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Clinical Trial Results:
A Phase 1/2 Study of CPI-0610, a Small Molecule Inhibitor of BET Proteins: Phase 1 (Dose Escalation of CPI-0610 in Patients with Hematological Malignancies) and Phase 2 (Dose Expansion of CPI-0610 with and without Ruxolitinib in Patients with Myeloproliferative Neoplasms)

Summary
EudraCT number	2018-000579-34
Trial protocol	GB NL BE PL IT
Global end of trial date	09 Jan 2025

Results information
Results version number	v1(current)
This version publication date	20 Nov 2025
First version publication date	20 Nov 2025
Other versions

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

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Trial information

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Sponsor protocol code

0610-02

ISRCTN number

US NCT number

NCT02158858

WHO universal trial number (UTN)

Other trial identifiers

Novartis: CDAK539A12201

Sponsor organisation name

Novartis Pharma AG, on behalf of Constellation Pharmaceuticals

Sponsor organisation address

Lichtstrasse 35, Basel, Switzerland, 4056

Public contact

Clinical Disclosure Office, Novartis Pharma AG, on behalf of Constellation Pharmaceuticals, 41 613241111, Novartis.email@Novartis.com

Scientific contact

Clinical Disclosure Office, Novartis Pharma AG, on behalf of Constellation Pharmaceuticals, 41 613241111, Novartis.email@Novartis.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

09 Jan 2025

Is this the analysis of the primary completion data?

Yes

Primary completion date

09 Jan 2025

Global end of trial reached?

Yes

Global end of trial date

09 Jan 2025

Was the trial ended prematurely?

Main objective of the trial

The primary objective of Phase 1 (dose escalation) was to determine the dose-limiting toxicities (DLTs) and the maximum tolerated dose (MTD) of pelabresib (CPI-0610) in patients with acute leukemia, myelodysplastic syndromes (MDS), myelodysplastic/myeloproliferative neoplasms (MDS/MPN), or myelofibrosis (MF). The primary objective of Phase 2 (dose expansion of pelabresib with and without ruxolitinib in patients with MPN) was to evaluate in MF patients splenic response by imaging after 24 weeks of treatment and, for MF patients who were transfusion dependent, to assess the transfusion independence rate. In patients with essential thrombocytopenia (ET) the primary objective was to evaluate the complete hematological response rate of pelabresib monotherapy.

Protection of trial subjects

The study was in compliance with the ethical principles derived from the Declaration of Helsinki and the International Conference on Harmonization (ICH) Good Clinical Practice (GCP) guidelines. All the local regulatory requirements pertinent to safety of trial subjects were also followed during the conduct of the trial.

Background therapy

Evidence for comparator

Actual start date of recruitment

16 Jul 2014

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Number of subjects enrolled per country

Country: Number of subjects enrolled

Belgium: 17

Country: Number of subjects enrolled

Canada: 29

Country: Number of subjects enrolled

France: 10

Country: Number of subjects enrolled

Germany: 5

Country: Number of subjects enrolled

Italy: 55

Country: Number of subjects enrolled

Netherlands: 5

Country: Number of subjects enrolled

Poland: 8

Country: Number of subjects enrolled

United Kingdom: 44

Country: Number of subjects enrolled

United States: 163

Worldwide total number of subjects

336

EEA total number of subjects

100

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)

108

From 65 to 84 years

222

85 years and over

Subject disposition

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Recruitment details

This study was conducted at 54 centers across 9 countries (Belgium, Canada, France, Germany, Italy, Netherlands, Poland, United Kingdom, United States)

Screening details

Not completed = Participants who discontinued study treatment

Period 1 title

Overall Study (overall period)

Is this the baseline period?

Yes

Allocation method

Non-randomised - controlled

Blinding used

Not blinded

Are arms mutually exclusive

Yes

Phase 1 (24 mg capsule PO daily)

Arm description

Phase 1 (24 mg capsule PO daily): Eligible participants in Phase I were enrolled in sequential cohorts based on diagnosis and received escalating doses of pelabresib (CPI-0610) once daily for 14 days, followed by a 7-day break in each 21-day cycle. Treatment stopped upon disease progression, unacceptable toxicity, or pregnancy.

Arm type

Experimental

Investigational medicinal product name

Pelabresib

Investigational medicinal product code

Other name

CPI-0610, DAK539

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

Pelabresib was administered orally once daily for 14 consecutive days, followed by a 7-day break (1 cycle = 21 days)

Phase 1 (48 mg capsule PO daily)

Arm description

Phase 1 (48 mg capsule PO daily): Eligible participants in Phase I were enrolled in sequential cohorts based on diagnosis and received escalating doses of pelabresib (CPI-0610) once daily for 14 days, followed by a 7-day break in each 21-day cycle. Treatment stopped upon disease progression, unacceptable toxicity, or pregnancy.

Arm type

Experimental

Investigational medicinal product name

Pelabresib

Investigational medicinal product code

Other name

CPI-0610, DAK539

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

Pelabresib was administered orally once daily for 14 consecutive days, followed by a 7-day break (1 cycle = 21 days)

Phase 1 (120 mg capsule PO daily)

Arm description

Phase 1 (120 mg capsule PO daily): Eligible participants in Phase I were enrolled in sequential cohorts based on diagnosis and received escalating doses of pelabresib (CPI-0610) once daily for 14 days, followed by a 7-day break in each 21-day cycle. Treatment stopped upon disease progression, unacceptable toxicity, or pregnancy.

Arm type

Experimental

Investigational medicinal product name

Pelabresib

Investigational medicinal product code

Other name

CPI-0610, DAK539

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

Pelabresib was administered orally once daily for 14 consecutive days, followed by a 7-day break (1 cycle = 21 days)

Phase 1 (170 mg capsule PO daily)

Arm description

Phase 1 (170 mg capsule PO daily): Eligible participants in Phase I were enrolled in sequential cohorts based on diagnosis and received escalating doses of pelabresib (CPI-0610) once daily for 14 days, followed by a 7-day break in each 21-day cycle. Treatment stopped upon disease progression, unacceptable toxicity, or pregnancy.

Arm type

Experimental

Investigational medicinal product name

Pelabresib

Investigational medicinal product code

Other name

CPI-0610, DAK539

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

Pelabresib was administered orally once daily for 14 consecutive days, followed by a 7-day break (1 cycle = 21 days)

Phase 1 (230 mg capsule PO daily)

Arm description

Phase 1 (230 mg capsule PO daily): Eligible participants in Phase I were enrolled in sequential cohorts based on diagnosis and received escalating doses of pelabresib (CPI-0610) once daily for 14 days, followed by a 7-day break in each 21-day cycle. Treatment stopped upon disease progression, unacceptable toxicity, or pregnancy.

Arm type

Experimental

Investigational medicinal product name

Pelabresib

Investigational medicinal product code

Other name

CPI-0610, DAK539

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

Pelabresib was administered orally once daily for 14 consecutive days, followed by a 7-day break (1 cycle = 21 days)

Phase 1 (300 mg capsule PO daily)

Arm description

Phase 1 (300 mg capsule PO daily): Eligible participants in Phase I were enrolled in sequential cohorts based on diagnosis and received escalating doses of pelabresib (CPI-0610) once daily for 14 days, followed by a 7-day break in each 21-day cycle. Treatment stopped upon disease progression, unacceptable toxicity, or pregnancy.

Arm type

Experimental

Investigational medicinal product name

Pelabresib

Investigational medicinal product code

Other name

CPI-0610, DAK539

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

Pelabresib was administered orally once daily for 14 consecutive days, followed by a 7-day break (1 cycle = 21 days)

Phase 1 (400 mg capsule PO daily)

Arm description

Phase 1 (400 mg capsule PO daily): Eligible participants in Phase I were enrolled in sequential cohorts based on diagnosis and received escalating doses of pelabresib (CPI-0610) once daily for 14 days, followed by a 7-day break in each 21-day cycle. Treatment stopped upon disease progression, unacceptable toxicity, or pregnancy.

Arm type

Experimental

Investigational medicinal product name

Pelabresib

Investigational medicinal product code

Other name

CPI-0610, DAK539

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

Pelabresib was administered orally once daily for 14 consecutive days, followed by a 7-day break (1 cycle = 21 days)

Phase 1 (225 mg tablet PO daily)

Arm description

Phase 1 (225 mg tablet PO daily): Eligible participants in Phase I were enrolled in sequential cohorts based on diagnosis and received escalating doses of pelabresib (CPI-0610) once daily for 14 days, followed by a 7-day break in each 21-day cycle. Treatment stopped upon disease progression, unacceptable toxicity, or pregnancy.

Arm type

Experimental

Investigational medicinal product name

Pelabresib

Investigational medicinal product code

Other name

CPI-0610, DAK539

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Pelabresib was administered orally once daily for 14 consecutive days, followed by a 7-day break (1 cycle = 21 days)

Phase 1 (275 mg tablet PO daily)

Arm description

Phase 1 (275 mg tablet PO daily): Eligible participants in Phase I were enrolled in sequential cohorts based on diagnosis and received escalating doses of pelabresib (CPI-0610) once daily for 14 days, followed by a 7-day break in each 21-day cycle. Treatment stopped upon disease progression, unacceptable toxicity, or pregnancy.

Arm type

Experimental

Investigational medicinal product name

Pelabresib

Investigational medicinal product code

Other name

CPI-0610, DAK539

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Pelabresib was administered orally once daily for 14 consecutive days, followed by a 7-day break (1 cycle = 21 days)

Ph2 Arm1 MF w/ prior JAKi – Cohort 1A

Arm description

In Phase 2 (Arm 1) - Cohort 1A, eligible transfusion-dependent (TD) participants received Pelabresib 125 mg QD (tablet) for 14 days, then 7-day break (21-day cycle). Upward titration allowed up to 225 mg QD based on platelet count, hemoglobin, and safety. Treatment stopped upon disease progression, unacceptable toxicity, or pregnancy.

Arm type

Experimental

Investigational medicinal product name

Pelabresib

Investigational medicinal product code

Other name

CPI-0610, DAK539

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Pelabresib was administered orally once daily for 14 consecutive days, followed by a 7-day break (1 cycle = 21 days)

Ph2 Arm1 MF w/ prior JAKi – Cohort 1B

Arm description

In Phase 2 (Arm 1) - Cohort 1B, eligible non-transfusion-dependent (non-TD) participants received Pelabresib 125 mg QD (tablet) for 14 days, then 7-day break (21-day cycle). Upward titration allowed up to 225 mg QD based on platelet count, hemoglobin, and safety. Treatment stopped upon disease progression, unacceptable toxicity, or pregnancy.

Arm type

Experimental

Investigational medicinal product name

Pelabresib

Investigational medicinal product code

Other name

CPI-0610, DAK539

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Pelabresib was administered orally once daily for 14 consecutive days, followed by a 7-day break (1 cycle = 21 days)

Ph2 Arm2 MF JAKi combo – Cohort 2A

Arm description

In Phase 2 (Arm 2) – Cohort 2A, eligible transfusion-dependent (TD) participants already on ruxolitinib received Pelabresib 125 mg once daily for 14 days followed by a 7-day break (21-day cycle), alongside their stable dose of ruxolitinib. Pelabresib could be titrated up to 225 mg daily. Treatment was discontinued upon disease progression, unacceptable toxicity, or pregnancy.

Arm type

Experimental

Investigational medicinal product name

Pelabresib

Investigational medicinal product code

Other name

CPI-0610, DAK539

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Pelabresib was administered orally once daily for 14 consecutive days, followed by a 7-day break (1 cycle = 21 days)

Investigational medicinal product name

Ruxolitinib

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Ruxolitinib was given orally, twice daily (BID), on a continuous basis for 21 consecutive days of each 21-day cycle.

Ph2 Arm2 MF JAKi combo – Cohort 2B

Arm description

In Phase 2 (Arm 2) – Cohort 2B, eligible non-transfusion-dependent (non-TD) participants already receiving ruxolitinib were treated with Pelabresib 125 mg once daily for 14 days, followed by a 7-day break (21-day cycle), alongside their stable ruxolitinib dose. Pelabresib could be titrated up to 225 mg daily. Treatment was discontinued upon disease progression, unacceptable toxicity, or pregnancy.

Arm type

Experimental

Investigational medicinal product name

Ruxolitinib

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Ruxolitinib was given orally, twice daily (BID), on a continuous basis for 21 consecutive days of each 21-day cycle.

Investigational medicinal product name

Pelabresib

Investigational medicinal product code

Other name

CPI-0610, DAK539

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Pelabresib was administered orally once daily for 14 consecutive days, followed by a 7-day break (1 cycle = 21 days)

Ph2 Arm3 MF JAKi-naïve – Combo Tx

Arm description

Eligible participants in Phase 2 (Arm 3) received Pelabresib 125 mg once daily for 14 days followed by a 7-day break (21-day cycle), combined with Ruxolitinib, initiated at one dose level below the recommended amount based on baseline platelet count. Dose escalation: a) Ruxolitinib: Required increase of 5 mg twice daily at Cycle 3 Day 1 if criteria were met, up to 25 mg twice daily; b) Pelabresib: Optional increase from Cycle 5 Day 1 in 25 mg steps, no more than once every two cycles, up to 175 mg once daily. Treatment was discontinued in cases of disease progression, unacceptable toxicity, or pregnancy.

Arm type

Experimental

Investigational medicinal product name

Pelabresib

Investigational medicinal product code

Other name

CPI-0610, DAK539

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Pelabresib was administered orally once daily for 14 consecutive days, followed by a 7-day break (1 cycle = 21 days)

Investigational medicinal product name

Ruxolitinib

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Ruxolitinib was given orally, twice daily (BID), on a continuous basis for 21 consecutive days of each 21-day cycle.

Ph2 Arm4 ET – Monotherapy

Arm description

Eligible participants in Phase 2 (Arm 4) received Pelabresib 225 mg once daily (tablet) was administered for 14 days followed by a 7-day break (21-day cycle). No dose increases beyond 225 mg once daily were permitted. Treatment was discontinued in cases of disease progression, unacceptable toxicity, or pregnancy.

Arm type

Experimental

Investigational medicinal product name

Pelabresib

Investigational medicinal product code

Other name

CPI-0610, DAK539

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Pelabresib was administered orally once daily for 14 consecutive days, followed by a 7-day break (1 cycle = 21 days)

Number of subjects in period 1	Phase 1 (24 mg capsule PO daily)	Phase 1 (48 mg capsule PO daily)	Phase 1 (120 mg capsule PO daily)	Phase 1 (170 mg capsule PO daily)	Phase 1 (230 mg capsule PO daily)	Phase 1 (300 mg capsule PO daily)	Phase 1 (400 mg capsule PO daily)	Phase 1 (225 mg tablet PO daily)	Phase 1 (275 mg tablet PO daily)	Ph2 Arm1 MF w/ prior JAKi – Cohort 1A	Ph2 Arm1 MF w/ prior JAKi – Cohort 1B	Ph2 Arm2 MF JAKi combo – Cohort 2A	Ph2 Arm2 MF JAKi combo – Cohort 2B	Ph2 Arm3 MF JAKi-naïve – Combo Tx	Ph2 Arm4 ET – Monotherapy
Started	3	5	5	3	3	4	7	8	6	48	52	59	28	84	21
Completed	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0
Not completed	3	5	5	3	3	4	7	8	6	48	52	59	28	84	21
Adverse event, serious fatal	-	-	-	-	-	-	-	1	1	4	3	4	1	8	-
Consent withdrawn by subject	1	1	1	-	-	-	1	3	2	5	8	6	3	10	4
Physician decision	-	-	-	-	-	-	1	-	2	20	13	14	6	10	3
Disease progression	1	3	3	2	3	2	3	1	-	5	9	13	7	12	1
Adverse event, non-fatal	-	1	1	1	-	2	1	3	1	10	7	17	6	14	4
Transitioned to pelabresib extension study	-	-	-	-	-	-	-	-	-	2	7	3	-	14	9
Other protocol defined stopping criteria	1	-	-	-	-	-	1	-	-	2	1	-	2	3	-
Cell transplant	-	-	-	-	-	-	-	-	-	-	4	2	3	13	-

Baseline characteristics

Top of page

Reporting group title

Phase 1 (24 mg capsule PO daily)

Reporting group description

Reporting group title

Phase 1 (48 mg capsule PO daily)

Reporting group description

Reporting group title

Phase 1 (120 mg capsule PO daily)

Reporting group description

Reporting group title

Phase 1 (170 mg capsule PO daily)

Reporting group description

Reporting group title

Phase 1 (230 mg capsule PO daily)

Reporting group description

Reporting group title

Phase 1 (300 mg capsule PO daily)

Reporting group description

Reporting group title

Phase 1 (400 mg capsule PO daily)

Reporting group description

Reporting group title

Phase 1 (225 mg tablet PO daily)

Reporting group description

Reporting group title

Phase 1 (275 mg tablet PO daily)

Reporting group description

Reporting group title

Ph2 Arm1 MF w/ prior JAKi – Cohort 1A

Reporting group description

Reporting group title

Ph2 Arm1 MF w/ prior JAKi – Cohort 1B

Reporting group description

Reporting group title

Ph2 Arm2 MF JAKi combo – Cohort 2A

Reporting group description

Reporting group title

Ph2 Arm2 MF JAKi combo – Cohort 2B

Reporting group description

Reporting group title

Ph2 Arm3 MF JAKi-naïve – Combo Tx

Reporting group description

Reporting group title

Ph2 Arm4 ET – Monotherapy

Reporting group description

Reporting group values	Phase 1 (24 mg capsule PO daily)	Phase 1 (48 mg capsule PO daily)	Phase 1 (120 mg capsule PO daily)	Phase 1 (170 mg capsule PO daily)	Phase 1 (230 mg capsule PO daily)	Phase 1 (300 mg capsule PO daily)	Phase 1 (400 mg capsule PO daily)	Phase 1 (225 mg tablet PO daily)	Phase 1 (275 mg tablet PO daily)	Ph2 Arm1 MF w/ prior JAKi – Cohort 1A	Ph2 Arm1 MF w/ prior JAKi – Cohort 1B	Ph2 Arm2 MF JAKi combo – Cohort 2A	Ph2 Arm2 MF JAKi combo – Cohort 2B	Ph2 Arm3 MF JAKi-naïve – Combo Tx	Ph2 Arm4 ET – Monotherapy	Total
Number of subjects	3	5	5	3	3	4	7	8	6	48	52	59	28	84	21	336
Age categorical
Units: Subjects
In utero	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0
Preterm newborn infants (gestational age < 37 wks)	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0
Newborns (0-27 days)	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0
Infants and toddlers (28 days-23 months)	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0
Children (2-11 years)	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0
Adolescents (12-17 years)	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0
Adults (18-64 years)	1	2	2	0	1	2	4	4	3	8	15	11	13	31	11	108
From 65-84 years	2	3	3	3	2	2	3	4	3	37	35	48	15	52	10	222
85 years and over	0	0	0	0	0	0	0	0	0	3	2	0	0	1	0	6
Age Continuous
Units: Years
median (full range (min-max))	79.0 (37 to 79)	65.0 (55 to 76)	69.0 (34 to 80)	76.0 (69 to 79)	80.0 (57 to 82)	66.5 (27 to 76)	63.0 (59 to 77)	65.5 (54 to 82)	61.0 (18 to 80)	73.0 (60 to 88)	69.5 (43 to 85)	72.0 (41 to 83)	65.5 (49 to 78)	68.0 (37 to 85)	64.0 (42 to 83)	-
Sex: Female, Male
Units: Participants
Female	3	1	1	3	1	0	2	1	2	16	29	18	13	25	13	128
Male	0	4	4	0	2	4	5	7	4	32	23	41	15	59	8	208
Race (NIH/OMB)
Units: Subjects
American Indian or Alaska Native	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0
Asian	0	1	0	0	0	0	0	0	0	1	1	1	1	3	0	8
Native Hawaiian or Other Pacific Islander	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0
Black or African American	0	0	1	0	0	1	1	0	2	4	1	2	4	3	0	19
White	3	4	4	3	3	1	6	8	4	42	47	54	22	75	19	295
More than one race	0	0	0	0	0	2	0	0	0	1	2	1	1	3	2	12
Unknown or Not Reported	0	0	0	0	0	0	0	0	0	0	1	1	0	0	0	2

End points

Top of page

Reporting group title

Phase 1 (24 mg capsule PO daily)

Reporting group description

Reporting group title

Phase 1 (48 mg capsule PO daily)

Reporting group description

Reporting group title

Phase 1 (120 mg capsule PO daily)

Reporting group description

Reporting group title

Phase 1 (170 mg capsule PO daily)

Reporting group description

Reporting group title

Phase 1 (230 mg capsule PO daily)

Reporting group description

Reporting group title

Phase 1 (300 mg capsule PO daily)

Reporting group description

Reporting group title

Phase 1 (400 mg capsule PO daily)

Reporting group description

Reporting group title

Phase 1 (225 mg tablet PO daily)

Reporting group description

Reporting group title

Phase 1 (275 mg tablet PO daily)

Reporting group description

Reporting group title

Ph2 Arm1 MF w/ prior JAKi – Cohort 1A

Reporting group description

Reporting group title

Ph2 Arm1 MF w/ prior JAKi – Cohort 1B

Reporting group description

Reporting group title

Ph2 Arm2 MF JAKi combo – Cohort 2A

Reporting group description

Reporting group title

Ph2 Arm2 MF JAKi combo – Cohort 2B

Reporting group description

Reporting group title

Ph2 Arm3 MF JAKi-naïve – Combo Tx

Reporting group description

Reporting group title

Ph2 Arm4 ET – Monotherapy

Reporting group description

Primary: Phase 1: Frequency of Dose-limiting toxicities (DLTs)

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End point title

Phase 1: Frequency of Dose-limiting toxicities (DLTs) ^[1] ^[2]

End point description

A dose-limiting toxicity (DLT) was defined as an adverse event or abnormal laboratory value assessed by the Investigator as unrelated to disease progression, intercurrent illness, or concomitant medications that occurred within the first cycle of treatment (21-day cycle) with pelabresib (CPI-0610), and that met any of the criteria specified in the protocol.

End point type

Primary

End point timeframe

Up to 21 days

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 only applicable to Phase I
[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: Endpoint only applicable to Phase I

End point values	Phase 1 (24 mg capsule PO daily)	Phase 1 (48 mg capsule PO daily)	Phase 1 (120 mg capsule PO daily)	Phase 1 (170 mg capsule PO daily)	Phase 1 (230 mg capsule PO daily)	Phase 1 (300 mg capsule PO daily)	Phase 1 (400 mg capsule PO daily)	Phase 1 (225 mg tablet PO daily)	Phase 1 (275 mg tablet PO daily)
Number of subjects analysed	3	4	5	3	3	3	6	6	5
Units: Participants	0	0	0	0	0	0	1	2	4

No statistical analyses for this end point

Primary: Phase 2 (Cohorts 1B, 2B, and Arm 3): Number of Participants with Splenic Response Rate (SVR35) at week 24

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End point title

Phase 2 (Cohorts 1B, 2B, and Arm 3): Number of Participants with Splenic Response Rate (SVR35) at week 24 ^[3] ^[4]

End point description

Splenic Response Rate (SVR35) at Week 24 was defined as the proportion of participants who demonstrated a reduction of at least 35% in spleen size from baseline, as measured by imaging techniques (MRI or CT), following 24 weeks of treatment.

End point type

Primary

End point timeframe

Week 24 (Cycle 9 Day 1)

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 only applicable to Phase II (Cohort 1B, 2B and Arm 3)
[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: Endpoint only applicable to Phase II (Cohort 1B, 2B and Arm 3)

End point values	Ph2 Arm1 MF w/ prior JAKi – Cohort 1B	Ph2 Arm2 MF JAKi combo – Cohort 2B	Ph2 Arm3 MF JAKi-naïve – Combo Tx
Number of subjects analysed	52	28	84
Units: Percentage of Participants
number (confidence interval 95%)	19.2 (9.6 to 32.5)	21.4 (8.3 to 41.0)	67.9 (56.8 to 77.6)

No statistical analyses for this end point

Primary: Phase 2 (Cohorts 1A and 2A): Number of Participants enrolled as Transfusion Dependent (TD) with Conversion rate from Red Blood Cell (RBC) transfusion dependence (TD) to transfusion independence (TI)

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End point title

Phase 2 (Cohorts 1A and 2A): Number of Participants enrolled as Transfusion Dependent (TD) with Conversion rate from Red Blood Cell (RBC) transfusion dependence (TD) to transfusion independence (TI) ^[5] ^[6]

End point description

Conversion rate was defined as the proportion of participants who converted from transfusion dependence (TD) to transfusion independence (TI). TD was characterized by receiving an average of at least 2 units of red blood cell (RBC) transfusions per month—amounting to a minimum of 6 units over the 12 weeks prior to enrollment—while TI was defined as the absence of RBC transfusions during any consecutive 12-week period.

End point type

Primary

End point timeframe

12 consecutive weeks (rolling window) up to 7 days following the last dose of pelabresib (CPI-0610)

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 only applicable to Phase II (Cohort 1A and 2A)
[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 only applicable to Phase II (Cohort 1A and 2A)

End point values	Ph2 Arm1 MF w/ prior JAKi – Cohort 1A	Ph2 Arm2 MF JAKi combo – Cohort 2A
Number of subjects analysed	48	59
Units: Percentage of Participants
number (confidence interval 95%)	25.6 (13.5 to 41.2)	26.1 (14.3 to 41.1)

No statistical analyses for this end point

Primary: Phase 2 (Arm 4): Number of Participants with Complete Hematological Response (CHR) Rate

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End point title

Phase 2 (Arm 4): Number of Participants with Complete Hematological Response (CHR) Rate ^[7] ^[8]

End point description

Complete Hematological Response (CHR) Rate was defined as the proportion of participants who fulfilled the criteria for CHR, based on the modified European LeukemiaNet (ELN) guidelines (Barosi et al 2009): platelet count ≤400 × 10⁹/L, white blood cell (WBC) count ≤10 × 10⁹/L, confirmation of laboratory values after one treatment cycle, and normal spleen size determined by palpation or imaging.

End point type

Primary

End point timeframe

Over 2 consecutive cycles (rolling window) (1 cycle = 21 days)

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 only applicable to Phase II (Arm 4)
[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: Endpoint only applicable to Phase II (Arm 4)

End point values	Ph2 Arm4 ET – Monotherapy
Number of subjects analysed	21
Units: Percentage of Participants
number (confidence interval 95%)	57.1 (34.0 to 78.2)

No statistical analyses for this end point

Secondary: Phase 1: Number of adverse events and serious adverse events as assessed by CTCAE criteria

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End point title

Phase 1: Number of adverse events and serious adverse events as assessed by CTCAE criteria ^[9]

End point description

The distribution of adverse events was performed through the analysis of frequencies for treatment-emergent adverse events (TEAEs) and serious adverse events (TESAEs), based on the monitoring of relevant clinical and laboratory safety parameters. Treatment-emergent adverse events (TEAEs) in this study were defined as events that began after the first dose of study treatment and continued until 30 days after the last dose, or events that were present prior to the first dose and increased in severity based on preferred term within 30 days following the last dose of pelabresib (CPI-0610).

End point type

Secondary

End point timeframe

Up to approximately 25 weeks

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

End point values	Phase 1 (24 mg capsule PO daily)	Phase 1 (48 mg capsule PO daily)	Phase 1 (120 mg capsule PO daily)	Phase 1 (170 mg capsule PO daily)	Phase 1 (230 mg capsule PO daily)	Phase 1 (300 mg capsule PO daily)	Phase 1 (400 mg capsule PO daily)	Phase 1 (225 mg tablet PO daily)	Phase 1 (275 mg tablet PO daily)
Number of subjects analysed	3	5	5	3	3	4	7	8	6
Units: Participants
Participants with at least 1 TEAE	3	5	5	3	3	4	7	8	6
Participants with ≥ Grade 3 TEAEs	2	4	3	3	2	4	7	8	6
Pts w/ any drug-related TEAE	3	3	5	3	3	3	6	7	5
Pts w/ drug-related TEAEs ≥ Gr3 (CTCAE)	1	1	1	0	0	0	5	3	4
Participants with any serious TEAEs	1	4	3	1	2	4	6	6	6
Participants with any drug-related serious TEAEs	0	0	1	0	0	0	1	0	3
Pts w/ TEAEs leading to drug discontinuation	0	2	2	1	0	2	2	4	3

No statistical analyses for this end point

Secondary: Phase 2 (All Arms): Number of adverse events and serious adverse events as assessed by CTCAE criteria

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End point title

Phase 2 (All Arms): Number of adverse events and serious adverse events as assessed by CTCAE criteria ^[10]

End point description

End point type

Secondary

End point timeframe

Up to approximately 387 weeks

Notes
[10] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Endpoint only applicable to Phase II (All Arms)

End point values	Ph2 Arm1 MF w/ prior JAKi – Cohort 1A	Ph2 Arm1 MF w/ prior JAKi – Cohort 1B	Ph2 Arm2 MF JAKi combo – Cohort 2A	Ph2 Arm2 MF JAKi combo – Cohort 2B	Ph2 Arm3 MF JAKi-naïve – Combo Tx	Ph2 Arm4 ET – Monotherapy
Number of subjects analysed	48	52	59	28	84	21
Units: Participants
Participants with at least 1 TEAE	48	51	59	28	84	21
Participants with ≥ Grade 3 TEAEs	38	40	49	21	66	10
Pts w/ ≥1 TEAE related to pelabresib	45	44	53	27	74	20
Pts w/ ≥Gr3 TEAEs related to pelabresib	27	21	33	14	41	6
Participants with any serious TEAEs	21	27	29	18	41	7
Pts w/ serious TEAEs related to pelabresib	4	4	2	6	16	3
Pts w/ TEAEs causing pelabresib interruption	20	16	32	13	39	9
Pts w/ TEAEs causing pelabresib dose reduction	16	10	15	7	38	6
Pts w/ TEAEs causing pelabresib discontinuation	12	12	17	7	22	3
Pts w/ TEAEs causing study discontinuation	11	11	18	9	22	5

No statistical analyses for this end point

Secondary: Phase 2 (All Arms): Symptom improvement from the Patient Global Impression of Change (PGIC) at 12 and 24 weeks

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End point title

Phase 2 (All Arms): Symptom improvement from the Patient Global Impression of Change (PGIC) at 12 and 24 weeks ^[11]

End point description

The Patient Global Impression of Change (PGIC) was a single-question, patient-reported assessment that asked individuals to rate their overall change in myeloproliferative neoplasm (MPN) symptoms since starting study treatment. The participants selected one of seven options, ranging from 'Very much improved' to 'Very much worse'. 'No Change from Baseline' indicated stable symptoms (no improvement or worsening), negative change from Baseline indicated a reduction in symptom severity (improvement), and positive change from Baseline indicated an increase in symptom severity (worsening).

End point type

Secondary

End point timeframe

Week 12 (Cycle 5 Day 1), Week 24 weeks (Cycle 9 Day 1)

Notes
[11] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Endpoint only applicable to Phase II (All Arms)

End point values	Ph2 Arm1 MF w/ prior JAKi – Cohort 1A	Ph2 Arm1 MF w/ prior JAKi – Cohort 1B	Ph2 Arm2 MF JAKi combo – Cohort 2A	Ph2 Arm2 MF JAKi combo – Cohort 2B	Ph2 Arm3 MF JAKi-naïve – Combo Tx	Ph2 Arm4 ET – Monotherapy
Number of subjects analysed	39	43	47	25	80	19
Units: Participants
PGIC status at Week 12\|Improvement	28	36	22	18	66	13
PGIC status at Week 24\|Improvement	20	29	27	16	58	8
PGIC status at Week 12\|No change	7	2	15	4	9	4
PGIC status at Week 24\|No change	10	3	12	6	15	3
PGIC status at Week 12\|Worsening	4	5	10	3	5	2
PGIC status at Week 24\|Worsening	2	5	4	0	6	4

No statistical analyses for this end point

Secondary: Phase 2 (Arms 1, 2 and 3): Percent Change from Baseline in Total Symptom Score (TSS) from the Myelofibrosis Symptom Assessment Form (MFSAF v4.0) at 12 and 24 weeks

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End point title

Phase 2 (Arms 1, 2 and 3): Percent Change from Baseline in Total Symptom Score (TSS) from the Myelofibrosis Symptom Assessment Form (MFSAF v4.0) at 12 and 24 weeks ^[12]

End point description

The MFSAF (Myelofibrosis Symptom Assessment Form) was completed by participants every day for 7 days before Day 1 of each treatment cycle, including the 7 days before starting Cycle 1. It used a 24-hour recall format, asking participants to rate the worst severity of seven symptoms (fatigue, night sweats, pruritus, abdominal discomfort, pain under the ribs on the left side, early satiety, and bone pain) during the past 24 hours. Each symptom was rated on a scale from 0 (Absent) to 10 (Worst Imaginable). The Total Symptom Score (TSS) was the sum of 7 symptoms (range: 0–70). 'No Change from Baseline' indicated stable symptoms (no improvement or worsening), negative change from Baseline indicated a reduction in symptom severity (improvement), and positive change from Baseline indicated an increase in symptom severity (worsening).

End point type

Secondary

End point timeframe

Baseline, Week 12 (Cycle 5 Day 1), Week 24 (Cycle 9 Day 1)

Notes
[12] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Endpoint only applicable to Phase II (Arms 1, 2 and 3)

End point values	Ph2 Arm1 MF w/ prior JAKi – Cohort 1A	Ph2 Arm1 MF w/ prior JAKi – Cohort 1B	Ph2 Arm2 MF JAKi combo – Cohort 2A	Ph2 Arm2 MF JAKi combo – Cohort 2B	Ph2 Arm3 MF JAKi-naïve – Combo Tx
Number of subjects analysed	38	43	48	25	82
Units: Score on a scale
arithmetic mean (standard deviation)
Percent Change from baseline to Week 12	-38.77 ( 38.637 )	-30.98 ( 35.394 )	-27.18 ( 75.391 )	-29.70 ( 36.106 )	-39.91 ( 69.251 )
Percent Change from baseline to Week 24	-32.69 ( 36.474 )	-39.82 ( 42.228 )	-38.93 ( 61.818 )	-44.73 ( 35.224 )	-47.43 ( 52.460 )

No statistical analyses for this end point

Secondary: Phase 2 (Arms 1, 2 and 3): Number of Participants who achieved a ≥ 50% reduction in Total Symptom Score (TSS) at 12 and 24 weeks

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End point title

Phase 2 (Arms 1, 2 and 3): Number of Participants who achieved a ≥ 50% reduction in Total Symptom Score (TSS) at 12 and 24 weeks ^[13]

End point description

The proportion of study participants who experienced a reduction of at least 50% in their Total Symptom Score (TSS), as assessed using the Myelofibrosis Symptom Assessment Form (MFSAF v4.0), was evaluated at both 12 and 24 weeks relative to their baseline score.

End point type

Secondary

End point timeframe

Week 12 (Cycle 5 Day 1), Week 24 (Cycle 9 Day 1)

Notes
[13] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Endpoint only applicable to Phase II (Arms 1, 2 and 3)

End point values	Ph2 Arm1 MF w/ prior JAKi – Cohort 1A	Ph2 Arm1 MF w/ prior JAKi – Cohort 1B	Ph2 Arm2 MF JAKi combo – Cohort 2A	Ph2 Arm2 MF JAKi combo – Cohort 2B	Ph2 Arm3 MF JAKi-naïve – Combo Tx
Number of subjects analysed	48	52	59	28	84
Units: Percentage of Participants
number (confidence interval 95%)
MFSAF TSS50 response at week 12	33.3 (20.0 to 49.0)	31.3 (18.7 to 46.3)	36.2 (24.0 to 49.9)	33.3 (16.5 to 54.0)	52.4 (41.1 to 63.6)
MFSAF TSS50 response at week 24	15.6 (6.5 to 29.5)	34.7 (21.7 to 49.6)	36.2 (24.0 to 49.9)	40.7 (22.4 to 61.2)	56.1 (44.7 to 67.0)

No statistical analyses for this end point

Secondary: Phase 2 (Arms 1, 2 and 3): Number of Participants with Overall Splenic Response Rate (overall SVR35)

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End point title

Phase 2 (Arms 1, 2 and 3): Number of Participants with Overall Splenic Response Rate (overall SVR35) ^[14]

End point description

Overall Splenic Response Rate (SVR35) was defined as the proportion of participants who achieved a reduction of at least 35% in spleen size from baseline, as measured by imaging (MRI or CT), at any point between Cycle 1 Day 1 and the End of Study Visit, whichever occurred first.

End point type

Secondary

End point timeframe

Through Phase II completion, an average of 6 years

Notes
[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 only applicable to Phase II (Arms 1, 2 and 3)

End point values	Ph2 Arm1 MF w/ prior JAKi – Cohort 1A	Ph2 Arm1 MF w/ prior JAKi – Cohort 1B	Ph2 Arm2 MF JAKi combo – Cohort 2A	Ph2 Arm2 MF JAKi combo – Cohort 2B	Ph2 Arm3 MF JAKi-naïve – Combo Tx
Number of subjects analysed	48	52	59	28	84
Units: Percentage of Participants
number (confidence interval 95%)	16.7 (7.0 to 31.4)	28.8 (17.1 to 43.1)	30.8 (18.7 to 45.1)	25.0 (10.7 to 44.9)	79.8 (69.6 to 87.7)

No statistical analyses for this end point

Secondary: Phase 2 (Arms 1, 2 and 3): Duration of Overall Splenic Response (overall SVR35)

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End point title

Phase 2 (Arms 1, 2 and 3): Duration of Overall Splenic Response (overall SVR35) ^[15]

End point description

Duration of Overall Splenic Response (overall SVR35) was defined as the time from the first occurrence of a at least 35% reduction in spleen volume from baseline until the earliest of the following: a reduction of less than 35% from baseline combined with an increase of more than 25% from the nadir in spleen volume (as measured by MRI or CT), or death. The nadir was defined as the lowest spleen volume recorded after baseline and up to the evaluation point at which the initial splenic response was achieved.

End point type

Secondary

End point timeframe

From first onset of splenic response until loss of response, assessed up to approximately 6 years

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: Endpoint only applicable to Phase II (Arms 1, 2 and 3)

End point values	Ph2 Arm1 MF w/ prior JAKi – Cohort 1A	Ph2 Arm1 MF w/ prior JAKi – Cohort 1B	Ph2 Arm2 MF JAKi combo – Cohort 2A	Ph2 Arm2 MF JAKi combo – Cohort 2B	Ph2 Arm3 MF JAKi-naïve – Combo Tx
Number of subjects analysed	48	52	59	28	84
Units: Weeks
median (confidence interval 95%)	24.1 (12.4 to 999)	73.1 (27.1 to 106.4)	180.9 (73.0 to 999)	228.4 (36.1 to 999)	197.6 (95.7 to 999)

No statistical analyses for this end point

Secondary: Phase 2 (Cohorts 1A and 2A): Number of Participants with Splenic Response Rate (SVR35) at 12 and 24 weeks

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End point title

Phase 2 (Cohorts 1A and 2A): Number of Participants with Splenic Response Rate (SVR35) at 12 and 24 weeks ^[16]

End point description

Splenic Response Rate (SVR35) at 12 and 24 weeks was defined as the proportion of participants who achieved a reduction of at least 35% in spleen size from baseline, as determined by imaging (MRI or CT), following 12 and 24 weeks of treatment, respectively.

End point type

Secondary

End point timeframe

Week 12 (Cycle 5 Day 1), Week 24 weeks (Cycle 9 Day 1)

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: Endpoint only applicable to Phase II (Cohort 1A and 2A)

End point values	Ph2 Arm1 MF w/ prior JAKi – Cohort 1A	Ph2 Arm2 MF JAKi combo – Cohort 2A
Number of subjects analysed	48	59
Units: Percentage of Participants
number (confidence interval 95%)
SVR35 at week 12	9.3 (2.6 to 22.1)	9.4 (3.1 to 20.7)
SVR35 at week 24	0 (0 to 999)	16.4 (7.8 to 28.8)

No statistical analyses for this end point

Secondary: Phase 2 (Cohorts 1A and 2A): Duration of Red Blood Cell (RBC) Transfusion Independence (TI) in participants who enroll as Transfusion Dependent (TD)

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End point title

Phase 2 (Cohorts 1A and 2A): Duration of Red Blood Cell (RBC) Transfusion Independence (TI) in participants who enroll as Transfusion Dependent (TD) ^[17]

End point description

Duration of Red Blood Cell (RBC) Transfusion Independence (TI) was defined as the longest continuous period during which participants, having achieved at least 12 weeks of transfusion independence, remained free from RBC transfusions.

End point type

Secondary

End point timeframe

From first onset of TI to earliest onset of loss of TI, assessed up to approximately 6 years

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: Endpoint only applicable to Phase II (Cohort 1A and 2A)

End point values	Ph2 Arm1 MF w/ prior JAKi – Cohort 1A	Ph2 Arm2 MF JAKi combo – Cohort 2A
Number of subjects analysed	48	59
Units: Weeks
median (full range (min-max))	35.8 (15.3 to 999)	68.0 (34.7 to 999)

No statistical analyses for this end point

Secondary: Phase 2 (Cohorts 1A and 2A): Early anemic response rate in participants who enroll as Transfusion Dependent (TD)

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End point title

Phase 2 (Cohorts 1A and 2A): Early anemic response rate in participants who enroll as Transfusion Dependent (TD) ^[18]

End point description

Early anemic response rate was defined as the proportion of participants who achieved an average increase of at least 1 g/dL in hemoglobin concentration over any rolling 8-week (56-day) period following baseline. This calculation was performed after applying the 14/3 day rule, which stipulates that hemoglobin measurements must be spaced at least 14 days apart, and that at least 3 such measurements are required within the 8-week window to ensure a reliable average. Importantly, this increase had to occur without any red blood cell (RBC) transfusions during the treatment period and up to the time of the latest hemoglobin assessment for each patient.

End point type

Secondary

End point timeframe

Through Phase II completion, an average of 6 years

Notes
[18] - 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 only applicable to Phase II (Cohort 1A and 2A)

End point values	Ph2 Arm1 MF w/ prior JAKi – Cohort 1A	Ph2 Arm2 MF JAKi combo – Cohort 2A
Number of subjects analysed	48	59
Units: Percentage of Participants
number (confidence interval 95%)	18.6 (8.4 to 33.4)	21.7 (10.9 to 36.4)

No statistical analyses for this end point

Secondary: Phase 2 (Cohorts 1B, 2B, and Arm 3): Number of Participants with Splenic Response Rate (SVR35) at 12 weeks

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End point title

Phase 2 (Cohorts 1B, 2B, and Arm 3): Number of Participants with Splenic Response Rate (SVR35) at 12 weeks ^[19]

End point description

Splenic Response Rate (SVR35) at Week 12 was defined as the proportion of participants who achieved a reduction of at least 35% in spleen size from baseline, as measured by imaging (MRI or CT), following 12 weeks of treatment.

End point type

Secondary

End point timeframe

Week 12 (Cycle 5 Day 1)

Notes
[19] - 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 only applicable to Phase II (Cohort 1B, 2B and Arm 3)

End point values	Ph2 Arm1 MF w/ prior JAKi – Cohort 1B	Ph2 Arm2 MF JAKi combo – Cohort 2B	Ph2 Arm3 MF JAKi-naïve – Combo Tx
Number of subjects analysed	52	28	84
Units: Percentage of Participants
number (confidence interval 95%)	15.4 (6.9 to 28.1)	10.7 (2.3 to 28.2)	66.7 (55.5 to 76.6)

No statistical analyses for this end point

Secondary: Phase 2 (Cohorts 1B, 2B, and Arm 3): Anemic response rate in participants who enroll as non-transfusion-dependent (non-TD)

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End point title

Phase 2 (Cohorts 1B, 2B, and Arm 3): Anemic response rate in participants who enroll as non-transfusion-dependent (non-TD) ^[20]

End point description

Anemic response was defined as a sustained average increase in hemoglobin concentration of at least 1.5 g/dL over any rolling 12-week (84-day) period following baseline. This calculation excluded periods involving red blood cell (RBC) transfusions and was performed after applying the 14/3-day rule for valid hemoglobin assessments. The response had to be maintained through to the most recent available hemoglobin measurement for each patient.

End point type

Secondary

End point timeframe

Through Phase II completion, an average of 6 years

Notes
[20] - 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 only applicable to Phase II (Cohort 1B, 2B and Arm 3)

End point values	Ph2 Arm1 MF w/ prior JAKi – Cohort 1B	Ph2 Arm2 MF JAKi combo – Cohort 2B	Ph2 Arm3 MF JAKi-naïve – Combo Tx
Number of subjects analysed	52	28	84
Units: Percentage of Participants
number (confidence interval 95%)	47.1 (32.9 to 61.5)	21.4 (8.3 to 41.0)	35.4 (25.0 to 47.0)

No statistical analyses for this end point

Secondary: Phase 2 (Arm 4): Percentage of participants who achieve a ≥50% reduction from baseline in the Myeloproliferative Neoplasm Symptom Assessment Form (MPN-SAF) total score

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End point title

Phase 2 (Arm 4): Percentage of participants who achieve a ≥50% reduction from baseline in the Myeloproliferative Neoplasm Symptom Assessment Form (MPN-SAF) total score ^[21]

End point description

The Myeloproliferative Neoplasm Symptom Assessment Form (MPN-SAF) is a patient-reported questionnaire designed to measure symptom burden in participants with myeloproliferative neoplasms (MPNs). Participants rate the severity of several symptoms (such as fatigue, night sweats, itching, abdominal discomfort, bone pain, early satiety, and others) over the past 24 hours. Each symptom is scored on a scale from 0 (absent/as good as it can be) to 10 (worst imaginable/as bad as it can be). The total score is the sum of all individual symptom scores, providing an overall measure of symptom burden. A 50% reduction in the MPN-SAF total score at 12 or 24 weeks means the patient’s overall symptom burden has improved by half compared to their baseline (pre-treatment) score.

End point type

Secondary

End point timeframe

Baseline, 12 weeks (Cycle 5, Day 1), 24 weeks (Cycle 9, Day 1)

Notes
[21] - 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 only applicable to Phase II (Arm 4)

End point values	Ph2 Arm4 ET – Monotherapy
Number of subjects analysed	21
Units: Percentage of Participants
number (confidence interval 95%)
MPN-SAF TSS50 response at week 12	25.0 (8.7 to 49.1)
MPN-SAF TSS50 response at week 24	20.0 (5.7 to 43.7)

No statistical analyses for this end point

Secondary: Phase 2 (Arm 4): Partial Hematological Response Rate (PHR)

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End point title

Phase 2 (Arm 4): Partial Hematological Response Rate (PHR) ^[22]

End point description

Partial Hematological Response Rate (PHR) was defined as the proportion of participants who met the following criteria over two consecutive cycles up to the last administration of study treatment: • Platelet count > 400-600 x 10^9/L • WBC count within normal range (i.e., ≤ 10 x 10^9/L) • Laboratory results confirmed after 1 cycle (after 3weeks)

End point type

Secondary

End point timeframe

Over 2 consecutive cycles (rolling window) (1 cycle = 21 days)

Notes
[22] - 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 only applicable to Phase II (Arm 4)

End point values	Ph2 Arm4 ET – Monotherapy
Number of subjects analysed	21
Units: Percentage of Participants
number (confidence interval 95%)	38.1 (18.1 to 61.6)

No statistical analyses for this end point

Secondary: Phase 2 (Arm 4): Overall Hematological Response Rate (OHR)

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End point title

Phase 2 (Arm 4): Overall Hematological Response Rate (OHR) ^[23]

End point description

Confirmed Overall Hematological Response (OHR) Rate was defined as the proportion of participants with either a confirmed complete or a partial hematological response at any time.

End point type

Secondary

End point timeframe

Through Phase II completion, an average of 6 years

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: Endpoint only applicable to Phase II (Arm 4)

End point values	Ph2 Arm4 ET – Monotherapy
Number of subjects analysed	21
Units: Percentage of Participants
number (confidence interval 95%)	66.7 (43.0 to 85.4)

No statistical analyses for this end point

Secondary: Phase 2 (Arm 4): Duration of Overall Hematological Response Rate (OHR)

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End point title

Phase 2 (Arm 4): Duration of Overall Hematological Response Rate (OHR) ^[24]

End point description

Duration of Overall Hematological Response (OHR) Rate was defined as the time from when the overall hematological response was first met until the time at which the overall hematological response was lost, i.e., the criteria for an overall hematological response (CHR or PHR) were not observed or death occurred, whichever came first.

End point type

Secondary

End point timeframe

Through Phase II completion, an average of 6 years

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: Endpoint only applicable to Phase II (Arm 4)

End point values	Ph2 Arm4 ET – Monotherapy
Number of subjects analysed	21
Units: Weeks
median (confidence interval 95%)	21.1 (9.1 to 33.1)

No statistical analyses for this end point

Secondary: Phase 2 (Arm 4): Rate of hemorrhagic and thromboembolic (TE) events

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End point title

Phase 2 (Arm 4): Rate of hemorrhagic and thromboembolic (TE) events ^[25]

End point description

Rate of hemorrhagic and thromboembolic (TE) events was defined as the proportion of participants with hemorrhagic or thromboembolic events throughout the study.

End point type

Secondary

End point timeframe

Through Phase II completion, an average of 6 years

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: Endpoint only applicable to Phase II (Arm 4)

End point values	Ph2 Arm4 ET – Monotherapy
Number of subjects analysed	21
Units: Percentage of Participants
number (confidence interval 95%)	61.9 (38.4 to 81.9)

No statistical analyses for this end point

Secondary: Phase 2 (All Arms): Maximum observed plasma concentration (Cmax) of pelabresib

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End point title

Phase 2 (All Arms): Maximum observed plasma concentration (Cmax) of pelabresib ^[26]

End point description

Pharmacokinetic (PK) parameters were calculated based on Pelabresib plasma concentrations and actual sampling time points. Cmax was listed and summarized using descriptive statistics.

End point type

Secondary

End point timeframe

Cycle 1 Day 14 (30 minutes, 1 hour, 2 hours, 4 hours, 6 hours, and 8 hours post-dose). 1 cycle = 21 days.

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: Endpoint only applicable to Phase II (All Arms)

End point values	Ph2 Arm1 MF w/ prior JAKi – Cohort 1A	Ph2 Arm1 MF w/ prior JAKi – Cohort 1B	Ph2 Arm2 MF JAKi combo – Cohort 2A	Ph2 Arm2 MF JAKi combo – Cohort 2B	Ph2 Arm3 MF JAKi-naïve – Combo Tx	Ph2 Arm4 ET – Monotherapy
Number of subjects analysed	32	39	38	16	64	14
Units: ng/mL
geometric mean (geometric coefficient of variation)	1280 ( 29.1 )	1350 ( 37.0 )	1210 ( 40.0 )	1190 ( 29.0 )	1070 ( 26.3 )	2130 ( 24.7 )

No statistical analyses for this end point

Secondary: Phase 2 (All Arms): Time to reach maximum concentration (Tmax) of pelabresib

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End point title

Phase 2 (All Arms): Time to reach maximum concentration (Tmax) of pelabresib ^[27]

End point description

Pharmacokinetic (PK) parameters were calculated based on Pelabresib plasma concentrations and actual sampling time points. Tmax was listed and summarized using descriptive statistics.

End point type

Secondary

End point timeframe

Cycle 1 Day 14 (30 minutes, 1 hour, 2 hours, 4 hours, 6 hours, and 8 hours post-dose). 1 cycle = 21 days.

Notes
[27] - 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 only applicable to Phase II (All Arms)

End point values	Ph2 Arm1 MF w/ prior JAKi – Cohort 1A	Ph2 Arm1 MF w/ prior JAKi – Cohort 1B	Ph2 Arm2 MF JAKi combo – Cohort 2A	Ph2 Arm2 MF JAKi combo – Cohort 2B	Ph2 Arm3 MF JAKi-naïve – Combo Tx	Ph2 Arm4 ET – Monotherapy
Number of subjects analysed	32	39	38	16	64	14
Units: Hour
median (full range (min-max))	1.94 (0.85 to 4.02)	1.58 (0.83 to 3.63)	1.90 (0.50 to 4.00)	1.81 (0.92 to 3.13)	1.71 (0.50 to 3.87)	2.08 (1.07 to 6.00)

No statistical analyses for this end point

Secondary: Phase 2 (All Arms): Predose (trough) concentration at the end of a dosing interval (Ctrough) of pelabresib

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End point title

Phase 2 (All Arms): Predose (trough) concentration at the end of a dosing interval (Ctrough) of pelabresib ^[28]

End point description

Pharmacokinetic (PK) parameters were calculated based on Pelabresib plasma concentrations and actual sampling time points. Ctrough was listed and summarized using descriptive statistics.

End point type

Secondary

End point timeframe

Cycle 1 Day 14 (30 minutes, 1 hour, 2 hours, 4 hours, 6 hours, and 8 hours post-dose). 1 cycle = 21 days.

Notes
[28] - 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 only applicable to Phase II (All Arms)

End point values	Ph2 Arm1 MF w/ prior JAKi – Cohort 1A	Ph2 Arm1 MF w/ prior JAKi – Cohort 1B	Ph2 Arm2 MF JAKi combo – Cohort 2A	Ph2 Arm2 MF JAKi combo – Cohort 2B	Ph2 Arm3 MF JAKi-naïve – Combo Tx	Ph2 Arm4 ET – Monotherapy
Number of subjects analysed	31	37	36	16	63	12
Units: ng/mL
geometric mean (geometric coefficient of variation)	120 ( 489.0 )	201 ( 107.0 )	244 ( 151.0 )	162 ( 84.0 )	240 ( 79.1 )	174 ( 112.0 )

No statistical analyses for this end point

Secondary: Phase 2 (All Arms): Area under the concentration–time curve from time zero to the last observed concentration (AUClast) of pelabresib

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End point title

Phase 2 (All Arms): Area under the concentration–time curve from time zero to the last observed concentration (AUClast) of pelabresib ^[29]

End point description

Pharmacokinetic (PK) parameters were calculated based on Pelabresib plasma concentrations and actual sampling time points. AUClast was listed and summarized using descriptive statistics.

End point type

Secondary

End point timeframe

Cycle 1 Day 14 (30 minutes, 1 hour, 2 hours, 4 hours, 6 hours, and 8 hours post-dose). 1 cycle = 21 days.

Notes
[29] - 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 only applicable to Phase II (All Arms)

End point values	Ph2 Arm1 MF w/ prior JAKi – Cohort 1A	Ph2 Arm1 MF w/ prior JAKi – Cohort 1B	Ph2 Arm2 MF JAKi combo – Cohort 2A	Ph2 Arm2 MF JAKi combo – Cohort 2B	Ph2 Arm3 MF JAKi-naïve – Combo Tx	Ph2 Arm4 ET – Monotherapy
Number of subjects analysed	32	39	38	16	64	14
Units: h*ng/mL
geometric mean (geometric coefficient of variation)	5660 ( 36.7 )	5610 ( 35.5 )	5190 ( 40.9 )	4760 ( 26.7 )	4380 ( 26.8 )	9590 ( 28.7 )

No statistical analyses for this end point

Secondary: Phase 2 (All Arms): Area under the concentration–time curve from time zero to 8 hours post-dose at steady state (AUC0-8,ss) of pelabresib

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End point title

Phase 2 (All Arms): Area under the concentration–time curve from time zero to 8 hours post-dose at steady state (AUC0-8,ss) of pelabresib ^[30]

End point description

Pharmacokinetic (PK) parameters were calculated based on Pelabresib plasma concentrations and actual sampling time points. AUC0-8,ss was listed and summarized using descriptive statistics.

End point type

Secondary

End point timeframe

Cycle 1 Day 14 (30 minutes, 1 hour, 2 hours, 4 hours, 6 hours, and 8 hours post-dose). 1 cycle = 21 days.

Notes
[30] - 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 only applicable to Phase II (All Arms)

End point values	Ph2 Arm1 MF w/ prior JAKi – Cohort 1A	Ph2 Arm1 MF w/ prior JAKi – Cohort 1B	Ph2 Arm2 MF JAKi combo – Cohort 2A	Ph2 Arm2 MF JAKi combo – Cohort 2B	Ph2 Arm3 MF JAKi-naïve – Combo Tx	Ph2 Arm4 ET – Monotherapy
Number of subjects analysed	24	31	34	14	57	10
Units: h*ng/mL
geometric mean (geometric coefficient of variation)	6200 ( 35.3 )	6470 ( 31.7 )	5320 ( 38.1 )	4930 ( 28.8 )	4540 ( 25.3 )	10800 ( 29.0 )

No statistical analyses for this end point

Secondary: Phase 2 (All Arms): Time of Last Measurable Concentration (Tlast) of pelabresib

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End point title

Phase 2 (All Arms): Time of Last Measurable Concentration (Tlast) of pelabresib ^[31]

End point description

Pharmacokinetic (PK) parameters were calculated based on Pelabresib plasma concentrations and actual sampling time points. Tlast was listed and summarized using descriptive statistics.

End point type

Secondary

End point timeframe

Cycle 1 Day 14 (30 minutes, 1 hour, 2 hours, 4 hours, 6 hours, and 8 hours post-dose). 1 cycle = 21 days.

Notes
[31] - 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 only applicable to Phase II (All Arms)

End point values	Ph2 Arm1 MF w/ prior JAKi – Cohort 1A	Ph2 Arm1 MF w/ prior JAKi – Cohort 1B	Ph2 Arm2 MF JAKi combo – Cohort 2A	Ph2 Arm2 MF JAKi combo – Cohort 2B	Ph2 Arm3 MF JAKi-naïve – Combo Tx	Ph2 Arm4 ET – Monotherapy
Number of subjects analysed	32	39	38	16	64	14
Units: Hour
median (full range (min-max))	7.08 (4.50 to 9.00)	7.07 (2.58 to 8.08)	7.19 (6.10 to 8.05)	7.12 (7.00 to 8.17)	7.08 (5.07 to 8.58)	7.08 (5.88 to 10.08)

No statistical analyses for this end point

Secondary: Phase 2 (Arm 2 - Cohort 2A): Maximum observed plasma concentration (Cmax) of ruxolitinib

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End point title

Phase 2 (Arm 2 - Cohort 2A): Maximum observed plasma concentration (Cmax) of ruxolitinib ^[32]

End point description

Pharmacokinetic (PK) parameters were calculated based on ruxolitinib plasma concentrations and actual sampling time points. Cmax was listed and summarized using descriptive statistics.

End point type

Secondary

End point timeframe

Cycle 1 Day 14 (30 minutes, 1 hour, 2 hours, 4 hours, 6 hours, and 8 hours post-dose). 1 cycle = 21 days.

Notes
[32] - 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 only applicable to Phase II (Arm 2 - Cohort 2A)

End point values	Ph2 Arm2 MF JAKi combo – Cohort 2A
Number of subjects analysed	8
Units: ng/mL
geometric mean (geometric coefficient of variation)
Cohort 2A, 5 mg	65.9 ( 56.5 )
Cohort 2A, 7.5 mg	142.0 ( 31.0 )
Cohort 2A, 10 mg	108.0 ( 29.3 )
Cohort 2A, 15 mg	310.0 ( 88.9 )
Cohort 2A, 20 mg	325.0 ( 37.7 )

No statistical analyses for this end point

Secondary: Phase 2 (Arm 2 - Cohort 2A): Time to reach maximum concentration (Tmax) of ruxolitinib

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End point title

Phase 2 (Arm 2 - Cohort 2A): Time to reach maximum concentration (Tmax) of ruxolitinib ^[33]

End point description

Pharmacokinetic (PK) parameters were calculated based on ruxolitinib plasma concentrations and actual sampling time points. Tmax was listed and summarized using descriptive statistics.

End point type

Secondary

End point timeframe

Cycle 1 Day 14 (30 minutes, 1 hour, 2 hours, 4 hours, 6 hours, and 8 hours post-dose). 1 cycle = 21 days.

Notes
[33] - 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 only applicable to Phase II (Arm 2 - Cohort 2A)

End point values	Ph2 Arm2 MF JAKi combo – Cohort 2A
Number of subjects analysed	8
Units: Hour
median (full range (min-max))
Cohort 2A, 5 mg	0.92 (0.50 to 2.00)
Cohort 2A, 7.5 mg	1.00 (0.50 to 2.02)
Cohort 2A, 10 mg	0.76 (0.50 to 1.50)
Cohort 2A, 15 mg	1.55 (0.67 to 3.50)
Cohort 2A, 20 mg	0.53 (0.33 to 1.58)

No statistical analyses for this end point

Secondary: Phase 2 (Arm 2 - Cohort 2A): Predose (trough) concentration at the end of a dosing interval (Ctrough) of ruxolitinib

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End point title

Phase 2 (Arm 2 - Cohort 2A): Predose (trough) concentration at the end of a dosing interval (Ctrough) of ruxolitinib ^[34]

End point description

Pharmacokinetic (PK) parameters were calculated based on ruxolitinib plasma concentrations and actual sampling time points. Ctrough was listed and summarized using descriptive statistics.

End point type

Secondary

End point timeframe

Cycle 1 Day 14 (30 minutes, 1 hour, 2 hours, 4 hours, 6 hours, and 8 hours post-dose). 1 cycle = 21 days.

Notes
[34] - 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 only applicable to Phase II (Arm 2 - Cohort 2A)

End point values	Ph2 Arm2 MF JAKi combo – Cohort 2A
Number of subjects analysed	8
Units: ng/mL
geometric mean (geometric coefficient of variation)
Cohort 2A, 5 mg	999 ( 999 )
Cohort 2A, 7.5 mg	14.7 ( 74.9 )
Cohort 2A, 10 mg	13.4 ( 81.6 )
Cohort 2A, 15 mg	74.6 ( 94.7 )
Cohort 2A, 20 mg	19.8 ( 54.2 )

No statistical analyses for this end point

Secondary: Phase 2 (Arm 2 - Cohort 2A): Area under the concentration–time curve from time zero to the last observed concentration (AUClast) of ruxolitinib

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End point title

Phase 2 (Arm 2 - Cohort 2A): Area under the concentration–time curve from time zero to the last observed concentration (AUClast) of ruxolitinib ^[35]

End point description

Pharmacokinetic (PK) parameters were calculated based on ruxolitinib plasma concentrations and actual sampling time points. AUClast was listed and summarized using descriptive statistics.

End point type

Secondary

End point timeframe

Cycle 1 Day 14 (30 minutes, 1 hour, 2 hours, 4 hours, 6 hours, and 8 hours post-dose). 1 cycle = 21 days.

Notes
[35] - 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 only applicable to Phase II (Arm 2 - Cohort 2A)

End point values	Ph2 Arm2 MF JAKi combo – Cohort 2A
Number of subjects analysed	8
Units: h*ng/mL
geometric mean (geometric coefficient of variation)
Cohort 2A, 5 mg	230 ( 63.3 )
Cohort 2A, 7.5 mg	390 ( 34.0 )
Cohort 2A, 10 mg	347 ( 44.7 )
Cohort 2A, 15 mg	1240 ( 64.7 )
Cohort 2A, 20 mg	829 ( 42.3 )

No statistical analyses for this end point

Secondary: Phase 2 (Arm 2 - Cohort 2A): Area under the concentration–time curve from time zero to 8 hours post-dose at steady state (AUC0-8,ss) of ruxolitinib

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End point title

Phase 2 (Arm 2 - Cohort 2A): Area under the concentration–time curve from time zero to 8 hours post-dose at steady state (AUC0-8,ss) of ruxolitinib ^[36]

End point description

Pharmacokinetic (PK) parameters were calculated based on ruxolitinib plasma concentrations and actual sampling time points. AUC0-8,ss was listed and summarized using descriptive statistics.

End point type

Secondary

End point timeframe

Cycle 1 Day 14 (30 minutes, 1 hour, 2 hours, 4 hours, 6 hours, and 8 hours post-dose). 1 cycle = 21 days.

Notes
[36] - 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 only applicable to Phase 2 (Arm 2 - Cohort 2A)

End point values	Ph2 Arm2 MF JAKi combo – Cohort 2A
Number of subjects analysed	7
Units: h*ng/mL
geometric mean (geometric coefficient of variation)
Cohort 2A, 5 mg	239 ( 64.5 )
Cohort 2A, 7.5 mg	369 ( 35.9 )
Cohort 2A, 10 mg	375 ( 47.2 )
Cohort 2A, 15 mg	999 ( 999 )
Cohort 2A, 20 mg	887 ( 42.3 )

No statistical analyses for this end point

Secondary: Phase 2 (Arm 2 - Cohort 2B): Maximum observed plasma concentration (Cmax) of ruxolitinib

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End point title

Phase 2 (Arm 2 - Cohort 2B): Maximum observed plasma concentration (Cmax) of ruxolitinib ^[37]

End point description

Pharmacokinetic (PK) parameters were calculated based on ruxolitinib plasma concentrations and actual sampling time points. Cmax was listed and summarized using descriptive statistics.

End point type

Secondary

End point timeframe

Cycle 1 Day 14 (30 minutes, 1 hour, 2 hours, 4 hours, 6 hours, and 8 hours post-dose). 1 cycle = 21 days.

Notes
[37] - 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 only applicable to Phase 2 (Arm 2 - Cohort 2B)

End point values	Ph2 Arm2 MF JAKi combo – Cohort 2B
Number of subjects analysed	3
Units: ng/mL
geometric mean (geometric coefficient of variation)
Cohort 2B, 5 mg	69.5 ( 27.8 )
Cohort 2B, 15 mg	999 ( 999 )
Cohort 2B, 20 mg	999 ( 999 )
Cohort 2B, 25 mg	999 ( 999 )

No statistical analyses for this end point

Secondary: Phase 2 (Arm 2 - Cohort 2B): Time to reach maximum concentration (Tmax) of ruxolitinib

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End point title

Phase 2 (Arm 2 - Cohort 2B): Time to reach maximum concentration (Tmax) of ruxolitinib ^[38]

End point description

Pharmacokinetic (PK) parameters were calculated based on ruxolitinib plasma concentrations and actual sampling time points. Tmax was listed and summarized using descriptive statistics.

End point type

Secondary

End point timeframe

Cycle 1 Day 14 (30 minutes, 1 hour, 2 hours, 4 hours, 6 hours, and 8 hours post-dose). 1 cycle = 21 days.

Notes
[38] - 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 only applicable to Phase 2 (Arm 2 - Cohort 2B)

End point values	Ph2 Arm2 MF JAKi combo – Cohort 2B
Number of subjects analysed	3
Units: Hour
median (full range (min-max))
Cohort 2B, 5 mg	1.57 (0.47 to 1.60)
Cohort 2B, 15 mg	0.48 (0 to 999)
Cohort 2B, 20 mg	0.53 (0 to 999)
Cohort 2B, 25 mg	0.40 (0 to 999)

No statistical analyses for this end point

Secondary: Phase 2 (Arm 2 - Cohort 2B): Predose (trough) concentration at the end of a dosing interval (Ctrough) of ruxolitinib

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End point title

Phase 2 (Arm 2 - Cohort 2B): Predose (trough) concentration at the end of a dosing interval (Ctrough) of ruxolitinib ^[39]

End point description

Pharmacokinetic (PK) parameters were calculated based on ruxolitinib plasma concentrations and actual sampling time points. Ctrough was listed and summarized using descriptive statistics.

End point type

Secondary

End point timeframe

Cycle 1 Day 14 (30 minutes, 1 hour, 2 hours, 4 hours, 6 hours, and 8 hours post-dose). 1 cycle = 21 days.

Notes
[39] - 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 only applicable to Phase 2 (Arm 2 - Cohort 2B)

End point values	Ph2 Arm2 MF JAKi combo – Cohort 2B
Number of subjects analysed	3
Units: ng/mL
geometric mean (geometric coefficient of variation)
Cohort 2B, 5 mg	8.49 ( 28.4 )
Cohort 2B, 15 mg	999 ( 999 )
Cohort 2B, 20 mg	999 ( 999 )
Cohort 2B, 25 mg	999 ( 999 )

No statistical analyses for this end point

Secondary: Phase 2 (Arm 2 - Cohort 2B): Area under the concentration–time curve from time zero to the last observed concentration (AUClast) of ruxolitinib

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End point title

Phase 2 (Arm 2 - Cohort 2B): Area under the concentration–time curve from time zero to the last observed concentration (AUClast) of ruxolitinib ^[40]

End point description

Pharmacokinetic (PK) parameters were calculated based on ruxolitinib plasma concentrations and actual sampling time points. AUClast was listed and summarized using descriptive statistics.

End point type

Secondary

End point timeframe

Cycle 1 Day 14 (30 minutes, 1 hour, 2 hours, 4 hours, 6 hours, and 8 hours post-dose). 1 cycle = 21 days.

Notes
[40] - 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 only applicable to Phase 2 (Arm 2 - Cohort 2B)

End point values	Ph2 Arm2 MF JAKi combo – Cohort 2B
Number of subjects analysed	3
Units: h*ng/mL
geometric mean (geometric coefficient of variation)
Cohort 2B, 5 mg	207 ( 3.08 )
Cohort 2B, 15 mg	999 ( 999 )
Cohort 2B, 20 mg	999 ( 999 )
Cohort 2B, 25 mg	999 ( 999 )

No statistical analyses for this end point

Secondary: Phase 2 (Arm 2 - Cohort 2B): Area under the concentration–time curve from time zero to 8 hours post-dose at steady state (AUC0-8,ss) of ruxolitinib

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End point title

Phase 2 (Arm 2 - Cohort 2B): Area under the concentration–time curve from time zero to 8 hours post-dose at steady state (AUC0-8,ss) of ruxolitinib ^[41]

End point description

Pharmacokinetic (PK) parameters were calculated based on ruxolitinib plasma concentrations and actual sampling time points. AUC0-8,ss was listed and summarized using descriptive statistics.

End point type

Secondary

End point timeframe

Cycle 1 Day 14 (30 minutes, 1 hour, 2 hours, 4 hours, 6 hours, and 8 hours post-dose). 1 cycle = 21 days.

Notes
[41] - 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 only applicable to Phase 2 (Arm 2 - Cohort 2B)

End point values	Ph2 Arm2 MF JAKi combo – Cohort 2B
Number of subjects analysed	3
Units: ng/mL
geometric mean (geometric coefficient of variation)
Cohort 2B, 5 mg	214 ( 3.67 )
Cohort 2B, 15 mg	999 ( 999 )
Cohort 2B, 20 mg	999 ( 999 )
Cohort 2B, 25 mg	999 ( 999 )

No statistical analyses for this end point

Secondary: Phase 2 (Arm 3): Maximum observed plasma concentration (Cmax) of ruxolitinib

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End point title

Phase 2 (Arm 3): Maximum observed plasma concentration (Cmax) of ruxolitinib ^[42]

End point description

Pharmacokinetic (PK) parameters were calculated based on ruxolitinib plasma concentrations and actual sampling time points. Cmax was listed and summarized using descriptive statistics.

End point type

Secondary

End point timeframe

Cycle 1 Day 14 (30 minutes, 1 hour, 2 hours, 4 hours, 6 hours, and 8 hours post-dose). 1 cycle = 21 days.

Notes
[42] - 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 only applicable to Phase II (Arm 3)

End point values	Ph2 Arm3 MF JAKi-naïve – Combo Tx
Number of subjects analysed	22
Units: ng/mL
geometric mean (geometric coefficient of variation)
Cohort 3, 5 mg	999 ( 999 )
Cohort 3, 10 mg	190 ( 28.6 )
Cohort 3, 15 mg	213 ( 34.7 )
Cohort 3, 20 mg	999 ( 999 )

No statistical analyses for this end point

Secondary: Phase 2 (Arm 3): Time to reach maximum concentration (Tmax) of ruxolitinib

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End point title

Phase 2 (Arm 3): Time to reach maximum concentration (Tmax) of ruxolitinib ^[43]

End point description

Pharmacokinetic (PK) parameters were calculated based on ruxolitinib plasma concentrations and actual sampling time points. Tmax was listed and summarized using descriptive statistics.

End point type

Secondary

End point timeframe

Cycle 1 Day 14 (30 minutes, 1 hour, 2 hours, 4 hours, 6 hours, and 8 hours post-dose). 1 cycle = 21 days.

Notes
[43] - 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 only applicable to Phase II (Arm 3)

End point values	Ph2 Arm3 MF JAKi-naïve – Combo Tx
Number of subjects analysed	22
Units: Hour
median (full range (min-max))
Cohort 3, 5 mg	0.72 (0 to 999)
Cohort 3, 10 mg	0.62 (0.28 to 7.00)
Cohort 3, 15 mg	0.95 (0.22 to 3.87)
Cohort 3, 20 mg	1.25 (0 to 999)

No statistical analyses for this end point

Secondary: Phase 2 (Arm 3): Predose (trough) concentration at the end of a dosing interval (Ctrough) of ruxolitinib

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End point title

Phase 2 (Arm 3): Predose (trough) concentration at the end of a dosing interval (Ctrough) of ruxolitinib ^[44]

End point description

Pharmacokinetic (PK) parameters were calculated based on ruxolitinib plasma concentrations and actual sampling time points. Ctrough was listed and summarized using descriptive statistics.

End point type

Secondary

End point timeframe

Cycle 1 Day 14 (30 minutes, 1 hour, 2 hours, 4 hours, 6 hours, and 8 hours post-dose). 1 cycle = 21 days.

Notes
[44] - 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 only applicable to Phase II (Arm 3)

End point values	Ph2 Arm3 MF JAKi-naïve – Combo Tx
Number of subjects analysed	21
Units: ng/mL
geometric mean (geometric coefficient of variation)
Cohort 3, 5 mg	999 ( 999 )
Cohort 3, 10 mg	25.3 ( 99.2 )
Cohort 3, 15 mg	31.4 ( 58.1 )
Cohort 3, 20 mg	999 ( 999 )

No statistical analyses for this end point

Secondary: Phase 2 (Arm 3): Area under the concentration–time curve from time zero to the last observed concentration (AUClast) of ruxolitinib

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End point title

Phase 2 (Arm 3): Area under the concentration–time curve from time zero to the last observed concentration (AUClast) of ruxolitinib ^[45]

End point description

Pharmacokinetic (PK) parameters were calculated based on ruxolitinib plasma concentrations and actual sampling time points. AUClast was listed and summarized using descriptive statistics.

End point type

Secondary

End point timeframe

Cycle 1 Day 14 (30 minutes, 1 hour, 2 hours, 4 hours, 6 hours, and 8 hours post-dose). 1 cycle = 21 days.

Notes
[45] - 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 only applicable to Phase II (Arm 3)

End point values	Ph2 Arm3 MF JAKi-naïve – Combo Tx
Number of subjects analysed	22
Units: h*ng/mL
geometric mean (geometric coefficient of variation)
Cohort 3, 5 mg	999 ( 999 )
Cohort 3, 10 mg	519 ( 54.8 )
Cohort 3, 15 mg	677 ( 33.9 )
Cohort 3, 20 mg	999 ( 999 )

No statistical analyses for this end point

Secondary: Phase 2 (Arm 3): Area under the concentration–time curve from time zero to 8 hours post-dose at steady state (AUC0-8,ss) of ruxolitinib

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End point title

Phase 2 (Arm 3): Area under the concentration–time curve from time zero to 8 hours post-dose at steady state (AUC0-8,ss) of ruxolitinib ^[46]

End point description

Pharmacokinetic (PK) parameters were calculated based on ruxolitinib plasma concentrations and actual sampling time points. AUC0-8,ss was listed and summarized using descriptive statistics.

End point type

Secondary

End point timeframe

Cycle 1 Day 14 (30 minutes, 1 hour, 2 hours, 4 hours, 6 hours, and 8 hours post-dose). 1 cycle = 21 days.

Notes
[46] - 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 only applicable to Phase II (Arm 3)

End point values	Ph2 Arm3 MF JAKi-naïve – Combo Tx
Number of subjects analysed	19
Units: h*ng/mL
geometric mean (geometric coefficient of variation)
Cohort 3, 5 mg	999 ( 999 )
Cohort 3, 10 mg	587 ( 45.5 )
Cohort 3, 15 mg	696 ( 34.7 )
Cohort 3, 20 mg	999 ( 999 )

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

Adverse Events (AEs) were collected from first dose of study medication up to 30 days after last dose of pelabresib (CPI-0610) (end of study), assessed up to approximately 10 years.

Adverse event reporting additional description

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

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

26.0

Reporting group title

Phase 1 120 mg capsule PO daily

Reporting group description

Phase 1 120 mg capsule PO daily

Reporting group title

Phase 1 24 mg capsule PO daily

Reporting group description

Phase 1 24 mg capsule PO daily

Reporting group title

Phase 1 48 mg capsule PO daily

Reporting group description

Phase 1 48 mg capsule PO daily

Reporting group title

Phase 1 400 mg capsule PO daily

Reporting group description

Phase 1 400 mg capsule PO daily

Reporting group title

Phase 1 225 mg tablet PO daily

Reporting group description

Phase 1 225 mg tablet PO daily

Reporting group title

Phase 1 300 mg capsule PO daily

Reporting group description

Phase 1 300 mg capsule PO daily

Reporting group title

Phase 1 230 mg capsule PO daily

Reporting group description

Phase 1 230 mg capsule PO daily

Reporting group title

Phase 1 170 mg capsule PO daily

Reporting group description

Phase 1 170 mg capsule PO daily

Reporting group title

Phase 1 275 mg tablet PO daily

Reporting group description

Phase 1 275 mg tablet PO daily

Reporting group title

Phase 1 overall

Reporting group description

Phase 1 overall

Reporting group title

Phase 2 Arm 1 1A

Reporting group description

Phase 2 Arm 1 1A

Reporting group title

Phase 2 Arm 1 1B

Reporting group description

Phase 2 Arm 1 1B

Reporting group title

Phase 2 Arm 2 2A

Reporting group description

Phase 2 Arm 2 2A

Reporting group title

Phase 2 Arm 2 2B

Reporting group description

Phase 2 Arm 2 2B

Reporting group title

Phase 2 Arm 3

Reporting group description

Phase 2 Arm 3

Reporting group title

Phase 2 Arm 4

Reporting group description

Phase 2 Arm 4

Reporting group title

Phase 2 Overall

Reporting group description

Phase 2 Overall

Phase 1 120 mg capsule PO daily

Phase 1 24 mg capsule PO daily

Phase 1 48 mg capsule PO daily

Phase 1 400 mg capsule PO daily

Phase 1 225 mg tablet PO daily

Phase 1 300 mg capsule PO daily

Phase 1 230 mg capsule PO daily

Phase 1 170 mg capsule PO daily

Phase 1 275 mg tablet PO daily

Phase 1 overall

Phase 2 Arm 1 1A

Phase 2 Arm 1 1B

Phase 2 Arm 2 2A

Phase 2 Arm 2 2B

Phase 2 Arm 3

Phase 2 Arm 4

Phase 2 Overall

Total subjects affected by serious adverse events

subjects affected / exposed

3 / 5 (60.00%)

1 / 3 (33.33%)

4 / 5 (80.00%)

6 / 7 (85.71%)

6 / 8 (75.00%)

4 / 4 (100.00%)

2 / 3 (66.67%)

1 / 3 (33.33%)

6 / 6 (100.00%)

33 / 44 (75.00%)

18 / 48 (37.50%)

23 / 52 (44.23%)

29 / 59 (49.15%)

18 / 28 (64.29%)

40 / 84 (47.62%)

5 / 21 (23.81%)

133 / 292 (45.55%)

number of deaths (all causes)

number of deaths resulting from adverse events

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

Basal cell carcinoma

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 5 (0.00%)

0 / 7 (0.00%)

0 / 8 (0.00%)

0 / 4 (0.00%)

0 / 3 (0.00%)

0 / 6 (0.00%)

0 / 44 (0.00%)

0 / 48 (0.00%)

0 / 52 (0.00%)

0 / 59 (0.00%)

1 / 28 (3.57%)

1 / 84 (1.19%)

0 / 21 (0.00%)

2 / 292 (0.68%)

occurrences causally related to treatment / all

0 / 0

0 / 3

0 / 1

0 / 0

0 / 4

deaths causally related to treatment / all

0 / 0

Acute myeloid leukaemia

subjects affected / exposed

1 / 5 (20.00%)

0 / 3 (0.00%)

1 / 5 (20.00%)

1 / 7 (14.29%)

1 / 8 (12.50%)

0 / 4 (0.00%)

1 / 3 (33.33%)

0 / 3 (0.00%)

0 / 6 (0.00%)

5 / 44 (11.36%)

0 / 48 (0.00%)

0 / 52 (0.00%)

0 / 59 (0.00%)

1 / 28 (3.57%)

0 / 84 (0.00%)

0 / 21 (0.00%)

1 / 292 (0.34%)

occurrences causally related to treatment / all

0 / 1

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

0 / 5

0 / 0

0 / 1

0 / 0

0 / 1

deaths causally related to treatment / all

0 / 1

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

0 / 4

0 / 0

0 / 1

0 / 0

0 / 1

Bowen's disease

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 5 (0.00%)

0 / 7 (0.00%)

0 / 8 (0.00%)

0 / 4 (0.00%)

0 / 3 (0.00%)

0 / 6 (0.00%)

0 / 44 (0.00%)

0 / 48 (0.00%)

0 / 52 (0.00%)

0 / 59 (0.00%)

1 / 28 (3.57%)

0 / 84 (0.00%)

0 / 21 (0.00%)

1 / 292 (0.34%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

deaths causally related to treatment / all

0 / 0

Colon cancer metastatic

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 5 (0.00%)

0 / 7 (0.00%)

0 / 8 (0.00%)

0 / 4 (0.00%)

0 / 3 (0.00%)

0 / 6 (0.00%)

0 / 44 (0.00%)

0 / 48 (0.00%)

0 / 52 (0.00%)

1 / 59 (1.69%)

0 / 28 (0.00%)

0 / 84 (0.00%)

0 / 21 (0.00%)

1 / 292 (0.34%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

1 / 1

deaths causally related to treatment / all

0 / 0

Breast cancer

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 5 (0.00%)

0 / 7 (0.00%)

0 / 8 (0.00%)

0 / 4 (0.00%)

0 / 3 (0.00%)

0 / 6 (0.00%)

0 / 44 (0.00%)

0 / 48 (0.00%)

0 / 52 (0.00%)

0 / 59 (0.00%)

0 / 28 (0.00%)

0 / 84 (0.00%)

1 / 21 (4.76%)

1 / 292 (0.34%)

occurrences causally related to treatment / all

0 / 0

0 / 1

deaths causally related to treatment / all

0 / 0

Glioblastoma

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 5 (0.00%)

0 / 7 (0.00%)

0 / 8 (0.00%)

0 / 4 (0.00%)

0 / 3 (0.00%)

0 / 6 (0.00%)

0 / 44 (0.00%)

0 / 48 (0.00%)

0 / 52 (0.00%)

1 / 59 (1.69%)

0 / 28 (0.00%)

0 / 84 (0.00%)

0 / 21 (0.00%)

1 / 292 (0.34%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

deaths causally related to treatment / all

0 / 0

Haematopoietic neoplasm

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 5 (0.00%)

0 / 7 (0.00%)

0 / 8 (0.00%)

0 / 4 (0.00%)

0 / 3 (0.00%)

0 / 6 (0.00%)

0 / 44 (0.00%)

0 / 48 (0.00%)

1 / 52 (1.92%)

0 / 59 (0.00%)

0 / 28 (0.00%)

0 / 84 (0.00%)

0 / 21 (0.00%)

1 / 292 (0.34%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

deaths causally related to treatment / all

0 / 0

Lung neoplasm malignant

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 5 (0.00%)

0 / 7 (0.00%)

0 / 8 (0.00%)

0 / 4 (0.00%)

0 / 3 (0.00%)

0 / 6 (0.00%)

0 / 44 (0.00%)

0 / 48 (0.00%)

0 / 52 (0.00%)

1 / 59 (1.69%)

0 / 28 (0.00%)

1 / 84 (1.19%)

0 / 21 (0.00%)

2 / 292 (0.68%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

0 / 2

deaths causally related to treatment / all

0 / 0

Invasive breast carcinoma

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 5 (0.00%)

0 / 7 (0.00%)

0 / 8 (0.00%)

0 / 4 (0.00%)

0 / 3 (0.00%)

0 / 6 (0.00%)

0 / 44 (0.00%)

0 / 48 (0.00%)

0 / 52 (0.00%)

0 / 59 (0.00%)

1 / 28 (3.57%)

0 / 84 (0.00%)

0 / 21 (0.00%)

1 / 292 (0.34%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

deaths causally related to treatment / all

0 / 0

Keratoacanthoma

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 5 (0.00%)

0 / 7 (0.00%)

0 / 8 (0.00%)

0 / 4 (0.00%)

0 / 3 (0.00%)

0 / 6 (0.00%)

0 / 44 (0.00%)

0 / 48 (0.00%)

0 / 52 (0.00%)

1 / 59 (1.69%)

0 / 28 (0.00%)

0 / 84 (0.00%)

0 / 21 (0.00%)

1 / 292 (0.34%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

deaths causally related to treatment / all

0 / 0

Malignant melanoma

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 5 (0.00%)

0 / 7 (0.00%)

0 / 8 (0.00%)

0 / 4 (0.00%)

0 / 3 (0.00%)

0 / 6 (0.00%)

0 / 44 (0.00%)

0 / 48 (0.00%)

0 / 52 (0.00%)

0 / 59 (0.00%)

0 / 28 (0.00%)

1 / 84 (1.19%)

0 / 21 (0.00%)

1 / 292 (0.34%)

occurrences causally related to treatment / all

0 / 0

1 / 2

0 / 0

1 / 2

deaths causally related to treatment / all

0 / 0

Metastatic squamous cell carcinoma

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 5 (0.00%)

0 / 7 (0.00%)

0 / 8 (0.00%)

0 / 4 (0.00%)

0 / 3 (0.00%)

0 / 6 (0.00%)

0 / 44 (0.00%)

0 / 48 (0.00%)

0 / 52 (0.00%)

1 / 59 (1.69%)

0 / 28 (0.00%)

0 / 84 (0.00%)

0 / 21 (0.00%)

1 / 292 (0.34%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

deaths causally related to treatment / all

0 / 0

Neuroendocrine carcinoma of the skin

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 5 (0.00%)

0 / 7 (0.00%)

0 / 8 (0.00%)

0 / 4 (0.00%)

0 / 3 (0.00%)

0 / 6 (0.00%)

0 / 44 (0.00%)

1 / 48 (2.08%)

0 / 52 (0.00%)

0 / 59 (0.00%)

0 / 28 (0.00%)

0 / 84 (0.00%)

0 / 21 (0.00%)

1 / 292 (0.34%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

deaths causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

Oropharyngeal squamous cell carcinoma

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 5 (0.00%)

0 / 7 (0.00%)

0 / 8 (0.00%)

0 / 4 (0.00%)

0 / 3 (0.00%)

0 / 6 (0.00%)

0 / 44 (0.00%)

0 / 48 (0.00%)

0 / 52 (0.00%)

1 / 59 (1.69%)

0 / 28 (0.00%)

0 / 84 (0.00%)

0 / 21 (0.00%)

1 / 292 (0.34%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

deaths causally related to treatment / all

0 / 0

Ovarian neoplasm

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 5 (0.00%)

0 / 7 (0.00%)

0 / 8 (0.00%)

0 / 4 (0.00%)

0 / 3 (0.00%)

0 / 6 (0.00%)

0 / 44 (0.00%)

1 / 48 (2.08%)

0 / 52 (0.00%)

0 / 59 (0.00%)

0 / 28 (0.00%)

0 / 84 (0.00%)

0 / 21 (0.00%)

1 / 292 (0.34%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

deaths causally related to treatment / all

0 / 0

Squamous cell carcinoma of head and neck

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 5 (0.00%)

0 / 7 (0.00%)

0 / 8 (0.00%)

0 / 4 (0.00%)

0 / 3 (0.00%)

0 / 6 (0.00%)

0 / 44 (0.00%)

0 / 48 (0.00%)

0 / 52 (0.00%)

0 / 59 (0.00%)

1 / 28 (3.57%)

1 / 84 (1.19%)

0 / 21 (0.00%)

2 / 292 (0.68%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 2

deaths causally related to treatment / all

0 / 0

Squamous cell carcinoma of skin

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 5 (0.00%)

0 / 7 (0.00%)

0 / 8 (0.00%)

0 / 4 (0.00%)

0 / 3 (0.00%)

0 / 6 (0.00%)

0 / 44 (0.00%)

1 / 48 (2.08%)

0 / 52 (0.00%)

0 / 59 (0.00%)

1 / 28 (3.57%)

1 / 84 (1.19%)

0 / 21 (0.00%)

3 / 292 (1.03%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

4 / 5

0 / 0

4 / 7

deaths causally related to treatment / all

0 / 0

Transformation to acute myeloid leukaemia

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 5 (0.00%)

0 / 7 (0.00%)

0 / 8 (0.00%)

0 / 4 (0.00%)

0 / 3 (0.00%)

0 / 6 (0.00%)

0 / 44 (0.00%)

0 / 48 (0.00%)

2 / 52 (3.85%)

0 / 59 (0.00%)

1 / 28 (3.57%)

6 / 84 (7.14%)

0 / 21 (0.00%)

9 / 292 (3.08%)

occurrences causally related to treatment / all

0 / 0

0 / 2

0 / 0

0 / 1

0 / 6

0 / 0

0 / 9

deaths causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

Vascular disorders

Aortic dissection

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 5 (0.00%)

0 / 7 (0.00%)

0 / 8 (0.00%)

0 / 4 (0.00%)

0 / 3 (0.00%)

0 / 6 (0.00%)

0 / 44 (0.00%)

0 / 48 (0.00%)

0 / 52 (0.00%)

0 / 59 (0.00%)

1 / 28 (3.57%)

0 / 84 (0.00%)

0 / 21 (0.00%)

1 / 292 (0.34%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

deaths causally related to treatment / all

0 / 0

Haematoma

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 5 (0.00%)

0 / 7 (0.00%)

0 / 8 (0.00%)

0 / 4 (0.00%)

0 / 3 (0.00%)

0 / 6 (0.00%)

0 / 44 (0.00%)

0 / 48 (0.00%)

1 / 52 (1.92%)

0 / 59 (0.00%)

0 / 28 (0.00%)

0 / 84 (0.00%)

0 / 21 (0.00%)

1 / 292 (0.34%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

deaths causally related to treatment / all

0 / 0

Hypertension

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 5 (0.00%)

0 / 7 (0.00%)

0 / 8 (0.00%)

0 / 4 (0.00%)

0 / 3 (0.00%)

1 / 6 (16.67%)

1 / 44 (2.27%)

0 / 48 (0.00%)

0 / 52 (0.00%)

0 / 59 (0.00%)

0 / 28 (0.00%)

0 / 84 (0.00%)

0 / 21 (0.00%)

0 / 292 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Hypotension

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

1 / 5 (20.00%)

0 / 7 (0.00%)

0 / 8 (0.00%)

0 / 4 (0.00%)

0 / 3 (0.00%)

1 / 6 (16.67%)

2 / 44 (4.55%)

0 / 48 (0.00%)

0 / 52 (0.00%)

0 / 59 (0.00%)

0 / 28 (0.00%)

0 / 84 (0.00%)

0 / 21 (0.00%)

0 / 292 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

0 / 2

0 / 0

deaths causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

Peripheral ischaemia

subjects affected / exposed

1 / 5 (20.00%)

0 / 3 (0.00%)

0 / 5 (0.00%)

0 / 7 (0.00%)

0 / 8 (0.00%)

0 / 4 (0.00%)

0 / 3 (0.00%)

0 / 6 (0.00%)

1 / 44 (2.27%)

0 / 48 (0.00%)

0 / 52 (0.00%)

2 / 59 (3.39%)

0 / 28 (0.00%)

1 / 84 (1.19%)

0 / 21 (0.00%)

3 / 292 (1.03%)

occurrences causally related to treatment / all

0 / 2

0 / 0

0 / 2

0 / 0

0 / 2

0 / 0

0 / 1

0 / 0

0 / 3

deaths causally related to treatment / all

0 / 0

General disorders and administration site conditions

Asthenia

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

1 / 5 (20.00%)

0 / 7 (0.00%)

0 / 8 (0.00%)

0 / 4 (0.00%)

0 / 3 (0.00%)

0 / 6 (0.00%)

1 / 44 (2.27%)

0 / 48 (0.00%)

0 / 52 (0.00%)

0 / 59 (0.00%)

0 / 28 (0.00%)

0 / 84 (0.00%)

0 / 21 (0.00%)

0 / 292 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Chest pain

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 5 (0.00%)

0 / 7 (0.00%)

0 / 8 (0.00%)

0 / 4 (0.00%)

0 / 3 (0.00%)

0 / 6 (0.00%)

0 / 44 (0.00%)

0 / 48 (0.00%)

0 / 52 (0.00%)

0 / 59 (0.00%)

0 / 28 (0.00%)

1 / 84 (1.19%)

0 / 21 (0.00%)

1 / 292 (0.34%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

deaths causally related to treatment / all

0 / 0

Chills

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 5 (0.00%)

0 / 7 (0.00%)

1 / 8 (12.50%)

0 / 4 (0.00%)

0 / 3 (0.00%)

0 / 6 (0.00%)

1 / 44 (2.27%)

0 / 48 (0.00%)

0 / 52 (0.00%)

0 / 59 (0.00%)

0 / 28 (0.00%)

0 / 84 (0.00%)

0 / 21 (0.00%)

0 / 292 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Disease progression

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 5 (0.00%)

1 / 7 (14.29%)

0 / 8 (0.00%)

0 / 4 (0.00%)

0 / 3 (0.00%)

0 / 6 (0.00%)

1 / 44 (2.27%)

0 / 48 (0.00%)

0 / 52 (0.00%)

0 / 59 (0.00%)

1 / 28 (3.57%)

0 / 84 (0.00%)

0 / 21 (0.00%)

1 / 292 (0.34%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

0 / 1

deaths causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

0 / 1

Drug withdrawal syndrome

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 5 (0.00%)

0 / 7 (0.00%)

0 / 8 (0.00%)

0 / 4 (0.00%)

0 / 3 (0.00%)

0 / 6 (0.00%)

0 / 44 (0.00%)

0 / 48 (0.00%)

0 / 52 (0.00%)

0 / 59 (0.00%)

0 / 28 (0.00%)

1 / 84 (1.19%)

0 / 21 (0.00%)

1 / 292 (0.34%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

deaths causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

Fatigue

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

2 / 5 (40.00%)

0 / 7 (0.00%)

0 / 8 (0.00%)

0 / 4 (0.00%)

1 / 3 (33.33%)

0 / 3 (0.00%)

1 / 6 (16.67%)

4 / 44 (9.09%)

0 / 48 (0.00%)

0 / 52 (0.00%)

0 / 59 (0.00%)

0 / 28 (0.00%)

0 / 84 (0.00%)

0 / 21 (0.00%)

0 / 292 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 2

0 / 0

0 / 2

0 / 0

0 / 1

0 / 5

0 / 0

deaths causally related to treatment / all

0 / 0

Malaise

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 5 (0.00%)

0 / 7 (0.00%)

0 / 8 (0.00%)

0 / 4 (0.00%)

0 / 3 (0.00%)

0 / 6 (0.00%)

0 / 44 (0.00%)

0 / 48 (0.00%)

1 / 52 (1.92%)

0 / 59 (0.00%)

0 / 28 (0.00%)

0 / 84 (0.00%)

0 / 21 (0.00%)

1 / 292 (0.34%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

deaths causally related to treatment / all

0 / 0

Multiple organ dysfunction syndrome

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 5 (0.00%)

0 / 7 (0.00%)

0 / 8 (0.00%)

0 / 4 (0.00%)

0 / 3 (0.00%)

0 / 6 (0.00%)

0 / 44 (0.00%)

0 / 48 (0.00%)

0 / 52 (0.00%)

0 / 59 (0.00%)

0 / 28 (0.00%)

2 / 84 (2.38%)

0 / 21 (0.00%)

2 / 292 (0.68%)

occurrences causally related to treatment / all

0 / 0

1 / 2

0 / 0

1 / 2

deaths causally related to treatment / all

0 / 0

1 / 2

0 / 0

1 / 2

Non-cardiac chest pain

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 5 (0.00%)

0 / 7 (0.00%)

1 / 8 (12.50%)

0 / 4 (0.00%)

0 / 3 (0.00%)

0 / 6 (0.00%)

1 / 44 (2.27%)

0 / 48 (0.00%)

0 / 52 (0.00%)

2 / 59 (3.39%)

0 / 28 (0.00%)

0 / 84 (0.00%)

0 / 21 (0.00%)

2 / 292 (0.68%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

0 / 2

0 / 0

0 / 2

deaths causally related to treatment / all

0 / 0

Pyrexia

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 5 (0.00%)

1 / 7 (14.29%)

0 / 8 (0.00%)

0 / 4 (0.00%)

0 / 3 (0.00%)

1 / 3 (33.33%)

1 / 6 (16.67%)

3 / 44 (6.82%)

1 / 48 (2.08%)

0 / 52 (0.00%)

1 / 59 (1.69%)

1 / 28 (3.57%)

3 / 84 (3.57%)

0 / 21 (0.00%)

6 / 292 (2.05%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

0 / 3

1 / 1

0 / 0

0 / 1

0 / 2

1 / 3

0 / 0

2 / 7

deaths causally related to treatment / all

0 / 0

Oedema

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 5 (0.00%)

0 / 7 (0.00%)

0 / 8 (0.00%)

0 / 4 (0.00%)

0 / 3 (0.00%)

0 / 6 (0.00%)

0 / 44 (0.00%)

0 / 48 (0.00%)

0 / 52 (0.00%)

0 / 59 (0.00%)

0 / 28 (0.00%)

1 / 84 (1.19%)

0 / 21 (0.00%)

1 / 292 (0.34%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

deaths causally related to treatment / all

0 / 0

Immune system disorders

Serum sickness

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 5 (0.00%)

0 / 7 (0.00%)

0 / 8 (0.00%)

0 / 4 (0.00%)

0 / 3 (0.00%)

1 / 6 (16.67%)

1 / 44 (2.27%)

0 / 48 (0.00%)

0 / 52 (0.00%)

0 / 59 (0.00%)

0 / 28 (0.00%)

0 / 84 (0.00%)

0 / 21 (0.00%)

0 / 292 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Respiratory, thoracic and mediastinal disorders

Acute respiratory failure

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 5 (0.00%)

0 / 7 (0.00%)

0 / 8 (0.00%)

0 / 4 (0.00%)

0 / 3 (0.00%)

0 / 6 (0.00%)

0 / 44 (0.00%)

0 / 48 (0.00%)

1 / 52 (1.92%)

0 / 59 (0.00%)

0 / 28 (0.00%)

0 / 84 (0.00%)

0 / 21 (0.00%)

1 / 292 (0.34%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

deaths causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

Bronchospasm

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 5 (0.00%)

0 / 7 (0.00%)

0 / 8 (0.00%)

0 / 4 (0.00%)

0 / 3 (0.00%)

0 / 6 (0.00%)

0 / 44 (0.00%)

1 / 48 (2.08%)

0 / 52 (0.00%)

0 / 59 (0.00%)

0 / 28 (0.00%)

0 / 84 (0.00%)

0 / 21 (0.00%)

1 / 292 (0.34%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

deaths causally related to treatment / all

0 / 0

Dyspnoea

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 5 (0.00%)

0 / 7 (0.00%)

0 / 8 (0.00%)

0 / 4 (0.00%)

0 / 3 (0.00%)

0 / 6 (0.00%)

0 / 44 (0.00%)

0 / 48 (0.00%)

2 / 52 (3.85%)

0 / 59 (0.00%)

1 / 28 (3.57%)

1 / 84 (1.19%)

1 / 21 (4.76%)

5 / 292 (1.71%)

occurrences causally related to treatment / all

0 / 0

0 / 3

0 / 0

1 / 1

0 / 1

1 / 1

2 / 6

deaths causally related to treatment / all

0 / 0

Epistaxis

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 5 (0.00%)

0 / 7 (0.00%)

0 / 8 (0.00%)

0 / 4 (0.00%)

0 / 3 (0.00%)

0 / 6 (0.00%)

0 / 44 (0.00%)

0 / 48 (0.00%)

0 / 52 (0.00%)

0 / 59 (0.00%)

1 / 28 (3.57%)

1 / 84 (1.19%)

0 / 21 (0.00%)

2 / 292 (0.68%)

occurrences causally related to treatment / all

0 / 0

0 / 1

1 / 2

0 / 0

1 / 3

deaths causally related to treatment / all

0 / 0

Organising pneumonia

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 5 (0.00%)

0 / 7 (0.00%)

0 / 8 (0.00%)

0 / 4 (0.00%)

0 / 3 (0.00%)

0 / 6 (0.00%)

0 / 44 (0.00%)

0 / 48 (0.00%)

0 / 52 (0.00%)

0 / 59 (0.00%)

1 / 28 (3.57%)

0 / 84 (0.00%)

0 / 21 (0.00%)

1 / 292 (0.34%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

deaths causally related to treatment / all

0 / 0

Pleuritic pain

subjects affected / exposed

0 / 5 (0.00%)

1 / 3 (33.33%)

0 / 5 (0.00%)

0 / 7 (0.00%)

0 / 8 (0.00%)

0 / 4 (0.00%)

0 / 3 (0.00%)

0 / 6 (0.00%)

1 / 44 (2.27%)

0 / 48 (0.00%)

0 / 52 (0.00%)

0 / 59 (0.00%)

0 / 28 (0.00%)

0 / 84 (0.00%)

0 / 21 (0.00%)

0 / 292 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Pneumonia aspiration

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 5 (0.00%)

0 / 7 (0.00%)

0 / 8 (0.00%)

0 / 4 (0.00%)

0 / 3 (0.00%)

1 / 6 (16.67%)

1 / 44 (2.27%)

0 / 48 (0.00%)

0 / 52 (0.00%)

0 / 59 (0.00%)

0 / 28 (0.00%)

0 / 84 (0.00%)

0 / 21 (0.00%)

0 / 292 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Pneumonitis

subjects affected / exposed

0 / 5 (0.00%)

1 / 3 (33.33%)

0 / 5 (0.00%)

0 / 7 (0.00%)

0 / 8 (0.00%)

0 / 4 (0.00%)

0 / 3 (0.00%)

0 / 6 (0.00%)

1 / 44 (2.27%)

0 / 48 (0.00%)

0 / 52 (0.00%)

0 / 59 (0.00%)

0 / 28 (0.00%)

0 / 84 (0.00%)

0 / 21 (0.00%)

0 / 292 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Pneumothorax

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 5 (0.00%)

0 / 7 (0.00%)

0 / 8 (0.00%)

0 / 4 (0.00%)

0 / 3 (0.00%)

0 / 6 (0.00%)

0 / 44 (0.00%)

0 / 48 (0.00%)

1 / 52 (1.92%)

0 / 59 (0.00%)

0 / 28 (0.00%)

0 / 84 (0.00%)

0 / 21 (0.00%)

1 / 292 (0.34%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

deaths causally related to treatment / all

0 / 0

Pulmonary embolism

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 5 (0.00%)

0 / 7 (0.00%)

0 / 8 (0.00%)

0 / 4 (0.00%)

0 / 3 (0.00%)

0 / 6 (0.00%)

0 / 44 (0.00%)

0 / 48 (0.00%)

0 / 52 (0.00%)

0 / 59 (0.00%)

0 / 28 (0.00%)

1 / 84 (1.19%)

1 / 21 (4.76%)

2 / 292 (0.68%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 2

deaths causally related to treatment / all

0 / 0

Pulmonary haemorrhage

subjects affected / exposed

1 / 5 (20.00%)

0 / 3 (0.00%)

0 / 5 (0.00%)

0 / 7 (0.00%)

0 / 8 (0.00%)

0 / 4 (0.00%)

0 / 3 (0.00%)

0 / 6 (0.00%)

1 / 44 (2.27%)

0 / 48 (0.00%)

0 / 52 (0.00%)

0 / 59 (0.00%)

0 / 28 (0.00%)

0 / 84 (0.00%)

0 / 21 (0.00%)

0 / 292 (0.00%)

occurrences causally related to treatment / all

0 / 1

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Pulmonary hypertension

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 5 (0.00%)

0 / 7 (0.00%)

0 / 8 (0.00%)

0 / 4 (0.00%)

0 / 3 (0.00%)

1 / 6 (16.67%)

1 / 44 (2.27%)

1 / 48 (2.08%)

0 / 52 (0.00%)

0 / 59 (0.00%)

0 / 28 (0.00%)

0 / 84 (0.00%)

0 / 21 (0.00%)

1 / 292 (0.34%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

deaths causally related to treatment / all

0 / 0

Pulmonary oedema

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 5 (0.00%)

0 / 7 (0.00%)

0 / 8 (0.00%)

0 / 4 (0.00%)

0 / 3 (0.00%)

0 / 6 (0.00%)

0 / 44 (0.00%)

1 / 48 (2.08%)

0 / 52 (0.00%)

1 / 59 (1.69%)

0 / 28 (0.00%)

0 / 84 (0.00%)

0 / 21 (0.00%)

2 / 292 (0.68%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

0 / 2

deaths causally related to treatment / all

0 / 0

Respiratory failure

subjects affected / exposed

1 / 5 (20.00%)

0 / 3 (0.00%)

0 / 5 (0.00%)

0 / 7 (0.00%)

0 / 8 (0.00%)

0 / 4 (0.00%)

0 / 3 (0.00%)

1 / 6 (16.67%)

2 / 44 (4.55%)

1 / 48 (2.08%)

0 / 52 (0.00%)

0 / 59 (0.00%)

2 / 28 (7.14%)

1 / 84 (1.19%)

0 / 21 (0.00%)

4 / 292 (1.37%)

occurrences causally related to treatment / all

0 / 1

0 / 0

0 / 1

0 / 2

0 / 1

0 / 0

0 / 2

0 / 1

0 / 0

0 / 4

deaths causally related to treatment / all

0 / 1

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

0 / 3

Psychiatric disorders

Confusional state

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 5 (0.00%)

2 / 7 (28.57%)

0 / 8 (0.00%)

0 / 4 (0.00%)

0 / 3 (0.00%)

0 / 6 (0.00%)

2 / 44 (4.55%)

0 / 48 (0.00%)

0 / 52 (0.00%)

0 / 59 (0.00%)

0 / 28 (0.00%)

1 / 84 (1.19%)

0 / 21 (0.00%)

1 / 292 (0.34%)

occurrences causally related to treatment / all

0 / 0

0 / 2

0 / 0

0 / 2

0 / 0

0 / 1

0 / 0

0 / 1

deaths causally related to treatment / all

0 / 0

Delirium

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

1 / 5 (20.00%)

0 / 7 (0.00%)

0 / 8 (0.00%)

0 / 4 (0.00%)

0 / 3 (0.00%)

0 / 6 (0.00%)

1 / 44 (2.27%)

0 / 48 (0.00%)

0 / 52 (0.00%)

0 / 59 (0.00%)

0 / 28 (0.00%)

0 / 84 (0.00%)

0 / 21 (0.00%)

0 / 292 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Depression

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 5 (0.00%)

0 / 7 (0.00%)

0 / 8 (0.00%)

0 / 4 (0.00%)

0 / 3 (0.00%)

0 / 6 (0.00%)

0 / 44 (0.00%)

0 / 48 (0.00%)

0 / 52 (0.00%)

0 / 59 (0.00%)

1 / 28 (3.57%)

0 / 84 (0.00%)

0 / 21 (0.00%)

1 / 292 (0.34%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

deaths causally related to treatment / all

0 / 0

Suicide attempt

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 5 (0.00%)

0 / 7 (0.00%)

0 / 8 (0.00%)

0 / 4 (0.00%)

0 / 3 (0.00%)

0 / 6 (0.00%)

0 / 44 (0.00%)

0 / 48 (0.00%)

0 / 52 (0.00%)

0 / 59 (0.00%)

1 / 28 (3.57%)

0 / 84 (0.00%)

0 / 21 (0.00%)

1 / 292 (0.34%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

deaths causally related to treatment / all

0 / 0

Investigations

Blast cell count increased

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 5 (0.00%)

0 / 7 (0.00%)

0 / 8 (0.00%)

0 / 4 (0.00%)

0 / 3 (0.00%)

0 / 6 (0.00%)

0 / 44 (0.00%)

0 / 48 (0.00%)

0 / 52 (0.00%)

1 / 59 (1.69%)

3 / 28 (10.71%)

5 / 84 (5.95%)

0 / 21 (0.00%)

9 / 292 (3.08%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 3

2 / 5

0 / 0

2 / 9

deaths causally related to treatment / all

0 / 0

Blood bilirubin increased

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 5 (0.00%)

0 / 7 (0.00%)

0 / 8 (0.00%)

0 / 4 (0.00%)

0 / 3 (0.00%)

0 / 6 (0.00%)

0 / 44 (0.00%)

0 / 48 (0.00%)

1 / 52 (1.92%)

0 / 59 (0.00%)

0 / 28 (0.00%)

0 / 84 (0.00%)

0 / 21 (0.00%)

1 / 292 (0.34%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

deaths causally related to treatment / all

0 / 0

Blood creatinine increased

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 5 (0.00%)

0 / 7 (0.00%)

0 / 8 (0.00%)

0 / 4 (0.00%)

0 / 3 (0.00%)

0 / 6 (0.00%)

0 / 44 (0.00%)

1 / 48 (2.08%)

0 / 52 (0.00%)

0 / 59 (0.00%)

0 / 28 (0.00%)

0 / 84 (0.00%)

0 / 21 (0.00%)

1 / 292 (0.34%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

1 / 1

deaths causally related to treatment / all

0 / 0

Ejection fraction decreased

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 5 (0.00%)

0 / 7 (0.00%)

0 / 8 (0.00%)

0 / 4 (0.00%)

0 / 3 (0.00%)

0 / 6 (0.00%)

0 / 44 (0.00%)

1 / 48 (2.08%)

0 / 52 (0.00%)

0 / 59 (0.00%)

0 / 28 (0.00%)

0 / 84 (0.00%)

0 / 21 (0.00%)

1 / 292 (0.34%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

deaths causally related to treatment / all

0 / 0

Platelet count decreased

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 5 (0.00%)

0 / 7 (0.00%)

0 / 8 (0.00%)

0 / 4 (0.00%)

0 / 3 (0.00%)

1 / 3 (33.33%)

0 / 6 (0.00%)

1 / 44 (2.27%)

0 / 48 (0.00%)

0 / 52 (0.00%)

0 / 59 (0.00%)

1 / 28 (3.57%)

0 / 84 (0.00%)

0 / 21 (0.00%)

1 / 292 (0.34%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

0 / 1

deaths causally related to treatment / all

0 / 0

Injury, poisoning and procedural complications

Extradural haematoma

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 5 (0.00%)

0 / 7 (0.00%)

0 / 8 (0.00%)

0 / 4 (0.00%)

0 / 3 (0.00%)

0 / 6 (0.00%)

0 / 44 (0.00%)

0 / 48 (0.00%)

0 / 52 (0.00%)

1 / 59 (1.69%)

0 / 28 (0.00%)

0 / 84 (0.00%)

0 / 21 (0.00%)

1 / 292 (0.34%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

deaths causally related to treatment / all

0 / 0

Fall

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 5 (0.00%)

0 / 7 (0.00%)

0 / 8 (0.00%)

0 / 4 (0.00%)

0 / 3 (0.00%)

0 / 6 (0.00%)

0 / 44 (0.00%)

1 / 48 (2.08%)

0 / 52 (0.00%)

0 / 59 (0.00%)

0 / 28 (0.00%)

2 / 84 (2.38%)

0 / 21 (0.00%)

3 / 292 (1.03%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 2

0 / 0

0 / 3

deaths causally related to treatment / all

0 / 0

Hip fracture

subjects affected / exposed

1 / 5 (20.00%)

0 / 3 (0.00%)

0 / 5 (0.00%)

0 / 7 (0.00%)

0 / 8 (0.00%)

0 / 4 (0.00%)

0 / 3 (0.00%)

0 / 6 (0.00%)

1 / 44 (2.27%)

0 / 48 (0.00%)

0 / 52 (0.00%)

0 / 59 (0.00%)

0 / 28 (0.00%)

1 / 84 (1.19%)

0 / 21 (0.00%)

1 / 292 (0.34%)

occurrences causally related to treatment / all

0 / 1

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

0 / 1

deaths causally related to treatment / all

0 / 0

Pelvic fracture

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 5 (0.00%)

0 / 7 (0.00%)

0 / 8 (0.00%)

0 / 4 (0.00%)

0 / 3 (0.00%)

0 / 6 (0.00%)

0 / 44 (0.00%)

0 / 48 (0.00%)

0 / 52 (0.00%)

0 / 59 (0.00%)

0 / 28 (0.00%)

1 / 84 (1.19%)

0 / 21 (0.00%)

1 / 292 (0.34%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

deaths causally related to treatment / all

0 / 0

Post procedural haemorrhage

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 5 (0.00%)

0 / 7 (0.00%)

0 / 8 (0.00%)

0 / 4 (0.00%)

0 / 3 (0.00%)

0 / 6 (0.00%)

0 / 44 (0.00%)

0 / 48 (0.00%)

0 / 52 (0.00%)

1 / 59 (1.69%)

0 / 28 (0.00%)

0 / 84 (0.00%)

0 / 21 (0.00%)

1 / 292 (0.34%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

deaths causally related to treatment / all

0 / 0

Subdural haematoma

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 5 (0.00%)

0 / 7 (0.00%)

1 / 8 (12.50%)

0 / 4 (0.00%)

0 / 3 (0.00%)

0 / 6 (0.00%)

1 / 44 (2.27%)

0 / 48 (0.00%)

0 / 52 (0.00%)

0 / 59 (0.00%)

0 / 28 (0.00%)

0 / 84 (0.00%)

0 / 21 (0.00%)

0 / 292 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Cardiac disorders

Acute left ventricular failure

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 5 (0.00%)

0 / 7 (0.00%)

0 / 8 (0.00%)

0 / 4 (0.00%)

0 / 3 (0.00%)

0 / 6 (0.00%)

0 / 44 (0.00%)

0 / 48 (0.00%)

0 / 52 (0.00%)

0 / 59 (0.00%)

0 / 28 (0.00%)

1 / 84 (1.19%)

0 / 21 (0.00%)

1 / 292 (0.34%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

deaths causally related to treatment / all

0 / 0

Acute myocardial infarction

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 5 (0.00%)

0 / 7 (0.00%)

0 / 8 (0.00%)

0 / 4 (0.00%)

0 / 3 (0.00%)

0 / 6 (0.00%)

0 / 44 (0.00%)

0 / 48 (0.00%)

0 / 52 (0.00%)

0 / 59 (0.00%)

0 / 28 (0.00%)

1 / 84 (1.19%)

0 / 21 (0.00%)

1 / 292 (0.34%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

deaths causally related to treatment / all

0 / 0

Angina pectoris

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 5 (0.00%)

0 / 7 (0.00%)

0 / 8 (0.00%)

0 / 4 (0.00%)

0 / 3 (0.00%)

0 / 6 (0.00%)

0 / 44 (0.00%)

1 / 48 (2.08%)

1 / 52 (1.92%)

0 / 59 (0.00%)

0 / 28 (0.00%)

0 / 84 (0.00%)

0 / 21 (0.00%)

2 / 292 (0.68%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 2

deaths causally related to treatment / all

0 / 0

Atrial fibrillation

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 5 (0.00%)

0 / 7 (0.00%)

0 / 8 (0.00%)

0 / 4 (0.00%)

0 / 3 (0.00%)

0 / 6 (0.00%)

0 / 44 (0.00%)

1 / 48 (2.08%)

0 / 52 (0.00%)

0 / 59 (0.00%)

0 / 28 (0.00%)

2 / 84 (2.38%)

0 / 21 (0.00%)

3 / 292 (1.03%)

occurrences causally related to treatment / all

0 / 0

0 / 3

0 / 0

0 / 2

0 / 0

0 / 5

deaths causally related to treatment / all

0 / 0

Cardiac arrest

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 5 (0.00%)

0 / 7 (0.00%)

0 / 8 (0.00%)

0 / 4 (0.00%)

0 / 3 (0.00%)

0 / 6 (0.00%)

0 / 44 (0.00%)

1 / 48 (2.08%)

1 / 52 (1.92%)

0 / 59 (0.00%)

0 / 28 (0.00%)

0 / 84 (0.00%)

0 / 21 (0.00%)

2 / 292 (0.68%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 2

deaths causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 2

Cardiac failure

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 5 (0.00%)

0 / 7 (0.00%)

0 / 8 (0.00%)

0 / 4 (0.00%)

0 / 3 (0.00%)

0 / 6 (0.00%)

0 / 44 (0.00%)

0 / 48 (0.00%)

1 / 52 (1.92%)

0 / 59 (0.00%)

0 / 28 (0.00%)

2 / 84 (2.38%)

0 / 21 (0.00%)

3 / 292 (1.03%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

1 / 2

0 / 0

1 / 3

deaths causally related to treatment / all

0 / 0

Cardiac failure congestive

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 5 (0.00%)

0 / 7 (0.00%)

0 / 8 (0.00%)

0 / 4 (0.00%)

0 / 3 (0.00%)

0 / 6 (0.00%)

0 / 44 (0.00%)

1 / 48 (2.08%)

1 / 52 (1.92%)

1 / 59 (1.69%)

0 / 28 (0.00%)

0 / 84 (0.00%)

0 / 21 (0.00%)

3 / 292 (1.03%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 3

deaths causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

Cardiac iron overload

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 5 (0.00%)

0 / 7 (0.00%)

0 / 8 (0.00%)

0 / 4 (0.00%)

0 / 3 (0.00%)

0 / 6 (0.00%)

0 / 44 (0.00%)

0 / 48 (0.00%)

0 / 52 (0.00%)

1 / 59 (1.69%)

0 / 28 (0.00%)

0 / 84 (0.00%)

0 / 21 (0.00%)

1 / 292 (0.34%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

deaths causally related to treatment / all

0 / 0

Chronic coronary syndrome

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 5 (0.00%)

0 / 7 (0.00%)

0 / 8 (0.00%)

0 / 4 (0.00%)

0 / 3 (0.00%)

0 / 6 (0.00%)

0 / 44 (0.00%)

0 / 48 (0.00%)

0 / 52 (0.00%)

0 / 59 (0.00%)

0 / 28 (0.00%)

1 / 84 (1.19%)

0 / 21 (0.00%)

1 / 292 (0.34%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

deaths causally related to treatment / all

0 / 0

Dilated cardiomyopathy

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 5 (0.00%)

0 / 7 (0.00%)

0 / 8 (0.00%)

0 / 4 (0.00%)

0 / 3 (0.00%)

0 / 6 (0.00%)

0 / 44 (0.00%)

0 / 48 (0.00%)

0 / 52 (0.00%)

0 / 59 (0.00%)

0 / 28 (0.00%)

1 / 84 (1.19%)

0 / 21 (0.00%)

1 / 292 (0.34%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

deaths causally related to treatment / all

0 / 0

Left ventricular dysfunction

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 5 (0.00%)

0 / 7 (0.00%)

0 / 8 (0.00%)

0 / 4 (0.00%)

0 / 3 (0.00%)

0 / 6 (0.00%)

0 / 44 (0.00%)

0 / 48 (0.00%)

0 / 52 (0.00%)

0 / 59 (0.00%)

0 / 28 (0.00%)

1 / 84 (1.19%)

0 / 21 (0.00%)

1 / 292 (0.34%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

1 / 1

deaths causally related to treatment / all

0 / 0

Left ventricular failure

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 5 (0.00%)

0 / 7 (0.00%)

0 / 8 (0.00%)

0 / 4 (0.00%)

0 / 3 (0.00%)

0 / 6 (0.00%)

0 / 44 (0.00%)

0 / 48 (0.00%)

1 / 52 (1.92%)

0 / 59 (0.00%)

0 / 28 (0.00%)

0 / 84 (0.00%)

0 / 21 (0.00%)

1 / 292 (0.34%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

deaths causally related to treatment / all

0 / 0

Pericarditis

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 5 (0.00%)

0 / 7 (0.00%)

0 / 8 (0.00%)

0 / 4 (0.00%)

0 / 3 (0.00%)

0 / 6 (0.00%)

0 / 44 (0.00%)

0 / 48 (0.00%)

0 / 52 (0.00%)

0 / 59 (0.00%)

1 / 28 (3.57%)

0 / 84 (0.00%)

0 / 21 (0.00%)

1 / 292 (0.34%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

deaths causally related to treatment / all

0 / 0

Right ventricular failure

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 5 (0.00%)

0 / 7 (0.00%)

0 / 8 (0.00%)

0 / 4 (0.00%)

0 / 3 (0.00%)

0 / 6 (0.00%)

0 / 44 (0.00%)

1 / 48 (2.08%)

0 / 52 (0.00%)

0 / 59 (0.00%)

0 / 28 (0.00%)

0 / 84 (0.00%)

0 / 21 (0.00%)

1 / 292 (0.34%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

deaths causally related to treatment / all

0 / 0

Sinus tachycardia

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 5 (0.00%)

0 / 7 (0.00%)

0 / 8 (0.00%)

0 / 4 (0.00%)

0 / 3 (0.00%)

1 / 3 (33.33%)

0 / 6 (0.00%)

1 / 44 (2.27%)

0 / 48 (0.00%)

0 / 52 (0.00%)

0 / 59 (0.00%)

0 / 28 (0.00%)

0 / 84 (0.00%)

0 / 21 (0.00%)

0 / 292 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Nervous system disorders

Brain stem haemorrhage

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 5 (0.00%)

0 / 7 (0.00%)

0 / 8 (0.00%)

0 / 4 (0.00%)

0 / 3 (0.00%)

0 / 6 (0.00%)

0 / 44 (0.00%)

0 / 48 (0.00%)

0 / 52 (0.00%)

1 / 59 (1.69%)

0 / 28 (0.00%)

0 / 84 (0.00%)

0 / 21 (0.00%)

1 / 292 (0.34%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

deaths causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

Cerebral infarction

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 5 (0.00%)

0 / 7 (0.00%)

0 / 8 (0.00%)

0 / 4 (0.00%)

0 / 3 (0.00%)

0 / 6 (0.00%)

0 / 44 (0.00%)

0 / 48 (0.00%)

0 / 52 (0.00%)

1 / 59 (1.69%)

0 / 28 (0.00%)

0 / 84 (0.00%)

0 / 21 (0.00%)

1 / 292 (0.34%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

deaths causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

Cerebrovascular accident

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 5 (0.00%)

0 / 7 (0.00%)

0 / 8 (0.00%)

0 / 4 (0.00%)

0 / 3 (0.00%)

0 / 6 (0.00%)

0 / 44 (0.00%)

0 / 48 (0.00%)

0 / 52 (0.00%)

0 / 59 (0.00%)

0 / 28 (0.00%)

1 / 84 (1.19%)

0 / 21 (0.00%)

1 / 292 (0.34%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

deaths causally related to treatment / all

0 / 0

Haemorrhage intracranial

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 5 (0.00%)

0 / 7 (0.00%)

0 / 8 (0.00%)

0 / 4 (0.00%)

0 / 3 (0.00%)

0 / 6 (0.00%)

0 / 44 (0.00%)

0 / 48 (0.00%)

0 / 52 (0.00%)

1 / 59 (1.69%)

0 / 28 (0.00%)

0 / 84 (0.00%)

0 / 21 (0.00%)

1 / 292 (0.34%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

deaths causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

Metabolic encephalopathy

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 5 (0.00%)

0 / 7 (0.00%)

0 / 8 (0.00%)

0 / 4 (0.00%)

0 / 3 (0.00%)

0 / 6 (0.00%)

0 / 44 (0.00%)

1 / 48 (2.08%)

0 / 52 (0.00%)

0 / 59 (0.00%)

0 / 28 (0.00%)

0 / 84 (0.00%)

0 / 21 (0.00%)

1 / 292 (0.34%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

deaths causally related to treatment / all

0 / 0

Paraesthesia

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 5 (0.00%)

0 / 7 (0.00%)

0 / 8 (0.00%)

0 / 4 (0.00%)

0 / 3 (0.00%)

0 / 6 (0.00%)

0 / 44 (0.00%)

0 / 48 (0.00%)

1 / 52 (1.92%)

0 / 59 (0.00%)

0 / 28 (0.00%)

0 / 84 (0.00%)

0 / 21 (0.00%)

1 / 292 (0.34%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

deaths causally related to treatment / all

0 / 0

Spinal cord compression

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 5 (0.00%)

0 / 7 (0.00%)

0 / 8 (0.00%)

0 / 4 (0.00%)

0 / 3 (0.00%)

0 / 6 (0.00%)

0 / 44 (0.00%)

0 / 48 (0.00%)

0 / 52 (0.00%)

0 / 59 (0.00%)

0 / 28 (0.00%)

1 / 84 (1.19%)

0 / 21 (0.00%)

1 / 292 (0.34%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

deaths causally related to treatment / all

0 / 0

Subarachnoid haemorrhage

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 5 (0.00%)

0 / 7 (0.00%)

0 / 8 (0.00%)

0 / 4 (0.00%)

0 / 3 (0.00%)

0 / 6 (0.00%)

0 / 44 (0.00%)

1 / 48 (2.08%)

0 / 52 (0.00%)

0 / 59 (0.00%)

0 / 28 (0.00%)

0 / 84 (0.00%)

0 / 21 (0.00%)

1 / 292 (0.34%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

deaths causally related to treatment / all

0 / 0

Superior sagittal sinus thrombosis

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 5 (0.00%)

0 / 7 (0.00%)

0 / 8 (0.00%)

0 / 4 (0.00%)

0 / 3 (0.00%)

0 / 6 (0.00%)

0 / 44 (0.00%)

0 / 48 (0.00%)

0 / 52 (0.00%)

1 / 59 (1.69%)

0 / 28 (0.00%)

0 / 84 (0.00%)

0 / 21 (0.00%)

1 / 292 (0.34%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

deaths causally related to treatment / all

0 / 0

Syncope

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 5 (0.00%)

0 / 7 (0.00%)

0 / 8 (0.00%)

0 / 4 (0.00%)

0 / 3 (0.00%)

0 / 6 (0.00%)

0 / 44 (0.00%)

1 / 48 (2.08%)

1 / 52 (1.92%)

1 / 59 (1.69%)

0 / 28 (0.00%)

0 / 84 (0.00%)

0 / 21 (0.00%)

3 / 292 (1.03%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 3

deaths causally related to treatment / all

0 / 0

Blood and lymphatic system disorders

Anaemia

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 5 (0.00%)

1 / 7 (14.29%)

0 / 8 (0.00%)

0 / 4 (0.00%)

0 / 3 (0.00%)

1 / 3 (33.33%)

0 / 6 (0.00%)

2 / 44 (4.55%)

1 / 48 (2.08%)

2 / 52 (3.85%)

2 / 59 (3.39%)

5 / 28 (17.86%)

1 / 84 (1.19%)

0 / 21 (0.00%)

11 / 292 (3.77%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

0 / 2

0 / 4

0 / 2

2 / 5

0 / 1

0 / 0

2 / 14

deaths causally related to treatment / all

0 / 0

Febrile neutropenia

subjects affected / exposed

1 / 5 (20.00%)

1 / 3 (33.33%)

2 / 5 (40.00%)

2 / 7 (28.57%)

1 / 8 (12.50%)

0 / 4 (0.00%)

0 / 3 (0.00%)

2 / 6 (33.33%)

9 / 44 (20.45%)

0 / 48 (0.00%)

0 / 52 (0.00%)

0 / 59 (0.00%)

0 / 28 (0.00%)

1 / 84 (1.19%)

0 / 21 (0.00%)

1 / 292 (0.34%)

occurrences causally related to treatment / all

0 / 1

0 / 2

0 / 1

0 / 0

0 / 2

0 / 9

0 / 0

0 / 1

0 / 0

0 / 1

deaths causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

Leukocytosis

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 5 (0.00%)

0 / 7 (0.00%)

1 / 8 (12.50%)

0 / 4 (0.00%)

0 / 3 (0.00%)

0 / 6 (0.00%)

1 / 44 (2.27%)

0 / 48 (0.00%)

0 / 52 (0.00%)

0 / 59 (0.00%)

1 / 28 (3.57%)

0 / 84 (0.00%)

0 / 21 (0.00%)

1 / 292 (0.34%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

0 / 1

deaths causally related to treatment / all

0 / 0

Leukostasis syndrome

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 5 (0.00%)

0 / 7 (0.00%)

1 / 8 (12.50%)

0 / 4 (0.00%)

0 / 3 (0.00%)

0 / 6 (0.00%)

1 / 44 (2.27%)

0 / 48 (0.00%)

0 / 52 (0.00%)

0 / 59 (0.00%)

0 / 28 (0.00%)

0 / 84 (0.00%)

0 / 21 (0.00%)

0 / 292 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Splenic infarction

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 5 (0.00%)

0 / 7 (0.00%)

0 / 8 (0.00%)

0 / 4 (0.00%)

0 / 3 (0.00%)

0 / 6 (0.00%)

0 / 44 (0.00%)

0 / 48 (0.00%)

0 / 52 (0.00%)

0 / 59 (0.00%)

1 / 28 (3.57%)

0 / 84 (0.00%)

0 / 21 (0.00%)

1 / 292 (0.34%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

deaths causally related to treatment / all

0 / 0

Splenomegaly

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 5 (0.00%)

0 / 7 (0.00%)

0 / 8 (0.00%)

0 / 4 (0.00%)

0 / 3 (0.00%)

0 / 6 (0.00%)

0 / 44 (0.00%)

0 / 48 (0.00%)

0 / 52 (0.00%)

0 / 59 (0.00%)

0 / 28 (0.00%)

1 / 84 (1.19%)

0 / 21 (0.00%)

1 / 292 (0.34%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

deaths causally related to treatment / all

0 / 0

Thrombocytopenia

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 5 (0.00%)

1 / 7 (14.29%)

0 / 8 (0.00%)

0 / 4 (0.00%)

0 / 3 (0.00%)

0 / 6 (0.00%)

1 / 44 (2.27%)

0 / 48 (0.00%)

0 / 52 (0.00%)

0 / 59 (0.00%)

0 / 28 (0.00%)

0 / 84 (0.00%)

0 / 21 (0.00%)

0 / 292 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Ear and labyrinth disorders

Vertigo

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 5 (0.00%)

0 / 7 (0.00%)

0 / 8 (0.00%)

0 / 4 (0.00%)

0 / 3 (0.00%)

0 / 6 (0.00%)

0 / 44 (0.00%)

1 / 48 (2.08%)

0 / 52 (0.00%)

0 / 59 (0.00%)

0 / 28 (0.00%)

0 / 84 (0.00%)

0 / 21 (0.00%)

1 / 292 (0.34%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

deaths causally related to treatment / all

0 / 0

Gastrointestinal disorders

Abdominal pain

subjects affected / exposed

1 / 5 (20.00%)

0 / 3 (0.00%)

0 / 5 (0.00%)

0 / 7 (0.00%)

0 / 8 (0.00%)

0 / 4 (0.00%)

0 / 3 (0.00%)

1 / 6 (16.67%)

2 / 44 (4.55%)

0 / 48 (0.00%)

1 / 52 (1.92%)

1 / 59 (1.69%)

1 / 28 (3.57%)

0 / 84 (0.00%)

0 / 21 (0.00%)

3 / 292 (1.03%)

occurrences causally related to treatment / all

0 / 1

0 / 0

1 / 1

1 / 2

0 / 0

0 / 1

1 / 1

0 / 1

0 / 0

1 / 3

deaths causally related to treatment / all

0 / 0

Abdominal wall haematoma

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 5 (0.00%)

0 / 7 (0.00%)

0 / 8 (0.00%)

0 / 4 (0.00%)

0 / 3 (0.00%)

0 / 6 (0.00%)

0 / 44 (0.00%)

0 / 48 (0.00%)

0 / 52 (0.00%)

0 / 59 (0.00%)

0 / 28 (0.00%)

1 / 84 (1.19%)

0 / 21 (0.00%)

1 / 292 (0.34%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

1 / 1

deaths causally related to treatment / all

0 / 0

Colitis

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 5 (0.00%)

0 / 7 (0.00%)

0 / 8 (0.00%)

0 / 4 (0.00%)

0 / 3 (0.00%)

1 / 6 (16.67%)

1 / 44 (2.27%)

0 / 48 (0.00%)

1 / 52 (1.92%)

0 / 59 (0.00%)

0 / 28 (0.00%)

0 / 84 (0.00%)

0 / 21 (0.00%)

1 / 292 (0.34%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

2 / 3

0 / 0

2 / 3

deaths causally related to treatment / all

0 / 0

Constipation

subjects affected / exposed

1 / 5 (20.00%)

0 / 3 (0.00%)

0 / 5 (0.00%)

0 / 7 (0.00%)

0 / 8 (0.00%)

0 / 4 (0.00%)

0 / 3 (0.00%)

1 / 6 (16.67%)

2 / 44 (4.55%)

0 / 48 (0.00%)

0 / 52 (0.00%)

0 / 59 (0.00%)

0 / 28 (0.00%)

0 / 84 (0.00%)

0 / 21 (0.00%)

0 / 292 (0.00%)

occurrences causally related to treatment / all

0 / 1

0 / 0

0 / 1

0 / 2

0 / 0

deaths causally related to treatment / all

0 / 0

Diarrhoea

subjects affected / exposed

1 / 5 (20.00%)

0 / 3 (0.00%)

0 / 5 (0.00%)

0 / 7 (0.00%)

0 / 8 (0.00%)

0 / 4 (0.00%)

0 / 3 (0.00%)

1 / 3 (33.33%)

1 / 6 (16.67%)

3 / 44 (6.82%)

0 / 48 (0.00%)

1 / 52 (1.92%)

0 / 59 (0.00%)

0 / 28 (0.00%)

0 / 84 (0.00%)

0 / 21 (0.00%)

1 / 292 (0.34%)

occurrences causally related to treatment / all

1 / 1

0 / 0

0 / 1

1 / 1

2 / 3

0 / 0

1 / 1

0 / 0

1 / 1

deaths causally related to treatment / all

0 / 0

Duodenal ulcer haemorrhage

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 5 (0.00%)

0 / 7 (0.00%)

0 / 8 (0.00%)

0 / 4 (0.00%)

0 / 3 (0.00%)

0 / 6 (0.00%)

0 / 44 (0.00%)

0 / 48 (0.00%)

0 / 52 (0.00%)

0 / 59 (0.00%)

0 / 28 (0.00%)

1 / 84 (1.19%)

0 / 21 (0.00%)

1 / 292 (0.34%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

1 / 1

deaths causally related to treatment / all

0 / 0

Gastric ulcer

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 5 (0.00%)

0 / 7 (0.00%)

0 / 8 (0.00%)

0 / 4 (0.00%)

0 / 3 (0.00%)

0 / 6 (0.00%)

0 / 44 (0.00%)

0 / 48 (0.00%)

0 / 52 (0.00%)

1 / 59 (1.69%)

0 / 28 (0.00%)

0 / 84 (0.00%)

0 / 21 (0.00%)

1 / 292 (0.34%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

deaths causally related to treatment / all

0 / 0

Gastrointestinal disorder

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 5 (0.00%)

0 / 7 (0.00%)

0 / 8 (0.00%)

0 / 4 (0.00%)

0 / 3 (0.00%)

0 / 6 (0.00%)

0 / 44 (0.00%)

0 / 48 (0.00%)

1 / 52 (1.92%)

0 / 59 (0.00%)

0 / 28 (0.00%)

0 / 84 (0.00%)

0 / 21 (0.00%)

1 / 292 (0.34%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

deaths causally related to treatment / all

0 / 0

Gastrointestinal haemorrhage

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 5 (0.00%)

0 / 7 (0.00%)

0 / 8 (0.00%)

0 / 4 (0.00%)

0 / 3 (0.00%)

0 / 6 (0.00%)

0 / 44 (0.00%)

0 / 48 (0.00%)

0 / 52 (0.00%)

0 / 59 (0.00%)

0 / 28 (0.00%)

2 / 84 (2.38%)

1 / 21 (4.76%)

3 / 292 (1.03%)

occurrences causally related to treatment / all

0 / 0

0 / 2

0 / 1

0 / 3

deaths causally related to treatment / all

0 / 0

Haemorrhoids

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 5 (0.00%)

0 / 7 (0.00%)

1 / 8 (12.50%)

0 / 4 (0.00%)

0 / 3 (0.00%)

0 / 6 (0.00%)

1 / 44 (2.27%)

0 / 48 (0.00%)

0 / 52 (0.00%)

0 / 59 (0.00%)

0 / 28 (0.00%)

0 / 84 (0.00%)

0 / 21 (0.00%)

0 / 292 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Intestinal haematoma

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 5 (0.00%)

0 / 7 (0.00%)

0 / 8 (0.00%)

0 / 4 (0.00%)

0 / 3 (0.00%)

0 / 6 (0.00%)

0 / 44 (0.00%)

0 / 48 (0.00%)

0 / 52 (0.00%)

0 / 59 (0.00%)

0 / 28 (0.00%)

1 / 84 (1.19%)

0 / 21 (0.00%)

1 / 292 (0.34%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

deaths causally related to treatment / all

0 / 0

Intestinal obstruction

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 5 (0.00%)

0 / 7 (0.00%)

0 / 8 (0.00%)

0 / 4 (0.00%)

0 / 3 (0.00%)

0 / 6 (0.00%)

0 / 44 (0.00%)

0 / 48 (0.00%)

0 / 52 (0.00%)

0 / 59 (0.00%)

0 / 28 (0.00%)

1 / 84 (1.19%)

0 / 21 (0.00%)

1 / 292 (0.34%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

deaths causally related to treatment / all

0 / 0

Lower gastrointestinal haemorrhage

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 5 (0.00%)

0 / 7 (0.00%)

0 / 8 (0.00%)

0 / 4 (0.00%)

0 / 3 (0.00%)

0 / 6 (0.00%)

0 / 44 (0.00%)

0 / 48 (0.00%)

1 / 52 (1.92%)

0 / 59 (0.00%)

0 / 28 (0.00%)

0 / 84 (0.00%)

0 / 21 (0.00%)

1 / 292 (0.34%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

deaths causally related to treatment / all

0 / 0

Nausea

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 5 (0.00%)

0 / 7 (0.00%)

0 / 8 (0.00%)

0 / 4 (0.00%)

0 / 3 (0.00%)

2 / 6 (33.33%)

2 / 44 (4.55%)

0 / 48 (0.00%)

0 / 52 (0.00%)

0 / 59 (0.00%)

0 / 28 (0.00%)

0 / 84 (0.00%)

0 / 21 (0.00%)

0 / 292 (0.00%)

occurrences causally related to treatment / all

0 / 0

2 / 2

0 / 0

deaths causally related to treatment / all

0 / 0

Rectal haemorrhage

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 5 (0.00%)

0 / 7 (0.00%)

0 / 8 (0.00%)

0 / 4 (0.00%)

0 / 3 (0.00%)

0 / 6 (0.00%)

0 / 44 (0.00%)

0 / 48 (0.00%)

0 / 52 (0.00%)

0 / 59 (0.00%)

0 / 28 (0.00%)

1 / 84 (1.19%)

0 / 21 (0.00%)

1 / 292 (0.34%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

deaths causally related to treatment / all

0 / 0

Small intestinal obstruction

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 5 (0.00%)

0 / 7 (0.00%)

0 / 8 (0.00%)

1 / 4 (25.00%)

0 / 3 (0.00%)

0 / 6 (0.00%)

1 / 44 (2.27%)

0 / 48 (0.00%)

1 / 52 (1.92%)

1 / 59 (1.69%)

0 / 28 (0.00%)

0 / 84 (0.00%)

0 / 21 (0.00%)

2 / 292 (0.68%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

0 / 2

deaths causally related to treatment / all

0 / 0

Vomiting

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 5 (0.00%)

0 / 7 (0.00%)

0 / 8 (0.00%)

0 / 4 (0.00%)

0 / 3 (0.00%)

3 / 6 (50.00%)

3 / 44 (6.82%)

0 / 48 (0.00%)

0 / 52 (0.00%)

0 / 59 (0.00%)

1 / 28 (3.57%)

0 / 84 (0.00%)

0 / 21 (0.00%)

1 / 292 (0.34%)

occurrences causally related to treatment / all

0 / 0

2 / 3

0 / 0

1 / 1

0 / 0

1 / 1

deaths causally related to treatment / all

0 / 0

Hepatobiliary disorders

Biliary dilatation

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 5 (0.00%)

0 / 7 (0.00%)

0 / 8 (0.00%)

0 / 4 (0.00%)

0 / 3 (0.00%)

0 / 6 (0.00%)

0 / 44 (0.00%)

0 / 48 (0.00%)

0 / 52 (0.00%)

0 / 59 (0.00%)

1 / 28 (3.57%)

0 / 84 (0.00%)

0 / 21 (0.00%)

1 / 292 (0.34%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

deaths causally related to treatment / all

0 / 0

Hepatocellular injury

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 5 (0.00%)

0 / 7 (0.00%)

0 / 8 (0.00%)

0 / 4 (0.00%)

0 / 3 (0.00%)

0 / 6 (0.00%)

0 / 44 (0.00%)

0 / 48 (0.00%)

0 / 52 (0.00%)

1 / 59 (1.69%)

0 / 28 (0.00%)

0 / 84 (0.00%)

0 / 21 (0.00%)

1 / 292 (0.34%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

deaths causally related to treatment / all

0 / 0

Hypertransaminasaemia

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 5 (0.00%)

0 / 7 (0.00%)

0 / 8 (0.00%)

0 / 4 (0.00%)

0 / 3 (0.00%)

0 / 6 (0.00%)

0 / 44 (0.00%)

0 / 48 (0.00%)

0 / 52 (0.00%)

0 / 59 (0.00%)

0 / 28 (0.00%)

1 / 84 (1.19%)

0 / 21 (0.00%)

1 / 292 (0.34%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

1 / 1

deaths causally related to treatment / all

0 / 0

Skin and subcutaneous tissue disorders

Cutaneous vasculitis

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 5 (0.00%)

0 / 7 (0.00%)

0 / 8 (0.00%)

0 / 4 (0.00%)

0 / 3 (0.00%)

0 / 6 (0.00%)

0 / 44 (0.00%)

0 / 48 (0.00%)

0 / 52 (0.00%)

1 / 59 (1.69%)

0 / 28 (0.00%)

0 / 84 (0.00%)

0 / 21 (0.00%)

1 / 292 (0.34%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

deaths causally related to treatment / all

0 / 0

Drug eruption

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 5 (0.00%)

0 / 7 (0.00%)

0 / 8 (0.00%)

0 / 4 (0.00%)

0 / 3 (0.00%)

0 / 6 (0.00%)

0 / 44 (0.00%)

0 / 48 (0.00%)

1 / 52 (1.92%)

0 / 59 (0.00%)

0 / 28 (0.00%)

0 / 84 (0.00%)

0 / 21 (0.00%)

1 / 292 (0.34%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

1 / 1

deaths causally related to treatment / all

0 / 0

Renal and urinary disorders

Haematuria

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 5 (0.00%)

0 / 7 (0.00%)

0 / 8 (0.00%)

0 / 4 (0.00%)

0 / 3 (0.00%)

0 / 6 (0.00%)

0 / 44 (0.00%)

0 / 48 (0.00%)

0 / 52 (0.00%)

1 / 59 (1.69%)

0 / 28 (0.00%)

0 / 84 (0.00%)

0 / 21 (0.00%)

1 / 292 (0.34%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

deaths causally related to treatment / all

0 / 0

Acute kidney injury

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 5 (0.00%)

0 / 7 (0.00%)

0 / 8 (0.00%)

0 / 4 (0.00%)

0 / 3 (0.00%)

1 / 6 (16.67%)

1 / 44 (2.27%)

1 / 48 (2.08%)

1 / 52 (1.92%)

1 / 59 (1.69%)

1 / 28 (3.57%)

1 / 84 (1.19%)

1 / 21 (4.76%)

6 / 292 (2.05%)

occurrences causally related to treatment / all

0 / 0

0 / 1

1 / 1

0 / 1

1 / 1

2 / 6

deaths causally related to treatment / all

0 / 0

1 / 1

0 / 0

1 / 1

Renal cyst ruptured

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 5 (0.00%)

0 / 7 (0.00%)

0 / 8 (0.00%)

0 / 4 (0.00%)

0 / 3 (0.00%)

0 / 6 (0.00%)

0 / 44 (0.00%)

0 / 48 (0.00%)

1 / 52 (1.92%)

0 / 59 (0.00%)

0 / 28 (0.00%)

0 / 84 (0.00%)

0 / 21 (0.00%)

1 / 292 (0.34%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

deaths causally related to treatment / all

0 / 0

Renal haemorrhage

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 5 (0.00%)

0 / 7 (0.00%)

0 / 8 (0.00%)

0 / 4 (0.00%)

0 / 3 (0.00%)

0 / 6 (0.00%)

0 / 44 (0.00%)

1 / 48 (2.08%)

0 / 52 (0.00%)

0 / 59 (0.00%)

0 / 28 (0.00%)

0 / 84 (0.00%)

0 / 21 (0.00%)

1 / 292 (0.34%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

deaths causally related to treatment / all

0 / 0

Endocrine disorders

Adrenal haematoma

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 5 (0.00%)

0 / 7 (0.00%)

0 / 8 (0.00%)

0 / 4 (0.00%)

0 / 3 (0.00%)

0 / 6 (0.00%)

0 / 44 (0.00%)

0 / 48 (0.00%)

1 / 52 (1.92%)

0 / 59 (0.00%)

0 / 28 (0.00%)

0 / 84 (0.00%)

0 / 21 (0.00%)

1 / 292 (0.34%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

deaths causally related to treatment / all

0 / 0

Inappropriate antidiuretic hormone secretion

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 5 (0.00%)

0 / 7 (0.00%)

0 / 8 (0.00%)

0 / 4 (0.00%)

0 / 3 (0.00%)

0 / 6 (0.00%)

0 / 44 (0.00%)

0 / 48 (0.00%)

0 / 52 (0.00%)

1 / 59 (1.69%)

0 / 28 (0.00%)

0 / 84 (0.00%)

0 / 21 (0.00%)

1 / 292 (0.34%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

deaths causally related to treatment / all

0 / 0

Musculoskeletal and connective tissue disorders

Back pain

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 5 (0.00%)

0 / 7 (0.00%)

0 / 8 (0.00%)

0 / 4 (0.00%)

0 / 3 (0.00%)

0 / 6 (0.00%)

0 / 44 (0.00%)

0 / 48 (0.00%)

0 / 52 (0.00%)

1 / 59 (1.69%)

0 / 28 (0.00%)

0 / 84 (0.00%)

0 / 21 (0.00%)

1 / 292 (0.34%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

deaths causally related to treatment / all

0 / 0

Bone pain

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 5 (0.00%)

0 / 7 (0.00%)

0 / 8 (0.00%)

0 / 4 (0.00%)

0 / 3 (0.00%)

0 / 6 (0.00%)

0 / 44 (0.00%)

0 / 48 (0.00%)

0 / 52 (0.00%)

0 / 59 (0.00%)

1 / 28 (3.57%)

0 / 84 (0.00%)

0 / 21 (0.00%)

1 / 292 (0.34%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

deaths causally related to treatment / all

0 / 0

Joint effusion

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 5 (0.00%)

0 / 7 (0.00%)

0 / 8 (0.00%)

0 / 4 (0.00%)

0 / 3 (0.00%)

0 / 6 (0.00%)

0 / 44 (0.00%)

0 / 48 (0.00%)

0 / 52 (0.00%)

0 / 59 (0.00%)

1 / 28 (3.57%)

0 / 84 (0.00%)

0 / 21 (0.00%)

1 / 292 (0.34%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

deaths causally related to treatment / all

0 / 0

Neck pain

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 5 (0.00%)

0 / 7 (0.00%)

0 / 8 (0.00%)

0 / 4 (0.00%)

0 / 3 (0.00%)

0 / 6 (0.00%)

0 / 44 (0.00%)

0 / 48 (0.00%)

0 / 52 (0.00%)

1 / 59 (1.69%)

0 / 28 (0.00%)

0 / 84 (0.00%)

0 / 21 (0.00%)

1 / 292 (0.34%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

deaths causally related to treatment / all

0 / 0

Musculoskeletal pain

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

1 / 5 (20.00%)

0 / 7 (0.00%)

0 / 8 (0.00%)

0 / 4 (0.00%)

0 / 3 (0.00%)

0 / 6 (0.00%)

1 / 44 (2.27%)

0 / 48 (0.00%)

0 / 52 (0.00%)

0 / 59 (0.00%)

0 / 28 (0.00%)

0 / 84 (0.00%)

0 / 21 (0.00%)

0 / 292 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Muscular weakness

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 5 (0.00%)

0 / 7 (0.00%)

0 / 8 (0.00%)

0 / 4 (0.00%)

0 / 3 (0.00%)

0 / 6 (0.00%)

0 / 44 (0.00%)

0 / 48 (0.00%)

0 / 52 (0.00%)

1 / 59 (1.69%)

0 / 28 (0.00%)

0 / 84 (0.00%)

0 / 21 (0.00%)

1 / 292 (0.34%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

deaths causally related to treatment / all

0 / 0

Infections and infestations

Abscess limb

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 5 (0.00%)

0 / 7 (0.00%)

0 / 8 (0.00%)

0 / 4 (0.00%)

0 / 3 (0.00%)

0 / 6 (0.00%)

0 / 44 (0.00%)

0 / 48 (0.00%)

0 / 52 (0.00%)

0 / 59 (0.00%)

0 / 28 (0.00%)

1 / 84 (1.19%)

0 / 21 (0.00%)

1 / 292 (0.34%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

deaths causally related to treatment / all

0 / 0

Aspergillus infection

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 5 (0.00%)

0 / 7 (0.00%)

0 / 8 (0.00%)

0 / 4 (0.00%)

0 / 3 (0.00%)

1 / 6 (16.67%)

1 / 44 (2.27%)

0 / 48 (0.00%)

0 / 52 (0.00%)

0 / 59 (0.00%)

0 / 28 (0.00%)

0 / 84 (0.00%)

0 / 21 (0.00%)

0 / 292 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 2

0 / 0

deaths causally related to treatment / all

0 / 0

0 / 1

0 / 0

Bacteraemia

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 5 (0.00%)

1 / 7 (14.29%)

0 / 8 (0.00%)

0 / 4 (0.00%)

0 / 3 (0.00%)

0 / 6 (0.00%)

1 / 44 (2.27%)

0 / 48 (0.00%)

0 / 52 (0.00%)

0 / 59 (0.00%)

0 / 28 (0.00%)

0 / 84 (0.00%)

0 / 21 (0.00%)

0 / 292 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Bronchiolitis

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 5 (0.00%)

0 / 7 (0.00%)

0 / 8 (0.00%)

0 / 4 (0.00%)

0 / 3 (0.00%)

0 / 6 (0.00%)

0 / 44 (0.00%)

0 / 48 (0.00%)

0 / 52 (0.00%)

0 / 59 (0.00%)

0 / 28 (0.00%)

1 / 84 (1.19%)

0 / 21 (0.00%)

1 / 292 (0.34%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

1 / 1

deaths causally related to treatment / all

0 / 0

Bronchopulmonary aspergillosis

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 5 (0.00%)

0 / 7 (0.00%)

0 / 8 (0.00%)

0 / 4 (0.00%)

0 / 3 (0.00%)

0 / 6 (0.00%)

0 / 44 (0.00%)

1 / 48 (2.08%)

0 / 52 (0.00%)

0 / 59 (0.00%)

0 / 28 (0.00%)

1 / 84 (1.19%)

0 / 21 (0.00%)

2 / 292 (0.68%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

0 / 2

deaths causally related to treatment / all

0 / 0

COVID-19

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 5 (0.00%)

0 / 7 (0.00%)

0 / 8 (0.00%)

0 / 4 (0.00%)

0 / 3 (0.00%)

0 / 6 (0.00%)

0 / 44 (0.00%)

0 / 48 (0.00%)

1 / 52 (1.92%)

0 / 59 (0.00%)

1 / 28 (3.57%)

3 / 84 (3.57%)

0 / 21 (0.00%)

5 / 292 (1.71%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

1 / 3

0 / 0

1 / 5

deaths causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

0 / 2

COVID-19 pneumonia

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 5 (0.00%)

0 / 7 (0.00%)

0 / 8 (0.00%)

0 / 4 (0.00%)

0 / 3 (0.00%)

0 / 6 (0.00%)

0 / 44 (0.00%)

0 / 48 (0.00%)

0 / 52 (0.00%)

1 / 59 (1.69%)

0 / 28 (0.00%)

4 / 84 (4.76%)

0 / 21 (0.00%)

5 / 292 (1.71%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

2 / 4

0 / 0

2 / 5

deaths causally related to treatment / all

0 / 0

1 / 1

0 / 0

1 / 1

Clostridium difficile infection

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 5 (0.00%)

0 / 7 (0.00%)

1 / 8 (12.50%)

0 / 4 (0.00%)

0 / 3 (0.00%)

0 / 6 (0.00%)

1 / 44 (2.27%)

0 / 48 (0.00%)

0 / 52 (0.00%)

0 / 59 (0.00%)

0 / 28 (0.00%)

0 / 84 (0.00%)

0 / 21 (0.00%)

0 / 292 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Cellulitis

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 5 (0.00%)

0 / 7 (0.00%)

0 / 8 (0.00%)

0 / 4 (0.00%)

0 / 3 (0.00%)

0 / 6 (0.00%)

0 / 44 (0.00%)

0 / 48 (0.00%)

0 / 52 (0.00%)

0 / 59 (0.00%)

0 / 28 (0.00%)

1 / 84 (1.19%)

0 / 21 (0.00%)

1 / 292 (0.34%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

deaths causally related to treatment / all

0 / 0

Dermo-hypodermitis

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 5 (0.00%)

0 / 7 (0.00%)

0 / 8 (0.00%)

0 / 4 (0.00%)

0 / 3 (0.00%)

0 / 6 (0.00%)

0 / 44 (0.00%)

1 / 48 (2.08%)

0 / 52 (0.00%)

0 / 59 (0.00%)

0 / 28 (0.00%)

0 / 84 (0.00%)

0 / 21 (0.00%)

1 / 292 (0.34%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

deaths causally related to treatment / all

0 / 0

Device related infection

subjects affected / exposed

0 / 5 (0.00%)

1 / 3 (33.33%)

0 / 5 (0.00%)

0 / 7 (0.00%)

1 / 8 (12.50%)

0 / 4 (0.00%)

0 / 3 (0.00%)

0 / 6 (0.00%)

2 / 44 (4.55%)

0 / 48 (0.00%)

0 / 52 (0.00%)

0 / 59 (0.00%)

0 / 28 (0.00%)

0 / 84 (0.00%)

0 / 21 (0.00%)

0 / 292 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

0 / 2

0 / 0

deaths causally related to treatment / all

0 / 0

Device related sepsis

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 5 (0.00%)

0 / 7 (0.00%)

0 / 8 (0.00%)

1 / 4 (25.00%)

0 / 3 (0.00%)

0 / 6 (0.00%)

1 / 44 (2.27%)

0 / 48 (0.00%)

0 / 52 (0.00%)

0 / 59 (0.00%)

0 / 28 (0.00%)

0 / 84 (0.00%)

0 / 21 (0.00%)

0 / 292 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Diverticulitis

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 5 (0.00%)

0 / 7 (0.00%)

0 / 8 (0.00%)

0 / 4 (0.00%)

0 / 3 (0.00%)

0 / 6 (0.00%)

0 / 44 (0.00%)

1 / 48 (2.08%)

0 / 52 (0.00%)

0 / 59 (0.00%)

0 / 28 (0.00%)

0 / 84 (0.00%)

0 / 21 (0.00%)

1 / 292 (0.34%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

deaths causally related to treatment / all

0 / 0

Empyema

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 5 (0.00%)

0 / 7 (0.00%)

0 / 8 (0.00%)

0 / 4 (0.00%)

0 / 3 (0.00%)

0 / 6 (0.00%)

0 / 44 (0.00%)

0 / 48 (0.00%)

0 / 52 (0.00%)

1 / 59 (1.69%)

0 / 28 (0.00%)

0 / 84 (0.00%)

0 / 21 (0.00%)

1 / 292 (0.34%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

deaths causally related to treatment / all

0 / 0

Enterococcal bacteraemia

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 5 (0.00%)

0 / 7 (0.00%)

0 / 8 (0.00%)

1 / 4 (25.00%)

0 / 3 (0.00%)

0 / 6 (0.00%)

1 / 44 (2.27%)

0 / 48 (0.00%)

0 / 52 (0.00%)

0 / 59 (0.00%)

0 / 28 (0.00%)

0 / 84 (0.00%)

0 / 21 (0.00%)

0 / 292 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

Endocarditis bacterial

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 5 (0.00%)

0 / 7 (0.00%)

0 / 8 (0.00%)

0 / 4 (0.00%)

0 / 3 (0.00%)

0 / 6 (0.00%)

0 / 44 (0.00%)

0 / 48 (0.00%)

0 / 52 (0.00%)

0 / 59 (0.00%)

0 / 28 (0.00%)

1 / 84 (1.19%)

0 / 21 (0.00%)

1 / 292 (0.34%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

deaths causally related to treatment / all

0 / 0

Escherichia bacteraemia

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 5 (0.00%)

0 / 7 (0.00%)

0 / 8 (0.00%)

0 / 4 (0.00%)

0 / 3 (0.00%)

1 / 6 (16.67%)

1 / 44 (2.27%)

0 / 48 (0.00%)

0 / 52 (0.00%)

0 / 59 (0.00%)

0 / 28 (0.00%)

0 / 84 (0.00%)

0 / 21 (0.00%)

0 / 292 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 2

0 / 0

deaths causally related to treatment / all

0 / 0

0 / 1

0 / 0

Escherichia infection

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 5 (0.00%)

0 / 7 (0.00%)

0 / 8 (0.00%)

0 / 4 (0.00%)

0 / 3 (0.00%)

0 / 6 (0.00%)

0 / 44 (0.00%)

1 / 48 (2.08%)

0 / 52 (0.00%)

0 / 59 (0.00%)

0 / 28 (0.00%)

0 / 84 (0.00%)

0 / 21 (0.00%)

1 / 292 (0.34%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

deaths causally related to treatment / all

0 / 0

Escherichia urinary tract infection

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 5 (0.00%)

0 / 7 (0.00%)

0 / 8 (0.00%)

0 / 4 (0.00%)

0 / 3 (0.00%)

0 / 6 (0.00%)

0 / 44 (0.00%)

1 / 48 (2.08%)

0 / 52 (0.00%)

0 / 59 (0.00%)

0 / 28 (0.00%)

0 / 84 (0.00%)

0 / 21 (0.00%)

1 / 292 (0.34%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

deaths causally related to treatment / all

0 / 0

Fournier's gangrene

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 5 (0.00%)

0 / 7 (0.00%)

0 / 8 (0.00%)

0 / 4 (0.00%)

0 / 3 (0.00%)

0 / 6 (0.00%)

0 / 44 (0.00%)

0 / 48 (0.00%)

0 / 52 (0.00%)

1 / 59 (1.69%)

0 / 28 (0.00%)

0 / 84 (0.00%)

0 / 21 (0.00%)

1 / 292 (0.34%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

deaths causally related to treatment / all

0 / 0

Gastroenteritis viral

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 5 (0.00%)

0 / 7 (0.00%)

0 / 8 (0.00%)

0 / 4 (0.00%)

0 / 3 (0.00%)

0 / 6 (0.00%)

0 / 44 (0.00%)

0 / 48 (0.00%)

0 / 52 (0.00%)

1 / 59 (1.69%)

0 / 28 (0.00%)

0 / 84 (0.00%)

0 / 21 (0.00%)

1 / 292 (0.34%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

deaths causally related to treatment / all

0 / 0

Herpes simplex reactivation

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 5 (0.00%)

0 / 7 (0.00%)

1 / 8 (12.50%)

0 / 4 (0.00%)

0 / 3 (0.00%)

0 / 6 (0.00%)

1 / 44 (2.27%)

0 / 48 (0.00%)

0 / 52 (0.00%)

0 / 59 (0.00%)

0 / 28 (0.00%)

0 / 84 (0.00%)

0 / 21 (0.00%)

0 / 292 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Herpes zoster

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 5 (0.00%)

0 / 7 (0.00%)

0 / 8 (0.00%)

0 / 4 (0.00%)

0 / 3 (0.00%)

0 / 6 (0.00%)

0 / 44 (0.00%)

0 / 48 (0.00%)

0 / 52 (0.00%)

0 / 59 (0.00%)

0 / 28 (0.00%)

1 / 84 (1.19%)

0 / 21 (0.00%)

1 / 292 (0.34%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

deaths causally related to treatment / all

0 / 0

Influenza

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 5 (0.00%)

0 / 7 (0.00%)

0 / 8 (0.00%)

0 / 4 (0.00%)

0 / 3 (0.00%)

0 / 6 (0.00%)

0 / 44 (0.00%)

0 / 48 (0.00%)

0 / 52 (0.00%)

0 / 59 (0.00%)

0 / 28 (0.00%)

1 / 84 (1.19%)

0 / 21 (0.00%)

1 / 292 (0.34%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

deaths causally related to treatment / all

0 / 0

Localised infection

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 5 (0.00%)

0 / 7 (0.00%)

0 / 8 (0.00%)

0 / 4 (0.00%)

0 / 3 (0.00%)

0 / 6 (0.00%)

0 / 44 (0.00%)

0 / 48 (0.00%)

0 / 52 (0.00%)

0 / 59 (0.00%)

0 / 28 (0.00%)

1 / 84 (1.19%)

0 / 21 (0.00%)

1 / 292 (0.34%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

deaths causally related to treatment / all

0 / 0

Nocardiosis

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 5 (0.00%)

0 / 7 (0.00%)

0 / 8 (0.00%)

0 / 4 (0.00%)

0 / 3 (0.00%)

0 / 6 (0.00%)

0 / 44 (0.00%)

0 / 48 (0.00%)

0 / 52 (0.00%)

0 / 59 (0.00%)

0 / 28 (0.00%)

1 / 84 (1.19%)

0 / 21 (0.00%)

1 / 292 (0.34%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

deaths causally related to treatment / all

0 / 0

Pneumonia

subjects affected / exposed

1 / 5 (20.00%)

0 / 3 (0.00%)

1 / 5 (20.00%)

0 / 7 (0.00%)

0 / 8 (0.00%)

1 / 4 (25.00%)

0 / 3 (0.00%)

1 / 6 (16.67%)

4 / 44 (9.09%)

4 / 48 (8.33%)

3 / 52 (5.77%)

4 / 59 (6.78%)

2 / 28 (7.14%)

5 / 84 (5.95%)

0 / 21 (0.00%)

18 / 292 (6.16%)

occurrences causally related to treatment / all

0 / 1

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

0 / 2

0 / 5

1 / 4

0 / 3

0 / 4

1 / 2

2 / 5

0 / 0

4 / 18

deaths causally related to treatment / all

0 / 0

0 / 1

0 / 0

Pneumonia acinetobacter

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 5 (0.00%)

0 / 7 (0.00%)

0 / 8 (0.00%)

0 / 4 (0.00%)

0 / 3 (0.00%)

0 / 6 (0.00%)

0 / 44 (0.00%)

0 / 48 (0.00%)

0 / 52 (0.00%)

0 / 59 (0.00%)

0 / 28 (0.00%)

1 / 84 (1.19%)

0 / 21 (0.00%)

1 / 292 (0.34%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

deaths causally related to treatment / all

0 / 0

Pneumonia bacterial

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 5 (0.00%)

0 / 7 (0.00%)

0 / 8 (0.00%)

0 / 4 (0.00%)

0 / 3 (0.00%)

0 / 6 (0.00%)

0 / 44 (0.00%)

0 / 48 (0.00%)

0 / 52 (0.00%)

0 / 59 (0.00%)

0 / 28 (0.00%)

1 / 84 (1.19%)

0 / 21 (0.00%)

1 / 292 (0.34%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

deaths causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

Pneumonia pneumococcal

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 5 (0.00%)

0 / 7 (0.00%)

0 / 8 (0.00%)

0 / 4 (0.00%)

0 / 3 (0.00%)

0 / 6 (0.00%)

0 / 44 (0.00%)

0 / 48 (0.00%)

0 / 52 (0.00%)

1 / 59 (1.69%)

0 / 28 (0.00%)

0 / 84 (0.00%)

0 / 21 (0.00%)

1 / 292 (0.34%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

deaths causally related to treatment / all

0 / 0

Pneumonia staphylococcal

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 5 (0.00%)

0 / 7 (0.00%)

0 / 8 (0.00%)

0 / 4 (0.00%)

0 / 3 (0.00%)

0 / 6 (0.00%)

0 / 44 (0.00%)

0 / 48 (0.00%)

0 / 52 (0.00%)

0 / 59 (0.00%)

0 / 28 (0.00%)

1 / 84 (1.19%)

0 / 21 (0.00%)

1 / 292 (0.34%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

1 / 1

deaths causally related to treatment / all

0 / 0

1 / 1

0 / 0

1 / 1

Post procedural infection

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 5 (0.00%)

0 / 7 (0.00%)

0 / 8 (0.00%)

0 / 4 (0.00%)

0 / 3 (0.00%)

0 / 6 (0.00%)

0 / 44 (0.00%)

0 / 48 (0.00%)

0 / 52 (0.00%)

1 / 59 (1.69%)

0 / 28 (0.00%)

0 / 84 (0.00%)

0 / 21 (0.00%)

1 / 292 (0.34%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

deaths causally related to treatment / all

0 / 0

Pyelonephritis

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 5 (0.00%)

0 / 7 (0.00%)

0 / 8 (0.00%)

0 / 4 (0.00%)

0 / 3 (0.00%)

0 / 6 (0.00%)

0 / 44 (0.00%)

0 / 48 (0.00%)

0 / 52 (0.00%)

0 / 59 (0.00%)

2 / 28 (7.14%)

0 / 84 (0.00%)

0 / 21 (0.00%)

2 / 292 (0.68%)

occurrences causally related to treatment / all

0 / 0

1 / 2

0 / 0

1 / 2

deaths causally related to treatment / all

0 / 0

Pyelonephritis acute

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 5 (0.00%)

0 / 7 (0.00%)

0 / 8 (0.00%)

0 / 4 (0.00%)

0 / 3 (0.00%)

0 / 6 (0.00%)

0 / 44 (0.00%)

0 / 48 (0.00%)

0 / 52 (0.00%)

1 / 59 (1.69%)

0 / 28 (0.00%)

0 / 84 (0.00%)

0 / 21 (0.00%)

1 / 292 (0.34%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

deaths causally related to treatment / all

0 / 0

Respiratory tract infection

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 5 (0.00%)

0 / 7 (0.00%)

0 / 8 (0.00%)

0 / 4 (0.00%)

0 / 3 (0.00%)

0 / 6 (0.00%)

0 / 44 (0.00%)

0 / 48 (0.00%)

0 / 52 (0.00%)

0 / 59 (0.00%)

0 / 28 (0.00%)

2 / 84 (2.38%)

0 / 21 (0.00%)

2 / 292 (0.68%)

occurrences causally related to treatment / all

0 / 0

0 / 2

0 / 0

0 / 2

deaths causally related to treatment / all

0 / 0

Sepsis

subjects affected / exposed

1 / 5 (20.00%)

0 / 3 (0.00%)

0 / 5 (0.00%)

0 / 7 (0.00%)

0 / 8 (0.00%)

0 / 4 (0.00%)

0 / 3 (0.00%)

2 / 6 (33.33%)

3 / 44 (6.82%)

1 / 48 (2.08%)

1 / 52 (1.92%)

0 / 59 (0.00%)

0 / 28 (0.00%)

2 / 84 (2.38%)

0 / 21 (0.00%)

4 / 292 (1.37%)

occurrences causally related to treatment / all

0 / 1

0 / 0

0 / 2

0 / 3

0 / 1

0 / 0

1 / 2

0 / 0

1 / 4

deaths causally related to treatment / all

0 / 0

1 / 2

0 / 0

1 / 2

Septic shock

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 5 (0.00%)

0 / 7 (0.00%)

0 / 8 (0.00%)

0 / 4 (0.00%)

0 / 3 (0.00%)

0 / 6 (0.00%)

0 / 44 (0.00%)

2 / 48 (4.17%)

0 / 52 (0.00%)

0 / 59 (0.00%)

0 / 28 (0.00%)

1 / 84 (1.19%)

0 / 21 (0.00%)

3 / 292 (1.03%)

occurrences causally related to treatment / all

0 / 0

1 / 2

0 / 0

0 / 1

0 / 0

1 / 3

deaths causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

Streptococcal sepsis

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 5 (0.00%)

0 / 7 (0.00%)

0 / 8 (0.00%)

0 / 4 (0.00%)

0 / 3 (0.00%)

0 / 6 (0.00%)

0 / 44 (0.00%)

0 / 48 (0.00%)

0 / 52 (0.00%)

0 / 59 (0.00%)

0 / 28 (0.00%)

1 / 84 (1.19%)

0 / 21 (0.00%)

1 / 292 (0.34%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

1 / 1

deaths causally related to treatment / all

0 / 0

Tooth infection

subjects affected / exposed

0 / 5 (0.00%)

1 / 3 (33.33%)

0 / 5 (0.00%)

0 / 7 (0.00%)

0 / 8 (0.00%)

0 / 4 (0.00%)

0 / 3 (0.00%)

0 / 6 (0.00%)

1 / 44 (2.27%)

0 / 48 (0.00%)

0 / 52 (0.00%)

0 / 59 (0.00%)

0 / 28 (0.00%)

0 / 84 (0.00%)

0 / 21 (0.00%)

0 / 292 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Urinary tract infection

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 5 (0.00%)

0 / 7 (0.00%)

0 / 8 (0.00%)

1 / 4 (25.00%)

0 / 3 (0.00%)

0 / 6 (0.00%)

1 / 44 (2.27%)

2 / 48 (4.17%)

0 / 52 (0.00%)

1 / 59 (1.69%)

1 / 28 (3.57%)

2 / 84 (2.38%)

0 / 21 (0.00%)

6 / 292 (2.05%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

0 / 2

0 / 0

0 / 1

0 / 2

0 / 0

0 / 6

deaths causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

Urosepsis

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 5 (0.00%)

0 / 7 (0.00%)

0 / 8 (0.00%)

0 / 4 (0.00%)

0 / 3 (0.00%)

0 / 6 (0.00%)

0 / 44 (0.00%)

0 / 48 (0.00%)

1 / 52 (1.92%)

0 / 59 (0.00%)

0 / 28 (0.00%)

0 / 84 (0.00%)

0 / 21 (0.00%)

1 / 292 (0.34%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

deaths causally related to treatment / all

0 / 0

Viral infection

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 5 (0.00%)

0 / 7 (0.00%)

0 / 8 (0.00%)

0 / 4 (0.00%)

0 / 3 (0.00%)

0 / 6 (0.00%)

0 / 44 (0.00%)

0 / 48 (0.00%)

0 / 52 (0.00%)

0 / 59 (0.00%)

0 / 28 (0.00%)

1 / 84 (1.19%)

1 / 21 (4.76%)

2 / 292 (0.68%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 2

deaths causally related to treatment / all

0 / 0

Metabolism and nutrition disorders

Decreased appetite

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

1 / 5 (20.00%)

0 / 7 (0.00%)

0 / 8 (0.00%)

0 / 4 (0.00%)

0 / 3 (0.00%)

0 / 6 (0.00%)

1 / 44 (2.27%)

0 / 48 (0.00%)

0 / 52 (0.00%)

0 / 59 (0.00%)

0 / 28 (0.00%)

0 / 84 (0.00%)

1 / 21 (4.76%)

1 / 292 (0.34%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

1 / 1

deaths causally related to treatment / all

0 / 0

Failure to thrive

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

1 / 5 (20.00%)

0 / 7 (0.00%)

0 / 8 (0.00%)

0 / 4 (0.00%)

0 / 3 (0.00%)

0 / 6 (0.00%)

1 / 44 (2.27%)

0 / 48 (0.00%)

0 / 52 (0.00%)

0 / 59 (0.00%)

0 / 28 (0.00%)

0 / 84 (0.00%)

0 / 21 (0.00%)

0 / 292 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Dehydration

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 5 (0.00%)

0 / 7 (0.00%)

0 / 8 (0.00%)

0 / 4 (0.00%)

0 / 3 (0.00%)

1 / 6 (16.67%)

1 / 44 (2.27%)

0 / 48 (0.00%)

0 / 52 (0.00%)

0 / 59 (0.00%)

0 / 28 (0.00%)

0 / 84 (0.00%)

0 / 21 (0.00%)

0 / 292 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Gout

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 5 (0.00%)

0 / 7 (0.00%)

0 / 8 (0.00%)

0 / 4 (0.00%)

0 / 3 (0.00%)

0 / 6 (0.00%)

0 / 44 (0.00%)

0 / 48 (0.00%)

0 / 52 (0.00%)

0 / 59 (0.00%)

1 / 28 (3.57%)

0 / 84 (0.00%)

0 / 21 (0.00%)

1 / 292 (0.34%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

deaths causally related to treatment / all

0 / 0

Hypercalcaemia

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

1 / 5 (20.00%)

0 / 7 (0.00%)

0 / 8 (0.00%)

0 / 4 (0.00%)

0 / 3 (0.00%)

0 / 6 (0.00%)

1 / 44 (2.27%)

0 / 48 (0.00%)

0 / 52 (0.00%)

0 / 59 (0.00%)

0 / 28 (0.00%)

0 / 84 (0.00%)

0 / 21 (0.00%)

0 / 292 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Hyperglycaemia

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 5 (0.00%)

0 / 7 (0.00%)

0 / 8 (0.00%)

0 / 4 (0.00%)

0 / 3 (0.00%)

0 / 6 (0.00%)

0 / 44 (0.00%)

1 / 48 (2.08%)

0 / 52 (0.00%)

0 / 59 (0.00%)

1 / 28 (3.57%)

0 / 84 (0.00%)

0 / 21 (0.00%)

2 / 292 (0.68%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

1 / 1

0 / 0

2 / 2

deaths causally related to treatment / all

0 / 0

Hyponatraemia

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 5 (0.00%)

0 / 7 (0.00%)

0 / 8 (0.00%)

0 / 4 (0.00%)

0 / 3 (0.00%)

0 / 6 (0.00%)

0 / 44 (0.00%)

1 / 48 (2.08%)

2 / 52 (3.85%)

1 / 59 (1.69%)

0 / 28 (0.00%)

1 / 84 (1.19%)

0 / 21 (0.00%)

5 / 292 (1.71%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 2

0 / 1

0 / 0

1 / 1

0 / 0

1 / 5

deaths causally related to treatment / all

0 / 0

Hyperkalaemia

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 5 (0.00%)

0 / 7 (0.00%)

0 / 8 (0.00%)

0 / 4 (0.00%)

0 / 3 (0.00%)

1 / 6 (16.67%)

1 / 44 (2.27%)

2 / 48 (4.17%)

1 / 52 (1.92%)

0 / 59 (0.00%)

1 / 28 (3.57%)

0 / 84 (0.00%)

0 / 21 (0.00%)

4 / 292 (1.37%)

occurrences causally related to treatment / all

0 / 0

0 / 1

2 / 2

0 / 1

0 / 0

0 / 2

0 / 0

2 / 5

deaths causally related to treatment / all

0 / 0

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

Non-serious adverse events	Phase 1 120 mg capsule PO daily	Phase 1 24 mg capsule PO daily	Phase 1 48 mg capsule PO daily	Phase 1 400 mg capsule PO daily	Phase 1 225 mg tablet PO daily	Phase 1 300 mg capsule PO daily	Phase 1 230 mg capsule PO daily	Phase 1 170 mg capsule PO daily	Phase 1 275 mg tablet PO daily	Phase 1 overall	Phase 2 Arm 1 1A	Phase 2 Arm 1 1B	Phase 2 Arm 2 2A	Phase 2 Arm 2 2B	Phase 2 Arm 3	Phase 2 Arm 4	Phase 2 Overall
Total subjects affected by non serious adverse events
subjects affected / exposed	5 / 5 (100.00%)	3 / 3 (100.00%)	5 / 5 (100.00%)	7 / 7 (100.00%)	8 / 8 (100.00%)	4 / 4 (100.00%)	3 / 3 (100.00%)	3 / 3 (100.00%)	5 / 6 (83.33%)	43 / 44 (97.73%)	48 / 48 (100.00%)	50 / 52 (96.15%)	58 / 59 (98.31%)	28 / 28 (100.00%)	84 / 84 (100.00%)	21 / 21 (100.00%)	289 / 292 (98.97%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Basal cell carcinoma
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 44 (0.00%)	0 / 48 (0.00%)	1 / 52 (1.92%)	3 / 59 (5.08%)	0 / 28 (0.00%)	1 / 84 (1.19%)	0 / 21 (0.00%)	5 / 292 (1.71%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	3	3	0	3	0	9
Squamous cell carcinoma
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 44 (0.00%)	0 / 48 (0.00%)	1 / 52 (1.92%)	3 / 59 (5.08%)	1 / 28 (3.57%)	2 / 84 (2.38%)	1 / 21 (4.76%)	8 / 292 (2.74%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	1	3	1	2	2	9
Vascular disorders
Flushing
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 44 (0.00%)	0 / 48 (0.00%)	1 / 52 (1.92%)	0 / 59 (0.00%)	2 / 28 (7.14%)	0 / 84 (0.00%)	1 / 21 (4.76%)	4 / 292 (1.37%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	1	0	2	0	1	4
Haematoma
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	2 / 3 (66.67%)	0 / 3 (0.00%)	0 / 6 (0.00%)	2 / 44 (4.55%)	0 / 48 (0.00%)	3 / 52 (5.77%)	1 / 59 (1.69%)	3 / 28 (10.71%)	4 / 84 (4.76%)	1 / 21 (4.76%)	12 / 292 (4.11%)
occurrences all number	0	0	0	0	0	0	2	0	0	2	0	3	1	3	5	1	13
Hypertension
subjects affected / exposed	1 / 5 (20.00%)	0 / 3 (0.00%)	1 / 5 (20.00%)	1 / 7 (14.29%)	0 / 8 (0.00%)	0 / 4 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 6 (0.00%)	4 / 44 (9.09%)	1 / 48 (2.08%)	4 / 52 (7.69%)	3 / 59 (5.08%)	0 / 28 (0.00%)	6 / 84 (7.14%)	2 / 21 (9.52%)	16 / 292 (5.48%)
occurrences all number	1	0	1	1	0	0	1	0	0	4	1	5	8	0	10	3	27
Hot flush
subjects affected / exposed	0 / 5 (0.00%)	1 / 3 (33.33%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 6 (0.00%)	2 / 44 (4.55%)	0 / 48 (0.00%)	1 / 52 (1.92%)	1 / 59 (1.69%)	2 / 28 (7.14%)	1 / 84 (1.19%)	1 / 21 (4.76%)	6 / 292 (2.05%)
occurrences all number	0	1	0	0	0	0	1	0	0	2	0	1	1	2	1	1	6
Hypotension
subjects affected / exposed	1 / 5 (20.00%)	0 / 3 (0.00%)	1 / 5 (20.00%)	0 / 7 (0.00%)	1 / 8 (12.50%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 6 (16.67%)	4 / 44 (9.09%)	0 / 48 (0.00%)	3 / 52 (5.77%)	3 / 59 (5.08%)	0 / 28 (0.00%)	1 / 84 (1.19%)	0 / 21 (0.00%)	7 / 292 (2.40%)
occurrences all number	1	0	1	0	1	0	0	0	1	4	0	3	3	0	1	0	7
General disorders and administration site conditions
Chest pain
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 8 (0.00%)	1 / 4 (25.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 44 (2.27%)	0 / 48 (0.00%)	1 / 52 (1.92%)	1 / 59 (1.69%)	0 / 28 (0.00%)	0 / 84 (0.00%)	2 / 21 (9.52%)	4 / 292 (1.37%)
occurrences all number	0	0	0	0	0	1	0	0	0	1	0	1	1	0	0	2	4
Asthenia
subjects affected / exposed	2 / 5 (40.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	2 / 7 (28.57%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	4 / 44 (9.09%)	9 / 48 (18.75%)	3 / 52 (5.77%)	8 / 59 (13.56%)	3 / 28 (10.71%)	7 / 84 (8.33%)	0 / 21 (0.00%)	30 / 292 (10.27%)
occurrences all number	2	0	0	2	0	0	0	0	0	4	9	3	15	4	11	0	42
Chills
subjects affected / exposed	0 / 5 (0.00%)	1 / 3 (33.33%)	0 / 5 (0.00%)	0 / 7 (0.00%)	1 / 8 (12.50%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	2 / 44 (4.55%)	1 / 48 (2.08%)	2 / 52 (3.85%)	2 / 59 (3.39%)	6 / 28 (21.43%)	10 / 84 (11.90%)	0 / 21 (0.00%)	21 / 292 (7.19%)
occurrences all number	0	1	0	0	1	0	0	0	0	2	1	2	2	9	11	0	25
Early satiety
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 44 (0.00%)	2 / 48 (4.17%)	4 / 52 (7.69%)	0 / 59 (0.00%)	0 / 28 (0.00%)	5 / 84 (5.95%)	0 / 21 (0.00%)	11 / 292 (3.77%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	3	5	0	0	5	0	13
Fatigue
subjects affected / exposed	4 / 5 (80.00%)	2 / 3 (66.67%)	3 / 5 (60.00%)	5 / 7 (71.43%)	3 / 8 (37.50%)	0 / 4 (0.00%)	0 / 3 (0.00%)	2 / 3 (66.67%)	1 / 6 (16.67%)	20 / 44 (45.45%)	14 / 48 (29.17%)	17 / 52 (32.69%)	13 / 59 (22.03%)	13 / 28 (46.43%)	27 / 84 (32.14%)	5 / 21 (23.81%)	89 / 292 (30.48%)
occurrences all number	4	2	4	6	3	0	0	2	2	23	18	19	17	15	44	11	124
Gait disturbance
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 44 (0.00%)	0 / 48 (0.00%)	0 / 52 (0.00%)	0 / 59 (0.00%)	2 / 28 (7.14%)	1 / 84 (1.19%)	0 / 21 (0.00%)	3 / 292 (1.03%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	0	0	2	1	0	3
Malaise
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 6 (16.67%)	1 / 44 (2.27%)	1 / 48 (2.08%)	2 / 52 (3.85%)	2 / 59 (3.39%)	2 / 28 (7.14%)	3 / 84 (3.57%)	0 / 21 (0.00%)	10 / 292 (3.42%)
occurrences all number	0	0	0	0	0	0	0	0	1	1	1	2	2	2	3	0	10
Influenza like illness
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 44 (0.00%)	3 / 48 (6.25%)	2 / 52 (3.85%)	0 / 59 (0.00%)	3 / 28 (10.71%)	4 / 84 (4.76%)	1 / 21 (4.76%)	13 / 292 (4.45%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	5	2	0	7	6	2	22
Mucosal inflammation
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	1 / 5 (20.00%)	0 / 7 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 6 (0.00%)	2 / 44 (4.55%)	0 / 48 (0.00%)	0 / 52 (0.00%)	0 / 59 (0.00%)	0 / 28 (0.00%)	1 / 84 (1.19%)	0 / 21 (0.00%)	1 / 292 (0.34%)
occurrences all number	0	0	1	0	0	0	0	1	0	2	0	0	0	0	2	0	2
Nodule
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 6 (0.00%)	1 / 44 (2.27%)	0 / 48 (0.00%)	1 / 52 (1.92%)	0 / 59 (0.00%)	1 / 28 (3.57%)	1 / 84 (1.19%)	0 / 21 (0.00%)	3 / 292 (1.03%)
occurrences all number	0	0	0	0	0	0	0	1	0	1	0	1	0	1	1	0	3
Non-cardiac chest pain
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	1 / 8 (12.50%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 44 (2.27%)	2 / 48 (4.17%)	1 / 52 (1.92%)	1 / 59 (1.69%)	5 / 28 (17.86%)	5 / 84 (5.95%)	2 / 21 (9.52%)	16 / 292 (5.48%)
occurrences all number	0	0	0	0	1	0	0	0	0	1	3	1	2	5	8	3	22
Oedema peripheral
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	3 / 5 (60.00%)	1 / 7 (14.29%)	2 / 8 (25.00%)	1 / 4 (25.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	2 / 6 (33.33%)	9 / 44 (20.45%)	13 / 48 (27.08%)	8 / 52 (15.38%)	12 / 59 (20.34%)	6 / 28 (21.43%)	12 / 84 (14.29%)	0 / 21 (0.00%)	51 / 292 (17.47%)
occurrences all number	0	0	3	1	2	1	0	0	2	9	13	11	15	7	12	0	58
Pain
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 6 (16.67%)	1 / 44 (2.27%)	1 / 48 (2.08%)	0 / 52 (0.00%)	2 / 59 (3.39%)	0 / 28 (0.00%)	2 / 84 (2.38%)	0 / 21 (0.00%)	5 / 292 (1.71%)
occurrences all number	0	0	0	0	0	0	0	0	1	1	1	0	2	0	3	0	6
Pyrexia
subjects affected / exposed	1 / 5 (20.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	2 / 7 (28.57%)	0 / 8 (0.00%)	1 / 4 (25.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 6 (16.67%)	5 / 44 (11.36%)	8 / 48 (16.67%)	6 / 52 (11.54%)	8 / 59 (13.56%)	6 / 28 (21.43%)	14 / 84 (16.67%)	2 / 21 (9.52%)	44 / 292 (15.07%)
occurrences all number	1	0	0	2	0	1	0	0	1	5	10	8	9	9	17	3	56
Peripheral swelling
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 44 (0.00%)	3 / 48 (6.25%)	0 / 52 (0.00%)	0 / 59 (0.00%)	0 / 28 (0.00%)	1 / 84 (1.19%)	0 / 21 (0.00%)	4 / 292 (1.37%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	4	0	0	0	1	0	5
Reproductive system and breast disorders
Genital lesion
subjects affected / exposed	1 / 5 (20.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 44 (2.27%)	0 / 48 (0.00%)	0 / 52 (0.00%)	0 / 59 (0.00%)	0 / 28 (0.00%)	0 / 84 (0.00%)	0 / 21 (0.00%)	0 / 292 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0	0	1	0	0	0	0	0	0	0
Vaginal haemorrhage
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 6 (0.00%)	1 / 44 (2.27%)	0 / 48 (0.00%)	1 / 52 (1.92%)	0 / 59 (0.00%)	1 / 28 (3.57%)	1 / 84 (1.19%)	1 / 21 (4.76%)	4 / 292 (1.37%)
occurrences all number	0	0	0	0	0	0	0	1	0	1	0	1	0	1	1	1	4
Respiratory, thoracic and mediastinal disorders
Cough
subjects affected / exposed	1 / 5 (20.00%)	2 / 3 (66.67%)	0 / 5 (0.00%)	0 / 7 (0.00%)	1 / 8 (12.50%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	2 / 6 (33.33%)	6 / 44 (13.64%)	9 / 48 (18.75%)	11 / 52 (21.15%)	13 / 59 (22.03%)	14 / 28 (50.00%)	22 / 84 (26.19%)	4 / 21 (19.05%)	73 / 292 (25.00%)
occurrences all number	1	2	0	0	1	0	0	0	2	6	10	17	19	21	25	7	99
Dyspnoea
subjects affected / exposed	0 / 5 (0.00%)	1 / 3 (33.33%)	1 / 5 (20.00%)	0 / 7 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	1 / 6 (16.67%)	4 / 44 (9.09%)	11 / 48 (22.92%)	10 / 52 (19.23%)	9 / 59 (15.25%)	7 / 28 (25.00%)	20 / 84 (23.81%)	1 / 21 (4.76%)	58 / 292 (19.86%)
occurrences all number	0	1	1	0	0	0	1	0	1	4	14	12	11	7	21	1	66
Dyspnoea exertional
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 44 (0.00%)	1 / 48 (2.08%)	0 / 52 (0.00%)	2 / 59 (3.39%)	0 / 28 (0.00%)	5 / 84 (5.95%)	0 / 21 (0.00%)	8 / 292 (2.74%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	1	0	2	0	5	0	8
Epistaxis
subjects affected / exposed	1 / 5 (20.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	1 / 7 (14.29%)	3 / 8 (37.50%)	1 / 4 (25.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	6 / 44 (13.64%)	6 / 48 (12.50%)	7 / 52 (13.46%)	10 / 59 (16.95%)	9 / 28 (32.14%)	13 / 84 (15.48%)	2 / 21 (9.52%)	47 / 292 (16.10%)
occurrences all number	2	0	0	1	6	1	0	0	0	10	7	17	33	12	37	3	109
Hypoxia
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	1 / 5 (20.00%)	0 / 7 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 6 (16.67%)	2 / 44 (4.55%)	2 / 48 (4.17%)	0 / 52 (0.00%)	0 / 59 (0.00%)	1 / 28 (3.57%)	0 / 84 (0.00%)	0 / 21 (0.00%)	3 / 292 (1.03%)
occurrences all number	0	0	1	0	0	0	0	0	1	2	2	0	0	1	0	0	3
Nasal congestion
subjects affected / exposed	0 / 5 (0.00%)	1 / 3 (33.33%)	0 / 5 (0.00%)	0 / 7 (0.00%)	1 / 8 (12.50%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	2 / 44 (4.55%)	1 / 48 (2.08%)	1 / 52 (1.92%)	2 / 59 (3.39%)	2 / 28 (7.14%)	3 / 84 (3.57%)	1 / 21 (4.76%)	10 / 292 (3.42%)
occurrences all number	0	1	0	0	1	0	0	0	0	2	1	1	2	2	4	1	11
Oropharyngeal pain
subjects affected / exposed	0 / 5 (0.00%)	1 / 3 (33.33%)	0 / 5 (0.00%)	0 / 7 (0.00%)	1 / 8 (12.50%)	1 / 4 (25.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	3 / 44 (6.82%)	2 / 48 (4.17%)	2 / 52 (3.85%)	6 / 59 (10.17%)	5 / 28 (17.86%)	9 / 84 (10.71%)	2 / 21 (9.52%)	26 / 292 (8.90%)
occurrences all number	0	1	0	0	1	1	0	0	0	3	2	2	8	6	12	2	32
Pleural effusion
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 44 (2.27%)	1 / 48 (2.08%)	2 / 52 (3.85%)	2 / 59 (3.39%)	0 / 28 (0.00%)	2 / 84 (2.38%)	0 / 21 (0.00%)	7 / 292 (2.40%)
occurrences all number	0	0	0	0	0	0	1	0	0	1	1	2	2	0	2	0	7
Productive cough
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 44 (0.00%)	3 / 48 (6.25%)	2 / 52 (3.85%)	3 / 59 (5.08%)	1 / 28 (3.57%)	3 / 84 (3.57%)	0 / 21 (0.00%)	12 / 292 (4.11%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	3	2	4	1	3	0	13
Rhinorrhoea
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 44 (0.00%)	2 / 48 (4.17%)	2 / 52 (3.85%)	0 / 59 (0.00%)	2 / 28 (7.14%)	4 / 84 (4.76%)	3 / 21 (14.29%)	13 / 292 (4.45%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	2	2	0	2	4	3	13
Pulmonary oedema
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 6 (16.67%)	1 / 44 (2.27%)	1 / 48 (2.08%)	1 / 52 (1.92%)	1 / 59 (1.69%)	0 / 28 (0.00%)	0 / 84 (0.00%)	0 / 21 (0.00%)	3 / 292 (1.03%)
occurrences all number	0	0	0	0	0	0	0	0	1	1	1	1	1	0	0	0	3
Sinus pain
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	1 / 5 (20.00%)	0 / 7 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 44 (2.27%)	0 / 48 (0.00%)	0 / 52 (0.00%)	0 / 59 (0.00%)	1 / 28 (3.57%)	0 / 84 (0.00%)	0 / 21 (0.00%)	1 / 292 (0.34%)
occurrences all number	0	0	1	0	0	0	0	0	0	1	0	0	0	1	0	0	1
Upper-airway cough syndrome
subjects affected / exposed	0 / 5 (0.00%)	1 / 3 (33.33%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 44 (2.27%)	1 / 48 (2.08%)	3 / 52 (5.77%)	6 / 59 (10.17%)	1 / 28 (3.57%)	3 / 84 (3.57%)	1 / 21 (4.76%)	15 / 292 (5.14%)
occurrences all number	0	1	0	0	0	0	0	0	0	1	1	3	6	1	3	1	15
Wheezing
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 6 (16.67%)	1 / 44 (2.27%)	0 / 48 (0.00%)	1 / 52 (1.92%)	1 / 59 (1.69%)	0 / 28 (0.00%)	1 / 84 (1.19%)	0 / 21 (0.00%)	3 / 292 (1.03%)
occurrences all number	0	0	0	0	0	0	0	0	1	1	0	1	1	0	1	0	3
Psychiatric disorders
Confusional state
subjects affected / exposed	0 / 5 (0.00%)	1 / 3 (33.33%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 44 (2.27%)	2 / 48 (4.17%)	1 / 52 (1.92%)	1 / 59 (1.69%)	0 / 28 (0.00%)	2 / 84 (2.38%)	1 / 21 (4.76%)	7 / 292 (2.40%)
occurrences all number	0	1	0	0	0	0	0	0	0	1	2	1	1	0	2	1	7
Anxiety
subjects affected / exposed	0 / 5 (0.00%)	2 / 3 (66.67%)	1 / 5 (20.00%)	0 / 7 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	3 / 44 (6.82%)	0 / 48 (0.00%)	1 / 52 (1.92%)	3 / 59 (5.08%)	1 / 28 (3.57%)	4 / 84 (4.76%)	0 / 21 (0.00%)	9 / 292 (3.08%)
occurrences all number	0	2	1	0	0	0	0	0	0	3	0	1	3	1	4	0	9
Delirium
subjects affected / exposed	1 / 5 (20.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 44 (2.27%)	0 / 48 (0.00%)	1 / 52 (1.92%)	1 / 59 (1.69%)	0 / 28 (0.00%)	1 / 84 (1.19%)	0 / 21 (0.00%)	3 / 292 (1.03%)
occurrences all number	1	0	0	0	0	0	0	0	0	1	0	1	1	0	1	0	3
Insomnia
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	1 / 5 (20.00%)	1 / 7 (14.29%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	2 / 44 (4.55%)	2 / 48 (4.17%)	4 / 52 (7.69%)	4 / 59 (6.78%)	3 / 28 (10.71%)	7 / 84 (8.33%)	2 / 21 (9.52%)	22 / 292 (7.53%)
occurrences all number	0	0	1	1	0	0	0	0	0	2	2	4	5	3	7	2	23
Depression
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	1 / 7 (14.29%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 44 (2.27%)	2 / 48 (4.17%)	0 / 52 (0.00%)	1 / 59 (1.69%)	3 / 28 (10.71%)	2 / 84 (2.38%)	0 / 21 (0.00%)	8 / 292 (2.74%)
occurrences all number	0	0	0	1	0	0	0	0	0	1	2	0	2	3	2	0	9
Investigations
Alanine aminotransferase increased
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	1 / 5 (20.00%)	2 / 7 (28.57%)	1 / 8 (12.50%)	0 / 4 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 6 (0.00%)	5 / 44 (11.36%)	1 / 48 (2.08%)	4 / 52 (7.69%)	5 / 59 (8.47%)	6 / 28 (21.43%)	8 / 84 (9.52%)	0 / 21 (0.00%)	24 / 292 (8.22%)
occurrences all number	0	0	1	2	1	0	0	1	0	5	1	4	10	6	10	0	31
Activated partial thromboplastin time prolonged
subjects affected / exposed	1 / 5 (20.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 44 (2.27%)	0 / 48 (0.00%)	2 / 52 (3.85%)	0 / 59 (0.00%)	0 / 28 (0.00%)	0 / 84 (0.00%)	0 / 21 (0.00%)	2 / 292 (0.68%)
occurrences all number	1	0	0	0	0	0	0	0	0	1	0	2	0	0	0	0	2
Aspartate aminotransferase increased
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	1 / 5 (20.00%)	1 / 7 (14.29%)	1 / 8 (12.50%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	3 / 44 (6.82%)	3 / 48 (6.25%)	4 / 52 (7.69%)	5 / 59 (8.47%)	5 / 28 (17.86%)	6 / 84 (7.14%)	1 / 21 (4.76%)	24 / 292 (8.22%)
occurrences all number	0	0	1	2	1	0	0	0	0	4	3	4	10	5	7	1	30
Blast cell count increased
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 44 (0.00%)	0 / 48 (0.00%)	0 / 52 (0.00%)	1 / 59 (1.69%)	2 / 28 (7.14%)	2 / 84 (2.38%)	0 / 21 (0.00%)	5 / 292 (1.71%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	0	1	2	2	0	5
Bilirubin conjugated increased
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 44 (0.00%)	1 / 48 (2.08%)	0 / 52 (0.00%)	2 / 59 (3.39%)	2 / 28 (7.14%)	1 / 84 (1.19%)	0 / 21 (0.00%)	6 / 292 (2.05%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	1	0	2	3	1	0	7
Blood alkaline phosphatase increased
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	1 / 7 (14.29%)	1 / 8 (12.50%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	2 / 44 (4.55%)	3 / 48 (6.25%)	2 / 52 (3.85%)	0 / 59 (0.00%)	3 / 28 (10.71%)	5 / 84 (5.95%)	0 / 21 (0.00%)	13 / 292 (4.45%)
occurrences all number	0	0	0	2	1	0	0	0	0	3	4	2	0	3	5	0	14
Blood bilirubin increased
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	1 / 7 (14.29%)	1 / 8 (12.50%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	2 / 44 (4.55%)	3 / 48 (6.25%)	1 / 52 (1.92%)	5 / 59 (8.47%)	4 / 28 (14.29%)	5 / 84 (5.95%)	2 / 21 (9.52%)	20 / 292 (6.85%)
occurrences all number	0	0	0	1	1	0	0	0	0	2	3	1	5	4	8	4	25
Blood creatinine increased
subjects affected / exposed	1 / 5 (20.00%)	0 / 3 (0.00%)	1 / 5 (20.00%)	1 / 7 (14.29%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 6 (16.67%)	4 / 44 (9.09%)	3 / 48 (6.25%)	4 / 52 (7.69%)	5 / 59 (8.47%)	1 / 28 (3.57%)	11 / 84 (13.10%)	1 / 21 (4.76%)	25 / 292 (8.56%)
occurrences all number	1	0	1	2	0	0	0	0	1	5	3	5	6	1	15	1	31
Blood phosphorus increased
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	1 / 8 (12.50%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 44 (2.27%)	0 / 48 (0.00%)	0 / 52 (0.00%)	0 / 59 (0.00%)	0 / 28 (0.00%)	1 / 84 (1.19%)	0 / 21 (0.00%)	1 / 292 (0.34%)
occurrences all number	0	0	0	0	1	0	0	0	0	1	0	0	0	0	1	0	1
Blood uric acid increased
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	1 / 5 (20.00%)	0 / 7 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 44 (2.27%)	1 / 48 (2.08%)	0 / 52 (0.00%)	2 / 59 (3.39%)	0 / 28 (0.00%)	0 / 84 (0.00%)	0 / 21 (0.00%)	3 / 292 (1.03%)
occurrences all number	0	0	1	0	0	0	0	0	0	1	1	0	2	0	0	0	3
Cardiac murmur
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 44 (0.00%)	0 / 48 (0.00%)	2 / 52 (3.85%)	0 / 59 (0.00%)	2 / 28 (7.14%)	0 / 84 (0.00%)	1 / 21 (4.76%)	5 / 292 (1.71%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	2	0	3	0	1	6
Ejection fraction decreased
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	1 / 5 (20.00%)	0 / 7 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 44 (2.27%)	0 / 48 (0.00%)	1 / 52 (1.92%)	1 / 59 (1.69%)	0 / 28 (0.00%)	0 / 84 (0.00%)	0 / 21 (0.00%)	2 / 292 (0.68%)
occurrences all number	0	0	1	0	0	0	0	0	0	1	0	1	1	0	0	0	2
Electrocardiogram QRS complex abnormal
subjects affected / exposed	0 / 5 (0.00%)	1 / 3 (33.33%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 44 (2.27%)	0 / 48 (0.00%)	0 / 52 (0.00%)	0 / 59 (0.00%)	0 / 28 (0.00%)	0 / 84 (0.00%)	0 / 21 (0.00%)	0 / 292 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0	1	0	0	0	0	0	0	0
Electrocardiogram QT prolonged
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	1 / 5 (20.00%)	0 / 7 (0.00%)	1 / 8 (12.50%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	2 / 44 (4.55%)	0 / 48 (0.00%)	1 / 52 (1.92%)	0 / 59 (0.00%)	0 / 28 (0.00%)	1 / 84 (1.19%)	0 / 21 (0.00%)	2 / 292 (0.68%)
occurrences all number	0	0	1	0	1	0	0	0	0	2	0	1	0	0	1	0	2
Haematocrit increased
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 44 (0.00%)	0 / 48 (0.00%)	0 / 52 (0.00%)	0 / 59 (0.00%)	0 / 28 (0.00%)	0 / 84 (0.00%)	2 / 21 (9.52%)	2 / 292 (0.68%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	8	8
International normalised ratio increased
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	1 / 8 (12.50%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 44 (2.27%)	1 / 48 (2.08%)	2 / 52 (3.85%)	0 / 59 (0.00%)	0 / 28 (0.00%)	2 / 84 (2.38%)	0 / 21 (0.00%)	5 / 292 (1.71%)
occurrences all number	0	0	0	0	1	0	0	0	0	1	1	2	0	0	2	0	5
Lymphocyte count decreased
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	1 / 7 (14.29%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 44 (2.27%)	0 / 48 (0.00%)	1 / 52 (1.92%)	2 / 59 (3.39%)	0 / 28 (0.00%)	1 / 84 (1.19%)	0 / 21 (0.00%)	4 / 292 (1.37%)
occurrences all number	0	0	0	4	0	0	0	0	0	4	0	2	6	0	1	0	9
Neutrophil count decreased
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	2 / 7 (28.57%)	1 / 8 (12.50%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 6 (16.67%)	4 / 44 (9.09%)	0 / 48 (0.00%)	0 / 52 (0.00%)	1 / 59 (1.69%)	0 / 28 (0.00%)	4 / 84 (4.76%)	0 / 21 (0.00%)	5 / 292 (1.71%)
occurrences all number	0	0	0	5	2	0	0	0	1	8	0	0	1	0	12	0	13
Platelet count decreased
subjects affected / exposed	0 / 5 (0.00%)	2 / 3 (66.67%)	0 / 5 (0.00%)	2 / 7 (28.57%)	2 / 8 (25.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	1 / 6 (16.67%)	8 / 44 (18.18%)	5 / 48 (10.42%)	8 / 52 (15.38%)	11 / 59 (18.64%)	8 / 28 (28.57%)	22 / 84 (26.19%)	2 / 21 (9.52%)	56 / 292 (19.18%)
occurrences all number	0	3	0	2	2	0	0	1	1	9	8	12	22	13	37	2	94
Transaminases increased
subjects affected / exposed	1 / 5 (20.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 44 (2.27%)	0 / 48 (0.00%)	0 / 52 (0.00%)	0 / 59 (0.00%)	0 / 28 (0.00%)	0 / 84 (0.00%)	0 / 21 (0.00%)	0 / 292 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0	0	1	0	0	0	0	0	0	0
Troponin T increased
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 6 (16.67%)	1 / 44 (2.27%)	0 / 48 (0.00%)	0 / 52 (0.00%)	1 / 59 (1.69%)	0 / 28 (0.00%)	0 / 84 (0.00%)	0 / 21 (0.00%)	1 / 292 (0.34%)
occurrences all number	0	0	0	0	0	0	0	0	1	1	0	0	1	0	0	0	1
Weight decreased
subjects affected / exposed	0 / 5 (0.00%)	1 / 3 (33.33%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 8 (0.00%)	1 / 4 (25.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	3 / 6 (50.00%)	5 / 44 (11.36%)	9 / 48 (18.75%)	14 / 52 (26.92%)	8 / 59 (13.56%)	2 / 28 (7.14%)	2 / 84 (2.38%)	4 / 21 (19.05%)	39 / 292 (13.36%)
occurrences all number	0	1	0	0	0	1	0	0	5	7	9	16	8	2	2	4	41
Weight increased
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	1 / 8 (12.50%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 44 (2.27%)	0 / 48 (0.00%)	4 / 52 (7.69%)	0 / 59 (0.00%)	0 / 28 (0.00%)	4 / 84 (4.76%)	0 / 21 (0.00%)	8 / 292 (2.74%)
occurrences all number	0	0	0	0	1	0	0	0	0	1	0	5	0	0	4	0	9
White blood cell count decreased
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	2 / 7 (28.57%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	2 / 44 (4.55%)	1 / 48 (2.08%)	0 / 52 (0.00%)	5 / 59 (8.47%)	0 / 28 (0.00%)	4 / 84 (4.76%)	0 / 21 (0.00%)	10 / 292 (3.42%)
occurrences all number	0	0	0	7	0	0	0	0	0	7	2	0	5	0	10	0	17
Injury, poisoning and procedural complications
Contusion
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 6 (0.00%)	1 / 44 (2.27%)	4 / 48 (8.33%)	9 / 52 (17.31%)	9 / 59 (15.25%)	8 / 28 (28.57%)	16 / 84 (19.05%)	2 / 21 (9.52%)	48 / 292 (16.44%)
occurrences all number	0	0	0	0	0	0	0	1	0	1	4	11	11	11	21	4	62
Fall
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	1 / 8 (12.50%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 44 (2.27%)	3 / 48 (6.25%)	10 / 52 (19.23%)	4 / 59 (6.78%)	7 / 28 (25.00%)	9 / 84 (10.71%)	0 / 21 (0.00%)	33 / 292 (11.30%)
occurrences all number	0	0	0	0	1	0	0	0	0	1	3	12	4	10	15	0	44
Nail injury
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 44 (0.00%)	0 / 48 (0.00%)	0 / 52 (0.00%)	0 / 59 (0.00%)	0 / 28 (0.00%)	0 / 84 (0.00%)	2 / 21 (9.52%)	2 / 292 (0.68%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	3	3
Procedural pain
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 44 (2.27%)	0 / 48 (0.00%)	1 / 52 (1.92%)	1 / 59 (1.69%)	2 / 28 (7.14%)	1 / 84 (1.19%)	1 / 21 (4.76%)	6 / 292 (2.05%)
occurrences all number	0	0	0	0	0	0	1	0	0	1	0	1	1	2	1	1	6
Procedural site reaction
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	1 / 7 (14.29%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 44 (2.27%)	0 / 48 (0.00%)	0 / 52 (0.00%)	0 / 59 (0.00%)	0 / 28 (0.00%)	0 / 84 (0.00%)	0 / 21 (0.00%)	0 / 292 (0.00%)
occurrences all number	0	0	0	2	0	0	0	0	0	2	0	0	0	0	0	0	0
Skin laceration
subjects affected / exposed	1 / 5 (20.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 44 (2.27%)	2 / 48 (4.17%)	1 / 52 (1.92%)	1 / 59 (1.69%)	0 / 28 (0.00%)	1 / 84 (1.19%)	0 / 21 (0.00%)	5 / 292 (1.71%)
occurrences all number	1	0	0	0	0	0	0	0	0	1	2	1	2	0	1	0	6
Vascular access site complication
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 8 (0.00%)	1 / 4 (25.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 44 (2.27%)	0 / 48 (0.00%)	0 / 52 (0.00%)	0 / 59 (0.00%)	0 / 28 (0.00%)	0 / 84 (0.00%)	0 / 21 (0.00%)	0 / 292 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0	0	1	0	0	0	0	0	0	0
Wound
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 44 (0.00%)	0 / 48 (0.00%)	3 / 52 (5.77%)	2 / 59 (3.39%)	1 / 28 (3.57%)	1 / 84 (1.19%)	0 / 21 (0.00%)	7 / 292 (2.40%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	3	2	1	1	0	7
Cardiac disorders
Atrial fibrillation
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	1 / 5 (20.00%)	0 / 7 (0.00%)	0 / 8 (0.00%)	1 / 4 (25.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 6 (0.00%)	3 / 44 (6.82%)	3 / 48 (6.25%)	1 / 52 (1.92%)	0 / 59 (0.00%)	0 / 28 (0.00%)	3 / 84 (3.57%)	0 / 21 (0.00%)	7 / 292 (2.40%)
occurrences all number	0	0	1	0	0	1	1	0	0	3	4	1	0	0	3	0	8
Angina pectoris
subjects affected / exposed	0 / 5 (0.00%)	1 / 3 (33.33%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 44 (2.27%)	1 / 48 (2.08%)	0 / 52 (0.00%)	0 / 59 (0.00%)	1 / 28 (3.57%)	1 / 84 (1.19%)	0 / 21 (0.00%)	3 / 292 (1.03%)
occurrences all number	0	1	0	0	0	0	0	0	0	1	1	0	0	1	1	0	3
Atrioventricular block
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	1 / 8 (12.50%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 44 (2.27%)	0 / 48 (0.00%)	0 / 52 (0.00%)	0 / 59 (0.00%)	0 / 28 (0.00%)	0 / 84 (0.00%)	0 / 21 (0.00%)	0 / 292 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0	0	1	0	0	0	0	0	0	0
Hyperdynamic left ventricle
subjects affected / exposed	1 / 5 (20.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 44 (2.27%)	0 / 48 (0.00%)	0 / 52 (0.00%)	0 / 59 (0.00%)	0 / 28 (0.00%)	0 / 84 (0.00%)	0 / 21 (0.00%)	0 / 292 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0	0	1	0	0	0	0	0	0	0
Palpitations
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 6 (16.67%)	1 / 44 (2.27%)	2 / 48 (4.17%)	3 / 52 (5.77%)	2 / 59 (3.39%)	1 / 28 (3.57%)	3 / 84 (3.57%)	3 / 21 (14.29%)	14 / 292 (4.79%)
occurrences all number	0	0	0	0	0	0	0	0	1	1	2	3	2	2	9	5	23
Sinus tachycardia
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	1 / 7 (14.29%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 44 (2.27%)	0 / 48 (0.00%)	2 / 52 (3.85%)	1 / 59 (1.69%)	0 / 28 (0.00%)	0 / 84 (0.00%)	0 / 21 (0.00%)	3 / 292 (1.03%)
occurrences all number	0	0	0	1	0	0	0	0	0	1	0	3	1	0	0	0	4
Tachycardia
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 6 (16.67%)	1 / 44 (2.27%)	0 / 48 (0.00%)	3 / 52 (5.77%)	0 / 59 (0.00%)	0 / 28 (0.00%)	2 / 84 (2.38%)	1 / 21 (4.76%)	6 / 292 (2.05%)
occurrences all number	0	0	0	0	0	0	0	0	1	1	0	3	0	0	2	1	6
Nervous system disorders
Ageusia
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 44 (0.00%)	0 / 48 (0.00%)	0 / 52 (0.00%)	1 / 59 (1.69%)	0 / 28 (0.00%)	0 / 84 (0.00%)	6 / 21 (28.57%)	7 / 292 (2.40%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	0	1	0	0	7	8
Cerebrovascular accident
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	1 / 5 (20.00%)	0 / 7 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 44 (2.27%)	0 / 48 (0.00%)	0 / 52 (0.00%)	0 / 59 (0.00%)	0 / 28 (0.00%)	0 / 84 (0.00%)	0 / 21 (0.00%)	0 / 292 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0	0	1	0	0	0	0	0	0	0
Dizziness
subjects affected / exposed	1 / 5 (20.00%)	1 / 3 (33.33%)	0 / 5 (0.00%)	1 / 7 (14.29%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	3 / 44 (6.82%)	7 / 48 (14.58%)	10 / 52 (19.23%)	13 / 59 (22.03%)	5 / 28 (17.86%)	21 / 84 (25.00%)	4 / 21 (19.05%)	60 / 292 (20.55%)
occurrences all number	1	1	0	1	0	0	0	0	0	3	8	14	16	6	30	4	78
Dysgeusia
subjects affected / exposed	1 / 5 (20.00%)	0 / 3 (0.00%)	1 / 5 (20.00%)	1 / 7 (14.29%)	3 / 8 (37.50%)	1 / 4 (25.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	1 / 6 (16.67%)	9 / 44 (20.45%)	10 / 48 (20.83%)	16 / 52 (30.77%)	16 / 59 (27.12%)	7 / 28 (25.00%)	21 / 84 (25.00%)	9 / 21 (42.86%)	79 / 292 (27.05%)
occurrences all number	1	0	1	1	3	1	0	1	1	9	12	18	23	7	23	12	95
Dysarthria
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	1 / 8 (12.50%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 44 (2.27%)	0 / 48 (0.00%)	0 / 52 (0.00%)	1 / 59 (1.69%)	0 / 28 (0.00%)	1 / 84 (1.19%)	0 / 21 (0.00%)	2 / 292 (0.68%)
occurrences all number	0	0	0	0	1	0	0	0	0	1	0	0	2	0	1	0	3
Hypoaesthesia
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 44 (0.00%)	0 / 48 (0.00%)	2 / 52 (3.85%)	0 / 59 (0.00%)	2 / 28 (7.14%)	2 / 84 (2.38%)	0 / 21 (0.00%)	6 / 292 (2.05%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	2	0	2	5	0	9
Headache
subjects affected / exposed	2 / 5 (40.00%)	0 / 3 (0.00%)	2 / 5 (40.00%)	2 / 7 (28.57%)	1 / 8 (12.50%)	0 / 4 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 6 (0.00%)	8 / 44 (18.18%)	6 / 48 (12.50%)	14 / 52 (26.92%)	6 / 59 (10.17%)	3 / 28 (10.71%)	19 / 84 (22.62%)	6 / 21 (28.57%)	54 / 292 (18.49%)
occurrences all number	2	0	2	2	1	0	0	1	0	8	7	25	6	6	24	11	79
Lethargy
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	1 / 7 (14.29%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 44 (2.27%)	1 / 48 (2.08%)	0 / 52 (0.00%)	1 / 59 (1.69%)	1 / 28 (3.57%)	1 / 84 (1.19%)	0 / 21 (0.00%)	4 / 292 (1.37%)
occurrences all number	0	0	0	1	0	0	0	0	0	1	1	0	1	2	2	0	6
Memory impairment
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 44 (0.00%)	0 / 48 (0.00%)	0 / 52 (0.00%)	0 / 59 (0.00%)	2 / 28 (7.14%)	0 / 84 (0.00%)	1 / 21 (4.76%)	3 / 292 (1.03%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	0	0	2	0	1	3
Myoclonus
subjects affected / exposed	1 / 5 (20.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 44 (2.27%)	0 / 48 (0.00%)	0 / 52 (0.00%)	0 / 59 (0.00%)	0 / 28 (0.00%)	0 / 84 (0.00%)	0 / 21 (0.00%)	0 / 292 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0	0	1	0	0	0	0	0	0	0
Migraine
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 44 (0.00%)	0 / 48 (0.00%)	3 / 52 (5.77%)	0 / 59 (0.00%)	0 / 28 (0.00%)	4 / 84 (4.76%)	1 / 21 (4.76%)	8 / 292 (2.74%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	3	0	0	4	1	8
Neuropathy peripheral
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	1 / 5 (20.00%)	0 / 7 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 44 (2.27%)	0 / 48 (0.00%)	3 / 52 (5.77%)	1 / 59 (1.69%)	1 / 28 (3.57%)	2 / 84 (2.38%)	0 / 21 (0.00%)	7 / 292 (2.40%)
occurrences all number	0	0	1	0	0	0	0	0	0	1	0	3	1	1	2	0	7
Paraesthesia
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 44 (0.00%)	2 / 48 (4.17%)	1 / 52 (1.92%)	5 / 59 (8.47%)	4 / 28 (14.29%)	4 / 84 (4.76%)	1 / 21 (4.76%)	17 / 292 (5.82%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	2	1	7	4	7	1	22
Presyncope
subjects affected / exposed	1 / 5 (20.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 44 (2.27%)	0 / 48 (0.00%)	0 / 52 (0.00%)	0 / 59 (0.00%)	0 / 28 (0.00%)	4 / 84 (4.76%)	3 / 21 (14.29%)	7 / 292 (2.40%)
occurrences all number	1	0	0	0	0	0	0	0	0	1	0	0	0	0	4	3	7
Sciatica
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 44 (0.00%)	0 / 48 (0.00%)	0 / 52 (0.00%)	3 / 59 (5.08%)	1 / 28 (3.57%)	4 / 84 (4.76%)	0 / 21 (0.00%)	8 / 292 (2.74%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	0	7	1	6	0	14
Syncope
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 6 (16.67%)	1 / 44 (2.27%)	0 / 48 (0.00%)	0 / 52 (0.00%)	0 / 59 (0.00%)	1 / 28 (3.57%)	3 / 84 (3.57%)	1 / 21 (4.76%)	5 / 292 (1.71%)
occurrences all number	0	0	0	0	0	0	0	0	1	1	0	0	0	2	3	1	6
Taste disorder
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 44 (0.00%)	1 / 48 (2.08%)	2 / 52 (3.85%)	0 / 59 (0.00%)	0 / 28 (0.00%)	2 / 84 (2.38%)	2 / 21 (9.52%)	7 / 292 (2.40%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	2	2	0	0	2	3	9
Blood and lymphatic system disorders
Leukocytosis
subjects affected / exposed	0 / 5 (0.00%)	1 / 3 (33.33%)	1 / 5 (20.00%)	0 / 7 (0.00%)	1 / 8 (12.50%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	3 / 44 (6.82%)	1 / 48 (2.08%)	2 / 52 (3.85%)	1 / 59 (1.69%)	2 / 28 (7.14%)	4 / 84 (4.76%)	1 / 21 (4.76%)	11 / 292 (3.77%)
occurrences all number	0	1	1	0	1	0	0	0	0	3	1	2	1	2	4	3	13
Anaemia
subjects affected / exposed	1 / 5 (20.00%)	1 / 3 (33.33%)	1 / 5 (20.00%)	4 / 7 (57.14%)	1 / 8 (12.50%)	1 / 4 (25.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	2 / 6 (33.33%)	12 / 44 (27.27%)	17 / 48 (35.42%)	15 / 52 (28.85%)	18 / 59 (30.51%)	7 / 28 (25.00%)	41 / 84 (48.81%)	1 / 21 (4.76%)	99 / 292 (33.90%)
occurrences all number	2	1	1	7	1	1	1	0	2	16	28	19	23	16	76	1	163
Lymphadenopathy
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	1 / 5 (20.00%)	0 / 7 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 44 (2.27%)	0 / 48 (0.00%)	0 / 52 (0.00%)	2 / 59 (3.39%)	0 / 28 (0.00%)	2 / 84 (2.38%)	0 / 21 (0.00%)	4 / 292 (1.37%)
occurrences all number	0	0	1	0	0	0	0	0	0	1	0	0	2	0	3	0	5
Neutropenia
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	1 / 5 (20.00%)	1 / 7 (14.29%)	0 / 8 (0.00%)	1 / 4 (25.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 6 (0.00%)	4 / 44 (9.09%)	1 / 48 (2.08%)	1 / 52 (1.92%)	10 / 59 (16.95%)	1 / 28 (3.57%)	2 / 84 (2.38%)	1 / 21 (4.76%)	16 / 292 (5.48%)
occurrences all number	0	0	1	1	0	1	0	1	0	4	1	1	17	2	3	1	25
Spleen disorder
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 44 (0.00%)	3 / 48 (6.25%)	1 / 52 (1.92%)	2 / 59 (3.39%)	0 / 28 (0.00%)	0 / 84 (0.00%)	0 / 21 (0.00%)	6 / 292 (2.05%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	3	1	2	0	0	0	6
Thrombocytopenia
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	1 / 5 (20.00%)	1 / 7 (14.29%)	0 / 8 (0.00%)	1 / 4 (25.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 6 (0.00%)	4 / 44 (9.09%)	18 / 48 (37.50%)	12 / 52 (23.08%)	25 / 59 (42.37%)	9 / 28 (32.14%)	32 / 84 (38.10%)	0 / 21 (0.00%)	96 / 292 (32.88%)
occurrences all number	0	0	1	1	0	1	0	1	0	4	34	16	55	21	53	0	179
Thrombocytosis
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 44 (0.00%)	0 / 48 (0.00%)	4 / 52 (7.69%)	0 / 59 (0.00%)	0 / 28 (0.00%)	0 / 84 (0.00%)	1 / 21 (4.76%)	5 / 292 (1.71%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	4	0	0	0	8	12
Ear and labyrinth disorders
Ear discomfort
subjects affected / exposed	0 / 5 (0.00%)	1 / 3 (33.33%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 44 (2.27%)	0 / 48 (0.00%)	0 / 52 (0.00%)	0 / 59 (0.00%)	0 / 28 (0.00%)	2 / 84 (2.38%)	0 / 21 (0.00%)	2 / 292 (0.68%)
occurrences all number	0	1	0	0	0	0	0	0	0	1	0	0	0	0	2	0	2
Ear haemorrhage
subjects affected / exposed	0 / 5 (0.00%)	1 / 3 (33.33%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 44 (2.27%)	0 / 48 (0.00%)	0 / 52 (0.00%)	0 / 59 (0.00%)	1 / 28 (3.57%)	0 / 84 (0.00%)	0 / 21 (0.00%)	1 / 292 (0.34%)
occurrences all number	0	1	0	0	0	0	0	0	0	1	0	0	0	1	0	0	1
Ear pain
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	1 / 8 (12.50%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 44 (2.27%)	1 / 48 (2.08%)	1 / 52 (1.92%)	1 / 59 (1.69%)	1 / 28 (3.57%)	2 / 84 (2.38%)	0 / 21 (0.00%)	6 / 292 (2.05%)
occurrences all number	0	0	0	0	1	0	0	0	0	1	1	1	1	1	2	0	6
Hypoacusis
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	1 / 8 (12.50%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 44 (2.27%)	1 / 48 (2.08%)	1 / 52 (1.92%)	0 / 59 (0.00%)	0 / 28 (0.00%)	1 / 84 (1.19%)	0 / 21 (0.00%)	3 / 292 (1.03%)
occurrences all number	0	0	0	0	1	0	0	0	0	1	1	1	0	0	1	0	3
Tinnitus
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 44 (0.00%)	3 / 48 (6.25%)	0 / 52 (0.00%)	2 / 59 (3.39%)	0 / 28 (0.00%)	6 / 84 (7.14%)	1 / 21 (4.76%)	12 / 292 (4.11%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	3	0	2	0	8	1	14
Eye disorders
Eye haemorrhage
subjects affected / exposed	1 / 5 (20.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 44 (2.27%)	1 / 48 (2.08%)	0 / 52 (0.00%)	1 / 59 (1.69%)	0 / 28 (0.00%)	0 / 84 (0.00%)	0 / 21 (0.00%)	2 / 292 (0.68%)
occurrences all number	1	0	0	0	0	0	0	0	0	1	1	0	1	0	0	0	2
Vision blurred
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	1 / 8 (12.50%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 44 (2.27%)	0 / 48 (0.00%)	2 / 52 (3.85%)	2 / 59 (3.39%)	1 / 28 (3.57%)	3 / 84 (3.57%)	1 / 21 (4.76%)	9 / 292 (3.08%)
occurrences all number	0	0	0	0	1	0	0	0	0	1	0	2	3	1	3	1	10
Gastrointestinal disorders
Abdominal discomfort
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	1 / 8 (12.50%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 44 (2.27%)	2 / 48 (4.17%)	6 / 52 (11.54%)	5 / 59 (8.47%)	1 / 28 (3.57%)	4 / 84 (4.76%)	0 / 21 (0.00%)	18 / 292 (6.16%)
occurrences all number	0	0	0	0	1	0	0	0	0	1	3	6	6	1	4	0	20
Abdominal distension
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	1 / 3 (33.33%)	1 / 3 (33.33%)	0 / 6 (0.00%)	2 / 44 (4.55%)	6 / 48 (12.50%)	10 / 52 (19.23%)	6 / 59 (10.17%)	8 / 28 (28.57%)	13 / 84 (15.48%)	1 / 21 (4.76%)	44 / 292 (15.07%)
occurrences all number	0	0	0	0	0	0	1	1	0	2	6	15	7	12	14	1	55
Abdominal pain
subjects affected / exposed	1 / 5 (20.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	1 / 7 (14.29%)	1 / 8 (12.50%)	0 / 4 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	2 / 6 (33.33%)	6 / 44 (13.64%)	11 / 48 (22.92%)	11 / 52 (21.15%)	4 / 59 (6.78%)	7 / 28 (25.00%)	13 / 84 (15.48%)	6 / 21 (28.57%)	52 / 292 (17.81%)
occurrences all number	1	0	0	1	1	0	1	0	2	6	14	12	6	9	17	7	65
Abdominal pain upper
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	1 / 7 (14.29%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 44 (2.27%)	2 / 48 (4.17%)	6 / 52 (11.54%)	4 / 59 (6.78%)	4 / 28 (14.29%)	11 / 84 (13.10%)	3 / 21 (14.29%)	30 / 292 (10.27%)
occurrences all number	0	0	0	1	0	0	0	0	0	1	2	7	5	5	18	3	40
Anal incontinence
subjects affected / exposed	1 / 5 (20.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 44 (2.27%)	0 / 48 (0.00%)	0 / 52 (0.00%)	0 / 59 (0.00%)	1 / 28 (3.57%)	0 / 84 (0.00%)	0 / 21 (0.00%)	1 / 292 (0.34%)
occurrences all number	1	0	0	0	0	0	0	0	0	1	0	0	0	1	0	0	1
Constipation
subjects affected / exposed	1 / 5 (20.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	1 / 7 (14.29%)	1 / 8 (12.50%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 6 (16.67%)	4 / 44 (9.09%)	11 / 48 (22.92%)	14 / 52 (26.92%)	9 / 59 (15.25%)	6 / 28 (21.43%)	27 / 84 (32.14%)	10 / 21 (47.62%)	77 / 292 (26.37%)
occurrences all number	1	0	0	1	1	0	0	0	1	4	11	18	11	7	29	13	89
Diarrhoea
subjects affected / exposed	1 / 5 (20.00%)	1 / 3 (33.33%)	0 / 5 (0.00%)	3 / 7 (42.86%)	5 / 8 (62.50%)	4 / 4 (100.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	2 / 6 (33.33%)	17 / 44 (38.64%)	15 / 48 (31.25%)	26 / 52 (50.00%)	34 / 59 (57.63%)	18 / 28 (64.29%)	40 / 84 (47.62%)	10 / 21 (47.62%)	143 / 292 (48.97%)
occurrences all number	2	1	0	3	8	4	0	1	5	24	28	44	65	34	71	18	260
Dry mouth
subjects affected / exposed	1 / 5 (20.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 44 (2.27%)	1 / 48 (2.08%)	0 / 52 (0.00%)	0 / 59 (0.00%)	1 / 28 (3.57%)	3 / 84 (3.57%)	0 / 21 (0.00%)	5 / 292 (1.71%)
occurrences all number	1	0	0	0	0	0	0	0	0	1	1	0	0	1	3	0	5
Dyspepsia
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	1 / 8 (12.50%)	0 / 4 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 6 (0.00%)	2 / 44 (4.55%)	1 / 48 (2.08%)	1 / 52 (1.92%)	2 / 59 (3.39%)	1 / 28 (3.57%)	4 / 84 (4.76%)	1 / 21 (4.76%)	10 / 292 (3.42%)
occurrences all number	0	0	0	0	1	0	0	1	0	2	1	1	3	1	5	1	12
Dysphagia
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	1 / 7 (14.29%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 44 (2.27%)	0 / 48 (0.00%)	0 / 52 (0.00%)	1 / 59 (1.69%)	1 / 28 (3.57%)	1 / 84 (1.19%)	1 / 21 (4.76%)	4 / 292 (1.37%)
occurrences all number	0	0	0	1	0	0	0	0	0	1	0	0	1	1	1	1	4
Enterocolitis
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	1 / 5 (20.00%)	0 / 7 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 44 (2.27%)	0 / 48 (0.00%)	0 / 52 (0.00%)	0 / 59 (0.00%)	0 / 28 (0.00%)	0 / 84 (0.00%)	0 / 21 (0.00%)	0 / 292 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0	0	1	0	0	0	0	0	0	0
Eructation
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 44 (2.27%)	0 / 48 (0.00%)	0 / 52 (0.00%)	0 / 59 (0.00%)	0 / 28 (0.00%)	0 / 84 (0.00%)	0 / 21 (0.00%)	0 / 292 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0	1	0	0	0	0	0	0	0
Flatulence
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	1 / 7 (14.29%)	1 / 8 (12.50%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	2 / 44 (4.55%)	3 / 48 (6.25%)	1 / 52 (1.92%)	1 / 59 (1.69%)	0 / 28 (0.00%)	7 / 84 (8.33%)	1 / 21 (4.76%)	13 / 292 (4.45%)
occurrences all number	0	0	0	1	1	0	0	0	0	2	3	1	1	0	7	1	13
Gastrooesophageal reflux disease
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 6 (16.67%)	1 / 44 (2.27%)	3 / 48 (6.25%)	1 / 52 (1.92%)	0 / 59 (0.00%)	0 / 28 (0.00%)	1 / 84 (1.19%)	1 / 21 (4.76%)	6 / 292 (2.05%)
occurrences all number	0	0	0	0	0	0	0	0	1	1	3	1	0	0	1	1	6
Gingival bleeding
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 44 (0.00%)	1 / 48 (2.08%)	0 / 52 (0.00%)	3 / 59 (5.08%)	0 / 28 (0.00%)	2 / 84 (2.38%)	0 / 21 (0.00%)	6 / 292 (2.05%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	2	0	4	0	2	0	8
Gingival pain
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	2 / 5 (40.00%)	0 / 7 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	2 / 44 (4.55%)	0 / 48 (0.00%)	0 / 52 (0.00%)	0 / 59 (0.00%)	0 / 28 (0.00%)	1 / 84 (1.19%)	0 / 21 (0.00%)	1 / 292 (0.34%)
occurrences all number	0	0	3	0	0	0	0	0	0	3	0	0	0	0	1	0	1
Haemorrhoidal haemorrhage
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	1 / 7 (14.29%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 44 (2.27%)	0 / 48 (0.00%)	0 / 52 (0.00%)	0 / 59 (0.00%)	0 / 28 (0.00%)	1 / 84 (1.19%)	0 / 21 (0.00%)	1 / 292 (0.34%)
occurrences all number	0	0	0	1	0	0	0	0	0	1	0	0	0	0	2	0	2
Haemorrhoids
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	1 / 7 (14.29%)	1 / 8 (12.50%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	2 / 44 (4.55%)	0 / 48 (0.00%)	0 / 52 (0.00%)	0 / 59 (0.00%)	0 / 28 (0.00%)	5 / 84 (5.95%)	0 / 21 (0.00%)	5 / 292 (1.71%)
occurrences all number	0	0	0	1	1	0	0	0	0	2	0	0	0	0	6	0	6
Melaena
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	1 / 7 (14.29%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 44 (2.27%)	0 / 48 (0.00%)	0 / 52 (0.00%)	1 / 59 (1.69%)	1 / 28 (3.57%)	1 / 84 (1.19%)	0 / 21 (0.00%)	3 / 292 (1.03%)
occurrences all number	0	0	0	1	0	0	0	0	0	1	0	0	1	1	1	0	3
Mouth haemorrhage
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 44 (2.27%)	0 / 48 (0.00%)	0 / 52 (0.00%)	1 / 59 (1.69%)	0 / 28 (0.00%)	1 / 84 (1.19%)	0 / 21 (0.00%)	2 / 292 (0.68%)
occurrences all number	0	0	0	0	0	0	1	0	0	1	0	0	1	0	1	0	2
Mouth ulceration
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 44 (0.00%)	1 / 48 (2.08%)	1 / 52 (1.92%)	1 / 59 (1.69%)	0 / 28 (0.00%)	5 / 84 (5.95%)	1 / 21 (4.76%)	9 / 292 (3.08%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	1	2	1	0	6	1	11
Nausea
subjects affected / exposed	4 / 5 (80.00%)	2 / 3 (66.67%)	3 / 5 (60.00%)	2 / 7 (28.57%)	5 / 8 (62.50%)	2 / 4 (50.00%)	0 / 3 (0.00%)	3 / 3 (100.00%)	2 / 6 (33.33%)	23 / 44 (52.27%)	18 / 48 (37.50%)	23 / 52 (44.23%)	21 / 59 (35.59%)	12 / 28 (42.86%)	26 / 84 (30.95%)	16 / 21 (76.19%)	116 / 292 (39.73%)
occurrences all number	5	2	4	2	5	2	0	4	4	28	24	34	31	18	39	28	174
Stomatitis
subjects affected / exposed	1 / 5 (20.00%)	0 / 3 (0.00%)	1 / 5 (20.00%)	0 / 7 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 6 (16.67%)	3 / 44 (6.82%)	1 / 48 (2.08%)	2 / 52 (3.85%)	5 / 59 (8.47%)	3 / 28 (10.71%)	3 / 84 (3.57%)	0 / 21 (0.00%)	14 / 292 (4.79%)
occurrences all number	1	0	1	0	0	0	0	0	1	3	1	2	5	3	3	0	14
Oral disorder
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	1 / 5 (20.00%)	0 / 7 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 44 (2.27%)	0 / 48 (0.00%)	0 / 52 (0.00%)	0 / 59 (0.00%)	0 / 28 (0.00%)	1 / 84 (1.19%)	0 / 21 (0.00%)	1 / 292 (0.34%)
occurrences all number	0	0	1	0	0	0	0	0	0	1	0	0	0	0	1	0	1
Proctalgia
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	1 / 8 (12.50%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 44 (2.27%)	0 / 48 (0.00%)	0 / 52 (0.00%)	0 / 59 (0.00%)	1 / 28 (3.57%)	0 / 84 (0.00%)	0 / 21 (0.00%)	1 / 292 (0.34%)
occurrences all number	0	0	0	0	1	0	0	0	0	1	0	0	0	1	0	0	1
Vomiting
subjects affected / exposed	1 / 5 (20.00%)	0 / 3 (0.00%)	2 / 5 (40.00%)	3 / 7 (42.86%)	1 / 8 (12.50%)	1 / 4 (25.00%)	0 / 3 (0.00%)	2 / 3 (66.67%)	3 / 6 (50.00%)	13 / 44 (29.55%)	7 / 48 (14.58%)	10 / 52 (19.23%)	10 / 59 (16.95%)	8 / 28 (28.57%)	15 / 84 (17.86%)	9 / 21 (42.86%)	59 / 292 (20.21%)
occurrences all number	1	0	2	3	2	1	0	3	5	17	9	16	14	9	18	15	81
Hepatobiliary disorders
Hyperbilirubinaemia
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 44 (0.00%)	4 / 48 (8.33%)	1 / 52 (1.92%)	2 / 59 (3.39%)	0 / 28 (0.00%)	2 / 84 (2.38%)	0 / 21 (0.00%)	9 / 292 (3.08%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	10	1	4	0	6	0	21
Skin and subcutaneous tissue disorders
Dermatitis acneiform
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 44 (0.00%)	1 / 48 (2.08%)	2 / 52 (3.85%)	3 / 59 (5.08%)	0 / 28 (0.00%)	3 / 84 (3.57%)	1 / 21 (4.76%)	10 / 292 (3.42%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	1	4	5	0	3	1	14
Dry skin
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	1 / 7 (14.29%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 44 (2.27%)	0 / 48 (0.00%)	2 / 52 (3.85%)	1 / 59 (1.69%)	0 / 28 (0.00%)	4 / 84 (4.76%)	0 / 21 (0.00%)	7 / 292 (2.40%)
occurrences all number	0	0	0	1	0	0	0	0	0	1	0	2	1	0	4	0	7
Erythema
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 44 (0.00%)	0 / 48 (0.00%)	4 / 52 (7.69%)	0 / 59 (0.00%)	1 / 28 (3.57%)	1 / 84 (1.19%)	0 / 21 (0.00%)	6 / 292 (2.05%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	4	0	1	1	0	6
Hyperhidrosis
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 44 (0.00%)	2 / 48 (4.17%)	3 / 52 (5.77%)	2 / 59 (3.39%)	0 / 28 (0.00%)	2 / 84 (2.38%)	1 / 21 (4.76%)	10 / 292 (3.42%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	2	4	2	0	3	1	12
Night sweats
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	1 / 8 (12.50%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 44 (2.27%)	5 / 48 (10.42%)	7 / 52 (13.46%)	6 / 59 (10.17%)	2 / 28 (7.14%)	12 / 84 (14.29%)	0 / 21 (0.00%)	32 / 292 (10.96%)
occurrences all number	0	0	0	0	1	0	0	0	0	1	7	8	8	3	18	0	44
Petechiae
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 44 (0.00%)	0 / 48 (0.00%)	3 / 52 (5.77%)	1 / 59 (1.69%)	0 / 28 (0.00%)	1 / 84 (1.19%)	1 / 21 (4.76%)	6 / 292 (2.05%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	3	1	0	1	1	6
Pruritus
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	2 / 6 (33.33%)	2 / 44 (4.55%)	10 / 48 (20.83%)	22 / 52 (42.31%)	2 / 59 (3.39%)	7 / 28 (25.00%)	18 / 84 (21.43%)	3 / 21 (14.29%)	62 / 292 (21.23%)
occurrences all number	0	0	0	0	0	0	0	0	2	2	11	26	2	9	21	3	72
Rash
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	1 / 5 (20.00%)	1 / 7 (14.29%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	2 / 3 (66.67%)	0 / 6 (0.00%)	4 / 44 (9.09%)	2 / 48 (4.17%)	7 / 52 (13.46%)	3 / 59 (5.08%)	4 / 28 (14.29%)	6 / 84 (7.14%)	4 / 21 (19.05%)	26 / 292 (8.90%)
occurrences all number	0	0	1	1	0	0	0	2	0	4	3	11	3	5	8	5	35
Rash macular
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 6 (16.67%)	1 / 44 (2.27%)	0 / 48 (0.00%)	1 / 52 (1.92%)	0 / 59 (0.00%)	0 / 28 (0.00%)	0 / 84 (0.00%)	1 / 21 (4.76%)	2 / 292 (0.68%)
occurrences all number	0	0	0	0	0	0	0	0	1	1	0	1	0	0	0	1	2
Skin discolouration
subjects affected / exposed	0 / 5 (0.00%)	1 / 3 (33.33%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 6 (16.67%)	2 / 44 (4.55%)	0 / 48 (0.00%)	0 / 52 (0.00%)	0 / 59 (0.00%)	1 / 28 (3.57%)	0 / 84 (0.00%)	0 / 21 (0.00%)	1 / 292 (0.34%)
occurrences all number	0	1	0	0	0	0	0	0	1	2	0	0	0	1	0	0	1
Rash maculo-papular
subjects affected / exposed	0 / 5 (0.00%)	1 / 3 (33.33%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 6 (0.00%)	2 / 44 (4.55%)	1 / 48 (2.08%)	4 / 52 (7.69%)	0 / 59 (0.00%)	1 / 28 (3.57%)	4 / 84 (4.76%)	0 / 21 (0.00%)	10 / 292 (3.42%)
occurrences all number	0	1	0	0	0	0	0	1	0	2	1	7	0	2	7	0	17
Skin lesion
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 44 (0.00%)	0 / 48 (0.00%)	2 / 52 (3.85%)	2 / 59 (3.39%)	2 / 28 (7.14%)	5 / 84 (5.95%)	4 / 21 (19.05%)	15 / 292 (5.14%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	2	2	2	5	5	16
Skin induration
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	1 / 7 (14.29%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 44 (2.27%)	0 / 48 (0.00%)	0 / 52 (0.00%)	0 / 59 (0.00%)	0 / 28 (0.00%)	0 / 84 (0.00%)	0 / 21 (0.00%)	0 / 292 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0	0	1	0	0	0	0	0	0	0
Urticaria
subjects affected / exposed	0 / 5 (0.00%)	1 / 3 (33.33%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 44 (2.27%)	1 / 48 (2.08%)	0 / 52 (0.00%)	0 / 59 (0.00%)	0 / 28 (0.00%)	0 / 84 (0.00%)	0 / 21 (0.00%)	1 / 292 (0.34%)
occurrences all number	0	1	0	0	0	0	0	0	0	1	1	0	0	0	0	0	1
Skin ulcer
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 6 (16.67%)	1 / 44 (2.27%)	1 / 48 (2.08%)	4 / 52 (7.69%)	2 / 59 (3.39%)	0 / 28 (0.00%)	2 / 84 (2.38%)	0 / 21 (0.00%)	9 / 292 (3.08%)
occurrences all number	0	0	0	0	0	0	0	0	1	1	3	4	2	0	2	0	11
Renal and urinary disorders
Acute kidney injury
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 8 (0.00%)	1 / 4 (25.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 44 (2.27%)	2 / 48 (4.17%)	2 / 52 (3.85%)	1 / 59 (1.69%)	1 / 28 (3.57%)	0 / 84 (0.00%)	0 / 21 (0.00%)	6 / 292 (2.05%)
occurrences all number	0	0	0	0	0	1	0	0	0	1	2	2	1	1	0	0	6
Dysuria
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 44 (0.00%)	3 / 48 (6.25%)	4 / 52 (7.69%)	5 / 59 (8.47%)	0 / 28 (0.00%)	2 / 84 (2.38%)	1 / 21 (4.76%)	15 / 292 (5.14%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	3	5	6	0	3	1	18
Haematuria
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	1 / 8 (12.50%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 6 (16.67%)	2 / 44 (4.55%)	1 / 48 (2.08%)	2 / 52 (3.85%)	1 / 59 (1.69%)	0 / 28 (0.00%)	3 / 84 (3.57%)	2 / 21 (9.52%)	9 / 292 (3.08%)
occurrences all number	0	0	0	0	1	0	0	0	1	2	1	2	2	0	3	2	10
Micturition urgency
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 6 (0.00%)	1 / 44 (2.27%)	0 / 48 (0.00%)	0 / 52 (0.00%)	1 / 59 (1.69%)	0 / 28 (0.00%)	0 / 84 (0.00%)	0 / 21 (0.00%)	1 / 292 (0.34%)
occurrences all number	0	0	0	0	0	0	0	1	0	1	0	0	1	0	0	0	1
Nocturia
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 44 (0.00%)	0 / 48 (0.00%)	1 / 52 (1.92%)	0 / 59 (0.00%)	2 / 28 (7.14%)	2 / 84 (2.38%)	0 / 21 (0.00%)	5 / 292 (1.71%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	1	0	2	2	0	5
Pollakiuria
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 6 (0.00%)	1 / 44 (2.27%)	2 / 48 (4.17%)	3 / 52 (5.77%)	1 / 59 (1.69%)	2 / 28 (7.14%)	4 / 84 (4.76%)	1 / 21 (4.76%)	13 / 292 (4.45%)
occurrences all number	0	0	0	0	0	0	0	2	0	2	2	4	1	2	4	1	14
Urinary incontinence
subjects affected / exposed	1 / 5 (20.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 44 (2.27%)	0 / 48 (0.00%)	0 / 52 (0.00%)	0 / 59 (0.00%)	0 / 28 (0.00%)	0 / 84 (0.00%)	0 / 21 (0.00%)	0 / 292 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0	0	1	0	0	0	0	0	0	0
Musculoskeletal and connective tissue disorders
Arthralgia
subjects affected / exposed	1 / 5 (20.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 44 (2.27%)	4 / 48 (8.33%)	10 / 52 (19.23%)	11 / 59 (18.64%)	7 / 28 (25.00%)	21 / 84 (25.00%)	3 / 21 (14.29%)	56 / 292 (19.18%)
occurrences all number	1	0	0	0	0	0	0	0	0	1	4	13	12	8	26	6	69
Back pain
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	1 / 7 (14.29%)	0 / 8 (0.00%)	1 / 4 (25.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 6 (16.67%)	3 / 44 (6.82%)	7 / 48 (14.58%)	5 / 52 (9.62%)	8 / 59 (13.56%)	4 / 28 (14.29%)	17 / 84 (20.24%)	3 / 21 (14.29%)	44 / 292 (15.07%)
occurrences all number	0	0	0	1	0	1	0	0	1	3	7	6	9	4	23	3	52
Bone cyst
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	1 / 5 (20.00%)	0 / 7 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 44 (2.27%)	0 / 48 (0.00%)	0 / 52 (0.00%)	0 / 59 (0.00%)	0 / 28 (0.00%)	0 / 84 (0.00%)	0 / 21 (0.00%)	0 / 292 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0	0	1	0	0	0	0	0	0	0
Bursitis
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	1 / 8 (12.50%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 44 (2.27%)	0 / 48 (0.00%)	0 / 52 (0.00%)	0 / 59 (0.00%)	1 / 28 (3.57%)	1 / 84 (1.19%)	0 / 21 (0.00%)	2 / 292 (0.68%)
occurrences all number	0	0	0	0	1	0	0	0	0	1	0	0	0	1	1	0	2
Bone pain
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	1 / 7 (14.29%)	1 / 8 (12.50%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	2 / 44 (4.55%)	1 / 48 (2.08%)	7 / 52 (13.46%)	8 / 59 (13.56%)	2 / 28 (7.14%)	8 / 84 (9.52%)	2 / 21 (9.52%)	28 / 292 (9.59%)
occurrences all number	0	0	0	1	2	0	0	0	0	3	1	7	10	2	10	2	32
Gouty arthritis
subjects affected / exposed	1 / 5 (20.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 44 (2.27%)	0 / 48 (0.00%)	0 / 52 (0.00%)	0 / 59 (0.00%)	0 / 28 (0.00%)	0 / 84 (0.00%)	0 / 21 (0.00%)	0 / 292 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0	0	1	0	0	0	0	0	0	0
Groin pain
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	2 / 5 (40.00%)	0 / 7 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	2 / 44 (4.55%)	0 / 48 (0.00%)	1 / 52 (1.92%)	1 / 59 (1.69%)	1 / 28 (3.57%)	2 / 84 (2.38%)	0 / 21 (0.00%)	5 / 292 (1.71%)
occurrences all number	0	0	3	0	0	0	0	0	0	3	0	1	1	1	2	0	5
Joint swelling
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 44 (0.00%)	0 / 48 (0.00%)	1 / 52 (1.92%)	2 / 59 (3.39%)	2 / 28 (7.14%)	1 / 84 (1.19%)	2 / 21 (9.52%)	8 / 292 (2.74%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	1	3	2	1	2	9
Muscle spasms
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 44 (0.00%)	2 / 48 (4.17%)	7 / 52 (13.46%)	7 / 59 (11.86%)	10 / 28 (35.71%)	18 / 84 (21.43%)	6 / 21 (28.57%)	50 / 292 (17.12%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	2	8	7	11	24	9	61
Muscular weakness
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 6 (16.67%)	1 / 44 (2.27%)	1 / 48 (2.08%)	5 / 52 (9.62%)	7 / 59 (11.86%)	1 / 28 (3.57%)	5 / 84 (5.95%)	1 / 21 (4.76%)	20 / 292 (6.85%)
occurrences all number	0	0	0	0	0	0	0	0	1	1	1	6	9	1	7	1	25
Musculoskeletal chest pain
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 44 (0.00%)	0 / 48 (0.00%)	2 / 52 (3.85%)	3 / 59 (5.08%)	0 / 28 (0.00%)	6 / 84 (7.14%)	1 / 21 (4.76%)	12 / 292 (4.11%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	2	3	0	7	1	13
Musculoskeletal pain
subjects affected / exposed	0 / 5 (0.00%)	1 / 3 (33.33%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 8 (0.00%)	1 / 4 (25.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	2 / 44 (4.55%)	0 / 48 (0.00%)	0 / 52 (0.00%)	2 / 59 (3.39%)	0 / 28 (0.00%)	4 / 84 (4.76%)	0 / 21 (0.00%)	6 / 292 (2.05%)
occurrences all number	0	1	0	0	0	1	0	0	0	2	0	0	2	0	4	0	6
Musculoskeletal disorder
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 6 (0.00%)	1 / 44 (2.27%)	0 / 48 (0.00%)	0 / 52 (0.00%)	0 / 59 (0.00%)	0 / 28 (0.00%)	0 / 84 (0.00%)	0 / 21 (0.00%)	0 / 292 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0	1	0	0	0	0	0	0	0
Myalgia
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	1 / 5 (20.00%)	0 / 7 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 44 (2.27%)	3 / 48 (6.25%)	6 / 52 (11.54%)	5 / 59 (8.47%)	3 / 28 (10.71%)	10 / 84 (11.90%)	3 / 21 (14.29%)	30 / 292 (10.27%)
occurrences all number	0	0	1	0	0	0	0	0	0	1	3	8	7	5	12	3	38
Neck pain
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 44 (0.00%)	0 / 48 (0.00%)	1 / 52 (1.92%)	1 / 59 (1.69%)	0 / 28 (0.00%)	6 / 84 (7.14%)	0 / 21 (0.00%)	8 / 292 (2.74%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	1	1	0	6	0	8
Pain in extremity
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	1 / 8 (12.50%)	1 / 4 (25.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 6 (0.00%)	3 / 44 (6.82%)	2 / 48 (4.17%)	7 / 52 (13.46%)	8 / 59 (13.56%)	9 / 28 (32.14%)	15 / 84 (17.86%)	0 / 21 (0.00%)	41 / 292 (14.04%)
occurrences all number	0	0	0	0	1	1	2	0	0	4	2	7	11	10	20	0	50
Pain in jaw
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	1 / 5 (20.00%)	0 / 7 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 44 (2.27%)	0 / 48 (0.00%)	0 / 52 (0.00%)	0 / 59 (0.00%)	0 / 28 (0.00%)	1 / 84 (1.19%)	1 / 21 (4.76%)	2 / 292 (0.68%)
occurrences all number	0	0	1	0	0	0	0	0	0	1	0	0	0	0	1	1	2
Rhabdomyolysis
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 6 (16.67%)	1 / 44 (2.27%)	0 / 48 (0.00%)	0 / 52 (0.00%)	0 / 59 (0.00%)	0 / 28 (0.00%)	0 / 84 (0.00%)	0 / 21 (0.00%)	0 / 292 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	1	1	0	0	0	0	0	0	0
Infections and infestations
Bronchitis
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 44 (2.27%)	0 / 48 (0.00%)	4 / 52 (7.69%)	0 / 59 (0.00%)	3 / 28 (10.71%)	3 / 84 (3.57%)	1 / 21 (4.76%)	11 / 292 (3.77%)
occurrences all number	0	0	0	0	0	0	1	0	0	1	0	5	0	3	3	1	12
COVID-19
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 44 (0.00%)	6 / 48 (12.50%)	6 / 52 (11.54%)	9 / 59 (15.25%)	3 / 28 (10.71%)	24 / 84 (28.57%)	4 / 21 (19.05%)	52 / 292 (17.81%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	7	7	10	3	29	4	60
Cellulitis
subjects affected / exposed	1 / 5 (20.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 44 (2.27%)	2 / 48 (4.17%)	3 / 52 (5.77%)	2 / 59 (3.39%)	2 / 28 (7.14%)	2 / 84 (2.38%)	1 / 21 (4.76%)	12 / 292 (4.11%)
occurrences all number	1	0	0	0	0	0	0	0	0	1	3	5	2	2	3	1	16
Cystitis
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 44 (0.00%)	1 / 48 (2.08%)	0 / 52 (0.00%)	2 / 59 (3.39%)	0 / 28 (0.00%)	1 / 84 (1.19%)	2 / 21 (9.52%)	6 / 292 (2.05%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	1	0	2	0	1	4	8
Eye infection
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	1 / 7 (14.29%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 44 (2.27%)	0 / 48 (0.00%)	0 / 52 (0.00%)	0 / 59 (0.00%)	0 / 28 (0.00%)	2 / 84 (2.38%)	0 / 21 (0.00%)	2 / 292 (0.68%)
occurrences all number	0	0	0	1	0	0	0	0	0	1	0	0	0	0	2	0	2
Folliculitis
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 44 (0.00%)	1 / 48 (2.08%)	1 / 52 (1.92%)	2 / 59 (3.39%)	0 / 28 (0.00%)	2 / 84 (2.38%)	2 / 21 (9.52%)	8 / 292 (2.74%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	1	1	4	0	3	4	13
Fungal skin infection
subjects affected / exposed	1 / 5 (20.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 44 (2.27%)	0 / 48 (0.00%)	0 / 52 (0.00%)	0 / 59 (0.00%)	1 / 28 (3.57%)	0 / 84 (0.00%)	0 / 21 (0.00%)	1 / 292 (0.34%)
occurrences all number	1	0	0	0	0	0	0	0	0	1	0	0	0	1	0	0	1
Gastroenteritis
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 44 (0.00%)	0 / 48 (0.00%)	1 / 52 (1.92%)	1 / 59 (1.69%)	0 / 28 (0.00%)	2 / 84 (2.38%)	4 / 21 (19.05%)	8 / 292 (2.74%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	1	1	0	2	5	9
Herpes zoster
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 44 (0.00%)	4 / 48 (8.33%)	4 / 52 (7.69%)	4 / 59 (6.78%)	4 / 28 (14.29%)	14 / 84 (16.67%)	1 / 21 (4.76%)	31 / 292 (10.62%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	4	4	6	4	15	1	34
Herpes simplex reactivation
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	1 / 7 (14.29%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 44 (2.27%)	0 / 48 (0.00%)	0 / 52 (0.00%)	0 / 59 (0.00%)	0 / 28 (0.00%)	1 / 84 (1.19%)	0 / 21 (0.00%)	1 / 292 (0.34%)
occurrences all number	0	0	0	1	0	0	0	0	0	1	0	0	0	0	1	0	1
Influenza
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 44 (0.00%)	1 / 48 (2.08%)	0 / 52 (0.00%)	0 / 59 (0.00%)	0 / 28 (0.00%)	5 / 84 (5.95%)	0 / 21 (0.00%)	6 / 292 (2.05%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	1	0	0	0	7	0	8
Hordeolum
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 6 (16.67%)	1 / 44 (2.27%)	1 / 48 (2.08%)	1 / 52 (1.92%)	2 / 59 (3.39%)	0 / 28 (0.00%)	4 / 84 (4.76%)	0 / 21 (0.00%)	8 / 292 (2.74%)
occurrences all number	0	0	0	0	0	0	0	0	1	1	1	1	2	0	8	0	12
Localised infection
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 44 (0.00%)	0 / 48 (0.00%)	0 / 52 (0.00%)	3 / 59 (5.08%)	0 / 28 (0.00%)	1 / 84 (1.19%)	0 / 21 (0.00%)	4 / 292 (1.37%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	0	3	0	1	0	4
Lower respiratory tract infection
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 44 (0.00%)	1 / 48 (2.08%)	0 / 52 (0.00%)	2 / 59 (3.39%)	3 / 28 (10.71%)	2 / 84 (2.38%)	1 / 21 (4.76%)	9 / 292 (3.08%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	1	0	3	5	2	1	12
Oral herpes
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 44 (0.00%)	1 / 48 (2.08%)	0 / 52 (0.00%)	5 / 59 (8.47%)	4 / 28 (14.29%)	2 / 84 (2.38%)	1 / 21 (4.76%)	13 / 292 (4.45%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	1	0	6	8	3	1	19
Nasopharyngitis
subjects affected / exposed	0 / 5 (0.00%)	1 / 3 (33.33%)	0 / 5 (0.00%)	0 / 7 (0.00%)	1 / 8 (12.50%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	2 / 44 (4.55%)	1 / 48 (2.08%)	3 / 52 (5.77%)	0 / 59 (0.00%)	2 / 28 (7.14%)	10 / 84 (11.90%)	2 / 21 (9.52%)	18 / 292 (6.16%)
occurrences all number	0	2	0	0	1	0	0	0	0	3	1	4	0	2	17	4	28
Orchitis
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 8 (0.00%)	1 / 4 (25.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 44 (2.27%)	0 / 48 (0.00%)	0 / 52 (0.00%)	0 / 59 (0.00%)	0 / 28 (0.00%)	0 / 84 (0.00%)	0 / 21 (0.00%)	0 / 292 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0	0	1	0	0	0	0	0	0	0
Otitis media
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	1 / 8 (12.50%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 44 (2.27%)	0 / 48 (0.00%)	0 / 52 (0.00%)	2 / 59 (3.39%)	1 / 28 (3.57%)	0 / 84 (0.00%)	0 / 21 (0.00%)	3 / 292 (1.03%)
occurrences all number	0	0	0	0	1	0	0	0	0	1	0	0	2	1	0	0	3
Pharyngitis
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	1 / 8 (12.50%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 44 (2.27%)	0 / 48 (0.00%)	1 / 52 (1.92%)	0 / 59 (0.00%)	0 / 28 (0.00%)	0 / 84 (0.00%)	1 / 21 (4.76%)	2 / 292 (0.68%)
occurrences all number	0	0	0	0	1	0	0	0	0	1	0	1	0	0	0	1	2
Pneumonia
subjects affected / exposed	1 / 5 (20.00%)	0 / 3 (0.00%)	1 / 5 (20.00%)	0 / 7 (0.00%)	1 / 8 (12.50%)	0 / 4 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 6 (0.00%)	4 / 44 (9.09%)	2 / 48 (4.17%)	3 / 52 (5.77%)	5 / 59 (8.47%)	3 / 28 (10.71%)	8 / 84 (9.52%)	0 / 21 (0.00%)	21 / 292 (7.19%)
occurrences all number	1	0	1	0	1	0	1	0	0	4	2	3	6	5	8	0	24
Respiratory tract infection
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 44 (0.00%)	0 / 48 (0.00%)	0 / 52 (0.00%)	1 / 59 (1.69%)	0 / 28 (0.00%)	5 / 84 (5.95%)	0 / 21 (0.00%)	6 / 292 (2.05%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	0	1	0	6	0	7
Rhinitis
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 44 (0.00%)	0 / 48 (0.00%)	0 / 52 (0.00%)	1 / 59 (1.69%)	1 / 28 (3.57%)	3 / 84 (3.57%)	2 / 21 (9.52%)	7 / 292 (2.40%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	0	1	1	3	2	7
Septic shock
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	1 / 5 (20.00%)	0 / 7 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 44 (2.27%)	0 / 48 (0.00%)	0 / 52 (0.00%)	0 / 59 (0.00%)	0 / 28 (0.00%)	0 / 84 (0.00%)	0 / 21 (0.00%)	0 / 292 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0	0	1	0	0	0	0	0	0	0
Sinusitis
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	1 / 7 (14.29%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 44 (2.27%)	3 / 48 (6.25%)	6 / 52 (11.54%)	2 / 59 (3.39%)	1 / 28 (3.57%)	4 / 84 (4.76%)	0 / 21 (0.00%)	16 / 292 (5.48%)
occurrences all number	0	0	0	1	0	0	0	0	0	1	3	6	4	1	7	0	21
Staphylococcal infection
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 8 (0.00%)	1 / 4 (25.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 44 (2.27%)	0 / 48 (0.00%)	0 / 52 (0.00%)	0 / 59 (0.00%)	0 / 28 (0.00%)	0 / 84 (0.00%)	0 / 21 (0.00%)	0 / 292 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0	0	1	0	0	0	0	0	0	0
Skin infection
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 44 (0.00%)	2 / 48 (4.17%)	0 / 52 (0.00%)	0 / 59 (0.00%)	2 / 28 (7.14%)	2 / 84 (2.38%)	0 / 21 (0.00%)	6 / 292 (2.05%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	2	0	0	2	2	0	6
Tooth infection
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 44 (0.00%)	1 / 48 (2.08%)	1 / 52 (1.92%)	0 / 59 (0.00%)	2 / 28 (7.14%)	4 / 84 (4.76%)	0 / 21 (0.00%)	8 / 292 (2.74%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	1	1	0	2	5	0	9
Urinary tract infection
subjects affected / exposed	1 / 5 (20.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	1 / 7 (14.29%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 6 (0.00%)	3 / 44 (6.82%)	5 / 48 (10.42%)	7 / 52 (13.46%)	6 / 59 (10.17%)	3 / 28 (10.71%)	14 / 84 (16.67%)	4 / 21 (19.05%)	39 / 292 (13.36%)
occurrences all number	1	0	0	1	0	0	0	1	0	3	6	9	10	11	26	6	68
Upper respiratory tract infection
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 44 (0.00%)	2 / 48 (4.17%)	6 / 52 (11.54%)	11 / 59 (18.64%)	8 / 28 (28.57%)	14 / 84 (16.67%)	2 / 21 (9.52%)	43 / 292 (14.73%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	2	17	19	14	17	3	72
Urinary tract infection bacterial
subjects affected / exposed	1 / 5 (20.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 44 (2.27%)	0 / 48 (0.00%)	0 / 52 (0.00%)	0 / 59 (0.00%)	0 / 28 (0.00%)	0 / 84 (0.00%)	0 / 21 (0.00%)	0 / 292 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0	0	1	0	0	0	0	0	0	0
Metabolism and nutrition disorders
Decreased appetite
subjects affected / exposed	3 / 5 (60.00%)	0 / 3 (0.00%)	1 / 5 (20.00%)	2 / 7 (28.57%)	5 / 8 (62.50%)	1 / 4 (25.00%)	2 / 3 (66.67%)	2 / 3 (66.67%)	2 / 6 (33.33%)	18 / 44 (40.91%)	7 / 48 (14.58%)	13 / 52 (25.00%)	13 / 59 (22.03%)	7 / 28 (25.00%)	15 / 84 (17.86%)	4 / 21 (19.05%)	59 / 292 (20.21%)
occurrences all number	3	0	2	2	5	1	2	2	3	20	9	17	13	7	20	4	70
Dehydration
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 8 (0.00%)	1 / 4 (25.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 6 (16.67%)	2 / 44 (4.55%)	1 / 48 (2.08%)	1 / 52 (1.92%)	3 / 59 (5.08%)	0 / 28 (0.00%)	0 / 84 (0.00%)	0 / 21 (0.00%)	5 / 292 (1.71%)
occurrences all number	0	0	0	0	0	1	0	0	2	3	1	1	3	0	0	0	5
Folate deficiency
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 44 (0.00%)	5 / 48 (10.42%)	0 / 52 (0.00%)	0 / 59 (0.00%)	0 / 28 (0.00%)	0 / 84 (0.00%)	0 / 21 (0.00%)	5 / 292 (1.71%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	5	0	0	0	0	0	5
Gout
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 44 (0.00%)	1 / 48 (2.08%)	3 / 52 (5.77%)	2 / 59 (3.39%)	1 / 28 (3.57%)	2 / 84 (2.38%)	0 / 21 (0.00%)	9 / 292 (3.08%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	1	3	2	1	2	0	9
Hypercholesterolaemia
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 44 (0.00%)	0 / 48 (0.00%)	0 / 52 (0.00%)	0 / 59 (0.00%)	2 / 28 (7.14%)	3 / 84 (3.57%)	0 / 21 (0.00%)	5 / 292 (1.71%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	0	0	2	3	0	5
Hyperglycaemia
subjects affected / exposed	1 / 5 (20.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	2 / 8 (25.00%)	1 / 4 (25.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	1 / 6 (16.67%)	6 / 44 (13.64%)	1 / 48 (2.08%)	5 / 52 (9.62%)	4 / 59 (6.78%)	2 / 28 (7.14%)	1 / 84 (1.19%)	2 / 21 (9.52%)	15 / 292 (5.14%)
occurrences all number	1	0	0	0	2	1	1	0	2	7	1	7	5	2	1	2	18
Hyperkalaemia
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	1 / 7 (14.29%)	1 / 8 (12.50%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	2 / 44 (4.55%)	5 / 48 (10.42%)	4 / 52 (7.69%)	4 / 59 (6.78%)	2 / 28 (7.14%)	6 / 84 (7.14%)	1 / 21 (4.76%)	22 / 292 (7.53%)
occurrences all number	0	0	0	2	1	0	0	0	0	3	18	5	7	9	9	1	49
Hypermagnesaemia
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	1 / 7 (14.29%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 44 (2.27%)	0 / 48 (0.00%)	0 / 52 (0.00%)	0 / 59 (0.00%)	0 / 28 (0.00%)	0 / 84 (0.00%)	0 / 21 (0.00%)	0 / 292 (0.00%)
occurrences all number	0	0	0	2	0	0	0	0	0	2	0	0	0	0	0	0	0
Hyperphosphataemia
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 8 (0.00%)	1 / 4 (25.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 44 (2.27%)	1 / 48 (2.08%)	0 / 52 (0.00%)	1 / 59 (1.69%)	0 / 28 (0.00%)	2 / 84 (2.38%)	0 / 21 (0.00%)	4 / 292 (1.37%)
occurrences all number	0	0	0	0	0	1	0	0	0	1	1	0	1	0	7	0	9
Hypertriglyceridaemia
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 44 (0.00%)	0 / 48 (0.00%)	0 / 52 (0.00%)	1 / 59 (1.69%)	0 / 28 (0.00%)	5 / 84 (5.95%)	0 / 21 (0.00%)	6 / 292 (2.05%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	0	1	0	12	0	13
Hyperuricaemia
subjects affected / exposed	1 / 5 (20.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	2 / 7 (28.57%)	2 / 8 (25.00%)	0 / 4 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 6 (0.00%)	6 / 44 (13.64%)	5 / 48 (10.42%)	8 / 52 (15.38%)	5 / 59 (8.47%)	4 / 28 (14.29%)	5 / 84 (5.95%)	0 / 21 (0.00%)	27 / 292 (9.25%)
occurrences all number	1	0	0	3	2	0	1	0	0	7	10	11	5	4	6	0	36
Hypokalaemia
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	1 / 8 (12.50%)	1 / 4 (25.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	2 / 44 (4.55%)	1 / 48 (2.08%)	2 / 52 (3.85%)	4 / 59 (6.78%)	1 / 28 (3.57%)	4 / 84 (4.76%)	0 / 21 (0.00%)	12 / 292 (4.11%)
occurrences all number	0	0	0	0	1	1	0	0	0	2	1	2	4	1	4	0	12
Hypocalcaemia
subjects affected / exposed	1 / 5 (20.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	1 / 7 (14.29%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	2 / 44 (4.55%)	4 / 48 (8.33%)	2 / 52 (3.85%)	3 / 59 (5.08%)	1 / 28 (3.57%)	1 / 84 (1.19%)	0 / 21 (0.00%)	11 / 292 (3.77%)
occurrences all number	1	0	0	1	0	0	0	0	0	2	4	2	6	1	1	0	14
Hypomagnesaemia
subjects affected / exposed	1 / 5 (20.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	2 / 8 (25.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	3 / 44 (6.82%)	4 / 48 (8.33%)	2 / 52 (3.85%)	2 / 59 (3.39%)	1 / 28 (3.57%)	1 / 84 (1.19%)	0 / 21 (0.00%)	10 / 292 (3.42%)
occurrences all number	1	0	0	0	2	0	0	0	0	3	5	3	4	2	1	0	15
Hypophosphataemia
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	1 / 7 (14.29%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 44 (2.27%)	0 / 48 (0.00%)	0 / 52 (0.00%)	0 / 59 (0.00%)	1 / 28 (3.57%)	1 / 84 (1.19%)	1 / 21 (4.76%)	3 / 292 (1.03%)
occurrences all number	0	0	0	1	0	0	0	0	0	1	0	0	0	3	1	2	6
Hyponatraemia
subjects affected / exposed	1 / 5 (20.00%)	0 / 3 (0.00%)	1 / 5 (20.00%)	1 / 7 (14.29%)	0 / 8 (0.00%)	0 / 4 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 6 (0.00%)	4 / 44 (9.09%)	1 / 48 (2.08%)	2 / 52 (3.85%)	3 / 59 (5.08%)	2 / 28 (7.14%)	11 / 84 (13.10%)	1 / 21 (4.76%)	20 / 292 (6.85%)
occurrences all number	1	0	1	3	0	0	1	0	0	6	4	2	3	2	13	1	25
Iron overload
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 44 (0.00%)	4 / 48 (8.33%)	0 / 52 (0.00%)	4 / 59 (6.78%)	0 / 28 (0.00%)	2 / 84 (2.38%)	0 / 21 (0.00%)	10 / 292 (3.42%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	4	0	4	0	2	0	10
Tumour lysis syndrome
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	1 / 5 (20.00%)	0 / 7 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 44 (2.27%)	0 / 48 (0.00%)	1 / 52 (1.92%)	0 / 59 (0.00%)	0 / 28 (0.00%)	0 / 84 (0.00%)	0 / 21 (0.00%)	1 / 292 (0.34%)
occurrences all number	0	0	1	0	0	0	0	0	0	1	0	1	0	0	0	0	1
Type 2 diabetes mellitus
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 44 (0.00%)	1 / 48 (2.08%)	0 / 52 (0.00%)	0 / 59 (0.00%)	0 / 28 (0.00%)	0 / 84 (0.00%)	2 / 21 (9.52%)	3 / 292 (1.03%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	1	0	0	0	0	2	3
Vitamin D deficiency
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 44 (0.00%)	4 / 48 (8.33%)	0 / 52 (0.00%)	0 / 59 (0.00%)	1 / 28 (3.57%)	1 / 84 (1.19%)	1 / 21 (4.76%)	7 / 292 (2.40%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	4	0	0	1	1	1	7

More information

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Were there any global substantial amendments to the protocol? Yes

04 Jan 2018

Amendment 6: A Phase 2 component was added in place of the dose expansion phase of the study to evaluate the efficacy of pelabresib with or without ruxolitinib in patients with myelofibrosis (MF). The dose escalation component of the study was subsequently referred to as Phase 1. As of Amendment 6, Phase 1 was complete, and all new patients were enrolled in Phase 2.

07 Sep 2018

Amendment 7: * The two arms were stratified into transfusion-dependent (TD) and non-transfusion-dependent (non-TD) cohorts. Arm 1 (Prior Janus kinase inhibitor [JAKi] Monotherapy Arm; previously the Monotherapy Arm) was stratified into Cohort 1A (TD) and Cohort 1B (non-TD), and Arm 2 (Prior JAKi Combination Arm; previously the Combination Arm) was stratified into Cohort 2A (TD) and Cohort 2B (non-TD). * A new combination arm was added for patients with myelofibrosis (MF) who had not previously been treated with a JAKi (i.e., JAKi-naïve). This arm was designated Arm 3: JAKi-Naïve Combination Arm. * Key features related to these changes were expanded, including specification of eligibility criteria and primary endpoints for TD versus non-TD cohorts. * Guidelines for dose adjustments and rules for concomitant treatments were updated.

23 Sep 2019

Amendment 8: * The new starting doses of pelabresib and ruxolitinib were confirmed based on the recommendations of the Safety Review Committee. * Specific instructions for dose modifications due to toxicity were added, replacing the previous approach of following institutional practice. * The number of patients in the JAKi-Naïve Combination Arm 3 was increased to more fully evaluate the efficacy and safety of pelabresib in combination with ruxolitinib. * The anemia component of the required diagnosis of myelofibrosis (MF) for study entry was removed to ensure that study patients were representative of the intended patient population. * The methodology for determining spleen volume at screening was changed to ensure more consistent assessments of baseline disease and response to study drug. * A lower-dose pelabresib and ruxolitinib combination was added for a subset of patients in the JAKi-Naïve Combination Arm 3 to study the safety and efficacy of a reduced pelabresib dose. * The Dynamic International Prognostic Scoring System (DIPSS) category in Arms 1–3 was changed to intermediate-2 or higher.

14 Apr 2020

Amendment 9: * Adverse event (AE) prophylaxis was added. * Guidelines for managing infection, concomitant use of systemic corticosteroids, and hyperkalemia were added. * Recommendations for the dose regimen and dose modifications in Arm 3 were updated. * The AE relatedness criteria were revised to provide more specificity in possible responses.

25 Sep 2020

Amendment 10: * A study arm (Arm 4) was added to enroll high-risk essential thrombocythemia (ET) patients who were resistant or intolerant to hydroxyurea (HU). * Cohort 1B was expanded to enroll up to 50 patients. * Arm 3 was reduced to a maximum of 81 patients. * Guidance for dose reductions and modifications for pelabresib and ruxolitinib was revised and clarified. * Guidelines for handling unforeseen circumstances were added to address potential risks to patients.

16 Sep 2022

Amendment 11: * An exploratory objective was added to evaluate overall survival in Arm 3. * Acute respiratory distress syndrome (ARDS), considered a respiratory distress syndrome (RDS) event, was added as an adverse event of special interest (AESI). * Guidance regarding COVID-19 and contraception was updated. * Assessments of acute myeloid leukemia (AML) transformation, new anti-cancer therapy, and survival follow-up were added to the schedule of events.

27 Nov 2023

Amendment 12: * Guidance on contraception use during the study was updated. * Confirmation was added that no further pharmacokinetic (PK) samples or allele burden blood samples would be collected.

23 Feb 2024

Amendment 13: * A benefit-risk assessment was added. * Dose modification guidance and withdrawal criteria for increases in peripheral blood blasts were added. * Accelerated phase (AP) and transformation to blast phase (BP) were added as adverse events of special interest (AESIs). * Adverse event (AE) reporting guidance related to AESIs of AP and transformation to BP was updated.

Were there any global interruptions to the trial? No

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

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

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Clinical trials

Clinical Trial Results: A Phase 1/2 Study of CPI-0610, a Small Molecule Inhibitor of BET Proteins: Phase 1 (Dose Escalation of CPI-0610 in Patients with Hematological Malignancies) and Phase 2 (Dose Expansion of CPI-0610 with and without Ruxolitinib in Patients with Myeloproliferative Neoplasms)

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Phase 1: Frequency of Dose-limiting toxicities (DLTs)

Primary: Phase 1: Frequency of Dose-limiting toxicities (DLTs)

Primary: Phase 2 (Cohorts 1B, 2B, and Arm 3): Number of Participants with Splenic Response Rate (SVR35) at week 24

Primary: Phase 2 (Cohorts 1B, 2B, and Arm 3): Number of Participants with Splenic Response Rate (SVR35) at week 24

Primary: Phase 2 (Cohorts 1A and 2A): Number of Participants enrolled as Transfusion Dependent (TD) with Conversion rate from Red Blood Cell (RBC) transfusion dependence (TD) to transfusion independence (TI)

Primary: Phase 2 (Cohorts 1A and 2A): Number of Participants enrolled as Transfusion Dependent (TD) with Conversion rate from Red Blood Cell (RBC) transfusion dependence (TD) to transfusion independence (TI)

Primary: Phase 2 (Arm 4): Number of Participants with Complete Hematological Response (CHR) Rate

Primary: Phase 2 (Arm 4): Number of Participants with Complete Hematological Response (CHR) Rate

Secondary: Phase 1: Number of adverse events and serious adverse events as assessed by CTCAE criteria

Secondary: Phase 1: Number of adverse events and serious adverse events as assessed by CTCAE criteria

Secondary: Phase 2 (All Arms): Number of adverse events and serious adverse events as assessed by CTCAE criteria

Secondary: Phase 2 (All Arms): Number of adverse events and serious adverse events as assessed by CTCAE criteria

Secondary: Phase 2 (All Arms): Symptom improvement from the Patient Global Impression of Change (PGIC) at 12 and 24 weeks

Secondary: Phase 2 (All Arms): Symptom improvement from the Patient Global Impression of Change (PGIC) at 12 and 24 weeks

Secondary: Phase 2 (Arms 1, 2 and 3): Percent Change from Baseline in Total Symptom Score (TSS) from the Myelofibrosis Symptom Assessment Form (MFSAF v4.0) at 12 and 24 weeks

Secondary: Phase 2 (Arms 1, 2 and 3): Percent Change from Baseline in Total Symptom Score (TSS) from the Myelofibrosis Symptom Assessment Form (MFSAF v4.0) at 12 and 24 weeks

Secondary: Phase 2 (Arms 1, 2 and 3): Number of Participants who achieved a ≥ 50% reduction in Total Symptom Score (TSS) at 12 and 24 weeks

Secondary: Phase 2 (Arms 1, 2 and 3): Number of Participants who achieved a ≥ 50% reduction in Total Symptom Score (TSS) at 12 and 24 weeks

Secondary: Phase 2 (Arms 1, 2 and 3): Number of Participants with Overall Splenic Response Rate (overall SVR35)

Secondary: Phase 2 (Arms 1, 2 and 3): Number of Participants with Overall Splenic Response Rate (overall SVR35)

Secondary: Phase 2 (Arms 1, 2 and 3): Duration of Overall Splenic Response (overall SVR35)

Secondary: Phase 2 (Arms 1, 2 and 3): Duration of Overall Splenic Response (overall SVR35)

Secondary: Phase 2 (Cohorts 1A and 2A): Number of Participants with Splenic Response Rate (SVR35) at 12 and 24 weeks

Secondary: Phase 2 (Cohorts 1A and 2A): Number of Participants with Splenic Response Rate (SVR35) at 12 and 24 weeks

Secondary: Phase 2 (Cohorts 1A and 2A): Duration of Red Blood Cell (RBC) Transfusion Independence (TI) in participants who enroll as Transfusion Dependent (TD)

Secondary: Phase 2 (Cohorts 1A and 2A): Duration of Red Blood Cell (RBC) Transfusion Independence (TI) in participants who enroll as Transfusion Dependent (TD)

Secondary: Phase 2 (Cohorts 1A and 2A): Early anemic response rate in participants who enroll as Transfusion Dependent (TD)

Secondary: Phase 2 (Cohorts 1A and 2A): Early anemic response rate in participants who enroll as Transfusion Dependent (TD)

Secondary: Phase 2 (Cohorts 1B, 2B, and Arm 3): Number of Participants with Splenic Response Rate (SVR35) at 12 weeks

Secondary: Phase 2 (Cohorts 1B, 2B, and Arm 3): Number of Participants with Splenic Response Rate (SVR35) at 12 weeks

Secondary: Phase 2 (Cohorts 1B, 2B, and Arm 3): Anemic response rate in participants who enroll as non-transfusion-dependent (non-TD)

Secondary: Phase 2 (Cohorts 1B, 2B, and Arm 3): Anemic response rate in participants who enroll as non-transfusion-dependent (non-TD)

Secondary: Phase 2 (Arm 4): Percentage of participants who achieve a ≥50% reduction from baseline in the Myeloproliferative Neoplasm Symptom Assessment Form (MPN-SAF) total score

Secondary: Phase 2 (Arm 4): Percentage of participants who achieve a ≥50% reduction from baseline in the Myeloproliferative Neoplasm Symptom Assessment Form (MPN-SAF) total score

Secondary: Phase 2 (Arm 4): Partial Hematological Response Rate (PHR)

Secondary: Phase 2 (Arm 4): Partial Hematological Response Rate (PHR)

Secondary: Phase 2 (Arm 4): Overall Hematological Response Rate (OHR)

Secondary: Phase 2 (Arm 4): Overall Hematological Response Rate (OHR)

Secondary: Phase 2 (Arm 4): Duration of Overall Hematological Response Rate (OHR)

Secondary: Phase 2 (Arm 4): Duration of Overall Hematological Response Rate (OHR)

Secondary: Phase 2 (Arm 4): Rate of hemorrhagic and thromboembolic (TE) events

Secondary: Phase 2 (Arm 4): Rate of hemorrhagic and thromboembolic (TE) events

Secondary: Phase 2 (All Arms): Maximum observed plasma concentration (Cmax) of pelabresib

Secondary: Phase 2 (All Arms): Maximum observed plasma concentration (Cmax) of pelabresib

Secondary: Phase 2 (All Arms): Time to reach maximum concentration (Tmax) of pelabresib

Secondary: Phase 2 (All Arms): Time to reach maximum concentration (Tmax) of pelabresib

Secondary: Phase 2 (All Arms): Predose (trough) concentration at the end of a dosing interval (Ctrough) of pelabresib

Secondary: Phase 2 (All Arms): Predose (trough) concentration at the end of a dosing interval (Ctrough) of pelabresib

Secondary: Phase 2 (All Arms): Area under the concentration–time curve from time zero to the last observed concentration (AUClast) of pelabresib

Secondary: Phase 2 (All Arms): Area under the concentration–time curve from time zero to the last observed concentration (AUClast) of pelabresib

Secondary: Phase 2 (All Arms): Area under the concentration–time curve from time zero to 8 hours post-dose at steady state (AUC0-8,ss) of pelabresib

Secondary: Phase 2 (All Arms): Area under the concentration–time curve from time zero to 8 hours post-dose at steady state (AUC0-8,ss) of pelabresib

Secondary: Phase 2 (All Arms): Time of Last Measurable Concentration (Tlast) of pelabresib

Secondary: Phase 2 (All Arms): Time of Last Measurable Concentration (Tlast) of pelabresib

Secondary: Phase 2 (Arm 2 - Cohort 2A): Maximum observed plasma concentration (Cmax) of ruxolitinib

Secondary: Phase 2 (Arm 2 - Cohort 2A): Maximum observed plasma concentration (Cmax) of ruxolitinib

Secondary: Phase 2 (Arm 2 - Cohort 2A): Time to reach maximum concentration (Tmax) of ruxolitinib

Secondary: Phase 2 (Arm 2 - Cohort 2A): Time to reach maximum concentration (Tmax) of ruxolitinib

Secondary: Phase 2 (Arm 2 - Cohort 2A): Predose (trough) concentration at the end of a dosing interval (Ctrough) of ruxolitinib

Secondary: Phase 2 (Arm 2 - Cohort 2A): Predose (trough) concentration at the end of a dosing interval (Ctrough) of ruxolitinib

Secondary: Phase 2 (Arm 2 - Cohort 2A): Area under the concentration–time curve from time zero to the last observed concentration (AUClast) of ruxolitinib

Secondary: Phase 2 (Arm 2 - Cohort 2A): Area under the concentration–time curve from time zero to the last observed concentration (AUClast) of ruxolitinib

Secondary: Phase 2 (Arm 2 - Cohort 2A): Area under the concentration–time curve from time zero to 8 hours post-dose at steady state (AUC0-8,ss) of ruxolitinib

Secondary: Phase 2 (Arm 2 - Cohort 2A): Area under the concentration–time curve from time zero to 8 hours post-dose at steady state (AUC0-8,ss) of ruxolitinib

Secondary: Phase 2 (Arm 2 - Cohort 2B): Maximum observed plasma concentration (Cmax) of ruxolitinib

Secondary: Phase 2 (Arm 2 - Cohort 2B): Maximum observed plasma concentration (Cmax) of ruxolitinib

Secondary: Phase 2 (Arm 2 - Cohort 2B): Time to reach maximum concentration (Tmax) of ruxolitinib

Secondary: Phase 2 (Arm 2 - Cohort 2B): Time to reach maximum concentration (Tmax) of ruxolitinib

Secondary: Phase 2 (Arm 2 - Cohort 2B): Predose (trough) concentration at the end of a dosing interval (Ctrough) of ruxolitinib

Secondary: Phase 2 (Arm 2 - Cohort 2B): Predose (trough) concentration at the end of a dosing interval (Ctrough) of ruxolitinib

Clinical Trial Results:
A Phase 1/2 Study of CPI-0610, a Small Molecule Inhibitor of BET Proteins: Phase 1 (Dose Escalation of CPI-0610 in Patients with Hematological Malignancies) and Phase 2 (Dose Expansion of CPI-0610 with and without Ruxolitinib in Patients with Myeloproliferative Neoplasms)