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Clinical Trial Results:
A Phase 2, Prospective Study Of PRM-151 In Subjects With Primary Myelofibrosis (PMF), Post-Polycythemia Vera MF (post-PV MF), Or Post-Essential Thrombocythemia MF (post-ET MF)

Summary
EudraCT number	2015-001718-80
Trial protocol	NL FR DE IT
Global end of trial date	10 Jul 2020

Results information
Results version number	v5(current)
This version publication date	23 Dec 2021
First version publication date	16 Jul 2021
Other versions	v1 , v2 , v3 , v4
Version creation reason

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

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Trial information

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Sponsor protocol code

BO42355

ISRCTN number

US NCT number

NCT01981850

WHO universal trial number (UTN)

Sponsor organisation name

F. Hoffmann-La Roche AG

Sponsor organisation address

Grenzacherstrasse 124, Basel, Switzerland, CH-4070

Public contact

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

Scientific contact

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

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

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

10 Jul 2020

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

10 Jul 2020

Was the trial ended prematurely?

Main objective of the trial

Stage 1: The main objective of this part of the study was to evaluate the efficacy of two different dose schedules of single-agent RO7490677 or RO7490677 in combination with ruxolitinib in participants with PMF, post-PV MF, or post ET-MF. Stage 2: The main objective of this part of the study was to determine the effect size of three different doses of RO7490677 on the reduction in bone marrow fibrosis by >=1 grade in participants with PMF, post-PV MF, or post ET-MF.

Protection of trial subjects

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

Background therapy

Evidence for comparator

Actual start date of recruitment

01 Oct 2013

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

Canada: 8

Country: Number of subjects enrolled

Germany: 4

Country: Number of subjects enrolled

France: 2

Country: Number of subjects enrolled

Israel: 6

Country: Number of subjects enrolled

Italy: 9

Country: Number of subjects enrolled

Netherlands: 9

Country: Number of subjects enrolled

United Kingdom: 8

Country: Number of subjects enrolled

United States: 78

Worldwide total number of subjects

124

EEA total number of subjects

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

Adolescents (12-17 years)

Adults (18-64 years)

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

A total of 125 participants were enrolled at sites in 8 different countries.

Screening details

One randomized participant in Stage 2 did not receive the study treatment, bringing the total number of treated participants to 124.

Period 1 title

Main Phase

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Investigator, Carer, Assessor, Subject

Are arms mutually exclusive

Yes

Main Phase Stage 1: RO7490677 10 mg/kg IV Every Week (QW)

Arm description

Participants who received no treatment for Myelofibrosis (MF) in at least two weeks were assigned to treatment with single agent PRM-151 at a dose of 10 milligram per kilogram (mg/kg) administered as a 30 minute intravenous (IV) infusion on Days 1, 3, 5, 8, 15, and 22 of Cycle 1 and Days 1, 8, 15 and 22 of each subsequent 28 day cycle for six cycles.

Arm type

Experimental

Investigational medicinal product name

PRM-151

Investigational medicinal product code

Other name

recombinant human pentraxin-2

Pharmaceutical forms

Infusion

Routes of administration

Intravenous use

Dosage and administration details

Participants were administered 10 milligrams per killigram (mg/kg) of PRM-151 QW via intravenous (IV) infusion.

Main Phase Stage 1: RO7490677 10 mg/kg IV Every 4 Weeks (Q4W)

Arm description

Participants who received no treatment for MF in at least two weeks were assigned to treatment with single agent PRM-151 at a dose of 10 mg/kg administered as a 30 minute IV infusion on Days 1, 3, and 5 of Cycle 1 and Day 1 of each subsequent 28 day cycle for six cycles.

Arm type

Experimental

Investigational medicinal product name

PRM-151

Investigational medicinal product code

Other name

recombinant human pentraxin-2

Pharmaceutical forms

Infusion

Routes of administration

Intravenous use

Dosage and administration details

Participants were administered 10 mg/kg of PRM-151 Q4W via IV infusion.

Main Phase Stage 1: RO7490677 10 mg/kg IV QW + Ruxolitinib

Arm description

Participants on a stable dose of ruxolitinib for at least 12 weeks, with no improvement in spleen during the last four weeks were assigned to receive PRM-151 at a dose of 10 mg/kg administered as a 30 minute IV infusion in combination with daily oral ruxolitinib on Days 1, 3, 5, 8, 15, and 22 of Cycle 1 and Days 1, 8, 15 and 22 of each subsequent 28 day cycle for six cycles.

Arm type

Experimental

Investigational medicinal product name

Ruxolitinib

Investigational medicinal product code

Other name

Jakafi

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Participants who received ruxolitinib continued to take ruxolitinib orally twice a day at the dose at which they entered the study.

Investigational medicinal product name

PRM-151

Investigational medicinal product code

Other name

recombinant human pentraxin-2

Pharmaceutical forms

Infusion

Routes of administration

Intravenous use

Dosage and administration details

Participants were administered 10 mg/kg of PRM-151 QW via IV infusion.

Main Phase Stage 1: RO7490677 10 mg/kg IV Q4W+ Ruxolitinib

Arm description

Participants on a stable dose of ruxolitinib for at least 12 weeks, with no improvement in spleen during the last four weeks were assigned to receive PRM-151 at a dose of 10 mg/kg administered as a 30 minute IV infusion in combination with daily oral ruxolitinib on Days 1, 3, and 5 of Cycle 1 and Day 1 of each subsequent 28 day cycle for six cycles.

Arm type

Experimental

Investigational medicinal product name

PRM-151

Investigational medicinal product code

Other name

recombinant human pentraxin-2

Pharmaceutical forms

Infusion

Routes of administration

Intravenous use

Dosage and administration details

Participants were administered 10 mg/kg of PRM-151 Q4W via IV infusion and daily oral ruxolitinib.

Investigational medicinal product name

Ruxolitinib

Investigational medicinal product code

Other name

Jakafi

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Participants who received ruxolitinib continued to take ruxolitinib orally twice a day at the dose at which they entered the study.

Main Phase Stage 2: RO7490677 0.3 mg/kg IV Q4W

Arm description

Participants were treated with single agent PRM-151 at a dose of 0.3 mg/kg administered as a 60 minute IV infusion on Days 1, 3, and 5 of Cycle 1 and Day 1 of each subsequent 28 day cycle for nine cycles.

Arm type

Experimental

Investigational medicinal product name

PRM-151

Investigational medicinal product code

Other name

recombinant human pentraxin-2

Pharmaceutical forms

Infusion

Routes of administration

Intravenous use

Dosage and administration details

Participants were administered 0.3 mg/kg of PRM-151 Q4W via IV infusion.

Main Phase Stage 2: RO7490677 3 mg/kg IV Q4W

Arm description

Participants were treated with single agent PRM-151 at a dose of 3.0 mg/kg administered as a 60 minute IV infusion on Days 1, 3, and 5 of Cycle 1 and Day 1 of each subsequent 28 day cycle for nine cycles.

Arm type

Experimental

Investigational medicinal product name

PRM-151

Investigational medicinal product code

Other name

recombinant human pentraxin-2

Pharmaceutical forms

Infusion

Routes of administration

Intravenous use

Dosage and administration details

Participants were administered 3 mg/kg of PRM-151 Q4W via IV infusion.

Main Phase Stage 2: RO7490677 10 mg/kg IV Q4W

Arm description

Participants were treated with single agent PRM-151 at a dose of 10 mg/kg administered as a 60 minute IV infusion on Days 1, 3, and 5 of Cycle 1 and Day 1 of each subsequent 28 day cycle for nine cycles.

Arm type

Experimental

Investigational medicinal product name

PRM-151

Investigational medicinal product code

Other name

recombinant human pentraxin-2

Pharmaceutical forms

Infusion

Routes of administration

Intravenous use

Dosage and administration details

Participants were administered 10 mg/kg of PRM-151 Q4W via IV infusion.

Number of subjects in period 1	Main Phase Stage 1: RO7490677 10 mg/kg IV Every Week (QW)	Main Phase Stage 1: RO7490677 10 mg/kg IV Every 4 Weeks (Q4W)	Main Phase Stage 1: RO7490677 10 mg/kg IV QW + Ruxolitinib	Main Phase Stage 1: RO7490677 10 mg/kg IV Q4W+ Ruxolitinib	Main Phase Stage 2: RO7490677 0.3 mg/kg IV Q4W	Main Phase Stage 2: RO7490677 3 mg/kg IV Q4W	Main Phase Stage 2: RO7490677 10 mg/kg IV Q4W
Started	8	7	6	6	33	32	32
Completed	5	5	4	6	20	16	15
Not completed	3	2	2	0	13	16	17
Consent withdrawn by subject	1	-	-	-	4	3	3
Adverse Event	-	-	-	-	6	5	7
Death	2	-	-	-	-	-	-
Progressive Disease	-	-	-	-	-	6	6
Various reasons	-	-	2	-	2	-	1
Lack of efficacy	-	2	-	-	1	2	-

Period 2 title

Open Label Extension

Is this the baseline period?

Allocation method

Non-randomised - controlled

Blinding used

Not blinded

Are arms mutually exclusive

Yes

OLE Stage 1: RO7490677 10 mg/kg IV Q4W

Arm description

Participants who completed the main phase of treatment moved to the open label extension. They were treated with single agent PRM-151 at a dose of 10 mg/kg administered as an IV infusion on Days 1, 3, and 5 of Cycle 1 and Day 1 of each subsequent 28 day cycle.

Arm type

Experimental

Investigational medicinal product name

PRM-151

Investigational medicinal product code

Other name

recombinant human pentraxin-2

Pharmaceutical forms

Infusion

Routes of administration

Intravenous use

Dosage and administration details

Participants were administered 10 mg/kg of PRM-151 Q4W via IV infusion.

OLE Stage 1: RO7490677 10 mg/kg IV Q4W + Ruxolitinib

Arm description

Participants who completed the main phase of treatment moved to the open label extension. They were treated with PRM-151 at a dose of 10 mg/kg administered as an IV infusion in combination with daily oral ruxolitinib on Days 1, 3, and 5 of Cycle 1 and Day 1 of each subsequent 28 day cycle.

Arm type

Experimental

Investigational medicinal product name

Ruxolitinib

Investigational medicinal product code

Other name

Jakafi

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Participants who received ruxolitinib continued to take ruxolitinib orally twice a day at the dose at which they entered the study.

Investigational medicinal product name

PRM-151

Investigational medicinal product code

Other name

recombinant human pentraxin-2

Pharmaceutical forms

Infusion

Routes of administration

Intravenous use

Dosage and administration details

Participants were administered 10 mg/kg of PRM-151 Q4W via IV infusion.

OLE Stage 2: RO7490677 10 mg/kg IV Q4W

Arm description

Participants who completed 9 cycles of the originally assigned treatment could switch to the open label extension. Participants enrolled received PRM-151 at a dose of 10mg/kg Q4W on days 1, 3, and 5 of first cycle of the open label phase and Day 1 of each subsequent 28 day cycle.

Arm type

Experimental

Investigational medicinal product name

PRM-151

Investigational medicinal product code

Other name

recombinant human pentraxin-2

Pharmaceutical forms

Infusion

Routes of administration

Intravenous use

Dosage and administration details

Participants were administered 10 mg/kg of PRM-151 Q4W via IV infusion.

Number of subjects in period 2 ^[1]	OLE Stage 1: RO7490677 10 mg/kg IV Q4W	OLE Stage 1: RO7490677 10 mg/kg IV Q4W + Ruxolitinib	OLE Stage 2: RO7490677 10 mg/kg IV Q4W
Started	13	5	48
Completed	1	0	0
Not completed	12	5	48
Consent withdrawn by subject	-	-	8
Adverse Event	2	1	8
Progressive Disease	3	2	9
Various reasons	3	1	3
Lost to follow-up	-	-	1
Lack of efficacy	4	1	19

Notes
[1] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
Justification: Not all participants who completed the Main Phase entered the OLE.

Baseline characteristics

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Reporting group title

Main Phase Stage 1: RO7490677 10 mg/kg IV Every Week (QW)

Reporting group description

Reporting group title

Main Phase Stage 1: RO7490677 10 mg/kg IV Every 4 Weeks (Q4W)

Reporting group description

Reporting group title

Main Phase Stage 1: RO7490677 10 mg/kg IV QW + Ruxolitinib

Reporting group description

Reporting group title

Main Phase Stage 1: RO7490677 10 mg/kg IV Q4W+ Ruxolitinib

Reporting group description

Participants on a stable dose of ruxolitinib for at least 12 weeks, with no improvement in spleen during the last four weeks were assigned to receive PRM-151 at a dose of 10 mg/kg administered as a 30 minute IV infusion in combination with daily oral ruxolitinib on Days 1, 3, and 5 of Cycle 1 and Day 1 of each subsequent 28 day cycle for six cycles.

Reporting group title

Main Phase Stage 2: RO7490677 0.3 mg/kg IV Q4W

Reporting group description

Reporting group title

Main Phase Stage 2: RO7490677 3 mg/kg IV Q4W

Reporting group description

Reporting group title

Main Phase Stage 2: RO7490677 10 mg/kg IV Q4W

Reporting group description

Reporting group values	Main Phase Stage 1: RO7490677 10 mg/kg IV Every Week (QW)	Main Phase Stage 1: RO7490677 10 mg/kg IV Every 4 Weeks (Q4W)	Main Phase Stage 1: RO7490677 10 mg/kg IV QW + Ruxolitinib	Main Phase Stage 1: RO7490677 10 mg/kg IV Q4W+ Ruxolitinib	Main Phase Stage 2: RO7490677 0.3 mg/kg IV Q4W	Main Phase Stage 2: RO7490677 3 mg/kg IV Q4W	Main Phase Stage 2: RO7490677 10 mg/kg IV Q4W	Total
Number of subjects	8	7	6	6	33	32	32	124
Age Categorical
Units: Subjects
In utero	0	0	0	0	0	0	0	0
Preterm newborn infants (gestational age < 37 wks)	0	0	0	0	0	0	0	0
Newborns (0-27 days)	0	0	0	0	0	0	0	0
Infants and toddlers (28 days-23 months)	0	0	0	0	0	0	0	0
Children (2-11 years)	0	0	0	0	0	0	0	0
Adolescents (12-17 years)	0	0	0	0	0	0	0	0
Adults (18-64 years)	4	1	1	3	6	5	6	26
From 65-84 years	3	6	5	3	27	27	24	95
85 years and over	1	0	0	0	0	0	2	3
Age Continuous
Participants in the Main Phase
Units: years
arithmetic mean (standard deviation)	64.3 ( 11.4 )	70.7 ( 6.3 )	66.0 ( 7.3 )	66.2 ( 8.6 )	70.6 ( 7.1 )	70.2 ( 6.5 )	69.4 ( 8.9 )	-
Gender Categorical
Units: Subjects
Female	5	2	3	5	16	8	11	50
Male	3	5	3	1	17	24	21	74
Race (NIH/OMB)
Units: Subjects
American Indian or Alaska Native	0	0	1	0	0	0	0	1
Asian	0	0	1	0	0	1	2	4
Native Hawaiian or Other Pacific Islander	0	0	0	0	0	0	0	0
Black or African American	1	0	1	0	0	1	0	3
White	7	7	3	6	33	29	29	114
More than one race	0	0	0	0	0	0	0	0
Unknown or Not Reported	0	0	0	0	0	1	1	2

End points

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Reporting group title

Main Phase Stage 1: RO7490677 10 mg/kg IV Every Week (QW)

Reporting group description

Reporting group title

Main Phase Stage 1: RO7490677 10 mg/kg IV Every 4 Weeks (Q4W)

Reporting group description

Reporting group title

Main Phase Stage 1: RO7490677 10 mg/kg IV QW + Ruxolitinib

Reporting group description

Reporting group title

Main Phase Stage 1: RO7490677 10 mg/kg IV Q4W+ Ruxolitinib

Reporting group description

Participants on a stable dose of ruxolitinib for at least 12 weeks, with no improvement in spleen during the last four weeks were assigned to receive PRM-151 at a dose of 10 mg/kg administered as a 30 minute IV infusion in combination with daily oral ruxolitinib on Days 1, 3, and 5 of Cycle 1 and Day 1 of each subsequent 28 day cycle for six cycles.

Reporting group title

Main Phase Stage 2: RO7490677 0.3 mg/kg IV Q4W

Reporting group description

Reporting group title

Main Phase Stage 2: RO7490677 3 mg/kg IV Q4W

Reporting group description

Reporting group title

Main Phase Stage 2: RO7490677 10 mg/kg IV Q4W

Reporting group description

Reporting group title

OLE Stage 1: RO7490677 10 mg/kg IV Q4W

Reporting group description

Reporting group title

OLE Stage 1: RO7490677 10 mg/kg IV Q4W + Ruxolitinib

Reporting group description

Reporting group title

OLE Stage 2: RO7490677 10 mg/kg IV Q4W

Reporting group description

Subject analysis set title

Main Phase Stage 1: RO7490677 10 mg/kg IV QW; OLE: IV Q4W

Subject analysis set type

Sub-group analysis

Subject analysis set description

Participants were followed through their originally assigned treatment. If a participant achieved a clinical benefit in the main phase, they had the opportunity to remain on treatment. Participants who didn't achieve a clinical benefit had the opportunity to switch to a different dosing schedule in the OLE phase. Participants were not allowed to add ruxolitinib if they had been receiving monotherapy during the main phase. Participants who received no treatment for Myelofibrosis (MF) in at least two weeks were assigned to treatment with single agent PRM-151 at a dose of 10 milligram per kilogram (mg/kg) administered as a 30 minute intravenous (IV) infusion on Days 1, 3, 5, 8, 15, and 22 of Cycle 1 and Days 1, 8, 15 and 22 of each subsequent 28 day cycle for 6 cycles (main phase) and on Days 1, 3, and 5 of Cycle 7 and Day 1 of each subsequent 28 day cycle for 83 cycles (OLE).

Subject analysis set title

Main Phase Stage 1: RO7490677 10 mg/kg IV Q4W; OLE: IV Q4W

Subject analysis set type

Sub-group analysis

Subject analysis set description

Participants were followed through their originally assigned treatment. If a participant achieved a clinical benefit in the main phase, they had the opportunity to remain on treatment. Participants who didn't achieve a clinical benefit had the opportunity to switch to a different dosing schedule in the OLE phase. Participants were not allowed to add ruxolitinib if they had been receiving monotherapy during the main phase. Participants who received no treatment for MF in at least two weeks were assigned to treatment with single agent PRM-151 at a dose of 10 mg/kg administered as a 30 minute IV infusion on Days 1, 3, and 5 of Cycle 1 and Day 1 of each subsequent 28 day cycle for 6 cycles (main phase) and on Days 1, 3, and 5 of Cycle 7 and Day 1 of each subsequent 28 day cycle for 83 cycles (OLE).

Subject analysis set title

Main Phase Stage 1: IV QW + Ruxo.; OLE: IV Q4W + Ruxo.

Subject analysis set type

Sub-group analysis

Subject analysis set description

Participants were followed through their originally assigned treatment. If a participant achieved a clinical benefit in the main phase, they had the opportunity to remain on treatment. Participants who didn't achieve a clinical benefit had the opportunity to switch to a different dosing schedule in the OLE phase. Participants could drop ruxolitinib in the OLE, but were not allowed to add ruxolitinib if they had been receiving monotherapy during the main phase. Participants on a stable dose of ruxolitinib for at least 12 weeks, with no improvement in spleen during the last four weeks were assigned to receive PRM-151 at a dose of 10 mg/kg administered as a 30 minute IV infusion in combination with daily oral ruxolitinib on Days 1, 3, 5, 8, 15, and 22 of Cycle 1 and Days 1, 8, 15 and 22 of each subsequent 28 day cycle for 6 cycles (main phase) and on Days 1, 3, and 5 of Cycle 7 and Day 1 of each subsequent 28 day cycle for 83 cycles (OLE).

Subject analysis set title

Main Phase Stage 1: IV Q4W + Ruxo.; OLE: IV Q4W + Ruxo.

Subject analysis set type

Sub-group analysis

Subject analysis set description

Participants were followed through their originally assigned treatment. If a participant achieved a clinical benefit in the main phase, they had the opportunity to remain on treatment. Participants who didn't achieve a clinical benefit had the opportunity to switch to a different dosing schedule in the OLE phase. Participants could drop ruxolitinib in the OLE, but were not allowed to add ruxolitinib if they had been receiving monotherapy during the main phase. Participants on a stable dose of ruxolitinib for at least 12 weeks, with no improvement in spleen during the last four weeks were assigned to receive PRM-151 at a dose of 10 mg/kg administered as a 30 minute IV infusion in combination with daily oral ruxolitinib on Days 1, 3, and 5 of Cycle 1 and Day 1 of each subsequent 28 day cycle for 6 cycles (main phase) and on Days 1, 3, and 5 of Cycle 7 and Day 1 of each subsequent 28 day cycle for 83 cycles (OLE).

Subject analysis set title

Main Phase Stage 2: RO7490677 0.3 mg/kg IV Q4W; OLE: IV Q4W

Subject analysis set type

Sub-group analysis

Subject analysis set description

Participants were followed through their originally assigned treatment. Participants in the main phase had the opportunity to remain on treatment. Participants also had the option to switch to the OLE phase after completing 9 cycles of the originally assigned treatment as outlined below. Participants were treated with single agent PRM-151 at a dose of 0.3 mg/kg administered as a 60 minute IV infusion on Days 1, 3, and 5 of Cycle 1 and Day 1 of each subsequent 28 day cycle for 9 cycles (main phase) and PRM-151 at a dose of 10 mg/kg on Days 1, 3, and 5 of Cycle 10 and Day 1 of each subsequent 28 day cycle for 51 cycles (OLE).

Subject analysis set title

Main Phase Stage 2: PRM-151 3 mg/kg IV Q4W; OLE: IV Q4W

Subject analysis set type

Sub-group analysis

Subject analysis set description

Participants were followed through their originally assigned treatment. Participants in the main phase had the opportunity to remain on treatment. Participants also had the option to switch to the OLE phase after completing 9 cycles of the originally assigned treatment as outlined below. Participants were treated with single agent PRM-151 at a dose of 3.0 mg/kg administered as a 60 minute IV infusion on Days 1, 3, and 5 of Cycle 1 and Day 1 of each subsequent 28 day cycle for 9 cycles (main phase) and PRM-151 at a dose of 10 mg/kg on Days 1, 3, and 5 of Cycle 10 and Day 1 of each subsequent 28 day cycle for 51 cycles (OLE).

Subject analysis set title

Main Phase Stage 2: RO7490677 10 mg/kg IV Q4W; OLE: IV Q4W

Subject analysis set type

Sub-group analysis

Subject analysis set description

Participants were followed through their originally assigned treatment. Participants in the main phase had the opportunity to remain on treatment. Participants also had the option to switch to the OLE phase after completing 9 cycles of the originally assigned treatment as outlined below. Participants enrolled received PRM-151 at a dose of 10mg/kg Q4W on Days 1, 3, and 5 of Cycle 1 and Day 1 of each subsequent 28 day cycle for 9 cycles (main phase) and on Days 1, 3, and 5 of Cycle 10 and Day 1 of each subsequent 28 day cycle for 51 cycles (OLE).

Primary: Stage 1 Main Phase: Overall Response Rate (ORR)

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End point title

Stage 1 Main Phase: Overall Response Rate (ORR) ^[1] ^[2]

End point description

ORR was defined as the percent of participants with a response according to the International Working Group-Myeloproliferative Neoplasms Research and Treatment (IWG-MRT) criteria. This was defined as those participants who achieved clinical improvement (CI), partial remission (PR), or complete remission (CR) at a post-baseline assessment of treatment response OR had at least stable disease (SD) for three consecutive end-of-cycle response assessments (e.g. Day 1 of the subsequent cycle) in conjunction with improvement in the bone marrow fibrosis score relative to baseline by at least one grade at any time point during the period of stable disease. The all treated population included all participants who received at least one dose of RO7490667.

End point type

Primary

End point timeframe

Up until and including completion of 6 cycles. Each cycle is 28 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: For stage 1, the hypothesis test was performed separately in each of the 4 treatment groups and overall, each at 5% significance level (one-sided; statistical significance was concluded if the lower bound of the 2 sided 90% CI was above 10%).
[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: Data is being provided for each stage of this study rather than all arms in the baseline period at once.

End point values	Main Phase Stage 1: RO7490677 10 mg/kg IV Every Week (QW)	Main Phase Stage 1: RO7490677 10 mg/kg IV Every 4 Weeks (Q4W)	Main Phase Stage 1: RO7490677 10 mg/kg IV QW + Ruxolitinib	Main Phase Stage 1: RO7490677 10 mg/kg IV Q4W+ Ruxolitinib
Number of subjects analysed	8	7	6	6
Units: Percentage of Participants
number (confidence interval 90%)	37.5 (11.11 to 71.08)	14.3 (0.73 to 52.07)	33.3 (6.28 to 72.87)	50.0 (15.32 to 84.68)

No statistical analyses for this end point

Primary: Stage 2 Main Phase: Bone Marrow Response Rate (BMRR)

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End point title

Stage 2 Main Phase: Bone Marrow Response Rate (BMRR) ^[3] ^[4]

End point description

Response rate was defined as the percent of participants with a reduction in bone marrow fibrosis by at least one grade according to World Health Organization (WHO) criteria from baseline to any time during the study. This was determined by a central adjudication panel of expert hematopathologists, blinded to participant, treatment, and time of biopsy. The all treated population included all participants randomized and who received at least one administration of the drug.

End point type

Primary

End point timeframe

Up until and including completion of 9 cycles. Each cycle is 28 days.

Notes
[3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: For stage 2, two pairwise comparisons (3 mg/kg vs 0.3 mg/kg and 10 mg/kg vs 0.3 mg/kg were computed with aim to demonstrate superiority and therefore, used an adjusted two-sided level of significance of 0.025. The third comparison (10 mg/kg vs 3mg/kg) was not expected to have enough power to demonstrate any difference with the planned sample size. This comparison was considered exploratory and was conducted using an unadjusted two-sided 0.05 level of significance.
[4] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Data is being provided for each stage of this study rather than all arms in the baseline period at once.

End point values	Main Phase Stage 2: RO7490677 0.3 mg/kg IV Q4W	Main Phase Stage 2: RO7490677 3 mg/kg IV Q4W	Main Phase Stage 2: RO7490677 10 mg/kg IV Q4W
Number of subjects analysed	33	32	32
Units: Percentage of Participants
number (confidence interval 95%)	30.3 (14.62 to 45.98)	31.3 (15.19 to 47.31)	25.0 (10.00 to 40.00)

No statistical analyses for this end point

Primary: Stage 1 Main + Open-Label Extension (OLE): ORR

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End point title

Stage 1 Main + Open-Label Extension (OLE): ORR ^[5]

End point description

ORR was defined as the percent of participants with a response according to the IWG-MRT criteria. This was defined as those participants who achieved CI, PR, or CR at a post-baseline assessment of treatment response OR had at least SD for three consecutive end-of-cycle response assessments (e.g. Day 1 of the subsequent cycle) in conjunction with improvement in the bone marrow fibrosis score relative to baseline by at least one grade at any time point during the period of stable disease. Participants who achieved a clinical benefit in the main phase had the opportunity to remain on treatment. The determination of ORR in the main phase is outlined in the subject analysis set description. Participants who didn’t achieve a benefit had the opportunity to switch to a different dosing schedule in the OLE phase. The determination of ORR in the OLE phase is outlined in the subject analysis set description.

End point type

Primary

End point timeframe

From cycle 1 day 1 up until cycle 6, day 29 (Main Phase). From cycle 7 day 1 up until study discontinuation or study termination, up to 83 cycles (OLE). Each cycle is 28 days.

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: For stage 1, the hypothesis test was performed separately in each of the 4 treatment groups and overall, each at 5% significance level (one-sided; statistical significance was concluded if the lower bound of the 2 sided 90% CI was above 10%).

End point values	Main Phase Stage 1: RO7490677 10 mg/kg IV QW; OLE: IV Q4W	Main Phase Stage 1: RO7490677 10 mg/kg IV Q4W; OLE: IV Q4W	Main Phase Stage 1: IV QW + Ruxo.; OLE: IV Q4W + Ruxo.	Main Phase Stage 1: IV Q4W + Ruxo.; OLE: IV Q4W + Ruxo.
Number of subjects analysed	8	7	6	6
Units: Percentage of Participants
number (confidence interval 90%)	50.0 (19.29 to 80.71)	71.4 (34.13 to 94.66)	50.0 (15.32 to 84.68)	66.7 (27.13 to 93.72)

No statistical analyses for this end point

Primary: Stage 2 Main + Open-Label Extension (OLE): BMRR

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End point title

Stage 2 Main + Open-Label Extension (OLE): BMRR ^[6]

End point description

Defined as the percent of participants with a reduction in bone marrow fibrosis score by at least one grade according to WHO criteria at any time during the study. As determined by a central adjudication panel of expert hematopathologists, blinded to participant, treatment, and time of biopsy. Participants in the main phase had the opportunity to remain on treatment (as outlined in the subject analysis set description). Participants also had the option to switch to the OLE phase after completing 9 cycles of the originally assigned treatment and receive PRM-151 10 mg/kg/Q4W (as outlined in the subject analysis set description).

End point type

Primary

End point timeframe

From cycle 1 day 1 up until cycle 9 day 29 (main phase). From cycle 10 day 1 up until study discontinuation or study termination, up to 51 cycles (OLE). Each cycle is 28 days.

Notes
[6] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: For stage 2, two pairwise comparisons (3 mg/kg vs 0.3 mg/kg and 10 mg/kg vs 0.3 mg/kg were computed with aim to demonstrate superiority and therefore, used an adjusted two-sided level of significance of 0.025. The third comparison (10 mg/kg vs 3mg/kg) was not expected to have enough power to demonstrate any difference with the planned sample size. This comparison was considered exploratory and was conducted using an unadjusted two-sided 0.05 level of significance.

End point values	Main Phase Stage 2: RO7490677 0.3 mg/kg IV Q4W; OLE: IV Q4W	Main Phase Stage 2: PRM-151 3 mg/kg IV Q4W; OLE: IV Q4W	Main Phase Stage 2: RO7490677 10 mg/kg IV Q4W; OLE: IV Q4W
Number of subjects analysed	33	32	32
Units: Percentage of Participants
number (confidence interval 95%)	30.3 (14.62 to 45.98)	34.4 (17.92 to 50.83)	25.0 (10.00 to 40.00)

No statistical analyses for this end point

Secondary: Stage 1 Main Phase: BMRR

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End point title

Stage 1 Main Phase: BMRR ^[7]

End point description

Bone marrow response was defined as a reduction in bone marrow fibrosis score by at least one grade from baseline at anytime during the study. The all treated population included all participants who received at least one dose of RO7490667.

End point type

Secondary

End point timeframe

Baseline, Weeks 12 and 24

Notes
[7] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Data is being provided for each stage of this study rather than all arms in the baseline period at once.

End point values	Main Phase Stage 1: RO7490677 10 mg/kg IV Every Week (QW)	Main Phase Stage 1: RO7490677 10 mg/kg IV Every 4 Weeks (Q4W)	Main Phase Stage 1: RO7490677 10 mg/kg IV QW + Ruxolitinib	Main Phase Stage 1: RO7490677 10 mg/kg IV Q4W+ Ruxolitinib
Number of subjects analysed	8	7	6	6
Units: Percentage of Participants
number (confidence interval 95%)	37.5 (3.95 to 71.05)	14.3 (0.00 to 40.21)	16.7 (0.00 to 46.49)	50.0 (9.99 to 90.01)

No statistical analyses for this end point

Secondary: Stage 1 Main Phase: Modified Myeloproliferative Neoplasms Symptom Assessment Form Total Symptom Score (MPN-SAF TSS) Changes

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End point title

Stage 1 Main Phase: Modified Myeloproliferative Neoplasms Symptom Assessment Form Total Symptom Score (MPN-SAF TSS) Changes ^[8]

End point description

The MPN-SAF TSS total symptom score was the sum of the following 10 items: Filling up quickly when you eat (early satiety), abdominal discomfort, inactivity, Problems with concentration, Worst fatigue, Night sweats, Itching, Bone pain, Fever and Unintentional weight loss last 6 months. The MPN-SAF Total Symptom Score had a possible range of 0 to 100, where a lower score was more favorable. The values reported are the change from baseline scores. The all treated population included all participants who received at least one dose of RO7490667.

End point type

Secondary

End point timeframe

Baseline, beginning of each cycle (Cycle 2 onward). Each cycle is 28 days.

Notes
[8] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Data is being provided for each stage of this study rather than all arms in the baseline period at once.

End point values	Main Phase Stage 1: RO7490677 10 mg/kg IV Every Week (QW)	Main Phase Stage 1: RO7490677 10 mg/kg IV Every 4 Weeks (Q4W)	Main Phase Stage 1: RO7490677 10 mg/kg IV QW + Ruxolitinib	Main Phase Stage 1: RO7490677 10 mg/kg IV Q4W+ Ruxolitinib
Number of subjects analysed	8	7	6	6
Units: Score on a scale
arithmetic mean (standard deviation)
Baseline (n= 8,7,6,6)	23.1 ( 19.1 )	16.9 ( 7.2 )	26.8 ( 17.1 )	15.3 ( 10.4 )
Cycle(C) 2 Day(D) 1 (n= 7,6,6,6)	-5.3 ( 12.6 )	5.7 ( 11.8 )	0.5 ( 8.8 )	-2.0 ( 5.0 )
C3D1 (n= 7,7,6,5)	-9.1 ( 10.9 )	1.9 ( 5.3 )	-2.7 ( 14.8 )	4.2 ( 8.0 )
C4D1 (n= 7,7,6,6)	-8.7 ( 10.7 )	1.0 ( 8.0 )	-7.5 ( 6.0 )	5.7 ( 20.9 )
C5D1 (n= 5,7,6,6)	-13.2 ( 13.2 )	2.6 ( 6.9 )	-6.7 ( 10.6 )	1.5 ( 13.6 )
C6D1 (n= 5,5,5,6)	-12.2 ( 9.5 )	-0.8 ( 8.3 )	-5.4 ( 6.2 )	4.3 ( 11.5 )
C6D29 (n= 5,5,4,4)	-15.0 ( 13.7 )	-2.2 ( 5.3 )	-5.3 ( 4.6 )	2.3 ( 8.8 )

No statistical analyses for this end point

Secondary: Stage 2 Main Phase: BMRR

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End point title

Stage 2 Main Phase: BMRR ^[9]

End point description

Response rate was defined as the percent of participants with a reduction in bone marrow fibrosis by at least one grade according to World Health Organization (WHO) criteria at any time during the study. This was determined by a central adjudication panel of expert hematopathologists, blinded to participant, treatment, and time of biopsy. The all treated population included all participants randomized and who received at least one administration of the drug.

End point type

Secondary

End point timeframe

Up until and including completion of 9 cycles. Each cycle is 28 days.

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: Data is being provided for each stage of this study rather than all arms in the baseline period at once.

End point values	Main Phase Stage 2: RO7490677 0.3 mg/kg IV Q4W	Main Phase Stage 2: RO7490677 3 mg/kg IV Q4W	Main Phase Stage 2: RO7490677 10 mg/kg IV Q4W
Number of subjects analysed	33	32	32
Units: Percentage of Participants
number (confidence interval 95%)	30.3 (14.62 to 45.98)	31.3 (15.19 to 47.31)	25.0 (10.0 to 40.00)

No statistical analyses for this end point

Secondary: Stage 2 Main Phase: BMRR - Reduction of Bone Marrow Fibrosis by Visit

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End point title

Stage 2 Main Phase: BMRR - Reduction of Bone Marrow Fibrosis by Visit ^[10]

End point description

Reduction in bone marrow fibrosis score: Reduction of at least one grade from baseline. Bone marrow fibrosis grades according to WHO criteria (as determined by central adjudication). The all treated population included all participants randomized and who received at least one administration of the drug.

End point type

Secondary

End point timeframe

Day 1 on Cycles 4, 7, 10 and Cycle 9 Day 29. Each cycle is 28 days.

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: Data is being provided for each stage of this study rather than all arms in the baseline period at once.

End point values	Main Phase Stage 2: RO7490677 0.3 mg/kg IV Q4W	Main Phase Stage 2: RO7490677 3 mg/kg IV Q4W	Main Phase Stage 2: RO7490677 10 mg/kg IV Q4W
Number of subjects analysed	33	32	32
Units: Percentage of Participants
number (not applicable)
Cycle(C) 4 Day(D) 1 (n=28,25,26)	10.7	24.0	19.2
C7D1 (n=21,17,19)	23.8	11.8	10.5
C9D29/C10D1 (n=20,14,15)	30.0	21.4	13.3

No statistical analyses for this end point

Secondary: Stage 2 Main Phase: Duration of Bone Marrow Improvement

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End point title

Stage 2 Main Phase: Duration of Bone Marrow Improvement ^[11]

End point description

Duration of response was defined as time from first decrease from baseline >= 1 grade to time of return to baseline levels. The all treated population included all participants randomized and who received at least one administration of the drug. 9999999 = participants who had bone marrow improvement but did not return to baseline levels at the end of main phase were censored at their last bone marrow assessment in the main phase (the last timepoint in the main phase at which the improvement was still observed).

End point type

Secondary

End point timeframe

From first decrease from baseline of one grade to time of return to baseline levels, up to cycle 9 of 28-day cycles.

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: Data is being provided for each stage of this study rather than all arms in the baseline period at once.

End point values	Main Phase Stage 2: RO7490677 0.3 mg/kg IV Q4W	Main Phase Stage 2: RO7490677 3 mg/kg IV Q4W	Main Phase Stage 2: RO7490677 10 mg/kg IV Q4W
Number of subjects analysed	33	32	32
Units: Weeks
median (confidence interval 95%)	9999999 (12.0 to 9999999)	12.0 (12.0 to 9999999)	12.1 (11.4 to 13.0)

No statistical analyses for this end point

Secondary: Stage 2 Main Phase: Hemoglobin Improvement

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End point title

Stage 2 Main Phase: Hemoglobin Improvement ^[12]

End point description

Hemoglobin improvement was measured by the percent of participants with: Red cell transfusion independence (no transfusions for >= 12 consecutive weeks) OR 50% reduction in red blood cell (RBC) transfusions for >= 12 consecutive weeks OR percent of participants with >= 10 g/L and >= 20 g/L increase in hemoglobin for >= 12 consecutive weeks without transfusions (outcome parameter assessed was dependent on baseline hemoglobin/transfusion status). The all treated population included all participants randomized and who received at least one administration of the drug.

End point type

Secondary

End point timeframe

Up until and including completion of 9 cycles. Each cycle is 28 days.

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: Data is being provided for each stage of this study rather than all arms in the baseline period at once.

End point values	Main Phase Stage 2: RO7490677 0.3 mg/kg IV Q4W	Main Phase Stage 2: RO7490677 3 mg/kg IV Q4W	Main Phase Stage 2: RO7490677 10 mg/kg IV Q4W
Number of subjects analysed	33	32	32
Units: Percentage of Participants
number (not applicable)	15.2	15.6	6.3

No statistical analyses for this end point

Secondary: Stage 2 Main Phase: Platelet Improvement

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End point title

Stage 2 Main Phase: Platelet Improvement ^[13]

End point description

Platelet improvement was measured by the percent of participants with: Platelet transfusion independence (no transfusions for >= 12 consecutive weeks) OR 50% reduction in platelets transfusions for >= 12 consecutive weeks OR doubling of baseline platelet count for >= 12 consecutive weeks without platelet transfusions OR platelet count > 50 x 10e9/L for >=12 consecutive weeks without platelet transfusions OR doubling of baseline platelet count for >= 12 consecutive weeks without platelet transfusions OR platelet count > 25 x 10e9/L for >= 12 consecutive weeks without platelet transfusions (outcome parameter assessed is dependent on baseline platelet status). The all treated population included all participants randomized and who received at least one administration of the drug.

End point type

Secondary

End point timeframe

Up until and including completion of 9 cycles. Each cycle is 28 days.

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: Data is being provided for each stage of this study rather than all arms in the baseline period at once.

End point values	Main Phase Stage 2: RO7490677 0.3 mg/kg IV Q4W	Main Phase Stage 2: RO7490677 3 mg/kg IV Q4W	Main Phase Stage 2: RO7490677 10 mg/kg IV Q4W
Number of subjects analysed	33	32	32
Units: Percentage of Participants
number (not applicable)	27.3	34.4	37.5

No statistical analyses for this end point

Secondary: Stage 2 Main Phase: Symptom Improvement

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End point title

Stage 2 Main Phase: Symptom Improvement ^[14]

End point description

Symptom improvement was assessed as the percent of participants with 50% reduction in MPN-SAF TSS from baseline over time. The MPN-SAF TSS total symptom score was the sum of the following 10 items: Filling up quickly when you eat (early satiety), abdominal discomfort, inactivity, Problems with concentration, Worst fatigue, Night sweats, Itching, Bone pain, Fever and Unintentional weight loss last 6 months. The MPN-SAF Total Symptom Score had a possible range of 0 to 100, where a lower score was more favorable. The all treated population included all participants randomized and who received at least one administration of the drug.

End point type

Secondary

End point timeframe

Up until and including completion of 9 cycles. Each cycle is 28 days.

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: Data is being provided for each stage of this study rather than all arms in the baseline period at once.

End point values	Main Phase Stage 2: RO7490677 0.3 mg/kg IV Q4W	Main Phase Stage 2: RO7490677 3 mg/kg IV Q4W	Main Phase Stage 2: RO7490677 10 mg/kg IV Q4W
Number of subjects analysed	33	32	32
Units: Percentage of Participants
number (not applicable)
Cycle(C) 2 Day(D) 1 (n=31, 31, 29)	16.1	6.5	3.4
C3D1 (n=30, 29, 28)	20.0	10.3	7.1
C4D1 (n=28, 29, 28)	10.7	13.8	7.1
C5D1 (n=24, 25, 25)	20.8	8.0	4.0
C6D1 (n=23, 21, 25)	34.8	14.3	12.0
C7D1 (n=21, 18, 20)	38.1	27.8	0
C8D1 (n=20, 18, 19)	25.0	16.7	0
C9D1 (n=21, 17, 17)	23.8	17.6	5.9
C9D29/C10D1 (n=20, 16, 13)	25.0	12.5	0
End of Main Study (n=6, 7, 7)	16.7	0	14.3

No statistical analyses for this end point

Secondary: Stage 2 Main Phase: Percentage of Participants with Complete Response (CR), Partial Response (PR), Clinical Improvement (CI), Stable Disease (SD), and Progressive Disease (PD) According to IWG-MRT Criteria

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End point title

Stage 2 Main Phase: Percentage of Participants with Complete Response (CR), Partial Response (PR), Clinical Improvement (CI), Stable Disease (SD), and Progressive Disease (PD) According to IWG-MRT Criteria ^[15]

End point description

Best Overall Response: (CR Response, PR, CI), SD and PD according to the IWG-MRT Criteria. The all treated population included all participants randomized and who received at least one administration of the drug.

End point type

Secondary

End point timeframe

Up until and including completion of 9 cycles. Each cycle is 28 days.

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: Data is being provided for each stage of this study rather than all arms in the baseline period at once.

End point values	Main Phase Stage 2: RO7490677 0.3 mg/kg IV Q4W	Main Phase Stage 2: RO7490677 3 mg/kg IV Q4W	Main Phase Stage 2: RO7490677 10 mg/kg IV Q4W
Number of subjects analysed	33	32	32
Units: Percentage of Participants
number (not applicable)
CR	0	0	0
PR	0	0	0
CI	24.2	18.8	6.3
SD	60.6	65.6	81.3
PD	9.1	9.4	12.5
Not evaluable	6.1	6.3	0

No statistical analyses for this end point

Other pre-specified: Stage 1 Main Phase: Maximum Drug Concentration (Cmax)

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End point title

Stage 1 Main Phase: Maximum Drug Concentration (Cmax) ^[16]

End point description

Cmax is the maximum observed RO7490677 plasma concentration. The PK population included all participants who received at least one dose of rhPTX-2 and had at least one post-dose total PTX-2 concentration result. 9999999 = no samples were analyzed.

End point type

Other pre-specified

End point timeframe

Pre-dose on Cycles(C) 1, 2 and 6, Day(D) 1 and C1 D15. Each cycle is 28 days

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: Data is being provided for each stage of this study rather than all arms in the baseline period at once.

End point values	Main Phase Stage 1: RO7490677 10 mg/kg IV Every Week (QW)	Main Phase Stage 1: RO7490677 10 mg/kg IV Every 4 Weeks (Q4W)	Main Phase Stage 1: RO7490677 10 mg/kg IV QW + Ruxolitinib	Main Phase Stage 1: RO7490677 10 mg/kg IV Q4W+ Ruxolitinib
Number of subjects analysed	8	7	6	6
Units: Micrograms per Milliliter (ug/mL)
geometric mean (geometric coefficient of variation)
C1D1 (n=7,7,6,6)	133 ( 48.4 )	113 ( 28.1 )	164 ( 23.9 )	112 ( 90.4 )
C1D15 (n=7,0,6,0)	127 ( 31.9 )	9999999 ( 9999999 )	126 ( 27.5 )	9999999 ( 9999999 )
C2D1 (n=7,7,6,6)	107 ( 26.9 )	110 ( 20.9 )	149 ( 29.1 )	130 ( 80.2 )
C6D1 (n=5,5,5,6)	142 ( 70.0 )	111 ( 28.0 )	136 ( 34.1 )	142 ( 27.4 )

No statistical analyses for this end point

Other pre-specified: Stage 1 Main Phase: Time to Maximum Concentration (Tmax)

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End point title

Stage 1 Main Phase: Time to Maximum Concentration (Tmax) ^[17]

End point description

Time at which the maximum plasma concentration was observed. The PK population included all participants who received at least one dose of rhPTX-2 and had at least one post-dose total PTX-2 concentration result. 9999999 = no samples were analyzed.

End point type

Other pre-specified

End point timeframe

Pre-dose on Cycles(C) 1, 2 and 6, Day(D) 1 and C1 D15. Each cycle is 28 days

Notes
[17] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Data is being provided for each stage of this study rather than all arms in the baseline period at once.

End point values	Main Phase Stage 1: RO7490677 10 mg/kg IV Every Week (QW)	Main Phase Stage 1: RO7490677 10 mg/kg IV Every 4 Weeks (Q4W)	Main Phase Stage 1: RO7490677 10 mg/kg IV QW + Ruxolitinib	Main Phase Stage 1: RO7490677 10 mg/kg IV Q4W+ Ruxolitinib
Number of subjects analysed	8	7	6	6
Units: Hour (hr)
median (full range (min-max))
C1D1 (n=7,7,6,6)	1.12 (1.00 to 2.00)	1.10 (1.00 to 2.08)	1.14 (1.00 to 2.25)	1.13 (1.00 to 5.00)
C1D15 (n=7,0,6,0)	1.13 (1.03 to 1.80)	9999999 (9999999 to 9999999)	1.65 (1.02 to 2.50)	9999999 (9999999 to 9999999)
C2D1 (n=7,7,6,6)	1.10 (1.00 to 3.17)	1.08 (1.03 to 1.08)	1.05 (1.00 to 1.32)	1.44 (1.00 to 9.00)
C6D1 (n=5,5,5,6)	2.00 (1.03 to 5.20)	1.07 (1.00 to 2.03)	1.17 (1.05 to 5.00)	1.01 (1.00 to 1.08)

No statistical analyses for this end point

Other pre-specified: Stage 1 Main Phase: Area Under the Curve up to the Last Measurable Concentration (AUC0-last)

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End point title

Stage 1 Main Phase: Area Under the Curve up to the Last Measurable Concentration (AUC0-last) ^[18]

End point description

Area under the plasma concentration time curve from time 0 to time of last measurable plasma concentration. The PK population included all participants who received at least one dose of rhPTX-2 and had at least one post-dose total PTX-2 vconcentration result. 9999999 = no samples were analyzed.

End point type

Other pre-specified

End point timeframe

Pre-dose on Cycles(C) 1, 2 and 6, Day(D) 1 and C1 D15. Each cycle is 28 days

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: Data is being provided for each stage of this study rather than all arms in the baseline period at once.

End point values	Main Phase Stage 1: RO7490677 10 mg/kg IV Every Week (QW)	Main Phase Stage 1: RO7490677 10 mg/kg IV Every 4 Weeks (Q4W)	Main Phase Stage 1: RO7490677 10 mg/kg IV QW + Ruxolitinib	Main Phase Stage 1: RO7490677 10 mg/kg IV Q4W+ Ruxolitinib
Number of subjects analysed	8	7	6	6
Units: ug*hour/mL
geometric mean (geometric coefficient of variation)
C1D1 (n=7,7,6,6)	1810 ( 72.0 )	1690 ( 26.1 )	2590 ( 28.7 )	1500 ( 158.3 )
C1D15 (n=7,0,6,0)	1460 ( 142.0 )	9999999 ( 9999999 )	2590 ( 187.6 )	9999999 ( 9999999 )
C2D1 (n=7,7,6,6)	127.3 ( 904 )	504 ( 84.7 )	2990 ( 92.0 )	663 ( 79.5 )
C6D1 (n=5,5,5,6)	698 ( 63.0 )	570 ( 44.8 )	764 ( 28.9 )	703 ( 33.8 )

No statistical analyses for this end point

Other pre-specified: Stage 1 Main Phase: Area Under the Concentration-Time Curve Extrapolated to Infinity (AUC0-inf)

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End point title

Stage 1 Main Phase: Area Under the Concentration-Time Curve Extrapolated to Infinity (AUC0-inf) ^[19]

End point description

Area under the plasma concentration-time curve from 0-time extrapolated to infinity. The PK population included all participants who received at least one dose of rhPTX-2 and had at least one post-dose total PTX-2 concentration result. 9999999= no samples were analyzed (for C1D15), the geometric mean and geometric coefficient of variation weren't calculated due to terminal phase calculation criteria not being met and the data could not be calculated from data for a single participant.

End point type

Other pre-specified

End point timeframe

Pre-dose on Cycles(C) 1, 2 and 6, Day(D) 1 and C1 D15. Each cycle is 28 days

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: Data is being provided for each stage of this study rather than all arms in the baseline period at once.

End point values	Main Phase Stage 1: RO7490677 10 mg/kg IV Every Week (QW)	Main Phase Stage 1: RO7490677 10 mg/kg IV Every 4 Weeks (Q4W)	Main Phase Stage 1: RO7490677 10 mg/kg IV QW + Ruxolitinib	Main Phase Stage 1: RO7490677 10 mg/kg IV Q4W+ Ruxolitinib
Number of subjects analysed	8	7	6	6
Units: ug*hour/mL
geometric mean (geometric coefficient of variation)
C1D1 (n=3,7,5,3)	2830 ( 12.9 )	2050 ( 29.5 )	2970 ( 34.9 )	3130 ( 8.6 )
C1D15 (n=4,0,4,0)	3450 ( 2.8 )	9999999 ( 9999999 )	6060 ( 23.2 )	9999999 ( 9999999 )
C2D1 (n=3,0,5,0)	2170 ( 170.9 )	9999999 ( 9999999 )	4230 ( 34.8 )	9999999 ( 9999999 )
C6D1 (n=0,0,1,0)	9999999 ( 9999999 )	9999999 ( 9999999 )	819 ( 9999999 )	9999999 ( 9999999 )

No statistical analyses for this end point

Other pre-specified: Stage 1 Main Phase: Terminal Elimination Half-Life (T1/2)

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End point title

Stage 1 Main Phase: Terminal Elimination Half-Life (T1/2) ^[20]

End point description

Apparent terminal elimination half-life of RO7490677. The PK population included all participants who received at least one dose of rhPTX-2 and had at least one post-dose total PTX-2 concentration result. 9999999= no samples were analyzed (for C1D15), the geometric mean and geometric coefficient of variation weren't calculated due to terminal phase calculation criteria not being met and the data could not be calculated from data for a single participant.

End point type

Other pre-specified

End point timeframe

Pre-dose on Cycles(C) 1, 2 and 6, Day(D) 1 and C1 D15. Each cycle is 28 days

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: Data is being provided for each stage of this study rather than all arms in the baseline period at once.

End point values	Main Phase Stage 1: RO7490677 10 mg/kg IV Every Week (QW)	Main Phase Stage 1: RO7490677 10 mg/kg IV Every 4 Weeks (Q4W)	Main Phase Stage 1: RO7490677 10 mg/kg IV QW + Ruxolitinib	Main Phase Stage 1: RO7490677 10 mg/kg IV Q4W+ Ruxolitinib
Number of subjects analysed	8	7	6	6
Units: hr
geometric mean (geometric coefficient of variation)
C1D1 (n=3,7,5,3)	14.7 ( 19.2 )	17.2 ( 23.7 )	16.8 ( 17.7 )	18.4 ( 7.9 )
C1D15 (n=4,0,4,0)	31.2 ( 45.0 )	9999999 ( 9999999 )	40.4 ( 12.6 )	9999999 ( 9999999 )
C2D1 (n=3,0,5,0)	18.0 ( 220.6 )	9999999 ( 9999999 )	30.0 ( 48.6 )	9999999 ( 9999999 )
C6D1 (n=0,0,1,0)	9999999 ( 9999999 )	9999999 ( 9999999 )	1.95 ( 9999999 )	9999999 ( 9999999 )

No statistical analyses for this end point

Other pre-specified: Stage 1 Main Phase: Clearance (CL)

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End point title

Stage 1 Main Phase: Clearance (CL) ^[21]

End point description

The PK population included all participants who received at least one dose of rhPTX-2 and had at least one post-dose total PTX-2 concentration result. 9999999= no samples were analyzed (for C1D15), the geometric mean and geometric coefficient of variation weren't calculated due to terminal phase calculation criteria not being met and the data could not be calculated from data for a single participant.

End point type

Other pre-specified

End point timeframe

Pre-dose on Cycles(C) 1, 2 and 6, Day(D) 1 and C1 D15. Each cycle is 28 days

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: Data is being provided for each stage of this study rather than all arms in the baseline period at once.

End point values	Main Phase Stage 1: RO7490677 10 mg/kg IV Every Week (QW)	Main Phase Stage 1: RO7490677 10 mg/kg IV Every 4 Weeks (Q4W)	Main Phase Stage 1: RO7490677 10 mg/kg IV QW + Ruxolitinib	Main Phase Stage 1: RO7490677 10 mg/kg IV Q4W+ Ruxolitinib
Number of subjects analysed	8	7	6	6
Units: Litres per hour (L/hr)
geometric mean (geometric coefficient of variation)
C1D1 (n=3,7,5,3)	0.258 ( 9.0 )	0.362 ( 31.5 )	0.269 ( 32.9 )	0.233 ( 33.3 )
C1D15 (n=4,0,4,0)	0.233 ( 24.9 )	9999999 ( 9999999 )	0.147 ( 35.0 )	9999999 ( 9999999 )
C2D1 (n=3,0,5,0)	0.382 ( 229.9 )	9999999 ( 9999999 )	0.189 ( 55.5 )	9999999 ( 9999999 )
C6D1 (n=0,0,1,0)	9999999 ( 9999999 )	9999999 ( 9999999 )	1.42 ( 9999999 )	9999999 ( 9999999 )

No statistical analyses for this end point

Other pre-specified: Stage 1 Main Phase: Volume of Distribution (Vd)

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End point title

Stage 1 Main Phase: Volume of Distribution (Vd) ^[22]

End point description

End point type

Other pre-specified

End point timeframe

Pre-dose on Cycles(C) 1, 2 and 6, Day(D) 1 and C1 D15. Each cycle is 28 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: Data is being provided for each stage of this study rather than all arms in the baseline period at once.

End point values	Main Phase Stage 1: RO7490677 10 mg/kg IV Every Week (QW)	Main Phase Stage 1: RO7490677 10 mg/kg IV Every 4 Weeks (Q4W)	Main Phase Stage 1: RO7490677 10 mg/kg IV QW + Ruxolitinib	Main Phase Stage 1: RO7490677 10 mg/kg IV Q4W+ Ruxolitinib
Number of subjects analysed	8	7	6	6
Units: Litres (L)
geometric mean (geometric coefficient of variation)
C1D1 (n=3,7,5,3)	5.47 ( 10.9 )	9.00 ( 28.8 )	6.52 ( 2.64 )	6.17 ( 38.9 )
C1D15 (n=4,0,4,0)	10.5 ( 62.4 )	9999999 ( 9999999 )	8.57 ( 47.6 )	9999999 ( 9999999 )
C2D1 (n=3,0,5,0)	9.93 ( 63.0 )	9999999 ( 9999999 )	8.18 ( 24.5 )	9999999 ( 9999999 )
C6D1 (n=0,0,1,0)	9999999 ( 9999999 )	9999999 ( 9999999 )	4.01 ( 9999999 )	9999999 ( 9999999 )

No statistical analyses for this end point

Other pre-specified: Percentage of Participants with Adverse Events (AEs) and Infusion Related Reactions (IRRs)

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End point title

Percentage of Participants with Adverse Events (AEs) and Infusion Related Reactions (IRRs)

End point description

An AE was defined as any noxious, pathologic, or unintended change in anatomical, physiologic, or metabolic function as indicated by physical signs, symptoms, or laboratory changes occurring in any phase of a clinical study, whether or not considered investigational product-related. Pre-existing conditions which worsened during the study were also considered as adverse events. IRRs were considerd to be Adverse Events of Special Interest (AESI). Grading was completed according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE), version 4.0. The safety population included all participants who received at least one dose of study drug.

End point type

Other pre-specified

End point timeframe

Baseline up until 6.75 years

End point values	Main Phase Stage 1: RO7490677 10 mg/kg IV Every Week (QW)	OLE Stage 1: RO7490677 10 mg/kg IV Q4W	Main Phase Stage 1: RO7490677 10 mg/kg IV Every 4 Weeks (Q4W)	OLE Stage 1: RO7490677 10 mg/kg IV Q4W + Ruxolitinib	Main Phase Stage 1: RO7490677 10 mg/kg IV QW + Ruxolitinib	OLE Stage 2: RO7490677 10 mg/kg IV Q4W	Main Phase Stage 1: RO7490677 10 mg/kg IV Q4W+ Ruxolitinib	Main Phase Stage 2: RO7490677 0.3 mg/kg IV Q4W	Main Phase Stage 2: RO7490677 3 mg/kg IV Q4W	Main Phase Stage 2: RO7490677 10 mg/kg IV Q4W
Number of subjects analysed	8	13	7	5	6	48	6	33	32	32
Units: Percentage of Participants
number (not applicable)
AEs	100	92.3	85.7	100	100	89.6	100	100	100	100
IRRs	0	7.7	0	20.0	0	2.1	16.7	3.0	3.1	6.3

No statistical analyses for this end point

Other pre-specified: Percentage of Participants with Serious Adverse Events (SAEs) and AEs Leading to Study Drug Discontinuation

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End point title

Percentage of Participants with Serious Adverse Events (SAEs) and AEs Leading to Study Drug Discontinuation

End point description

An SAE was defined as any AE that occurred at any dose the resulted in death; was life-threatening; required hospitalization or prolongation of existing hospitalizations; a persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions; a congenital anomaly or birth defect. An AE was defined as any noxious, pathologic, or unintended change in anatomical, physiologic, or metabolic function as indicated by physical signs, symptoms, or laboratory changes occurring in any phase of a clinical study, whether or not considered investigational product-related. Pre-existing conditions which worsened during the study were also considered as adverse events. Grading was completed according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE), version 4.0. The safety population included all participants who received at least one dose of study drug.

End point type

Other pre-specified

End point timeframe

Baseline up until 6.75 years

End point values	Main Phase Stage 1: RO7490677 10 mg/kg IV Every Week (QW)	OLE Stage 1: RO7490677 10 mg/kg IV Q4W	Main Phase Stage 1: RO7490677 10 mg/kg IV Every 4 Weeks (Q4W)	OLE Stage 1: RO7490677 10 mg/kg IV Q4W + Ruxolitinib	Main Phase Stage 1: RO7490677 10 mg/kg IV QW + Ruxolitinib	OLE Stage 2: RO7490677 10 mg/kg IV Q4W	Main Phase Stage 1: RO7490677 10 mg/kg IV Q4W+ Ruxolitinib	Main Phase Stage 2: RO7490677 0.3 mg/kg IV Q4W	Main Phase Stage 2: RO7490677 3 mg/kg IV Q4W	Main Phase Stage 2: RO7490677 10 mg/kg IV Q4W
Number of subjects analysed	8	13	7	5	6	48	6	33	32	32
Units: Percentage of Participants
number (not applicable)
SAEs	25.0	7.7	0	0	0	22.9	0	15.2	15.6	28.1
AEs	25.0	30.8	0	0	0	27.1	0	21.2	34.4	37.5

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

Baseline up until 6.75 years

Adverse event reporting additional description

Treatment-emergent adverse events (TEAEs) were defined as any AE that occurred after the administration of any amount of the study drug, or any event that was present at baseline.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

23.0

Reporting group title

Main Phase Stage 2: RO7490677 0.3 mg/kg IV Q4W

Reporting group description

Reporting group title

Main Phase Stage 1: RO7490677 10 mg/kg IV QW + Ruxolitinib

Reporting group description

Reporting group title

Main Phase Stage 1: RO7490677 10 mg/kg IV Every Week (QW)

Reporting group description

Reporting group title

Main Phase Stage 2: RO7490677 10 mg/kg IV Q4W

Reporting group description

Reporting group title

OLE Stage 2: RO7490677 10 mg/kg IV Q4W

Reporting group description

Reporting group title

Main Phase Stage 1: RO7490677 10 mg/kg IV Every 4 Weeks (Q4W)

Reporting group description

Reporting group title

Main Phase Stage 1: RO7490677 10 mg/kg IV Q4W+ Ruxolitinib

Reporting group description

Participants on a stable dose of ruxolitinib for at least 12 weeks, with no improvement in spleen during the last four weeks were assigned to receive PRM-151 at a dose of 10 mg/kg administered as a 30 minute IV infusion in combination with daily oral ruxolitinib on Days 1, 3, and 5 of Cycle 1 and Day 1 of each subsequent 28 day cycle for six cycles.

Reporting group title

OLE Stage 1: RO7490677 10 mg/kg IV Q4W + Ruxolitinib

Reporting group description

Reporting group title

OLE Stage 1: RO7490677 10 mg/kg IV Q4W

Reporting group description

Reporting group title

Main Phase Stage 2: RO7490677 3 mg/kg IV Q4W

Reporting group description

Serious adverse events	Main Phase Stage 2: RO7490677 0.3 mg/kg IV Q4W	Main Phase Stage 1: RO7490677 10 mg/kg IV QW + Ruxolitinib	Main Phase Stage 1: RO7490677 10 mg/kg IV Every Week (QW)	Main Phase Stage 2: RO7490677 10 mg/kg IV Q4W	OLE Stage 2: RO7490677 10 mg/kg IV Q4W	Main Phase Stage 1: RO7490677 10 mg/kg IV Every 4 Weeks (Q4W)	Main Phase Stage 1: RO7490677 10 mg/kg IV Q4W+ Ruxolitinib	OLE Stage 1: RO7490677 10 mg/kg IV Q4W + Ruxolitinib	OLE Stage 1: RO7490677 10 mg/kg IV Q4W	Main Phase Stage 2: RO7490677 3 mg/kg IV Q4W
Total subjects affected by serious adverse events
subjects affected / exposed	11 / 33 (33.33%)	2 / 6 (33.33%)	2 / 8 (25.00%)	14 / 32 (43.75%)	22 / 48 (45.83%)	1 / 7 (14.29%)	0 / 6 (0.00%)	2 / 5 (40.00%)	5 / 13 (38.46%)	14 / 32 (43.75%)
number of deaths (all causes)	7	1	2	9	7	0	0	0	0	6
number of deaths resulting from adverse events
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Acute myeloid leukaemia
subjects affected / exposed	0 / 33 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	1 / 32 (3.13%)	0 / 48 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 13 (0.00%)	0 / 32 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hepatic cancer
subjects affected / exposed	0 / 33 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 32 (0.00%)	0 / 48 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	1 / 13 (7.69%)	0 / 32 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Malignant neoplasm progression
subjects affected / exposed	0 / 33 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 32 (0.00%)	0 / 48 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 13 (0.00%)	1 / 32 (3.13%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
Metastatic squamous cell carcinoma
subjects affected / exposed	0 / 33 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 32 (0.00%)	0 / 48 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	1 / 13 (7.69%)	0 / 32 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Myelofibrosis
subjects affected / exposed	0 / 33 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	1 / 32 (3.13%)	2 / 48 (4.17%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 13 (0.00%)	1 / 32 (3.13%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 2	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 2	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Primary myelofibrosis
subjects affected / exposed	1 / 33 (3.03%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 32 (0.00%)	0 / 48 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 13 (0.00%)	0 / 32 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Squamous cell carcinoma
subjects affected / exposed	0 / 33 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 32 (0.00%)	0 / 48 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	1 / 5 (20.00%)	0 / 13 (0.00%)	0 / 32 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Transformation to acute myeloid leukaemia
subjects affected / exposed	1 / 33 (3.03%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 32 (0.00%)	0 / 48 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 13 (0.00%)	0 / 32 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Vascular disorders
Dry gangrene
subjects affected / exposed	0 / 33 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	1 / 32 (3.13%)	0 / 48 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 13 (0.00%)	0 / 32 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Haematoma
subjects affected / exposed	0 / 33 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 32 (0.00%)	0 / 48 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	1 / 13 (7.69%)	0 / 32 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Surgical and medical procedures
Aortic valve replacement
subjects affected / exposed	0 / 33 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 32 (0.00%)	1 / 48 (2.08%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 13 (0.00%)	0 / 32 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
General disorders and administration site conditions
Asthenia
subjects affected / exposed	0 / 33 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 32 (0.00%)	0 / 48 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 13 (0.00%)	1 / 32 (3.13%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Chest pain
subjects affected / exposed	0 / 33 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	1 / 32 (3.13%)	0 / 48 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 13 (0.00%)	0 / 32 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Death
subjects affected / exposed	1 / 33 (3.03%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 32 (0.00%)	0 / 48 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 13 (0.00%)	0 / 32 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Disease progression
subjects affected / exposed	0 / 33 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	2 / 32 (6.25%)	0 / 48 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 13 (0.00%)	0 / 32 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 2	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 2	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Inflammation
subjects affected / exposed	0 / 33 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 32 (0.00%)	0 / 48 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 13 (0.00%)	1 / 32 (3.13%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Organ failure
subjects affected / exposed	0 / 33 (0.00%)	0 / 6 (0.00%)	1 / 8 (12.50%)	0 / 32 (0.00%)	0 / 48 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 13 (0.00%)	0 / 32 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Peripheral swelling
subjects affected / exposed	0 / 33 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 32 (0.00%)	0 / 48 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 13 (0.00%)	1 / 32 (3.13%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Unevaluable event
subjects affected / exposed	0 / 33 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	1 / 32 (3.13%)	1 / 48 (2.08%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 13 (0.00%)	0 / 32 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 2	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Immune system disorders
Anaphylactic reaction
subjects affected / exposed	0 / 33 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	1 / 32 (3.13%)	0 / 48 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 13 (0.00%)	0 / 32 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Chronic obstructive pulmonary disease
subjects affected / exposed	1 / 33 (3.03%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 32 (0.00%)	0 / 48 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 13 (0.00%)	0 / 32 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Epistaxis
subjects affected / exposed	2 / 33 (6.06%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 32 (0.00%)	1 / 48 (2.08%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 13 (0.00%)	1 / 32 (3.13%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pleural effusion
subjects affected / exposed	0 / 33 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	1 / 32 (3.13%)	1 / 48 (2.08%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 13 (0.00%)	0 / 32 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Investigations
Eastern Cooperative Oncology Group performance status worsened
subjects affected / exposed	0 / 33 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 32 (0.00%)	1 / 48 (2.08%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 13 (0.00%)	0 / 32 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hepatic enzyme increased
subjects affected / exposed	0 / 33 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 32 (0.00%)	0 / 48 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 13 (0.00%)	1 / 32 (3.13%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Injury, poisoning and procedural complications
Fall
subjects affected / exposed	0 / 33 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 32 (0.00%)	1 / 48 (2.08%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 13 (0.00%)	2 / 32 (6.25%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Infusion related reaction
subjects affected / exposed	0 / 33 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	1 / 32 (3.13%)	0 / 48 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 13 (0.00%)	0 / 32 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Multiple fractures
subjects affected / exposed	0 / 33 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 32 (0.00%)	0 / 48 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	1 / 13 (7.69%)	0 / 32 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Osteoradionecrosis
subjects affected / exposed	0 / 33 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 32 (0.00%)	1 / 48 (2.08%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 13 (0.00%)	0 / 32 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Post procedural haematoma
subjects affected / exposed	0 / 33 (0.00%)	0 / 6 (0.00%)	1 / 8 (12.50%)	0 / 32 (0.00%)	0 / 48 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 13 (0.00%)	0 / 32 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Procedural haemorrhage
subjects affected / exposed	0 / 33 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 32 (0.00%)	0 / 48 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 13 (0.00%)	1 / 32 (3.13%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Rib fracture
subjects affected / exposed	0 / 33 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 32 (0.00%)	0 / 48 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	1 / 13 (7.69%)	0 / 32 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Subdural haematoma
subjects affected / exposed	0 / 33 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 32 (0.00%)	0 / 48 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 13 (0.00%)	2 / 32 (6.25%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cardiac disorders
Acute coronary syndrome
subjects affected / exposed	0 / 33 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 32 (0.00%)	1 / 48 (2.08%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 13 (0.00%)	0 / 32 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Acute myocardial infarction
subjects affected / exposed	0 / 33 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 32 (0.00%)	1 / 48 (2.08%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 13 (0.00%)	0 / 32 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Aortic valve stenosis
subjects affected / exposed	0 / 33 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 32 (0.00%)	1 / 48 (2.08%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 13 (0.00%)	0 / 32 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cardiac arrest
subjects affected / exposed	0 / 33 (0.00%)	0 / 6 (0.00%)	1 / 8 (12.50%)	0 / 32 (0.00%)	0 / 48 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 13 (0.00%)	0 / 32 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cardiac failure
subjects affected / exposed	1 / 33 (3.03%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 32 (0.00%)	0 / 48 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 13 (0.00%)	0 / 32 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cardiopulmonary failure
subjects affected / exposed	1 / 33 (3.03%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 32 (0.00%)	0 / 48 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 13 (0.00%)	0 / 32 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Coronary artery disease
subjects affected / exposed	1 / 33 (3.03%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 32 (0.00%)	0 / 48 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 13 (0.00%)	0 / 32 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pericardial effusion
subjects affected / exposed	0 / 33 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	1 / 32 (3.13%)	1 / 48 (2.08%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 13 (0.00%)	0 / 32 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Nervous system disorders
Cerebral haemorrhage
subjects affected / exposed	0 / 33 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 32 (0.00%)	0 / 48 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 13 (0.00%)	1 / 32 (3.13%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
Hepatic encephalopathy
subjects affected / exposed	0 / 33 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	1 / 32 (3.13%)	0 / 48 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 13 (0.00%)	0 / 32 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Metabolic encephalopathy
subjects affected / exposed	0 / 33 (0.00%)	0 / 6 (0.00%)	1 / 8 (12.50%)	0 / 32 (0.00%)	0 / 48 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 13 (0.00%)	0 / 32 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Subarachnoid haemorrhage
subjects affected / exposed	0 / 33 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 32 (0.00%)	1 / 48 (2.08%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 13 (0.00%)	0 / 32 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Syncope
subjects affected / exposed	0 / 33 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 32 (0.00%)	0 / 48 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 13 (0.00%)	1 / 32 (3.13%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	0 / 33 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 32 (0.00%)	2 / 48 (4.17%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 13 (0.00%)	0 / 32 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 2	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Bone marrow failure
subjects affected / exposed	0 / 33 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 32 (0.00%)	1 / 48 (2.08%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 13 (0.00%)	0 / 32 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Extramedullary haemopoiesis
subjects affected / exposed	0 / 33 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 32 (0.00%)	1 / 48 (2.08%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 13 (0.00%)	0 / 32 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Leukocytosis
subjects affected / exposed	0 / 33 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 32 (0.00%)	0 / 48 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 13 (0.00%)	1 / 32 (3.13%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pancytopenia
subjects affected / exposed	0 / 33 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 32 (0.00%)	0 / 48 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 13 (0.00%)	1 / 32 (3.13%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
Thrombocytopenia
subjects affected / exposed	0 / 33 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 32 (0.00%)	0 / 48 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 13 (0.00%)	1 / 32 (3.13%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
Abdominal pain
subjects affected / exposed	0 / 33 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	1 / 32 (3.13%)	0 / 48 (0.00%)	1 / 7 (14.29%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 13 (0.00%)	0 / 32 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	1 / 3	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Femoral hernia, obstructive
subjects affected / exposed	0 / 33 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	1 / 32 (3.13%)	0 / 48 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 13 (0.00%)	0 / 32 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Intestinal ischaemia
subjects affected / exposed	0 / 33 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 32 (0.00%)	1 / 48 (2.08%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 13 (0.00%)	0 / 32 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Intestinal obstruction
subjects affected / exposed	0 / 33 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 32 (0.00%)	0 / 48 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	1 / 13 (7.69%)	0 / 32 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Melaena
subjects affected / exposed	0 / 33 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 32 (0.00%)	1 / 48 (2.08%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 13 (0.00%)	0 / 32 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Mouth haemorrhage
subjects affected / exposed	0 / 33 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 32 (0.00%)	0 / 48 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	1 / 13 (7.69%)	0 / 32 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Oesophageal varices haemorrhage
subjects affected / exposed	0 / 33 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 32 (0.00%)	1 / 48 (2.08%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 13 (0.00%)	0 / 32 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 2	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Rectal haemorrhage
subjects affected / exposed	0 / 33 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	1 / 32 (3.13%)	1 / 48 (2.08%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 13 (0.00%)	0 / 32 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Upper gastrointestinal haemorrhage
subjects affected / exposed	0 / 33 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 32 (0.00%)	0 / 48 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	1 / 5 (20.00%)	0 / 13 (0.00%)	0 / 32 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Varices oesophageal
subjects affected / exposed	0 / 33 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 32 (0.00%)	0 / 48 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 13 (0.00%)	1 / 32 (3.13%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hepatobiliary disorders
Cholecystitis
subjects affected / exposed	0 / 33 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 32 (0.00%)	0 / 48 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 13 (0.00%)	1 / 32 (3.13%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cholecystitis acute
subjects affected / exposed	0 / 33 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 32 (0.00%)	0 / 48 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 13 (0.00%)	1 / 32 (3.13%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cholelithiasis
subjects affected / exposed	1 / 33 (3.03%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 32 (0.00%)	0 / 48 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 13 (0.00%)	1 / 32 (3.13%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Portal hypertension
subjects affected / exposed	0 / 33 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 32 (0.00%)	0 / 48 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	1 / 13 (7.69%)	0 / 32 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Skin and subcutaneous tissue disorders
Eczema
subjects affected / exposed	0 / 33 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	1 / 32 (3.13%)	0 / 48 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 13 (0.00%)	0 / 32 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Skin ulcer
subjects affected / exposed	0 / 33 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 32 (0.00%)	1 / 48 (2.08%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 13 (0.00%)	0 / 32 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Renal and urinary disorders
Acute kidney injury
subjects affected / exposed	0 / 33 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 32 (0.00%)	1 / 48 (2.08%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 13 (0.00%)	1 / 32 (3.13%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 2	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Nephrolithiasis
subjects affected / exposed	0 / 33 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 32 (0.00%)	1 / 48 (2.08%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 13 (0.00%)	0 / 32 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Renal failure
subjects affected / exposed	0 / 33 (0.00%)	0 / 6 (0.00%)	1 / 8 (12.50%)	0 / 32 (0.00%)	0 / 48 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 13 (0.00%)	0 / 32 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Urinary bladder haemorrhage
subjects affected / exposed	0 / 33 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 32 (0.00%)	0 / 48 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	1 / 13 (7.69%)	0 / 32 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Urinary bladder rupture
subjects affected / exposed	0 / 33 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 32 (0.00%)	0 / 48 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	1 / 13 (7.69%)	0 / 32 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Back pain
subjects affected / exposed	0 / 33 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 32 (0.00%)	1 / 48 (2.08%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 13 (0.00%)	0 / 32 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Chondrocalcinosis pyrophosphate
subjects affected / exposed	1 / 33 (3.03%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 32 (0.00%)	0 / 48 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 13 (0.00%)	0 / 32 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Haemarthrosis
subjects affected / exposed	0 / 33 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 32 (0.00%)	1 / 48 (2.08%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 13 (0.00%)	0 / 32 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Haematoma muscle
subjects affected / exposed	0 / 33 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 32 (0.00%)	1 / 48 (2.08%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 13 (0.00%)	0 / 32 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Joint effusion
subjects affected / exposed	1 / 33 (3.03%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 32 (0.00%)	0 / 48 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 13 (0.00%)	0 / 32 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Infections and infestations
Abscess limb
subjects affected / exposed	0 / 33 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	1 / 32 (3.13%)	0 / 48 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 13 (0.00%)	0 / 32 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cellulitis
subjects affected / exposed	0 / 33 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	1 / 32 (3.13%)	0 / 48 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 13 (0.00%)	1 / 32 (3.13%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Endocarditis
subjects affected / exposed	0 / 33 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 32 (0.00%)	0 / 48 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 13 (0.00%)	1 / 32 (3.13%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Enterocolitis infectious
subjects affected / exposed	0 / 33 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 32 (0.00%)	0 / 48 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	1 / 5 (20.00%)	0 / 13 (0.00%)	0 / 32 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastroenteritis
subjects affected / exposed	0 / 33 (0.00%)	0 / 6 (0.00%)	1 / 8 (12.50%)	0 / 32 (0.00%)	0 / 48 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 13 (0.00%)	0 / 32 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Infection
subjects affected / exposed	0 / 33 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 32 (0.00%)	1 / 48 (2.08%)	0 / 7 (0.00%)	0 / 6 (0.00%)	1 / 5 (20.00%)	0 / 13 (0.00%)	0 / 32 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Influenza
subjects affected / exposed	0 / 33 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 32 (0.00%)	1 / 48 (2.08%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 13 (0.00%)	0 / 32 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Intervertebral discitis
subjects affected / exposed	0 / 33 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 32 (0.00%)	1 / 48 (2.08%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 13 (0.00%)	0 / 32 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Osteomyelitis
subjects affected / exposed	0 / 33 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 32 (0.00%)	2 / 48 (4.17%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 13 (0.00%)	0 / 32 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 2	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pneumonia
subjects affected / exposed	2 / 33 (6.06%)	1 / 6 (16.67%)	0 / 8 (0.00%)	2 / 32 (6.25%)	3 / 48 (6.25%)	0 / 7 (0.00%)	0 / 6 (0.00%)	1 / 5 (20.00%)	0 / 13 (0.00%)	1 / 32 (3.13%)
occurrences causally related to treatment / all	0 / 3	0 / 2	0 / 0	0 / 2	0 / 3	0 / 0	0 / 0	0 / 2	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
Pneumonia fungal
subjects affected / exposed	0 / 33 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	1 / 32 (3.13%)	0 / 48 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 13 (0.00%)	0 / 32 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pneumonia viral
subjects affected / exposed	0 / 33 (0.00%)	0 / 6 (0.00%)	1 / 8 (12.50%)	0 / 32 (0.00%)	0 / 48 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 13 (0.00%)	0 / 32 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pseudomonal sepsis
subjects affected / exposed	0 / 33 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 32 (0.00%)	1 / 48 (2.08%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 13 (0.00%)	0 / 32 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory syncytial virus infection
subjects affected / exposed	0 / 33 (0.00%)	1 / 6 (16.67%)	0 / 8 (0.00%)	0 / 32 (0.00%)	0 / 48 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 13 (0.00%)	0 / 32 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Sepsis
subjects affected / exposed	0 / 33 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	1 / 32 (3.13%)	1 / 48 (2.08%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 13 (0.00%)	0 / 32 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Septic shock
subjects affected / exposed	0 / 33 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	1 / 32 (3.13%)	1 / 48 (2.08%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 13 (0.00%)	0 / 32 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Sialoadenitis
subjects affected / exposed	0 / 33 (0.00%)	1 / 6 (16.67%)	0 / 8 (0.00%)	0 / 32 (0.00%)	0 / 48 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 13 (0.00%)	0 / 32 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Upper respiratory tract infection
subjects affected / exposed	0 / 33 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 32 (0.00%)	0 / 48 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 13 (0.00%)	1 / 32 (3.13%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Urinary tract infection
subjects affected / exposed	0 / 33 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 32 (0.00%)	1 / 48 (2.08%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 13 (0.00%)	1 / 32 (3.13%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Urosepsis
subjects affected / exposed	0 / 33 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 32 (0.00%)	0 / 48 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 13 (0.00%)	1 / 32 (3.13%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Wound infection
subjects affected / exposed	0 / 33 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 32 (0.00%)	0 / 48 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	1 / 5 (20.00%)	1 / 13 (7.69%)	0 / 32 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Metabolism and nutrition disorders
Cachexia
subjects affected / exposed	0 / 33 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	1 / 32 (3.13%)	0 / 48 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 13 (0.00%)	0 / 32 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hyperkalaemia
subjects affected / exposed	0 / 33 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 32 (0.00%)	0 / 48 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 13 (0.00%)	1 / 32 (3.13%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hyperuricaemia
subjects affected / exposed	0 / 33 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 32 (0.00%)	0 / 48 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 13 (0.00%)	1 / 32 (3.13%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0

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

Non-serious adverse events	Main Phase Stage 2: RO7490677 0.3 mg/kg IV Q4W	Main Phase Stage 1: RO7490677 10 mg/kg IV QW + Ruxolitinib	Main Phase Stage 1: RO7490677 10 mg/kg IV Every Week (QW)	Main Phase Stage 2: RO7490677 10 mg/kg IV Q4W	OLE Stage 2: RO7490677 10 mg/kg IV Q4W	Main Phase Stage 1: RO7490677 10 mg/kg IV Every 4 Weeks (Q4W)	Main Phase Stage 1: RO7490677 10 mg/kg IV Q4W+ Ruxolitinib	OLE Stage 1: RO7490677 10 mg/kg IV Q4W + Ruxolitinib	OLE Stage 1: RO7490677 10 mg/kg IV Q4W	Main Phase Stage 2: RO7490677 3 mg/kg IV Q4W
Total subjects affected by non serious adverse events
subjects affected / exposed	32 / 33 (96.97%)	6 / 6 (100.00%)	8 / 8 (100.00%)	31 / 32 (96.88%)	32 / 48 (66.67%)	6 / 7 (85.71%)	6 / 6 (100.00%)	5 / 5 (100.00%)	12 / 13 (92.31%)	30 / 32 (93.75%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Lipoma
subjects affected / exposed	0 / 33 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 32 (0.00%)	0 / 48 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	1 / 13 (7.69%)	0 / 32 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	1	0
Neoplasm
subjects affected / exposed	0 / 33 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 32 (0.00%)	0 / 48 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	1 / 13 (7.69%)	0 / 32 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	1	0
Squamous cell carcinoma
subjects affected / exposed	2 / 33 (6.06%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 32 (0.00%)	0 / 48 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	3 / 5 (60.00%)	0 / 13 (0.00%)	0 / 32 (0.00%)
occurrences all number	2	0	0	0	0	0	0	3	0	0
Vascular disorders
Haematoma
subjects affected / exposed	0 / 33 (0.00%)	0 / 6 (0.00%)	1 / 8 (12.50%)	0 / 32 (0.00%)	0 / 48 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	1 / 13 (7.69%)	0 / 32 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0	1	0
Hot flush
subjects affected / exposed	0 / 33 (0.00%)	0 / 6 (0.00%)	1 / 8 (12.50%)	0 / 32 (0.00%)	0 / 48 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 13 (0.00%)	0 / 32 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0	0	0
Hypertension
subjects affected / exposed	0 / 33 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 32 (0.00%)	0 / 48 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	1 / 5 (20.00%)	0 / 13 (0.00%)	0 / 32 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0	0
Hypotension
subjects affected / exposed	1 / 33 (3.03%)	0 / 6 (0.00%)	1 / 8 (12.50%)	1 / 32 (3.13%)	3 / 48 (6.25%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 13 (0.00%)	2 / 32 (6.25%)
occurrences all number	1	0	1	1	3	0	0	0	0	2
General disorders and administration site conditions
Asthenia
subjects affected / exposed	1 / 33 (3.03%)	0 / 6 (0.00%)	0 / 8 (0.00%)	2 / 32 (6.25%)	2 / 48 (4.17%)	1 / 7 (14.29%)	1 / 6 (16.67%)	0 / 5 (0.00%)	0 / 13 (0.00%)	4 / 32 (12.50%)
occurrences all number	1	0	0	2	2	1	1	0	0	4
Chest discomfort
subjects affected / exposed	0 / 33 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 32 (0.00%)	0 / 48 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 13 (0.00%)	2 / 32 (6.25%)
occurrences all number	0	0	0	0	0	0	0	0	0	3
Chest pain
subjects affected / exposed	0 / 33 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 32 (0.00%)	0 / 48 (0.00%)	0 / 7 (0.00%)	1 / 6 (16.67%)	0 / 5 (0.00%)	0 / 13 (0.00%)	0 / 32 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0	0
Chills
subjects affected / exposed	1 / 33 (3.03%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 32 (0.00%)	0 / 48 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	1 / 13 (7.69%)	2 / 32 (6.25%)
occurrences all number	1	0	0	0	0	0	0	0	2	5
Early satiety
subjects affected / exposed	0 / 33 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 32 (0.00%)	0 / 48 (0.00%)	0 / 7 (0.00%)	1 / 6 (16.67%)	0 / 5 (0.00%)	1 / 13 (7.69%)	0 / 32 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	1	0
Extravasation
subjects affected / exposed	0 / 33 (0.00%)	1 / 6 (16.67%)	0 / 8 (0.00%)	0 / 32 (0.00%)	0 / 48 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 13 (0.00%)	0 / 32 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0	0
Fatigue
subjects affected / exposed	8 / 33 (24.24%)	1 / 6 (16.67%)	3 / 8 (37.50%)	11 / 32 (34.38%)	5 / 48 (10.42%)	1 / 7 (14.29%)	1 / 6 (16.67%)	0 / 5 (0.00%)	2 / 13 (15.38%)	8 / 32 (25.00%)
occurrences all number	9	3	3	12	5	1	1	0	2	10
Gait disturbance
subjects affected / exposed	2 / 33 (6.06%)	0 / 6 (0.00%)	0 / 8 (0.00%)	1 / 32 (3.13%)	1 / 48 (2.08%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 13 (0.00%)	1 / 32 (3.13%)
occurrences all number	2	0	0	1	1	0	0	0	0	1
Ill-defined disorder
subjects affected / exposed	0 / 33 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 32 (0.00%)	0 / 48 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	1 / 13 (7.69%)	0 / 32 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	1	0
Injection site haemorrhage
subjects affected / exposed	0 / 33 (0.00%)	1 / 6 (16.67%)	0 / 8 (0.00%)	0 / 32 (0.00%)	0 / 48 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 13 (0.00%)	0 / 32 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0	0
Oedema peripheral
subjects affected / exposed	6 / 33 (18.18%)	0 / 6 (0.00%)	0 / 8 (0.00%)	9 / 32 (28.13%)	4 / 48 (8.33%)	1 / 7 (14.29%)	0 / 6 (0.00%)	0 / 5 (0.00%)	2 / 13 (15.38%)	3 / 32 (9.38%)
occurrences all number	8	0	0	10	5	1	0	0	2	4
Pain
subjects affected / exposed	0 / 33 (0.00%)	1 / 6 (16.67%)	0 / 8 (0.00%)	0 / 32 (0.00%)	0 / 48 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 13 (0.00%)	0 / 32 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0	0
Peripheral swelling
subjects affected / exposed	2 / 33 (6.06%)	1 / 6 (16.67%)	0 / 8 (0.00%)	2 / 32 (6.25%)	0 / 48 (0.00%)	0 / 7 (0.00%)	2 / 6 (33.33%)	0 / 5 (0.00%)	0 / 13 (0.00%)	1 / 32 (3.13%)
occurrences all number	3	1	0	2	0	0	2	0	0	1
Pyrexia
subjects affected / exposed	4 / 33 (12.12%)	0 / 6 (0.00%)	0 / 8 (0.00%)	3 / 32 (9.38%)	2 / 48 (4.17%)	0 / 7 (0.00%)	3 / 6 (50.00%)	1 / 5 (20.00%)	0 / 13 (0.00%)	7 / 32 (21.88%)
occurrences all number	4	0	0	3	3	0	3	2	0	8
Swelling
subjects affected / exposed	0 / 33 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 32 (0.00%)	0 / 48 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	1 / 5 (20.00%)	0 / 13 (0.00%)	0 / 32 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0	0
Vessel puncture site bruise
subjects affected / exposed	0 / 33 (0.00%)	2 / 6 (33.33%)	0 / 8 (0.00%)	0 / 32 (0.00%)	0 / 48 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 13 (0.00%)	0 / 32 (0.00%)
occurrences all number	0	5	0	0	0	0	0	0	0	0
Social circumstances
Blood product transfusion dependent
subjects affected / exposed	0 / 33 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 32 (0.00%)	0 / 48 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	1 / 13 (7.69%)	0 / 32 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	1	0
Reproductive system and breast disorders
Vaginal haemorrhage
subjects affected / exposed	0 / 33 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 32 (0.00%)	0 / 48 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	1 / 13 (7.69%)	0 / 32 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	1	0
Respiratory, thoracic and mediastinal disorders
Cough
subjects affected / exposed	10 / 33 (30.30%)	2 / 6 (33.33%)	1 / 8 (12.50%)	5 / 32 (15.63%)	4 / 48 (8.33%)	0 / 7 (0.00%)	1 / 6 (16.67%)	3 / 5 (60.00%)	2 / 13 (15.38%)	7 / 32 (21.88%)
occurrences all number	12	2	1	5	4	0	1	4	3	8
Dysphonia
subjects affected / exposed	0 / 33 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 32 (0.00%)	0 / 48 (0.00%)	0 / 7 (0.00%)	1 / 6 (16.67%)	0 / 5 (0.00%)	0 / 13 (0.00%)	0 / 32 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0	0
Dyspnoea
subjects affected / exposed	4 / 33 (12.12%)	0 / 6 (0.00%)	0 / 8 (0.00%)	7 / 32 (21.88%)	4 / 48 (8.33%)	2 / 7 (28.57%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 13 (0.00%)	8 / 32 (25.00%)
occurrences all number	7	0	0	8	4	2	0	0	0	10
Dyspnoea exertional
subjects affected / exposed	3 / 33 (9.09%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 32 (0.00%)	0 / 48 (0.00%)	0 / 7 (0.00%)	2 / 6 (33.33%)	0 / 5 (0.00%)	0 / 13 (0.00%)	1 / 32 (3.13%)
occurrences all number	3	0	0	0	0	0	2	0	0	1
Epistaxis
subjects affected / exposed	5 / 33 (15.15%)	2 / 6 (33.33%)	0 / 8 (0.00%)	4 / 32 (12.50%)	7 / 48 (14.58%)	0 / 7 (0.00%)	1 / 6 (16.67%)	1 / 5 (20.00%)	0 / 13 (0.00%)	4 / 32 (12.50%)
occurrences all number	7	3	0	11	16	0	1	1	0	4
Hypoxia
subjects affected / exposed	0 / 33 (0.00%)	0 / 6 (0.00%)	1 / 8 (12.50%)	0 / 32 (0.00%)	0 / 48 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 13 (0.00%)	0 / 32 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0	0	0
Nasal dryness
subjects affected / exposed	0 / 33 (0.00%)	1 / 6 (16.67%)	0 / 8 (0.00%)	0 / 32 (0.00%)	0 / 48 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 13 (0.00%)	0 / 32 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0	0
Oropharyngeal pain
subjects affected / exposed	0 / 33 (0.00%)	1 / 6 (16.67%)	0 / 8 (0.00%)	0 / 32 (0.00%)	1 / 48 (2.08%)	0 / 7 (0.00%)	0 / 6 (0.00%)	1 / 5 (20.00%)	0 / 13 (0.00%)	4 / 32 (12.50%)
occurrences all number	0	1	0	0	1	0	0	1	0	4
Paranasal sinus discomfort
subjects affected / exposed	0 / 33 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 32 (0.00%)	0 / 48 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	1 / 13 (7.69%)	0 / 32 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	1	0
Pleural effusion
subjects affected / exposed	0 / 33 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	1 / 32 (3.13%)	0 / 48 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 13 (0.00%)	2 / 32 (6.25%)
occurrences all number	0	0	0	1	0	0	0	0	0	2
Pneumothorax
subjects affected / exposed	0 / 33 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 32 (0.00%)	0 / 48 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	1 / 13 (7.69%)	0 / 32 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	1	0
Rhinitis allergic
subjects affected / exposed	0 / 33 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 32 (0.00%)	0 / 48 (0.00%)	1 / 7 (14.29%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 13 (0.00%)	0 / 32 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0	0	0
Sleep apnoea syndrome
subjects affected / exposed	0 / 33 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 32 (0.00%)	0 / 48 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	1 / 13 (7.69%)	0 / 32 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	1	0
Sneezing
subjects affected / exposed	0 / 33 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 32 (0.00%)	0 / 48 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	1 / 13 (7.69%)	0 / 32 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	1	0
Upper-airway cough syndrome
subjects affected / exposed	0 / 33 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 32 (0.00%)	0 / 48 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	1 / 5 (20.00%)	0 / 13 (0.00%)	0 / 32 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0	0
Psychiatric disorders
Delirium
subjects affected / exposed	0 / 33 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	1 / 32 (3.13%)	0 / 48 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 13 (0.00%)	2 / 32 (6.25%)
occurrences all number	0	0	0	1	0	0	0	0	0	3
Depression
subjects affected / exposed	0 / 33 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	1 / 32 (3.13%)	3 / 48 (6.25%)	0 / 7 (0.00%)	1 / 6 (16.67%)	0 / 5 (0.00%)	0 / 13 (0.00%)	4 / 32 (12.50%)
occurrences all number	0	0	0	1	3	0	1	0	0	4
Insomnia
subjects affected / exposed	1 / 33 (3.03%)	1 / 6 (16.67%)	1 / 8 (12.50%)	0 / 32 (0.00%)	3 / 48 (6.25%)	0 / 7 (0.00%)	1 / 6 (16.67%)	0 / 5 (0.00%)	0 / 13 (0.00%)	1 / 32 (3.13%)
occurrences all number	1	1	1	0	3	0	1	0	0	1
Sleep disorder
subjects affected / exposed	0 / 33 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 32 (0.00%)	0 / 48 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	1 / 5 (20.00%)	0 / 13 (0.00%)	0 / 32 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0	0
Investigations
Alanine aminotransferase increased
subjects affected / exposed	2 / 33 (6.06%)	0 / 6 (0.00%)	3 / 8 (37.50%)	1 / 32 (3.13%)	0 / 48 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	2 / 5 (40.00%)	0 / 13 (0.00%)	4 / 32 (12.50%)
occurrences all number	2	0	3	1	0	0	0	2	0	7
Aspartate aminotransferase increased
subjects affected / exposed	1 / 33 (3.03%)	0 / 6 (0.00%)	0 / 8 (0.00%)	1 / 32 (3.13%)	0 / 48 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	2 / 5 (40.00%)	0 / 13 (0.00%)	5 / 32 (15.63%)
occurrences all number	1	0	0	1	0	0	0	2	0	9
Blood alkaline phosphatase increased
subjects affected / exposed	2 / 33 (6.06%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 32 (0.00%)	2 / 48 (4.17%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 13 (0.00%)	2 / 32 (6.25%)
occurrences all number	6	0	0	0	2	0	0	0	0	4
Blood bilirubin increased
subjects affected / exposed	0 / 33 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 32 (0.00%)	0 / 48 (0.00%)	1 / 7 (14.29%)	0 / 6 (0.00%)	1 / 5 (20.00%)	0 / 13 (0.00%)	0 / 32 (0.00%)
occurrences all number	0	0	0	0	0	1	0	1	0	0
Blood creatine phosphokinase increased
subjects affected / exposed	0 / 33 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 32 (0.00%)	0 / 48 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	2 / 5 (40.00%)	0 / 13 (0.00%)	0 / 32 (0.00%)
occurrences all number	0	0	0	0	0	0	0	3	0	0
Blood creatinine increased
subjects affected / exposed	0 / 33 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 32 (0.00%)	0 / 48 (0.00%)	0 / 7 (0.00%)	1 / 6 (16.67%)	0 / 5 (0.00%)	0 / 13 (0.00%)	0 / 32 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0	0
Blood sodium decreased
subjects affected / exposed	2 / 33 (6.06%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 32 (0.00%)	0 / 48 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 13 (0.00%)	0 / 32 (0.00%)
occurrences all number	2	0	0	0	0	0	0	0	0	0
Blood urea increased
subjects affected / exposed	0 / 33 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 32 (0.00%)	0 / 48 (0.00%)	0 / 7 (0.00%)	1 / 6 (16.67%)	0 / 5 (0.00%)	0 / 13 (0.00%)	0 / 32 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0	0
Blood uric acid increased
subjects affected / exposed	0 / 33 (0.00%)	0 / 6 (0.00%)	2 / 8 (25.00%)	0 / 32 (0.00%)	0 / 48 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 13 (0.00%)	0 / 32 (0.00%)
occurrences all number	0	0	2	0	0	0	0	0	0	0
Neutrophil count decreased
subjects affected / exposed	1 / 33 (3.03%)	0 / 6 (0.00%)	0 / 8 (0.00%)	1 / 32 (3.13%)	1 / 48 (2.08%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 13 (0.00%)	3 / 32 (9.38%)
occurrences all number	3	0	0	1	1	0	0	0	0	4
Platelet count decreased
subjects affected / exposed	4 / 33 (12.12%)	0 / 6 (0.00%)	0 / 8 (0.00%)	1 / 32 (3.13%)	1 / 48 (2.08%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 13 (0.00%)	3 / 32 (9.38%)
occurrences all number	8	0	0	2	1	0	0	0	0	3
Weight decreased
subjects affected / exposed	6 / 33 (18.18%)	0 / 6 (0.00%)	0 / 8 (0.00%)	8 / 32 (25.00%)	5 / 48 (10.42%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 13 (0.00%)	8 / 32 (25.00%)
occurrences all number	7	0	0	11	6	0	0	0	0	8
Weight increased
subjects affected / exposed	0 / 33 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 32 (0.00%)	3 / 48 (6.25%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	1 / 13 (7.69%)	1 / 32 (3.13%)
occurrences all number	0	0	0	0	3	0	0	0	1	1
White blood cell count decreased
subjects affected / exposed	2 / 33 (6.06%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 32 (0.00%)	3 / 48 (6.25%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 13 (0.00%)	0 / 32 (0.00%)
occurrences all number	5	0	0	0	3	0	0	0	0	0
Injury, poisoning and procedural complications
Ankle fracture
subjects affected / exposed	0 / 33 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 32 (0.00%)	0 / 48 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	1 / 5 (20.00%)	0 / 13 (0.00%)	0 / 32 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0	0
Arthropod bite
subjects affected / exposed	0 / 33 (0.00%)	1 / 6 (16.67%)	0 / 8 (0.00%)	0 / 32 (0.00%)	0 / 48 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	1 / 13 (7.69%)	0 / 32 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	1	0
Contusion
subjects affected / exposed	0 / 33 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 32 (0.00%)	5 / 48 (10.42%)	0 / 7 (0.00%)	0 / 6 (0.00%)	1 / 5 (20.00%)	1 / 13 (7.69%)	2 / 32 (6.25%)
occurrences all number	0	0	0	0	5	0	0	3	1	2
Eye contusion
subjects affected / exposed	0 / 33 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 32 (0.00%)	0 / 48 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 13 (0.00%)	2 / 32 (6.25%)
occurrences all number	0	0	0	0	0	0	0	0	0	2
Fall
subjects affected / exposed	1 / 33 (3.03%)	0 / 6 (0.00%)	0 / 8 (0.00%)	2 / 32 (6.25%)	3 / 48 (6.25%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 13 (0.00%)	3 / 32 (9.38%)
occurrences all number	1	0	0	3	6	0	0	0	0	7
Foot fracture
subjects affected / exposed	0 / 33 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 32 (0.00%)	0 / 48 (0.00%)	1 / 7 (14.29%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 13 (0.00%)	0 / 32 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0	0	0
Infusion related reaction
subjects affected / exposed	0 / 33 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 32 (0.00%)	0 / 48 (0.00%)	0 / 7 (0.00%)	1 / 6 (16.67%)	1 / 5 (20.00%)	0 / 13 (0.00%)	0 / 32 (0.00%)
occurrences all number	0	0	0	0	0	0	1	1	0	0
Post-traumatic pain
subjects affected / exposed	0 / 33 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 32 (0.00%)	0 / 48 (0.00%)	0 / 7 (0.00%)	1 / 6 (16.67%)	0 / 5 (0.00%)	0 / 13 (0.00%)	0 / 32 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0	0
Procedural pain
subjects affected / exposed	1 / 33 (3.03%)	0 / 6 (0.00%)	0 / 8 (0.00%)	2 / 32 (6.25%)	0 / 48 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 13 (0.00%)	0 / 32 (0.00%)
occurrences all number	1	0	0	3	0	0	0	0	0	0
Road traffic accident
subjects affected / exposed	0 / 33 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 32 (0.00%)	0 / 48 (0.00%)	0 / 7 (0.00%)	1 / 6 (16.67%)	0 / 5 (0.00%)	0 / 13 (0.00%)	0 / 32 (0.00%)
occurrences all number	0	0	0	0	0	0	3	0	0	0
Transfusion reaction
subjects affected / exposed	0 / 33 (0.00%)	0 / 6 (0.00%)	1 / 8 (12.50%)	0 / 32 (0.00%)	0 / 48 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 13 (0.00%)	0 / 32 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0	0	0
Wound
subjects affected / exposed	0 / 33 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 32 (0.00%)	0 / 48 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	1 / 5 (20.00%)	0 / 13 (0.00%)	0 / 32 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0	0
Wrist fracture
subjects affected / exposed	0 / 33 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 32 (0.00%)	0 / 48 (0.00%)	0 / 7 (0.00%)	1 / 6 (16.67%)	0 / 5 (0.00%)	0 / 13 (0.00%)	0 / 32 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0	0
Cardiac disorders
Palpitations
subjects affected / exposed	0 / 33 (0.00%)	1 / 6 (16.67%)	0 / 8 (0.00%)	0 / 32 (0.00%)	0 / 48 (0.00%)	0 / 7 (0.00%)	1 / 6 (16.67%)	0 / 5 (0.00%)	0 / 13 (0.00%)	0 / 32 (0.00%)
occurrences all number	0	1	0	0	0	0	1	0	0	0
Supraventricular extrasystoles
subjects affected / exposed	0 / 33 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 32 (0.00%)	0 / 48 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	1 / 5 (20.00%)	0 / 13 (0.00%)	0 / 32 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0	0
Tachycardia
subjects affected / exposed	1 / 33 (3.03%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 32 (0.00%)	0 / 48 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 13 (0.00%)	2 / 32 (6.25%)
occurrences all number	1	0	0	0	0	0	0	0	0	2
Nervous system disorders
Dizziness
subjects affected / exposed	6 / 33 (18.18%)	1 / 6 (16.67%)	0 / 8 (0.00%)	1 / 32 (3.13%)	2 / 48 (4.17%)	0 / 7 (0.00%)	0 / 6 (0.00%)	1 / 5 (20.00%)	0 / 13 (0.00%)	3 / 32 (9.38%)
occurrences all number	9	1	0	1	2	0	0	1	0	3
Headache
subjects affected / exposed	4 / 33 (12.12%)	2 / 6 (33.33%)	0 / 8 (0.00%)	3 / 32 (9.38%)	3 / 48 (6.25%)	0 / 7 (0.00%)	1 / 6 (16.67%)	2 / 5 (40.00%)	2 / 13 (15.38%)	7 / 32 (21.88%)
occurrences all number	5	2	0	3	3	0	1	4	3	8
Hypoaesthesia
subjects affected / exposed	2 / 33 (6.06%)	0 / 6 (0.00%)	0 / 8 (0.00%)	1 / 32 (3.13%)	0 / 48 (0.00%)	0 / 7 (0.00%)	1 / 6 (16.67%)	1 / 5 (20.00%)	0 / 13 (0.00%)	1 / 32 (3.13%)
occurrences all number	2	0	0	1	0	0	1	1	0	1
Nerve compression
subjects affected / exposed	0 / 33 (0.00%)	1 / 6 (16.67%)	0 / 8 (0.00%)	0 / 32 (0.00%)	0 / 48 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 13 (0.00%)	0 / 32 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0	0
Neuropathy peripheral
subjects affected / exposed	3 / 33 (9.09%)	0 / 6 (0.00%)	0 / 8 (0.00%)	1 / 32 (3.13%)	1 / 48 (2.08%)	2 / 7 (28.57%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 13 (0.00%)	1 / 32 (3.13%)
occurrences all number	3	0	0	1	1	2	0	0	0	1
Sciatic nerve neuropathy
subjects affected / exposed	0 / 33 (0.00%)	0 / 6 (0.00%)	1 / 8 (12.50%)	0 / 32 (0.00%)	0 / 48 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 13 (0.00%)	0 / 32 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0	0	0
Sciatica
subjects affected / exposed	0 / 33 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 32 (0.00%)	0 / 48 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	1 / 5 (20.00%)	0 / 13 (0.00%)	0 / 32 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0	0
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	5 / 33 (15.15%)	1 / 6 (16.67%)	1 / 8 (12.50%)	3 / 32 (9.38%)	6 / 48 (12.50%)	0 / 7 (0.00%)	1 / 6 (16.67%)	1 / 5 (20.00%)	1 / 13 (7.69%)	6 / 32 (18.75%)
occurrences all number	11	1	1	6	12	0	1	1	2	8
Increased tendency to bruise
subjects affected / exposed	0 / 33 (0.00%)	1 / 6 (16.67%)	0 / 8 (0.00%)	0 / 32 (0.00%)	0 / 48 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 13 (0.00%)	0 / 32 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0	0
Leukocytosis
subjects affected / exposed	0 / 33 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 32 (0.00%)	0 / 48 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	1 / 5 (20.00%)	0 / 13 (0.00%)	0 / 32 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0	0
Leukopenia
subjects affected / exposed	0 / 33 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	1 / 32 (3.13%)	1 / 48 (2.08%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 13 (0.00%)	2 / 32 (6.25%)
occurrences all number	0	0	0	1	1	0	0	0	0	2
Neutropenia
subjects affected / exposed	0 / 33 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 32 (0.00%)	2 / 48 (4.17%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 13 (0.00%)	2 / 32 (6.25%)
occurrences all number	0	0	0	0	2	0	0	0	0	3
Splenomegaly
subjects affected / exposed	2 / 33 (6.06%)	0 / 6 (0.00%)	0 / 8 (0.00%)	2 / 32 (6.25%)	7 / 48 (14.58%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	3 / 13 (23.08%)	2 / 32 (6.25%)
occurrences all number	2	0	0	3	7	0	0	0	3	3
Thrombocytopenia
subjects affected / exposed	5 / 33 (15.15%)	1 / 6 (16.67%)	0 / 8 (0.00%)	1 / 32 (3.13%)	2 / 48 (4.17%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 13 (0.00%)	4 / 32 (12.50%)
occurrences all number	6	1	0	1	3	0	0	0	0	5
Eye disorders
Dry eye
subjects affected / exposed	0 / 33 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 32 (0.00%)	1 / 48 (2.08%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 13 (0.00%)	2 / 32 (6.25%)
occurrences all number	0	0	0	0	1	0	0	0	0	3
Vision blurred
subjects affected / exposed	0 / 33 (0.00%)	0 / 6 (0.00%)	1 / 8 (12.50%)	0 / 32 (0.00%)	0 / 48 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	1 / 13 (7.69%)	0 / 32 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0	1	0
Gastrointestinal disorders
Abdominal discomfort
subjects affected / exposed	0 / 33 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 32 (0.00%)	0 / 48 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	1 / 13 (7.69%)	0 / 32 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	1	0
Abdominal distension
subjects affected / exposed	3 / 33 (9.09%)	0 / 6 (0.00%)	0 / 8 (0.00%)	2 / 32 (6.25%)	1 / 48 (2.08%)	0 / 7 (0.00%)	0 / 6 (0.00%)	1 / 5 (20.00%)	0 / 13 (0.00%)	0 / 32 (0.00%)
occurrences all number	3	0	0	2	1	0	0	1	0	0
Abdominal pain
subjects affected / exposed	5 / 33 (15.15%)	0 / 6 (0.00%)	1 / 8 (12.50%)	4 / 32 (12.50%)	3 / 48 (6.25%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	1 / 13 (7.69%)	6 / 32 (18.75%)
occurrences all number	7	0	2	5	3	0	0	0	1	8
Abdominal pain lower
subjects affected / exposed	0 / 33 (0.00%)	0 / 6 (0.00%)	2 / 8 (25.00%)	0 / 32 (0.00%)	0 / 48 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 13 (0.00%)	0 / 32 (0.00%)
occurrences all number	0	0	2	0	0	0	0	0	0	0
Abdominal pain upper
subjects affected / exposed	1 / 33 (3.03%)	0 / 6 (0.00%)	1 / 8 (12.50%)	1 / 32 (3.13%)	2 / 48 (4.17%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	3 / 13 (23.08%)	2 / 32 (6.25%)
occurrences all number	1	0	1	2	2	0	0	0	4	2
Abdominal tenderness
subjects affected / exposed	0 / 33 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 32 (0.00%)	0 / 48 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	1 / 13 (7.69%)	0 / 32 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	1	0
Anal incontinence
subjects affected / exposed	0 / 33 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 32 (0.00%)	0 / 48 (0.00%)	0 / 7 (0.00%)	1 / 6 (16.67%)	0 / 5 (0.00%)	0 / 13 (0.00%)	0 / 32 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0	0
Aphthous ulcer
subjects affected / exposed	0 / 33 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 32 (0.00%)	0 / 48 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	1 / 13 (7.69%)	0 / 32 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	1	0
Constipation
subjects affected / exposed	4 / 33 (12.12%)	0 / 6 (0.00%)	0 / 8 (0.00%)	4 / 32 (12.50%)	3 / 48 (6.25%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 13 (0.00%)	4 / 32 (12.50%)
occurrences all number	5	0	0	6	3	0	0	0	0	4
Diarrhoea
subjects affected / exposed	8 / 33 (24.24%)	0 / 6 (0.00%)	2 / 8 (25.00%)	3 / 32 (9.38%)	7 / 48 (14.58%)	0 / 7 (0.00%)	2 / 6 (33.33%)	1 / 5 (20.00%)	0 / 13 (0.00%)	5 / 32 (15.63%)
occurrences all number	8	0	2	3	7	0	2	1	0	5
Flatulence
subjects affected / exposed	0 / 33 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 32 (0.00%)	0 / 48 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	1 / 13 (7.69%)	0 / 32 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	1	0
Gastrooesophageal reflux disease
subjects affected / exposed	0 / 33 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 32 (0.00%)	0 / 48 (0.00%)	0 / 7 (0.00%)	1 / 6 (16.67%)	0 / 5 (0.00%)	1 / 13 (7.69%)	0 / 32 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	1	0
Gingival bleeding
subjects affected / exposed	2 / 33 (6.06%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 32 (0.00%)	1 / 48 (2.08%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 13 (0.00%)	0 / 32 (0.00%)
occurrences all number	3	0	0	0	1	0	0	0	0	0
Gingival pain
subjects affected / exposed	0 / 33 (0.00%)	1 / 6 (16.67%)	0 / 8 (0.00%)	0 / 32 (0.00%)	0 / 48 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 13 (0.00%)	0 / 32 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0	0
Nausea
subjects affected / exposed	2 / 33 (6.06%)	1 / 6 (16.67%)	2 / 8 (25.00%)	5 / 32 (15.63%)	3 / 48 (6.25%)	1 / 7 (14.29%)	0 / 6 (0.00%)	2 / 5 (40.00%)	4 / 13 (30.77%)	2 / 32 (6.25%)
occurrences all number	2	1	2	5	5	1	0	3	5	2
Oral disorder
subjects affected / exposed	0 / 33 (0.00%)	0 / 6 (0.00%)	1 / 8 (12.50%)	0 / 32 (0.00%)	0 / 48 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 13 (0.00%)	0 / 32 (0.00%)
occurrences all number	0	0	2	0	0	0	0	0	0	0
Oral pain
subjects affected / exposed	0 / 33 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 32 (0.00%)	0 / 48 (0.00%)	0 / 7 (0.00%)	1 / 6 (16.67%)	0 / 5 (0.00%)	0 / 13 (0.00%)	0 / 32 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0	0
Retching
subjects affected / exposed	0 / 33 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	1 / 32 (3.13%)	0 / 48 (0.00%)	0 / 7 (0.00%)	1 / 6 (16.67%)	0 / 5 (0.00%)	0 / 13 (0.00%)	0 / 32 (0.00%)
occurrences all number	0	0	0	1	0	0	1	0	0	0
Stomatitis
subjects affected / exposed	1 / 33 (3.03%)	1 / 6 (16.67%)	0 / 8 (0.00%)	0 / 32 (0.00%)	3 / 48 (6.25%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 13 (0.00%)	2 / 32 (6.25%)
occurrences all number	1	1	0	0	4	0	0	0	0	2
Vomiting
subjects affected / exposed	1 / 33 (3.03%)	1 / 6 (16.67%)	0 / 8 (0.00%)	5 / 32 (15.63%)	0 / 48 (0.00%)	1 / 7 (14.29%)	0 / 6 (0.00%)	2 / 5 (40.00%)	2 / 13 (15.38%)	2 / 32 (6.25%)
occurrences all number	1	1	0	9	0	1	0	2	2	3
Hepatobiliary disorders
Hepatomegaly
subjects affected / exposed	0 / 33 (0.00%)	0 / 6 (0.00%)	1 / 8 (12.50%)	0 / 32 (0.00%)	0 / 48 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	1 / 13 (7.69%)	0 / 32 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0	1	0
Hepatosplenomegaly
subjects affected / exposed	0 / 33 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 32 (0.00%)	0 / 48 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	1 / 13 (7.69%)	0 / 32 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	1	0
Hyperbilirubinaemia
subjects affected / exposed	0 / 33 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	1 / 32 (3.13%)	0 / 48 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	1 / 5 (20.00%)	0 / 13 (0.00%)	0 / 32 (0.00%)
occurrences all number	0	0	0	1	0	0	0	1	0	0
Skin and subcutaneous tissue disorders
Ecchymosis
subjects affected / exposed	0 / 33 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	1 / 32 (3.13%)	0 / 48 (0.00%)	0 / 7 (0.00%)	1 / 6 (16.67%)	0 / 5 (0.00%)	0 / 13 (0.00%)	2 / 32 (6.25%)
occurrences all number	0	0	0	1	0	0	1	0	0	2
Erythema
subjects affected / exposed	0 / 33 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 32 (0.00%)	0 / 48 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	1 / 5 (20.00%)	0 / 13 (0.00%)	0 / 32 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0	0
Hyperhidrosis
subjects affected / exposed	0 / 33 (0.00%)	0 / 6 (0.00%)	1 / 8 (12.50%)	0 / 32 (0.00%)	0 / 48 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 13 (0.00%)	0 / 32 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0	0	0
Hyperkeratosis
subjects affected / exposed	0 / 33 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 32 (0.00%)	0 / 48 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	1 / 5 (20.00%)	0 / 13 (0.00%)	0 / 32 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0	0
Lichen planus
subjects affected / exposed	0 / 33 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 32 (0.00%)	0 / 48 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	1 / 13 (7.69%)	0 / 32 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	1	0
Night sweats
subjects affected / exposed	0 / 33 (0.00%)	1 / 6 (16.67%)	0 / 8 (0.00%)	1 / 32 (3.13%)	1 / 48 (2.08%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 13 (0.00%)	4 / 32 (12.50%)
occurrences all number	0	1	0	1	1	0	0	0	0	7
Petechiae
subjects affected / exposed	0 / 33 (0.00%)	1 / 6 (16.67%)	0 / 8 (0.00%)	0 / 32 (0.00%)	0 / 48 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 13 (0.00%)	0 / 32 (0.00%)
occurrences all number	0	2	0	0	0	0	0	0	0	0
Pruritus
subjects affected / exposed	0 / 33 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	3 / 32 (9.38%)	3 / 48 (6.25%)	1 / 7 (14.29%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 13 (0.00%)	4 / 32 (12.50%)
occurrences all number	0	0	0	3	3	1	0	0	0	6
Rash
subjects affected / exposed	0 / 33 (0.00%)	0 / 6 (0.00%)	1 / 8 (12.50%)	0 / 32 (0.00%)	0 / 48 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	1 / 5 (20.00%)	1 / 13 (7.69%)	0 / 32 (0.00%)
occurrences all number	0	0	1	0	0	0	0	1	1	0
Rash erythematous
subjects affected / exposed	0 / 33 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 32 (0.00%)	0 / 48 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	1 / 13 (7.69%)	0 / 32 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	1	0
Rash pruritic
subjects affected / exposed	0 / 33 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 32 (0.00%)	0 / 48 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	1 / 13 (7.69%)	0 / 32 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	1	0
Skin induration
subjects affected / exposed	0 / 33 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 32 (0.00%)	0 / 48 (0.00%)	0 / 7 (0.00%)	1 / 6 (16.67%)	0 / 5 (0.00%)	0 / 13 (0.00%)	0 / 32 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0	0
Skin lesion
subjects affected / exposed	0 / 33 (0.00%)	1 / 6 (16.67%)	0 / 8 (0.00%)	0 / 32 (0.00%)	0 / 48 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 13 (0.00%)	1 / 32 (3.13%)
occurrences all number	0	1	0	0	0	0	0	0	0	1
Urticaria
subjects affected / exposed	0 / 33 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	1 / 32 (3.13%)	0 / 48 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 13 (0.00%)	2 / 32 (6.25%)
occurrences all number	0	0	0	1	0	0	0	0	0	2
Renal and urinary disorders
Dysuria
subjects affected / exposed	0 / 33 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	2 / 32 (6.25%)	0 / 48 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 13 (0.00%)	0 / 32 (0.00%)
occurrences all number	0	0	0	2	0	0	0	0	0	0
Haematuria
subjects affected / exposed	0 / 33 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 32 (0.00%)	0 / 48 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	1 / 13 (7.69%)	0 / 32 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	1	0
Nocturia
subjects affected / exposed	0 / 33 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 32 (0.00%)	0 / 48 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	1 / 5 (20.00%)	0 / 13 (0.00%)	0 / 32 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0	0
Endocrine disorders
Hypothyroidism
subjects affected / exposed	0 / 33 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 32 (0.00%)	0 / 48 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	1 / 13 (7.69%)	0 / 32 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	1	0
Musculoskeletal and connective tissue disorders
Arthralgia
subjects affected / exposed	3 / 33 (9.09%)	1 / 6 (16.67%)	0 / 8 (0.00%)	2 / 32 (6.25%)	3 / 48 (6.25%)	0 / 7 (0.00%)	1 / 6 (16.67%)	4 / 5 (80.00%)	2 / 13 (15.38%)	5 / 32 (15.63%)
occurrences all number	3	1	0	2	3	0	1	4	2	5
Back pain
subjects affected / exposed	2 / 33 (6.06%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 32 (0.00%)	1 / 48 (2.08%)	0 / 7 (0.00%)	0 / 6 (0.00%)	1 / 5 (20.00%)	1 / 13 (7.69%)	3 / 32 (9.38%)
occurrences all number	2	0	0	0	1	0	0	1	1	3
Bone pain
subjects affected / exposed	3 / 33 (9.09%)	0 / 6 (0.00%)	0 / 8 (0.00%)	2 / 32 (6.25%)	0 / 48 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	1 / 5 (20.00%)	1 / 13 (7.69%)	3 / 32 (9.38%)
occurrences all number	3	0	0	2	0	0	0	1	1	3
Groin pain
subjects affected / exposed	0 / 33 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 32 (0.00%)	0 / 48 (0.00%)	0 / 7 (0.00%)	1 / 6 (16.67%)	0 / 5 (0.00%)	0 / 13 (0.00%)	0 / 32 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0	0
Joint lock
subjects affected / exposed	0 / 33 (0.00%)	1 / 6 (16.67%)	0 / 8 (0.00%)	0 / 32 (0.00%)	0 / 48 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 13 (0.00%)	0 / 32 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0	0
Joint swelling
subjects affected / exposed	0 / 33 (0.00%)	1 / 6 (16.67%)	1 / 8 (12.50%)	0 / 32 (0.00%)	0 / 48 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	1 / 13 (7.69%)	0 / 32 (0.00%)
occurrences all number	0	1	1	0	0	0	0	0	1	0
Muscle spasms
subjects affected / exposed	3 / 33 (9.09%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 32 (0.00%)	3 / 48 (6.25%)	0 / 7 (0.00%)	0 / 6 (0.00%)	1 / 5 (20.00%)	0 / 13 (0.00%)	2 / 32 (6.25%)
occurrences all number	3	0	0	0	3	0	0	1	0	3
Muscular weakness
subjects affected / exposed	0 / 33 (0.00%)	0 / 6 (0.00%)	2 / 8 (25.00%)	2 / 32 (6.25%)	0 / 48 (0.00%)	1 / 7 (14.29%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 13 (0.00%)	1 / 32 (3.13%)
occurrences all number	0	0	2	2	0	1	0	0	0	2
Musculoskeletal chest pain
subjects affected / exposed	0 / 33 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 32 (0.00%)	0 / 48 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	1 / 5 (20.00%)	1 / 13 (7.69%)	0 / 32 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	1	0
Musculoskeletal pain
subjects affected / exposed	2 / 33 (6.06%)	0 / 6 (0.00%)	0 / 8 (0.00%)	1 / 32 (3.13%)	2 / 48 (4.17%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 13 (0.00%)	3 / 32 (9.38%)
occurrences all number	2	0	0	1	2	0	0	0	0	3
Musculoskeletal stiffness
subjects affected / exposed	0 / 33 (0.00%)	0 / 6 (0.00%)	1 / 8 (12.50%)	0 / 32 (0.00%)	1 / 48 (2.08%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 13 (0.00%)	0 / 32 (0.00%)
occurrences all number	0	0	1	0	1	0	0	0	0	0
Myalgia
subjects affected / exposed	3 / 33 (9.09%)	0 / 6 (0.00%)	1 / 8 (12.50%)	2 / 32 (6.25%)	1 / 48 (2.08%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 13 (0.00%)	0 / 32 (0.00%)
occurrences all number	3	0	1	2	2	0	0	0	0	0
Neck pain
subjects affected / exposed	0 / 33 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 32 (0.00%)	0 / 48 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	1 / 5 (20.00%)	0 / 13 (0.00%)	0 / 32 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0	0
Pain in extremity
subjects affected / exposed	2 / 33 (6.06%)	1 / 6 (16.67%)	0 / 8 (0.00%)	1 / 32 (3.13%)	0 / 48 (0.00%)	1 / 7 (14.29%)	0 / 6 (0.00%)	1 / 5 (20.00%)	0 / 13 (0.00%)	5 / 32 (15.63%)
occurrences all number	3	2	0	1	0	1	0	1	0	5
Infections and infestations
Bronchitis
subjects affected / exposed	3 / 33 (9.09%)	0 / 6 (0.00%)	0 / 8 (0.00%)	1 / 32 (3.13%)	0 / 48 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	2 / 5 (40.00%)	0 / 13 (0.00%)	0 / 32 (0.00%)
occurrences all number	5	0	0	1	0	0	0	2	0	0
Cellulitis
subjects affected / exposed	0 / 33 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	1 / 32 (3.13%)	4 / 48 (8.33%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 13 (0.00%)	1 / 32 (3.13%)
occurrences all number	0	0	0	2	5	0	0	0	0	1
Diarrhoea infectious
subjects affected / exposed	0 / 33 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 32 (0.00%)	0 / 48 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	1 / 5 (20.00%)	0 / 13 (0.00%)	0 / 32 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0	0
Folliculitis
subjects affected / exposed	0 / 33 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	2 / 32 (6.25%)	0 / 48 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 13 (0.00%)	0 / 32 (0.00%)
occurrences all number	0	0	0	2	0	0	0	0	0	0
Gastroenteritis viral
subjects affected / exposed	0 / 33 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 32 (0.00%)	0 / 48 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	1 / 13 (7.69%)	0 / 32 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	1	0
Laryngitis
subjects affected / exposed	0 / 33 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 32 (0.00%)	0 / 48 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	1 / 5 (20.00%)	0 / 13 (0.00%)	0 / 32 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0	0
Localised infection
subjects affected / exposed	0 / 33 (0.00%)	1 / 6 (16.67%)	0 / 8 (0.00%)	0 / 32 (0.00%)	0 / 48 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 13 (0.00%)	0 / 32 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0	0
Lyme disease
subjects affected / exposed	0 / 33 (0.00%)	0 / 6 (0.00%)	1 / 8 (12.50%)	0 / 32 (0.00%)	0 / 48 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 13 (0.00%)	0 / 32 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0	0	0
Nasopharyngitis
subjects affected / exposed	1 / 33 (3.03%)	0 / 6 (0.00%)	1 / 8 (12.50%)	2 / 32 (6.25%)	3 / 48 (6.25%)	0 / 7 (0.00%)	1 / 6 (16.67%)	1 / 5 (20.00%)	0 / 13 (0.00%)	1 / 32 (3.13%)
occurrences all number	1	0	1	3	3	0	1	1	0	1
Oral herpes
subjects affected / exposed	0 / 33 (0.00%)	2 / 6 (33.33%)	1 / 8 (12.50%)	0 / 32 (0.00%)	0 / 48 (0.00%)	0 / 7 (0.00%)	1 / 6 (16.67%)	0 / 5 (0.00%)	1 / 13 (7.69%)	2 / 32 (6.25%)
occurrences all number	0	2	1	0	0	0	1	0	1	2
Pneumonia
subjects affected / exposed	3 / 33 (9.09%)	0 / 6 (0.00%)	0 / 8 (0.00%)	3 / 32 (9.38%)	1 / 48 (2.08%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 13 (0.00%)	1 / 32 (3.13%)
occurrences all number	4	0	0	3	1	0	0	0	0	1
Respiratory syncytial virus infection
subjects affected / exposed	0 / 33 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 32 (0.00%)	0 / 48 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	1 / 13 (7.69%)	0 / 32 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	1	0
Rhinitis
subjects affected / exposed	0 / 33 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 32 (0.00%)	0 / 48 (0.00%)	1 / 7 (14.29%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 13 (0.00%)	0 / 32 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0	0	0
Sialoadenitis
subjects affected / exposed	0 / 33 (0.00%)	1 / 6 (16.67%)	0 / 8 (0.00%)	0 / 32 (0.00%)	0 / 48 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 13 (0.00%)	0 / 32 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0	0
Sinusitis
subjects affected / exposed	2 / 33 (6.06%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 32 (0.00%)	1 / 48 (2.08%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	1 / 13 (7.69%)	0 / 32 (0.00%)
occurrences all number	2	0	0	0	2	0	0	0	3	0
Skin infection
subjects affected / exposed	0 / 33 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	2 / 32 (6.25%)	0 / 48 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	1 / 13 (7.69%)	0 / 32 (0.00%)
occurrences all number	0	0	0	2	0	0	0	0	1	0
Subcutaneous abscess
subjects affected / exposed	0 / 33 (0.00%)	1 / 6 (16.67%)	0 / 8 (0.00%)	0 / 32 (0.00%)	0 / 48 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 13 (0.00%)	0 / 32 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0	0
Tooth infection
subjects affected / exposed	0 / 33 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 32 (0.00%)	0 / 48 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	1 / 13 (7.69%)	0 / 32 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	1	0
Upper respiratory tract infection
subjects affected / exposed	2 / 33 (6.06%)	1 / 6 (16.67%)	0 / 8 (0.00%)	0 / 32 (0.00%)	2 / 48 (4.17%)	0 / 7 (0.00%)	2 / 6 (33.33%)	0 / 5 (0.00%)	3 / 13 (23.08%)	2 / 32 (6.25%)
occurrences all number	2	1	0	0	5	0	2	0	4	2
Urinary tract infection
subjects affected / exposed	2 / 33 (6.06%)	1 / 6 (16.67%)	0 / 8 (0.00%)	1 / 32 (3.13%)	4 / 48 (8.33%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	2 / 13 (15.38%)	2 / 32 (6.25%)
occurrences all number	4	2	0	1	4	0	0	0	3	2
Urosepsis
subjects affected / exposed	0 / 33 (0.00%)	1 / 6 (16.67%)	0 / 8 (0.00%)	0 / 32 (0.00%)	0 / 48 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 13 (0.00%)	0 / 32 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0	0
Viral upper respiratory tract infection
subjects affected / exposed	0 / 33 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 32 (0.00%)	0 / 48 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	1 / 13 (7.69%)	0 / 32 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	1	0
Metabolism and nutrition disorders
Cachexia
subjects affected / exposed	0 / 33 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 32 (0.00%)	0 / 48 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 13 (0.00%)	2 / 32 (6.25%)
occurrences all number	0	0	0	0	0	0	0	0	0	2
Decreased appetite
subjects affected / exposed	4 / 33 (12.12%)	0 / 6 (0.00%)	0 / 8 (0.00%)	4 / 32 (12.50%)	2 / 48 (4.17%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	1 / 13 (7.69%)	4 / 32 (12.50%)
occurrences all number	5	0	0	6	2	0	0	0	1	5
Gout
subjects affected / exposed	1 / 33 (3.03%)	0 / 6 (0.00%)	0 / 8 (0.00%)	1 / 32 (3.13%)	1 / 48 (2.08%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	1 / 13 (7.69%)	2 / 32 (6.25%)
occurrences all number	1	0	0	1	1	0	0	0	1	2
Hyperglycaemia
subjects affected / exposed	3 / 33 (9.09%)	0 / 6 (0.00%)	0 / 8 (0.00%)	1 / 32 (3.13%)	2 / 48 (4.17%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	1 / 13 (7.69%)	3 / 32 (9.38%)
occurrences all number	4	0	0	2	3	0	0	0	1	5
Hyperphosphataemia
subjects affected / exposed	0 / 33 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 32 (0.00%)	0 / 48 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	1 / 13 (7.69%)	0 / 32 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	1	0
Hyperuricaemia
subjects affected / exposed	1 / 33 (3.03%)	0 / 6 (0.00%)	1 / 8 (12.50%)	4 / 32 (12.50%)	0 / 48 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 13 (0.00%)	4 / 32 (12.50%)
occurrences all number	1	0	1	4	0	0	0	0	0	5
Hypocalcaemia
subjects affected / exposed	1 / 33 (3.03%)	1 / 6 (16.67%)	0 / 8 (0.00%)	2 / 32 (6.25%)	1 / 48 (2.08%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 13 (0.00%)	0 / 32 (0.00%)
occurrences all number	1	1	0	2	1	0	0	0	0	0
Hypokalaemia
subjects affected / exposed	0 / 33 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	2 / 32 (6.25%)	1 / 48 (2.08%)	0 / 7 (0.00%)	0 / 6 (0.00%)	1 / 5 (20.00%)	0 / 13 (0.00%)	0 / 32 (0.00%)
occurrences all number	0	0	0	2	2	0	0	1	0	0
Hypomagnesaemia
subjects affected / exposed	0 / 33 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 32 (0.00%)	0 / 48 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	1 / 5 (20.00%)	0 / 13 (0.00%)	0 / 32 (0.00%)
occurrences all number	0	0	0	0	0	0	0	3	0	0
Iron deficiency
subjects affected / exposed	0 / 33 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 32 (0.00%)	0 / 48 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	1 / 13 (7.69%)	0 / 32 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	1	0
Iron overload
subjects affected / exposed	0 / 33 (0.00%)	1 / 6 (16.67%)	0 / 8 (0.00%)	0 / 32 (0.00%)	0 / 48 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 13 (0.00%)	0 / 32 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0	0
Type 2 diabetes mellitus
subjects affected / exposed	0 / 33 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 32 (0.00%)	0 / 48 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	1 / 13 (7.69%)	0 / 32 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	1	0

More information

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Were there any global substantial amendments to the protocol? Yes

22 Feb 2013

The protocol was amended to clarify that participants could switch to different treatment arms after the completion of 6 cycles and that participants were evaluable for response after 4 weeks of treatment. The requirement for post infusion observation changed to four hours (from one hour) after all doses of PRM-151 through Cycle 2, Day 1 and for one hour after each subsequent dose. Specific instructions were provided for slowing or stopping PRM-151 infusion and for prophylaxis of infusion reactions (IR) for those who experienced IR(s). The IWG response criteria was assigned to the efficacy and some safety assessments. Gradation of treatment emergent non-hematological AEs considered applicable for the stopping rules to grade 3 was lowered. The timing of vital sign assessments were changed. Anti-drug antibody levels on Days 15 and 22 of Cycle 1 was included for participants receiving QW PRM-151, and on Day 15 for participants receiving Q4W dosing of PRM-151. The number of PK samples required was reduced.

10 May 2013

Added a summary of the acute infusion reactions seen in chronic toxicology studies and a summary of the root cause analysis and risk mitigation plan for humans; modified the PRM-151 infusion rate from 30 minutes to 60 minutes; clarified that participants in Cohort 2, receiving ruxolitinib should avoid strong CYP3A4 inhibitors; clarified that all acute infusion reactions should be managed according to guidelines; added Electrocardiogram (ECG) assessments at Day 1 of each cycle; clarified that if a participant experienced an acute infusion related reaction, a sample for anti-pentraxin-2 antibodies and a sample for cytokines would be collected; updated classification structure of AEs; increased safety surveillance measures; clarified that AEs would be followed beyond 30 days after the last dose if needed; clarified sample size calculations; clarified that no comparisons between treatment arms were to be performed; clarified that all participants that discontinued prior to completing 1 cycle of treatment were considered non responders; clarified that all participants that received at least 1 exposure to PRM-151 were included in the safety set; added the use of a Data Monitoring Committee (DMC).

14 Feb 2014

This protocol amendment clarified that stable disease with improvement in bone marrow fibrosis was called a bone marrow response. The requirements for continuing in the OLE portion of the study were included along with the dose calculated based on the participant’s weight of Day 1 of each cycle. It explained that although serious adverse events (SAEs) were captured from time of informed consent, only for participants that received at least one dose of PRM-151; SAEs in screen failures were not captured. A post infusion ECG for Cycle 6 only for Day 1 (both weekly and every 4 weekly schedules) and Day 15 (weekly schedule only) was added. A clarification that Response Assessments were performed on Day 1 of each cycle and that the first post dose PK sample was at the end of the 60 minute infusion. Revised response criteria for myelofibrosis based on the IWG-MRT and European LeukemiaNet (ELN) consensus report was included into this amendment.

04 May 2015

The protocol was amended to remove "Open Label" from the title of the study. The primary, secondary and exploratory objectives and endpoints were modified and additional exploratory objectives and endpoints were included. There were revisions to the study design. Modifications were made to the inclusion criteria as well as creating additional exclusion criteria. Efficacy assessments were modified by using the World Health Organization (WHO) bone marrow fibrosis grade, changes in hemoglobin, platelets, peripheral blood blasts, disease related symptoms, and spleen size. The role of the Data Monitoring Committee was clarified for Stage 2. The dosing amount for the study drug as well as the timing of the dose was modified and the use of ruxolitinib was clarified in this amendment. The method for assigning participants to treatment groups was clarified. Information regarding study blinding, and the procedure for breaking the blind was added. Removed the concomitant medication ruxolitinib and the requirement to record self administration of ruxolitinib. JAK kinase inhibitors were added to the list of excluded concomitant medications. The European Consensus on Grading of Bone Marrow Fibrosis to the WHO criteria for bone marrow fibrosis was revised. Testing for Cytokines and levels of mRNA and miRNA was removed and genetic testing of JAK2V617F, MPLW515, Calreticulin, ASXL1, EZH2, SRSF2, IDH1/2 was included. Information regarding the OLE portion of the study was included. The requirement to maintain a diary for all red blood cell (RBC) and platelet transfusions was added and the requirements for bone marrow biopsy and aspirate were updated. The reporting requirements and contact information for Adverse Events of Special Interest (AESIs) and reporting SAEs were updated.

15 Dec 2016

The protocol amendment added a loading dose for in participants in Stage 2 OLE portion of the study. Additional safety information from the IPF trial was included. Added clarification that DNA sampling was not mandatory for participants was added along with the note that the baseline blood sample for DNA sampling would also be used for the cytogenetic analysis. Removed cytogenetic analysis on marrow biopsy/aspirate. Modified the units of measurement of serum creatinine and clarified that spleen size would be measures by CT or MRI. Added clarification for contraception and adding highly effective methods to align with IB v10, which laboratories were considered central or local and information regarding pregnancy-testing requirements. Clarified that PRM-151 could be resumed when AE had resolved to Grade 1 or baseline. Added anti-pentraxin 2 antibodies collection for IRR and anti-pentraxin 2 antibodies and cytokines in the event of a suspected AE. Serious Treatment Emergent AEs (TEAEs) were removed from this version of the protocol. Clarification was added to allow for a wider visit window and to clarify window for visit, imaging procedures, laboratory assessments, transfusion diary and response assessments during Cycle 2 through 9, Day 1 as well as a wider visit window and to clarify the window allowed for visit, lab collection, transfusion diary recording at the end of study.

Were there any global interruptions to the trial? No

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

None reported

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Clinical trials

Clinical Trial Results: A Phase 2, Prospective Study Of PRM-151 In Subjects With Primary Myelofibrosis (PMF), Post-Polycythemia Vera MF (post-PV MF), Or Post-Essential Thrombocythemia MF (post-ET MF)

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Stage 1 Main Phase: Overall Response Rate (ORR)

Primary: Stage 1 Main Phase: Overall Response Rate (ORR)

Primary: Stage 2 Main Phase: Bone Marrow Response Rate (BMRR)

Primary: Stage 2 Main Phase: Bone Marrow Response Rate (BMRR)

Primary: Stage 1 Main + Open-Label Extension (OLE): ORR

Primary: Stage 1 Main + Open-Label Extension (OLE): ORR

Primary: Stage 2 Main + Open-Label Extension (OLE): BMRR

Primary: Stage 2 Main + Open-Label Extension (OLE): BMRR

Secondary: Stage 1 Main Phase: BMRR

Secondary: Stage 1 Main Phase: BMRR

Secondary: Stage 1 Main Phase: Modified Myeloproliferative Neoplasms Symptom Assessment Form Total Symptom Score (MPN-SAF TSS) Changes

Secondary: Stage 1 Main Phase: Modified Myeloproliferative Neoplasms Symptom Assessment Form Total Symptom Score (MPN-SAF TSS) Changes

Secondary: Stage 2 Main Phase: BMRR

Secondary: Stage 2 Main Phase: BMRR

Secondary: Stage 2 Main Phase: BMRR - Reduction of Bone Marrow Fibrosis by Visit

Secondary: Stage 2 Main Phase: BMRR - Reduction of Bone Marrow Fibrosis by Visit

Secondary: Stage 2 Main Phase: Duration of Bone Marrow Improvement

Secondary: Stage 2 Main Phase: Duration of Bone Marrow Improvement

Secondary: Stage 2 Main Phase: Hemoglobin Improvement

Secondary: Stage 2 Main Phase: Hemoglobin Improvement

Secondary: Stage 2 Main Phase: Platelet Improvement

Secondary: Stage 2 Main Phase: Platelet Improvement

Secondary: Stage 2 Main Phase: Symptom Improvement

Secondary: Stage 2 Main Phase: Symptom Improvement

Secondary: Stage 2 Main Phase: Percentage of Participants with Complete Response (CR), Partial Response (PR), Clinical Improvement (CI), Stable Disease (SD), and Progressive Disease (PD) According to IWG-MRT Criteria

Secondary: Stage 2 Main Phase: Percentage of Participants with Complete Response (CR), Partial Response (PR), Clinical Improvement (CI), Stable Disease (SD), and Progressive Disease (PD) According to IWG-MRT Criteria

Other pre-specified: Stage 1 Main Phase: Maximum Drug Concentration (Cmax)

Other pre-specified: Stage 1 Main Phase: Maximum Drug Concentration (Cmax)

Other pre-specified: Stage 1 Main Phase: Time to Maximum Concentration (Tmax)

Other pre-specified: Stage 1 Main Phase: Time to Maximum Concentration (Tmax)

Other pre-specified: Stage 1 Main Phase: Area Under the Curve up to the Last Measurable Concentration (AUC0-last)

Other pre-specified: Stage 1 Main Phase: Area Under the Curve up to the Last Measurable Concentration (AUC0-last)

Other pre-specified: Stage 1 Main Phase: Area Under the Concentration-Time Curve Extrapolated to Infinity (AUC0-inf)

Other pre-specified: Stage 1 Main Phase: Area Under the Concentration-Time Curve Extrapolated to Infinity (AUC0-inf)

Other pre-specified: Stage 1 Main Phase: Terminal Elimination Half-Life (T1/2)

Other pre-specified: Stage 1 Main Phase: Terminal Elimination Half-Life (T1/2)

Other pre-specified: Stage 1 Main Phase: Clearance (CL)

Other pre-specified: Stage 1 Main Phase: Clearance (CL)

Other pre-specified: Stage 1 Main Phase: Volume of Distribution (Vd)

Other pre-specified: Stage 1 Main Phase: Volume of Distribution (Vd)

Other pre-specified: Percentage of Participants with Adverse Events (AEs) and Infusion Related Reactions (IRRs)

Other pre-specified: Percentage of Participants with Adverse Events (AEs) and Infusion Related Reactions (IRRs)

Other pre-specified: Percentage of Participants with Serious Adverse Events (SAEs) and AEs Leading to Study Drug Discontinuation

Other pre-specified: Percentage of Participants with Serious Adverse Events (SAEs) and AEs Leading to Study Drug Discontinuation

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information

Clinical Trial Results:
A Phase 2, Prospective Study Of PRM-151 In Subjects With Primary Myelofibrosis (PMF), Post-Polycythemia Vera MF (post-PV MF), Or Post-Essential Thrombocythemia MF (post-ET MF)