.50%)	0 / 9 (0.00%)	1 / 9 (11.11%)	0 / 8 (0.00%)	0 / 30 (0.00%)
occurrences all number	0	0	0	1	0	1	0	0
Hypocalcaemia
subjects affected / exposed	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 9 (0.00%)	0 / 40 (0.00%)	0 / 9 (0.00%)	1 / 9 (11.11%)	0 / 8 (0.00%)	0 / 30 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0
Hypokalaemia
subjects affected / exposed	0 / 3 (0.00%)	0 / 8 (0.00%)	1 / 9 (11.11%)	2 / 40 (5.00%)	2 / 9 (22.22%)	0 / 9 (0.00%)	0 / 8 (0.00%)	1 / 30 (3.33%)
occurrences all number	0	0	1	2	2	0	0	1
Hyponatraemia
subjects affected / exposed	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 9 (0.00%)	4 / 40 (10.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	1 / 8 (12.50%)	1 / 30 (3.33%)
occurrences all number	0	0	0	7	0	0	1	1
Hypophosphataemia
subjects affected / exposed	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 9 (0.00%)	3 / 40 (7.50%)	0 / 9 (0.00%)	1 / 9 (11.11%)	1 / 8 (12.50%)	0 / 30 (0.00%)
occurrences all number	0	0	0	4	0	1	1	0

More information

Top of page

Were there any global substantial amendments to the protocol? Yes

23 Jul 2018

Overall Inclusion/Exclusion Criteria: Integrated comments received from MHRA regarding contraception language for both males and females and to align this protocol with other pamiparib studies and ensure consistency of language used in describing the process for management of safety. MGMT Analysis: Clarified that the provision of archival tumor tissue for central confirmation of MGMT status is mandatory in the expansion phase of the study because central testing of MGMT promoter status will be done. Criteria Specific to Arm C: To update the criterion for enrollment in Arm C of the study with more precise guidance as to what prior treatments are allowed or excluded and to define the timing of the first progression required for study entry. Overall Study Design: To update that after completion of RT, patients in Arm A (both dose escalation and expansion) and Arm B dose escalation have the option to continue receiving pamiparib in combination with TMZ (maintenance treatment); to note that for Arm B expansion, maintenance treatment of pamiparib in combination with TMZ will be mandatory; and lastly, overall, to make editorial and formatting changes throughout to enhance clarity and readability. Safety: Update the DLT criteria to reflect management of cytopenias in a GBM population and to align this protocol with other pamiparib studies and ensure consistency of language used in describing the process for management of safety.

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

Select Country:	Select Age Range:
Select Trial Status:	Select Trial Phase:
Select Gender:
Select Date Range: to
Select Rare Disease:
IMP with orphan designation in the indication
Orphan Designation Number:
Results Status:
Clear advanced search filters

Austria
Belgium
Bulgaria
Croatia
Cyprus
Czechia
Denmark
Estonia
Finland
France
Germany
Greece
Hungary
Iceland
Ireland
Italy
Latvia
Liechtenstein
Lithuania
Luxembourg
Malta
Netherlands
Norway
Poland
Portugal
Romania
Slovakia
Slovenia
Spain
Sweden
United Kingdom
Outside EU/EEA

Clinical trials

Clinical Trial Results: A Phase 1b/2 study to assess the safety, tolerability and efficacy of BGB-290 in combination with radiation therapy and/or temozolomide in subjects with first-line or recurrent/refractory glioblastoma

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Phase 1b Escalation Phase: Number of Participants with Dose-Limiting Toxicities (DLTs) as assessed by CTCAE

Primary: Phase 1b Escalation Phase: Number of Participants with Dose-Limiting Toxicities (DLTs) as assessed by CTCAE

Primary: Phase 1b Escalation Phase: Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) as Assessed by CTCAE

Primary: Phase 1b Escalation Phase: Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) as Assessed by CTCAE

Primary: Phase 1b Escalation Phase Arm C: Number of Participants with Clinically Relevant Changes in Vital signs and Clinical Laboratory Measurements

Primary: Phase 1b Escalation Phase Arm C: Number of Participants with Clinically Relevant Changes in Vital signs and Clinical Laboratory Measurements

Primary: Phase 2 Arm A Expansion Phase: Modified Disease Control Rate as Assessed by Response Assessment in Neuro-Oncology (RANO) Criteria

Primary: Phase 2 Arm A Expansion Phase: Modified Disease Control Rate as Assessed by Response Assessment in Neuro-Oncology (RANO) Criteria

Primary: Phase 2 Arm C: Objective Response Rate (ORR) as Assessed Using RANO Criteria

Primary: Phase 2 Arm C: Objective Response Rate (ORR) as Assessed Using RANO Criteria

Primary: Phase 1b Arm C: Number of Cycles of Treatment Received by Participants

Primary: Phase 1b Arm C: Number of Cycles of Treatment Received by Participants

Primary: Phase 1b Arm C: Average Dose Intensity of Pamiparib And TMZ Received per Participant

Primary: Phase 1b Arm C: Average Dose Intensity of Pamiparib And TMZ Received per Participant

Secondary: Phase 1B and Phase 2:Pharmacokinetics: Ctrough of Pamiparib

Secondary: Phase 1B and Phase 2:Pharmacokinetics: Ctrough of Pamiparib

Secondary: Phase 1b Arm A and Arm B Escalation Phase: Modified Disease Control Rate as Assessed by RANO Criteria

Secondary: Phase 1b Arm A and Arm B Escalation Phase: Modified Disease Control Rate as Assessed by RANO Criteria

Secondary: Phase 1b Escalation Phase Arm C: Disease Control Rate as Assessed by RANO Criteria

Secondary: Phase 1b Escalation Phase Arm C: Disease Control Rate as Assessed by RANO Criteria

Secondary: Phase 1b and Phase 2 Arms A and B: ORR as Assessed Using RANO Criteria

Secondary: Phase 1b and Phase 2 Arms A and B: ORR as Assessed Using RANO Criteria

Secondary: Phase 1b and Phase2 Arms A, B and C: Clinical Benefit Rate as Assessed Using RANO Criteria

Secondary: Phase 1b and Phase2 Arms A, B and C: Clinical Benefit Rate as Assessed Using RANO Criteria

Secondary: Phase 1b and Phase 2 Arms A, B and C: Duration of Response (DOR) as Assessed Using RANO Criteria

Secondary: Phase 1b and Phase 2 Arms A, B and C: Duration of Response (DOR) as Assessed Using RANO Criteria

Secondary: Phase 1b and Phase2 Arms A, B and C: Progression free survival (PFS) as Assessed Using RANO Criteria

Secondary: Phase 1b and Phase2 Arms A, B and C: Progression free survival (PFS) as Assessed Using RANO Criteria

Secondary: Phase 1b and Phase2 Arms A, B and C: Overall survival (OS)

Secondary: Phase 1b and Phase2 Arms A, B and C: Overall survival (OS)

Secondary: Phase 2 Arms A and C Expansion Phase: Number of Participants with Treatment Emergent adverse events (TEAEs) and Serious adverse events (SAEs)

Secondary: Phase 2 Arms A and C Expansion Phase: Number of Participants with Treatment Emergent adverse events (TEAEs) and Serious adverse events (SAEs)

Secondary: Phase 2 Expansion Phase Arm A and C: Number of Participants with Clinically Relevant Changes in Vital signs and Clinical Laboratory Measurements

Secondary: Phase 2 Expansion Phase Arm A and C: Number of Participants with Clinically Relevant Changes in Vital signs and Clinical Laboratory Measurements

Secondary: Phase 2 Arms A and C Expansion Phase: Number of Cycles of Treatment Received by Participants

Secondary: Phase 2 Arms A and C Expansion Phase: Number of Cycles of Treatment Received by Participants

Secondary: Phase 2 Arms A and C Expansion Phase: Average Dose Intensity of Pamiparib and TMZ Received per Participant

Secondary: Phase 2 Arms A and C Expansion Phase: Average Dose Intensity of Pamiparib and TMZ Received per Participant

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information

Clinical Trial Results:
A Phase 1b/2 study to assess the safety, tolerability and efficacy of BGB-290 in combination with radiation therapy and/or temozolomide in subjects with first-line or recurrent/refractory glioblastoma