Download PDF

Clinical Trial Results:
An Open Label, Dose Escalation, Multicenter Phase 1/2 Study of KW-2478 in Combination with Bortezomib in Subjects with Relapsed and/or Refractory Multiple Myeloma

Summary
EudraCT number	2009-016223-56
Trial protocol	GB
Global end of trial date	19 Sep 2013

Results information
Results version number	v1(current)
This version publication date	27 Jul 2016
First version publication date	27 Jul 2016
Other versions

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

Collapse all Expand all

Trial information

Top of page

Sponsor protocol code

2478-INT-001

ISRCTN number

US NCT number

WHO universal trial number (UTN)

Sponsor organisation name

Kyowa Hakko Kirin Pharma, Inc.

Sponsor organisation address

212 Carnegie Centre, Suite 101, Princeton, United States, NJ 08540

Public contact

Kurman, Kyowa Hakko Kirin Pharma, Inc., clinical.info@kyowa-kirin-pharma.com

Scientific contact

Kurman, Kyowa Hakko Kirin Pharma, Inc., clinical.info@kyowa-kirin-pharma.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

26 Mar 2014

Is this the analysis of the primary completion data?

Yes

Primary completion date

19 Sep 2013

Global end of trial reached?

Yes

Global end of trial date

19 Sep 2013

Was the trial ended prematurely?

Main objective of the trial

The purpose of this study is to assess the safety and benefits of the investigational study drug, KW-2478, when given with bortezomib (Velcade®), a drug approved for the treatment of Multiple Myeloma (MM). The primary objectives: - To establish the safety, tolerability, and recommended Phase II dose (RP2D) of KW-2478 in combination with bortezomib (Phase I); - To assess the overall response rate (ORR) when subjects with advanced MM are treated (Phase II). The secondary objectives: - To characterize the Pharmacokinetic (PK) and Pharmacodynamic (PD) of KW-2478 with bortezomib (Phase I only); - To evaluate for preliminary evidence of efficacy (Phase I); - To determine progression free survival (PFS) and duration of response of KW-2478 with bortezomib (Phase II).

Protection of trial subjects

ICF includes all details

Background therapy

Evidence for comparator

Actual start date of recruitment

01 Mar 2010

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Number of subjects enrolled per country

Country: Number of subjects enrolled

United Kingdom: 57

Country: Number of subjects enrolled

United States: 18

Country: Number of subjects enrolled

Philippines: 20

Worldwide total number of subjects

EEA total number of subjects

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

Adolescents (12-17 years)

Adults (18-64 years)

From 65 to 84 years

85 years and over

Subject disposition

Top of page

Recruitment details

Study centers in the USA and the UK participated in the Phase 1 portion, and study centers in the USA, UK, and Philippines participated in the Phase 2 portion.

Screening details

Inclusion / Exclusion criteria

Period 1 title

Overall Study (overall period)

Is this the baseline period?

Yes

Allocation method

Non-randomised - controlled

Blinding used

Not blinded

Are arms mutually exclusive

Phase 1: KW-2478 and Bortezomib

Arm description

The target population in Phase 1 were adults (≥18 years) of either gender with a confirmed history of MM by IMWG criteria had relapsed or failed to respond to 1–3 prior MM regimens with an Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2 and a life expectancy ≥ 3 months. Subjects had to have disease that could be evaluated by serum or urinary levels of M protein or serum free light chains in the absence of measurable M protein in serum or urine. For Phase 1, the design was a standard 3+3 study of KW-2478 (130 or 175 mg/m^2) and bortezomib(1.0 or 1.3 mg/m^2) on Days 1, 4, 8, and 11 of a 21-day cycle utilizing four dose-escalation cohorts.

Arm type

Experimental

Investigational medicinal product name

KW-2478

Investigational medicinal product code

Other name

Pharmaceutical forms

Solvent for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

130mg/m2

Investigational medicinal product name

Bortezomib

Investigational medicinal product code

Other name

Pharmaceutical forms

Powder for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

1.0mg/m2

Phase II: KW-2478 130mg/m^2 and Bortezomib 1.3mg/m^2

Arm description

The target population in Phase 2 were adults (≥18 years) of either gender with a confirmed history of MM by IMWG criteria had relapsed or failed to respond to 1–3 prior MM regimens with an Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2 and a life expectancy ≥ 3 months. Subjects had to have disease that could be evaluated by serum or urinary levels of M protein or serum free light chains in the absence of measurable M protein in serum or urine. For the Phase 2 portion of the study was designed to determine the preliminary efficacy of KW 2478 and bortezomib at the RP2D (KW-2478 175 mg/m^2/bortezomib1.3 mg/m^2).

Arm type

Experimental

Investigational medicinal product name

KW-2478

Investigational medicinal product code

Other name

Pharmaceutical forms

Solvent for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

175mg/m2

Investigational medicinal product name

Bortezomib

Investigational medicinal product code

Other name

Pharmaceutical forms

Powder for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

1.3mg/m2

KW-2478 and bortezomib

Arm description

The target population in both Phase 1 and 2 were adults (≥18 years) of either gender with a confirmed history of MM by IMWG criteria had relapsed or failed to respond to 1–3 prior MM regimens with an Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2 and a life expectancy ≥ 3 months. Subjects had to have disease that could be evaluated by serum or urinary levels of M protein or serum free light chains in the absence of measurable M protein in serum or urine. For Phase 1, the design was a standard 3+3 study of KW-2478 (130 or 175 mg/m^2) and Bortezomib(1.0 or 1.3 mg/m^2) on Days 1, 4, 8, and 11 of a 21-day cycle utilizing four dose-escalation cohorts (overall N=15). The Phase 2 portion of the study enrolled 80 subjects to determine the preliminary efficacy of KW 2478 and Bortezomib at the RP2D (KW-2478 175 mg/m^2 / Bortezomib 1.3 mg/m^2).

Arm type

Experimental

Investigational medicinal product name

KW-2478

Investigational medicinal product code

Other name

Pharmaceutical forms

Solvent for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

175mg/m2

Investigational medicinal product name

Bortezomib

Investigational medicinal product code

Other name

Pharmaceutical forms

Powder for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

1.3mg/m2

Phase 1 & 2: KW-2478 175 mg/m^2 and Bortezomib 1.3mg/m^2

Arm description

The target population in both Phase 1 and 2 were adults (≥18 years) of either gender with a confirmed history of MM by IMWG criteria had relapsed or failed to respond to 1–3 prior MM regimens with an Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2 and a life expectancy ≥ 3 months. Subjects had to have disease that could be evaluated by serum or urinary levels of M protein or serum free light chains in the absence of measurable M protein in serum or urine. The Phase 1 portion of the study was a standard 3+3 study design of KW-2478 (130 or 175 mg/m^2) and Bortezomib (1.0 or 1.3 mg/m^2) on Days 1, 4, 8, and 11 of a 21-day cycle utilizing four dose-escalation cohorts. The Phase 2 portion of the study was designed to determine the preliminary efficacy of KW 2478 and Bortezomib at the RP2D (KW-2478 175 mg/m^2/Bortezomib 1.3 mg/m^2).

Arm type

Experimental

Investigational medicinal product name

KW-2478

Investigational medicinal product code

Other name

Pharmaceutical forms

Solvent for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

175mg/m2

Investigational medicinal product name

Bortezomib

Investigational medicinal product code

Other name

Pharmaceutical forms

Powder for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

1.3mg/m2

Phase 1 Cohort 1: KW-2478 130 mg/m^2 and Bortezomib 1.0mg/m^2

Arm description

Cohort 1: Both agents administered on Days 1, 4, 8, and 11 of a 21-day cycle with a standard 3+3 study design.

Arm type

Experimental

Investigational medicinal product name

KW-2478

Investigational medicinal product code

Other name

Pharmaceutical forms

Solvent for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

130mg/m2

Investigational medicinal product name

Bortezomib

Investigational medicinal product code

Other name

Pharmaceutical forms

Powder for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

1.0mg/m2

Phase 1 Cohort 2: KW-2478 130 mg/m^2 and Bortezomib 1.3mg/m^2

Arm description

Cohort 2: Both agents administered on Days 1, 4, 8, and 11 of a 21-day cycle with a standard 3+3 study design.

Arm type

Experimental

Investigational medicinal product name

KW-2478

Investigational medicinal product code

Other name

Pharmaceutical forms

Solvent for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

130mg/m2

Investigational medicinal product name

Bortezomib

Investigational medicinal product code

Other name

Pharmaceutical forms

Powder for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

1.3mg/m2

Phase 1 Cohort 3: KW-2478 175 mg/m^2 and Bortezomib 1.0mg/m^2

Arm description

Cohort 3: Both agents administered on Days 1, 4, 8, and 11 of a 21-day cycle with a standard 3+3 study design.

Arm type

Experimental

Investigational medicinal product name

KW-2478

Investigational medicinal product code

Other name

Pharmaceutical forms

Solvent for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

175mg/m2

Investigational medicinal product name

Bortezomib

Investigational medicinal product code

Other name

Pharmaceutical forms

Powder for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

1.0mg/m2

Phase 1 Cohort 4: KW-2478 175 mg/m^2 and Bortezomib 1.3mg/m^2

Arm description

Cohort 4: Both agents administered on Days 1, 4, 8, and 11 of a 21-day cycle with a standard 3+3 study design.

Arm type

Experimental

Investigational medicinal product name

KW-2478

Investigational medicinal product code

Other name

Pharmaceutical forms

Solvent for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

175mg/m2

Investigational medicinal product name

Bortezomib

Investigational medicinal product code

Other name

Pharmaceutical forms

Powder for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

1.3mg/m2

Phase 2: KW-2478 175 mg/m^2 and Bortezomib 1.3mg/m^2

Arm description

Phase 2: Both agents administered on Days 1, 4, 8, and 11 of a 21-day cycle designed to determine the preliminary efficacy of KW 2478 and Bortezomib at the RP2D (KW-2478 175 mg/m^2/Bortezomib 1.3 mg/m^2).

Arm type

Experimental

Investigational medicinal product name

KW-2478

Investigational medicinal product code

Other name

Pharmaceutical forms

Solvent for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

175mg/m2

Investigational medicinal product name

Bortezomib

Investigational medicinal product code

Other name

Pharmaceutical forms

Powder for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

1.3mg/m2

Phase 1 Cohort 2: KW-2478 130 mg/m^2 and Bortezomib 1.3mg/m^2

Arm description

Both agents administered on Days 1, 4, 8 and 11 of a 21 day cycle

Arm type

Experimental

Investigational medicinal product name

KW-2478

Investigational medicinal product code

Other name

Pharmaceutical forms

Solvent for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

130mg/m2

Investigational medicinal product name

Bortezomib

Investigational medicinal product code

Other name

Pharmaceutical forms

Powder for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

1.3mg/m2

Phase 1 Cohort 3: KW-2478 175 mg/m^2 and Bortezomib 1.0mg/m^2

Arm description

Cohort 3: Both agents administered on Days 1, 4, 8, and 11 of a 21-day cycle with a standard 3+3 study design.

Arm type

Experimental

Investigational medicinal product name

KW-2478

Investigational medicinal product code

Other name

Pharmaceutical forms

Solvent for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

175mg/m2

Investigational medicinal product name

Bortezomib

Investigational medicinal product code

Other name

Pharmaceutical forms

Powder for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

1.0mg/m2

Number of subjects in period 1	Phase 1: KW-2478 and Bortezomib	Phase II: KW-2478 130mg/m^2 and Bortezomib 1.3mg/m^2	KW-2478 and bortezomib	Phase 1 & 2: KW-2478 175 mg/m^2 and Bortezomib 1.3mg/m^2	Phase 1 Cohort 1: KW-2478 130 mg/m^2 and Bortezomib 1.0mg/m^2	Phase 1 Cohort 2: KW-2478 130 mg/m^2 and Bortezomib 1.3mg/m^2	Phase 1 Cohort 3: KW-2478 175 mg/m^2 and Bortezomib 1.0mg/m^2	Phase 1 Cohort 4: KW-2478 175 mg/m^2 and Bortezomib 1.3mg/m^2	Phase 2: KW-2478 175 mg/m^2 and Bortezomib 1.3mg/m^2	Phase 1 Cohort 2: KW-2478 130 mg/m^2 and Bortezomib 1.3mg/m^2	Phase 1 Cohort 3: KW-2478 175 mg/m^2 and Bortezomib 1.0mg/m^2
Started	15	80	80	80	3	3	3	6	80	3	3
Completed	15	80	6	6	0	0	0	0	6	0	0
Not completed	0	0	74	74	3	3	3	6	74	3	3
Unknown	-	-	74	74	3	3	3	6	74	3	3

Baseline characteristics

Top of page

Reporting group title

Phase 1: KW-2478 and Bortezomib

Reporting group description

Reporting group title

Phase II: KW-2478 130mg/m^2 and Bortezomib 1.3mg/m^2

Reporting group description

Reporting group values	Phase 1: KW-2478 and Bortezomib	Phase II: KW-2478 130mg/m^2 and Bortezomib 1.3mg/m^2	Total
Number of subjects	15	80	95
Age categorical
Units: Subjects
In utero	0	0	0
Preterm newborn infants (gestational age < 37 wks)	0	0	0
Newborns (0-27 days)	0	0	0
Infants and toddlers (28 days-23 months)	0	0	0
Children (2-11 years)	0	0	0
Adolescents (12-17 years)	0	0	0
Adults (18-64 years)	7	41	48
From 65-84 years	8	39	47
85 years and over	0	0	0
Age Continuous
Units: years
arithmetic mean (standard deviation)	65.3 ( 8.2 )	64.1 ( 9.6 )	-
Gender, Male/Female
Units: participants
Female	4	37	41
Male	11	43	54
Race (NIH/OMB)
Units: Subjects
American Indian or Alaska Native	0	0	0
Asian	1	21	22
Native Hawaiian or Other Pacific Islander	0	0	0
Black or African American	3	5	8
White	10	51	61
More than one race	0	0	0
Unknown or Not Reported	1	3	4
Region of Enrollment
Units: Subjects
United States	4	14	18
Philippines	0	20	20
United Kingdom	11	46	57
Body Surface Area (BSA)
Units: m^2
arithmetic mean (standard deviation)	( )	( )	-

Subject analysis set title

KW-2478 and bortezomib

Subject analysis set type

Full analysis

Subject analysis set description

Subject analysis set title

Phase 1 & 2: KW-2478 175 mg/m^2 and Bortezomib 1.3mg/m^2

Subject analysis set type

Full analysis

Subject analysis set description

The target population in both Phase 1 and 2 were adults (≥18 years) of either gender with a confirmed history of MM by IMWG criteria had relapsed or failed to respond to 1–3 prior MM regimens with an Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2 and a life expectancy ≥ 3 months. Subjects had to have disease that could be evaluated by serum or urinary levels of M protein or serum free light chains in the absence of measurable M protein in serum or urine. The Phase 1 portion of the study was a standard 3+3 study design of KW-2478 (130 or 175 mg/m^2) and Bortezomib (1.0 or 1.3 mg/m^2) on Days 1, 4, 8, and 11 of a 21-day cycle utilizing four dose-escalation cohorts. The Phase 2 portion of the study was designed to determine the preliminary efficacy of KW 2478 and Bortezomib at the RP2D (KW-2478 175 mg/m^2/Bortezomib 1.3 mg/m^2).

Subject analysis set title

Phase 1 Cohort 1: KW-2478 130 mg/m^2 and Bortezomib 1.0mg/m^2

Subject analysis set type

Full analysis

Subject analysis set description

Cohort 1: Both agents administered on Days 1, 4, 8, and 11 of a 21-day cycle with a standard 3+3 study design.

Subject analysis set title

Phase 1 Cohort 2: KW-2478 130 mg/m^2 and Bortezomib 1.3mg/m^2

Subject analysis set type

Full analysis

Subject analysis set description

Cohort 2: Both agents administered on Days 1, 4, 8, and 11 of a 21-day cycle with a standard 3+3 study design.

Subject analysis set title

Phase 1 Cohort 3: KW-2478 175 mg/m^2 and Bortezomib 1.0mg/m^2

Subject analysis set type

Full analysis

Subject analysis set description

Cohort 3: Both agents administered on Days 1, 4, 8, and 11 of a 21-day cycle with a standard 3+3 study design.

Subject analysis set title

Phase 1 Cohort 4: KW-2478 175 mg/m^2 and Bortezomib 1.3mg/m^2

Subject analysis set type

Full analysis

Subject analysis set description

Cohort 4: Both agents administered on Days 1, 4, 8, and 11 of a 21-day cycle with a standard 3+3 study design.

Subject analysis set title

Phase 2: KW-2478 175 mg/m^2 and Bortezomib 1.3mg/m^2

Subject analysis set type

Full analysis

Subject analysis set description

Subject analysis set title

Phase 1 Cohort 1: KW-2478 130 mg/m^2 and Bortezomib 1.0mg/m^2

Subject analysis set type

Full analysis

Subject analysis set description

Both agents administered on Days 1, 4, 8 and 11 of a 21 day cycle

Subject analysis set title

Phase 1 Cohort 2: KW-2478 130 mg/m^2 and Bortezomib 1.3mg/m^2

Subject analysis set type

Full analysis

Subject analysis set description

Both agents administered on Days 1, 4, 8 and 11 of a 21 day cycle

Subject analysis set title

Phase 1 Cohort 3: KW-2478 175 mg/m^2 and Bortezomib 1.0mg/m^2

Subject analysis set type

Full analysis

Subject analysis set description

Both agents administered on Days 1, 4, 8 and 11 of a 21 day cycle

Subject analysis set title

Phase 1 Cohort 4: KW-2478 175 mg/m^2 and Bortezomib 1.3mg/m^2

Subject analysis set type

Full analysis

Subject analysis set description

Both agents administered on Days 1, 4, 8 and 11 of a 21 day cycle

Subject analysis sets values	KW-2478 and bortezomib	Phase 1 & 2: KW-2478 175 mg/m^2 and Bortezomib 1.3mg/m^2	Phase 1 Cohort 1: KW-2478 130 mg/m^2 and Bortezomib 1.0mg/m^2	Phase 1 Cohort 2: KW-2478 130 mg/m^2 and Bortezomib 1.3mg/m^2	Phase 1 Cohort 3: KW-2478 175 mg/m^2 and Bortezomib 1.0mg/m^2	Phase 1 Cohort 4: KW-2478 175 mg/m^2 and Bortezomib 1.3mg/m^2	Phase 2: KW-2478 175 mg/m^2 and Bortezomib 1.3mg/m^2	Phase 1 Cohort 1: KW-2478 130 mg/m^2 and Bortezomib 1.0mg/m^2	Phase 1 Cohort 2: KW-2478 130 mg/m^2 and Bortezomib 1.3mg/m^2	Phase 1 Cohort 3: KW-2478 175 mg/m^2 and Bortezomib 1.0mg/m^2	Phase 1 Cohort 4: KW-2478 175 mg/m^2 and Bortezomib 1.3mg/m^2
Number of subjects	95	95	3	3	3	6	80	3	3	3	6
Age categorical
Units: Subjects
In utero	0	0	0	0	0	0	0	0	0	0	0
Preterm newborn infants (gestational age < 37 wks)	0	0	0	0	0	0	0	0	0	0	0
Newborns (0-27 days)	0	0	0	0	0	0	0	0	0	0	0
Infants and toddlers (28 days-23 months)	0	0	0	0	0	0	0	0	0	0	0
Children (2-11 years)	0	0	0	0	0	0	0	0	0	0	0
Adolescents (12-17 years)	0	0	0	0	0	0	0	0	0	0	0
Adults (18-64 years)	48	48	1	2	0	3	41	1	2	0	3
From 65-84 years	47	47	2	1	3	3	39	2	1	3	3
85 years and over	0	0	0	0	0	0	0	0	0	0	0
Age Continuous
Units: years
arithmetic mean (standard deviation)	64.3 ( 9.3 )	64.3 ( 9.3 )	68 ( 5.6 )	61 ( 6.3 )	70.7 ( 3.8 )	63.5 ( 10.9 )	64.1 ( 9.6 )	68 ( 5.6 )	61 ( 6.3 )	70.7 ( 3.8 )	63.5 ( 10.9 )
Gender, Male/Female
Units: participants
Female	41	41	1	0	2	1	37	1	0	2	1
Male	54	54	2	3	1	5	43	2	3	1	5
Race (NIH/OMB)
Units: Subjects
American Indian or Alaska Native	0	0	0	0	0	0	0	0	0	0	0
Asian	22	22	0	0	0	1	21	0	0	0	1
Native Hawaiian or Other Pacific Islander	0	0	0	0	0	0	0	0	0	0	0
Black or African American	8	8	0	0	2	1	5	0	0	0	1
White	61	61	3	2	1	4	51	3	2	2	4
More than one race	0	0	0	0	0	0	0	0	0	0	0
Unknown or Not Reported	4	4	0	1	0	0	3	0	1	1	0
Region of Enrollment
Units: Subjects
United States	18	18	1	0	1	2		1	0	1	2
Philippines	20	20	0	0	0	0		0	0	0	0
United Kingdom	57	57	2	3	2	4		2	3	2	4
Body Surface Area (BSA)
Units: m^2
arithmetic mean (standard deviation)	1.87 ( 0.27 )	( )	( )	( )	( )	( )	( )	( )	( )	( )	( )

End points

Top of page

Reporting group title

Phase 1: KW-2478 and Bortezomib

Reporting group description

Reporting group title

Phase II: KW-2478 130mg/m^2 and Bortezomib 1.3mg/m^2

Reporting group description

Reporting group title

KW-2478 and bortezomib

Reporting group description

Reporting group title

Phase 1 & 2: KW-2478 175 mg/m^2 and Bortezomib 1.3mg/m^2

Reporting group description

The target population in both Phase 1 and 2 were adults (≥18 years) of either gender with a confirmed history of MM by IMWG criteria had relapsed or failed to respond to 1–3 prior MM regimens with an Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2 and a life expectancy ≥ 3 months. Subjects had to have disease that could be evaluated by serum or urinary levels of M protein or serum free light chains in the absence of measurable M protein in serum or urine. The Phase 1 portion of the study was a standard 3+3 study design of KW-2478 (130 or 175 mg/m^2) and Bortezomib (1.0 or 1.3 mg/m^2) on Days 1, 4, 8, and 11 of a 21-day cycle utilizing four dose-escalation cohorts. The Phase 2 portion of the study was designed to determine the preliminary efficacy of KW 2478 and Bortezomib at the RP2D (KW-2478 175 mg/m^2/Bortezomib 1.3 mg/m^2).

Reporting group title

Phase 1 Cohort 1: KW-2478 130 mg/m^2 and Bortezomib 1.0mg/m^2

Reporting group description

Cohort 1: Both agents administered on Days 1, 4, 8, and 11 of a 21-day cycle with a standard 3+3 study design.

Reporting group title

Phase 1 Cohort 2: KW-2478 130 mg/m^2 and Bortezomib 1.3mg/m^2

Reporting group description

Cohort 2: Both agents administered on Days 1, 4, 8, and 11 of a 21-day cycle with a standard 3+3 study design.

Reporting group title

Phase 1 Cohort 3: KW-2478 175 mg/m^2 and Bortezomib 1.0mg/m^2

Reporting group description

Cohort 3: Both agents administered on Days 1, 4, 8, and 11 of a 21-day cycle with a standard 3+3 study design.

Reporting group title

Phase 1 Cohort 4: KW-2478 175 mg/m^2 and Bortezomib 1.3mg/m^2

Reporting group description

Cohort 4: Both agents administered on Days 1, 4, 8, and 11 of a 21-day cycle with a standard 3+3 study design.

Reporting group title

Phase 2: KW-2478 175 mg/m^2 and Bortezomib 1.3mg/m^2

Reporting group description

Reporting group title

Phase 1 Cohort 2: KW-2478 130 mg/m^2 and Bortezomib 1.3mg/m^2

Reporting group description

Both agents administered on Days 1, 4, 8 and 11 of a 21 day cycle

Reporting group title

Phase 1 Cohort 3: KW-2478 175 mg/m^2 and Bortezomib 1.0mg/m^2

Reporting group description

Cohort 3: Both agents administered on Days 1, 4, 8, and 11 of a 21-day cycle with a standard 3+3 study design.

Subject analysis set title

KW-2478 and bortezomib

Subject analysis set type

Full analysis

Subject analysis set description

Subject analysis set title

Phase 1 & 2: KW-2478 175 mg/m^2 and Bortezomib 1.3mg/m^2

Subject analysis set type

Full analysis

Subject analysis set description

The target population in both Phase 1 and 2 were adults (≥18 years) of either gender with a confirmed history of MM by IMWG criteria had relapsed or failed to respond to 1–3 prior MM regimens with an Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2 and a life expectancy ≥ 3 months. Subjects had to have disease that could be evaluated by serum or urinary levels of M protein or serum free light chains in the absence of measurable M protein in serum or urine. The Phase 1 portion of the study was a standard 3+3 study design of KW-2478 (130 or 175 mg/m^2) and Bortezomib (1.0 or 1.3 mg/m^2) on Days 1, 4, 8, and 11 of a 21-day cycle utilizing four dose-escalation cohorts. The Phase 2 portion of the study was designed to determine the preliminary efficacy of KW 2478 and Bortezomib at the RP2D (KW-2478 175 mg/m^2/Bortezomib 1.3 mg/m^2).

Subject analysis set title

Phase 1 Cohort 1: KW-2478 130 mg/m^2 and Bortezomib 1.0mg/m^2

Subject analysis set type

Full analysis

Subject analysis set description

Cohort 1: Both agents administered on Days 1, 4, 8, and 11 of a 21-day cycle with a standard 3+3 study design.

Subject analysis set title

Phase 1 Cohort 2: KW-2478 130 mg/m^2 and Bortezomib 1.3mg/m^2

Subject analysis set type

Full analysis

Subject analysis set description

Cohort 2: Both agents administered on Days 1, 4, 8, and 11 of a 21-day cycle with a standard 3+3 study design.

Subject analysis set title

Phase 1 Cohort 3: KW-2478 175 mg/m^2 and Bortezomib 1.0mg/m^2

Subject analysis set type

Full analysis

Subject analysis set description

Cohort 3: Both agents administered on Days 1, 4, 8, and 11 of a 21-day cycle with a standard 3+3 study design.

Subject analysis set title

Phase 1 Cohort 4: KW-2478 175 mg/m^2 and Bortezomib 1.3mg/m^2

Subject analysis set type

Full analysis

Subject analysis set description

Cohort 4: Both agents administered on Days 1, 4, 8, and 11 of a 21-day cycle with a standard 3+3 study design.

Subject analysis set title

Phase 2: KW-2478 175 mg/m^2 and Bortezomib 1.3mg/m^2

Subject analysis set type

Full analysis

Subject analysis set description

Subject analysis set title

Phase 1 Cohort 1: KW-2478 130 mg/m^2 and Bortezomib 1.0mg/m^2

Subject analysis set type

Full analysis

Subject analysis set description

Both agents administered on Days 1, 4, 8 and 11 of a 21 day cycle

Subject analysis set title

Phase 1 Cohort 2: KW-2478 130 mg/m^2 and Bortezomib 1.3mg/m^2

Subject analysis set type

Full analysis

Subject analysis set description

Both agents administered on Days 1, 4, 8 and 11 of a 21 day cycle

Subject analysis set title

Phase 1 Cohort 3: KW-2478 175 mg/m^2 and Bortezomib 1.0mg/m^2

Subject analysis set type

Full analysis

Subject analysis set description

Both agents administered on Days 1, 4, 8 and 11 of a 21 day cycle

Subject analysis set title

Phase 1 Cohort 4: KW-2478 175 mg/m^2 and Bortezomib 1.3mg/m^2

Subject analysis set type

Full analysis

Subject analysis set description

Both agents administered on Days 1, 4, 8 and 11 of a 21 day cycle

Primary: To establish the safety, tolerability, and RP2D (Phase 1); To assess the overall response rate in subjects with advanced Multiple Myeloma (Phase 2).

Top of page

End point title

To establish the safety, tolerability, and RP2D (Phase 1); To assess the overall response rate in subjects with advanced Multiple Myeloma (Phase 2). ^[1]

End point description

The safety of KW-2478 was determined by reported TEAEs, observed DLTs, changes in PEs, vital sign measurements, ECGs, and laboratory analyses. The ORR, was defined as the best response over a specified number of cycles (calculated and summarized). Disease control rate (DCR) was defined as the best response over a specified number of cycles (calculated and summarized). Progression-free survival was defined as the time from the first day of treatment until the date of disease progression or death is first reported (calculated and summarized).

End point type

Primary

End point timeframe

21 day cycle, up to 52 weeks

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: Owing to the nonrandomized nature of this trial and the limited sample sizes involved, no formal statistical hypothesis testing was conducted. Data from all centers were pooled. Except as otherwise specified in the SAP, missing data were not imputed.

End point values	Phase 1 & 2: KW-2478 175 mg/m^2 and Bortezomib 1.3mg/m^2	Phase 1 Cohort 1: KW-2478 130 mg/m^2 and Bortezomib 1.0mg/m^2	Phase 1 Cohort 2: KW-2478 130 mg/m^2 and Bortezomib 1.3mg/m^2	Phase 1 Cohort 3: KW-2478 175 mg/m^2 and Bortezomib 1.0mg/m^2	Phase 1 Cohort 4: KW-2478 175 mg/m^2 and Bortezomib 1.3mg/m^2	Phase 2: KW-2478 175 mg/m^2 and Bortezomib 1.3mg/m^2
Number of subjects analysed	95	3	3	3	6	80
Units: participants
number (not applicable)
Subjects with Any TEAE	95	3	3	3	6	80
Related TEAE	88	3	3	2	6	74
Moderate (CTCAE 2) TEAE	22	0	0	0	0	22
Severe (CTCAE 3) TEAE	54	3	2	2	5	42
Life Threatening TEAE	13	0	1	0	0	12
Serious Treatment-Emergent AE	48	2	3	3	4	36
Subjects with Any DLT	1	0	0	1	0	0

No statistical analyses for this end point

Secondary: Phase 1: PK Absorption tmax hr Day 11

Top of page

End point title

Phase 1: PK Absorption tmax hr Day 11

End point description

Descriptive summary statistics (number, arithmetic mean, standard deviation [SDev], coefficient of variation [CV%]) for concentration and PK data for KW-2478 and Bortezomib in Phase 1 were presented by cohort, dose level and day.

End point type

Secondary

End point timeframe

PK collected Day 11 of 21-day cycle

End point values	Phase 1 Cohort 1: KW-2478 130 mg/m^2 and Bortezomib 1.0mg/m^2	Phase 1 Cohort 2: KW-2478 130 mg/m^2 and Bortezomib 1.3mg/m^2	Phase 1 Cohort 3: KW-2478 175 mg/m^2 and Bortezomib 1.0mg/m^2	Phase 1 Cohort 4: KW-2478 175 mg/m^2 and Bortezomib 1.3mg/m^2
Number of subjects analysed	3	3	3	6
Units: hr
arithmetic mean (standard deviation)	1.03 ( 0.0441 )	1.03 ( 0.0481 )	1.11 ( 0.129 )	1.07 ( 0.0638 )

No statistical analyses for this end point

Secondary: Phase 1: PK Exposure Cmax ng/mL Day 11

Top of page

End point title

Phase 1: PK Exposure Cmax ng/mL Day 11

End point description

End point type

Secondary

End point timeframe

PK collected Day 11 of 21-day cycle

End point values	Phase 1 Cohort 1: KW-2478 130 mg/m^2 and Bortezomib 1.0mg/m^2	Phase 1 Cohort 2: KW-2478 130 mg/m^2 and Bortezomib 1.3mg/m^2	Phase 1 Cohort 3: KW-2478 175 mg/m^2 and Bortezomib 1.0mg/m^2	Phase 1 Cohort 4: KW-2478 175 mg/m^2 and Bortezomib 1.3mg/m^2
Number of subjects analysed	3	3	3	6
Units: ng/mL
arithmetic mean (standard deviation)	7910 ( 5360 )	41000 ( 64100 )	5990 ( 2720 )	5280 ( 2290 )

No statistical analyses for this end point

Secondary: Phase 1: PK Exposure AUC0-t hr*ng/mL Day 11

Top of page

End point title

Phase 1: PK Exposure AUC0-t hr*ng/mL Day 11

End point description

End point type

Secondary

End point timeframe

PK collected Day 11 of 21-day cycle

End point values	Phase 1 Cohort 1: KW-2478 130 mg/m^2 and Bortezomib 1.0mg/m^2	Phase 1 Cohort 2: KW-2478 130 mg/m^2 and Bortezomib 1.3mg/m^2	Phase 1 Cohort 3: KW-2478 175 mg/m^2 and Bortezomib 1.0mg/m^2	Phase 1 Cohort 4: KW-2478 175 mg/m^2 and Bortezomib 1.3mg/m^2
Number of subjects analysed	3	3	3	6
Units: hr*ng/mL
arithmetic mean (standard deviation)	7940 ( 2580 )	26200 ( 36700 )	7190 ( 2150 )	6040 ( 2280 )

No statistical analyses for this end point

Secondary: Phase 1: PK Elimination t½ hr Day 11

Top of page

End point title

Phase 1: PK Elimination t½ hr Day 11

End point description

End point type

Secondary

End point timeframe

PK collected Day 11 of 21-day cycle

End point values	Phase 1 Cohort 1: KW-2478 130 mg/m^2 and Bortezomib 1.0mg/m^2	Phase 1 Cohort 2: KW-2478 130 mg/m^2 and Bortezomib 1.3mg/m^2	Phase 1 Cohort 3: KW-2478 175 mg/m^2 and Bortezomib 1.0mg/m^2	Phase 1 Cohort 4: KW-2478 175 mg/m^2 and Bortezomib 1.3mg/m^2
Number of subjects analysed	3	3	3	6
Units: hr
arithmetic mean (standard deviation)	1.88 ( 0.076 )	2.02 ( 0 )	1.84 ( 0.206 )	1.77 ( 0.262 )

No statistical analyses for this end point

Adverse events

Top of page

Timeframe for reporting adverse events

Throughout study

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

12.1

Reporting group title

Phase 1 Cohort 2: KW-2478 130 mg/m^2 and Bortezomib 1.3 mg/m^2

Reporting group description

Cohort 2: Both agents administered on Days 1, 4, 8, and 11 of a 21-day cycle with a standard 3+3 study design.

Reporting group title

Phase 1 and 2: KW-2478 and bortezomib

Reporting group description

KW-2478 and bortezomib: KW 2478 and bortezomib given on Days 1, 4, 8 and 11 of a 21 day cycle

Reporting group title

Phase 1 Cohort 1: KW-2478 130 mg/m^2 and Bortezomib 1.0 mg/m^2

Reporting group description

Cohort 1: Both agents administered on Days 1, 4, 8, and 11 of a 21-day cycle with a standard 3+3 study design.

Reporting group title

Phase 1 Cohort 4: KW-2478 175 mg/m^2 and Bortezomib 1.3 mg/m^2

Reporting group description

Cohort 4: Both agents administered on Days 1, 4, 8, and 11 of a 21-day cycle with a standard 3+3 study design.

Reporting group title

Phase 2: KW-2478 175 mg/m^2 and Bortezomib 1.3 mg/m^2

Reporting group description

Phase 2: Both agents administered on Days 1, 4, 8, and 11 of a 21-day cycle designed to determine the preliminary efficacy of KW 2478 + BTZ at the RP2D (KW-2478 175 mg/m^2/BTZ 1.3 mg/m^2).

Reporting group title

Phase 1 Cohort 3: KW-2478 175 mg/m^2 and Bortezomib 1.0 mg/m^2

Reporting group description

Cohort 3: Both agents administered on Days 1, 4, 8, and 11 of a 21-day cycle with a standard 3+3 study design.

Serious adverse events	Phase 1 Cohort 2: KW-2478 130 mg/m^2 and Bortezomib 1.3 mg/m^2	Phase 1 and 2: KW-2478 and bortezomib	Phase 1 Cohort 1: KW-2478 130 mg/m^2 and Bortezomib 1.0 mg/m^2	Phase 1 Cohort 4: KW-2478 175 mg/m^2 and Bortezomib 1.3 mg/m^2	Phase 2: KW-2478 175 mg/m^2 and Bortezomib 1.3 mg/m^2	Phase 1 Cohort 3: KW-2478 175 mg/m^2 and Bortezomib 1.0 mg/m^2
Total subjects affected by serious adverse events
subjects affected / exposed	3 / 3 (100.00%)	48 / 95 (50.53%)	2 / 3 (66.67%)	4 / 6 (66.67%)	36 / 80 (45.00%)	3 / 3 (100.00%)
number of deaths (all causes)	0	1	0	1	1	0
number of deaths resulting from adverse events
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Multiple myeloma
subjects affected / exposed	1 / 3 (33.33%)	2 / 95 (2.11%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 80 (0.00%)	1 / 3 (33.33%)
occurrences causally related to treatment / all	0 / 1	0 / 2	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
Vascular disorders
Circulatory collapse
subjects affected / exposed	0 / 3 (0.00%)	1 / 95 (1.05%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 80 (1.25%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
General disorders and administration site conditions
Chest pain
subjects affected / exposed	0 / 3 (0.00%)	1 / 95 (1.05%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 80 (0.00%)	1 / 3 (33.33%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Oedema peripheral
subjects affected / exposed	0 / 3 (0.00%)	1 / 95 (1.05%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 80 (0.00%)	1 / 3 (33.33%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pain
subjects affected / exposed	0 / 3 (0.00%)	1 / 95 (1.05%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 80 (1.25%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pyrexia
subjects affected / exposed	1 / 3 (33.33%)	3 / 95 (3.16%)	0 / 3 (0.00%)	0 / 6 (0.00%)	2 / 80 (2.50%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 4	0 / 0	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Dyspnoea
subjects affected / exposed	1 / 3 (33.33%)	4 / 95 (4.21%)	0 / 3 (0.00%)	0 / 6 (0.00%)	2 / 80 (2.50%)	1 / 3 (33.33%)
occurrences causally related to treatment / all	0 / 2	0 / 5	0 / 0	0 / 0	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Epistaxis
subjects affected / exposed	0 / 3 (0.00%)	3 / 95 (3.16%)	0 / 3 (0.00%)	0 / 6 (0.00%)	3 / 80 (3.75%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 3	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
Pneumonia aspiration
subjects affected / exposed	0 / 3 (0.00%)	1 / 95 (1.05%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 80 (1.25%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Psychiatric disorders
Confusional state
subjects affected / exposed	0 / 3 (0.00%)	3 / 95 (3.16%)	0 / 3 (0.00%)	0 / 6 (0.00%)	2 / 80 (2.50%)	1 / 3 (33.33%)
occurrences causally related to treatment / all	0 / 0	0 / 3	0 / 0	0 / 0	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Investigations
Blood creatinine increased
subjects affected / exposed	0 / 3 (0.00%)	2 / 95 (2.11%)	0 / 3 (0.00%)	0 / 6 (0.00%)	2 / 80 (2.50%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Troponin T increased
subjects affected / exposed	0 / 3 (0.00%)	1 / 95 (1.05%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 80 (0.00%)	1 / 3 (33.33%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Viral test positive
subjects affected / exposed	0 / 3 (0.00%)	1 / 95 (1.05%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 80 (1.25%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Weight decreased
subjects affected / exposed	1 / 3 (33.33%)	1 / 95 (1.05%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 80 (0.00%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Injury, poisoning and procedural complications
Accidental overdose
subjects affected / exposed	0 / 3 (0.00%)	1 / 95 (1.05%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 80 (1.25%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Clavicle fracture
subjects affected / exposed	0 / 3 (0.00%)	1 / 95 (1.05%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 80 (0.00%)	1 / 3 (33.33%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Fall
subjects affected / exposed	0 / 3 (0.00%)	2 / 95 (2.11%)	0 / 3 (0.00%)	0 / 6 (0.00%)	2 / 80 (2.50%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Femur fracture
subjects affected / exposed	0 / 3 (0.00%)	1 / 95 (1.05%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 80 (1.25%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hip fracture
subjects affected / exposed	0 / 3 (0.00%)	1 / 95 (1.05%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 80 (0.00%)	1 / 3 (33.33%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cardiac disorders
Angina pectoris
subjects affected / exposed	0 / 3 (0.00%)	1 / 95 (1.05%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 80 (0.00%)	1 / 3 (33.33%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Angina unstable
subjects affected / exposed	0 / 3 (0.00%)	1 / 95 (1.05%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 80 (1.25%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Myocardial ischaemia
subjects affected / exposed	0 / 3 (0.00%)	1 / 95 (1.05%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 80 (1.25%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Right ventricular failure
subjects affected / exposed	0 / 3 (0.00%)	1 / 95 (1.05%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 80 (1.25%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Nervous system disorders
Loss of consciousness
subjects affected / exposed	0 / 3 (0.00%)	1 / 95 (1.05%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 80 (1.25%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Neuropathy peripheral
subjects affected / exposed	0 / 3 (0.00%)	2 / 95 (2.11%)	0 / 3 (0.00%)	0 / 6 (0.00%)	2 / 80 (2.50%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Presyncope
subjects affected / exposed	0 / 3 (0.00%)	1 / 95 (1.05%)	0 / 3 (0.00%)	1 / 6 (16.67%)	0 / 80 (0.00%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Transient ischaemic attack
subjects affected / exposed	0 / 3 (0.00%)	1 / 95 (1.05%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 80 (1.25%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	0 / 3 (0.00%)	4 / 95 (4.21%)	0 / 3 (0.00%)	0 / 6 (0.00%)	4 / 80 (5.00%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 4	0 / 0	0 / 0	0 / 4	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Febrile neutropenia
subjects affected / exposed	0 / 3 (0.00%)	1 / 95 (1.05%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 80 (1.25%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Thrombocytopenia
subjects affected / exposed	0 / 3 (0.00%)	2 / 95 (2.11%)	0 / 3 (0.00%)	0 / 6 (0.00%)	2 / 80 (2.50%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 3	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
Eye disorders
Vision blurred
subjects affected / exposed	0 / 3 (0.00%)	1 / 95 (1.05%)	0 / 3 (0.00%)	1 / 6 (16.67%)	0 / 80 (0.00%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
Abdominal hernia
subjects affected / exposed	0 / 3 (0.00%)	1 / 95 (1.05%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 80 (1.25%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Abdominal pain
subjects affected / exposed	0 / 3 (0.00%)	1 / 95 (1.05%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 80 (1.25%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Constipation
subjects affected / exposed	0 / 3 (0.00%)	1 / 95 (1.05%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 80 (1.25%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Diarrhoea
subjects affected / exposed	1 / 3 (33.33%)	4 / 95 (4.21%)	1 / 3 (33.33%)	0 / 6 (0.00%)	2 / 80 (2.50%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 4	0 / 1	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Nausea
subjects affected / exposed	0 / 3 (0.00%)	1 / 95 (1.05%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 80 (1.25%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pancreatitis
subjects affected / exposed	0 / 3 (0.00%)	1 / 95 (1.05%)	0 / 3 (0.00%)	1 / 6 (16.67%)	0 / 80 (0.00%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Small intestinal obstruction
subjects affected / exposed	0 / 3 (0.00%)	1 / 95 (1.05%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 80 (1.25%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Vomiting
subjects affected / exposed	0 / 3 (0.00%)	3 / 95 (3.16%)	1 / 3 (33.33%)	1 / 6 (16.67%)	1 / 80 (1.25%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 3	0 / 1	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Skin and subcutaneous tissue disorders
Rash erythematous
subjects affected / exposed	0 / 3 (0.00%)	1 / 95 (1.05%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 80 (1.25%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Renal and urinary disorders
Haematuria
subjects affected / exposed	0 / 3 (0.00%)	1 / 95 (1.05%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 80 (1.25%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Neurogenic bladder
subjects affected / exposed	0 / 3 (0.00%)	1 / 95 (1.05%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 80 (1.25%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Endocrine disorders
Inappropriate antidiuretic hormone secretion
subjects affected / exposed	0 / 3 (0.00%)	2 / 95 (2.11%)	0 / 3 (0.00%)	0 / 6 (0.00%)	2 / 80 (2.50%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Arthralgia
subjects affected / exposed	0 / 3 (0.00%)	2 / 95 (2.11%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 80 (1.25%)	1 / 3 (33.33%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Back pain
subjects affected / exposed	0 / 3 (0.00%)	3 / 95 (3.16%)	0 / 3 (0.00%)	0 / 6 (0.00%)	3 / 80 (3.75%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 3	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
Bone pain
subjects affected / exposed	0 / 3 (0.00%)	1 / 95 (1.05%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 80 (1.25%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Musculoskeletal chest pain
subjects affected / exposed	0 / 3 (0.00%)	2 / 95 (2.11%)	0 / 3 (0.00%)	0 / 6 (0.00%)	2 / 80 (2.50%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Musculoskeletal pain
subjects affected / exposed	1 / 3 (33.33%)	2 / 95 (2.11%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 80 (1.25%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 2	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
Infections and infestations
Appendicitis
subjects affected / exposed	0 / 3 (0.00%)	1 / 95 (1.05%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 80 (1.25%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Bacteraemia
subjects affected / exposed	0 / 3 (0.00%)	1 / 95 (1.05%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 80 (1.25%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Catheter sepsis
subjects affected / exposed	0 / 3 (0.00%)	1 / 95 (1.05%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 80 (1.25%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastroenteritis
subjects affected / exposed	0 / 3 (0.00%)	1 / 95 (1.05%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 80 (1.25%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Influenza
subjects affected / exposed	0 / 3 (0.00%)	1 / 95 (1.05%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 80 (1.25%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Listeriosis
subjects affected / exposed	0 / 3 (0.00%)	1 / 95 (1.05%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 80 (1.25%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Lower respiratory tract infection
subjects affected / exposed	0 / 3 (0.00%)	4 / 95 (4.21%)	1 / 3 (33.33%)	1 / 6 (16.67%)	2 / 80 (2.50%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 4	0 / 1	0 / 1	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Lung infection
subjects affected / exposed	0 / 3 (0.00%)	1 / 95 (1.05%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 80 (1.25%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Lung infection pseudomonal
subjects affected / exposed	0 / 3 (0.00%)	1 / 95 (1.05%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 80 (1.25%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pneumonia
subjects affected / exposed	0 / 3 (0.00%)	7 / 95 (7.37%)	0 / 3 (0.00%)	1 / 6 (16.67%)	6 / 80 (7.50%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 7	0 / 0	0 / 1	0 / 6	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pneumonia respiratory syncytial viral
subjects affected / exposed	0 / 3 (0.00%)	1 / 95 (1.05%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 80 (1.25%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory tract infection
subjects affected / exposed	0 / 3 (0.00%)	1 / 95 (1.05%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 80 (1.25%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Sepsis
subjects affected / exposed	0 / 3 (0.00%)	1 / 95 (1.05%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 80 (1.25%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Upper respiratory tract infection
subjects affected / exposed	0 / 3 (0.00%)	1 / 95 (1.05%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 80 (0.00%)	1 / 3 (33.33%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Urinary tract infection
subjects affected / exposed	0 / 3 (0.00%)	1 / 95 (1.05%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 80 (1.25%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Metabolism and nutrition disorders
Dehydration
subjects affected / exposed	0 / 3 (0.00%)	2 / 95 (2.11%)	0 / 3 (0.00%)	0 / 6 (0.00%)	2 / 80 (2.50%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hypercalcaemia
subjects affected / exposed	0 / 3 (0.00%)	1 / 95 (1.05%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 80 (1.25%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hyponatraemia
subjects affected / exposed	0 / 3 (0.00%)	2 / 95 (2.11%)	0 / 3 (0.00%)	0 / 6 (0.00%)	2 / 80 (2.50%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0

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

Non-serious adverse events	Phase 1 Cohort 2: KW-2478 130 mg/m^2 and Bortezomib 1.3 mg/m^2	Phase 1 and 2: KW-2478 and bortezomib	Phase 1 Cohort 1: KW-2478 130 mg/m^2 and Bortezomib 1.0 mg/m^2	Phase 1 Cohort 4: KW-2478 175 mg/m^2 and Bortezomib 1.3 mg/m^2	Phase 2: KW-2478 175 mg/m^2 and Bortezomib 1.3 mg/m^2	Phase 1 Cohort 3: KW-2478 175 mg/m^2 and Bortezomib 1.0 mg/m^2
Total subjects affected by non serious adverse events
subjects affected / exposed	3 / 3 (100.00%)	95 / 95 (100.00%)	3 / 3 (100.00%)	6 / 6 (100.00%)	80 / 80 (100.00%)	3 / 3 (100.00%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Lipoma
subjects affected / exposed	0 / 3 (0.00%)	2 / 95 (2.11%)	0 / 3 (0.00%)	0 / 6 (0.00%)	2 / 80 (2.50%)	0 / 3 (0.00%)
occurrences all number	0	2	0	0	2	0
Vascular disorders
Haematoma
subjects affected / exposed	0 / 3 (0.00%)	2 / 95 (2.11%)	1 / 3 (33.33%)	0 / 6 (0.00%)	1 / 80 (1.25%)	0 / 3 (0.00%)
occurrences all number	0	2	1	0	1	0
Hot flush
subjects affected / exposed	0 / 3 (0.00%)	1 / 95 (1.05%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 80 (1.25%)	0 / 3 (0.00%)
occurrences all number	0	1	0	0	1	0
Hypertension
subjects affected / exposed	0 / 3 (0.00%)	3 / 95 (3.16%)	0 / 3 (0.00%)	0 / 6 (0.00%)	2 / 80 (2.50%)	1 / 3 (33.33%)
occurrences all number	0	3	0	0	2	1
Hypotension
subjects affected / exposed	0 / 3 (0.00%)	5 / 95 (5.26%)	0 / 3 (0.00%)	0 / 6 (0.00%)	5 / 80 (6.25%)	0 / 3 (0.00%)
occurrences all number	0	9	0	0	9	0
Orthostatic hypotension
subjects affected / exposed	0 / 3 (0.00%)	2 / 95 (2.11%)	0 / 3 (0.00%)	0 / 6 (0.00%)	2 / 80 (2.50%)	0 / 3 (0.00%)
occurrences all number	0	3	0	0	3	0
Phlebitis
subjects affected / exposed	0 / 3 (0.00%)	4 / 95 (4.21%)	1 / 3 (33.33%)	1 / 6 (16.67%)	2 / 80 (2.50%)	0 / 3 (0.00%)
occurrences all number	0	5	1	1	3	0
Thrombophlebitis
subjects affected / exposed	0 / 3 (0.00%)	1 / 95 (1.05%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 80 (1.25%)	0 / 3 (0.00%)
occurrences all number	0	2	0	0	2	0
Vasculitis
subjects affected / exposed	0 / 3 (0.00%)	1 / 95 (1.05%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 80 (1.25%)	0 / 3 (0.00%)
occurrences all number	0	2	0	0	2	0
Vein discolouration
subjects affected / exposed	0 / 3 (0.00%)	1 / 95 (1.05%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 80 (1.25%)	0 / 3 (0.00%)
occurrences all number	0	1	0	0	1	0
General disorders and administration site conditions
Asthenia
subjects affected / exposed	0 / 3 (0.00%)	15 / 95 (15.79%)	0 / 3 (0.00%)	2 / 6 (33.33%)	13 / 80 (16.25%)	0 / 3 (0.00%)
occurrences all number	0	17	0	2	15	0
Catheter site erythema
subjects affected / exposed	0 / 3 (0.00%)	1 / 95 (1.05%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 80 (1.25%)	0 / 3 (0.00%)
occurrences all number	0	1	0	0	1	0
Catheter site haemorrhage
subjects affected / exposed	0 / 3 (0.00%)	1 / 95 (1.05%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 80 (1.25%)	0 / 3 (0.00%)
occurrences all number	0	1	0	0	1	0
Catheter site pain
subjects affected / exposed	0 / 3 (0.00%)	1 / 95 (1.05%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 80 (1.25%)	0 / 3 (0.00%)
occurrences all number	0	1	0	0	1	0
Catheter site related reaction
subjects affected / exposed	0 / 3 (0.00%)	1 / 95 (1.05%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 80 (1.25%)	0 / 3 (0.00%)
occurrences all number	0	1	0	0	1	0
Catheter thrombosis
subjects affected / exposed	0 / 3 (0.00%)	1 / 95 (1.05%)	0 / 3 (0.00%)	1 / 6 (16.67%)	0 / 80 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	1	0	1	0	0
Chest discomfort
subjects affected / exposed	0 / 3 (0.00%)	2 / 95 (2.11%)	0 / 3 (0.00%)	0 / 6 (0.00%)	2 / 80 (2.50%)	0 / 3 (0.00%)
occurrences all number	0	3	0	0	3	0
Chest pain
subjects affected / exposed	0 / 3 (0.00%)	3 / 95 (3.16%)	0 / 3 (0.00%)	0 / 6 (0.00%)	2 / 80 (2.50%)	1 / 3 (33.33%)
occurrences all number	0	4	0	0	2	2
Chills
subjects affected / exposed	1 / 3 (33.33%)	4 / 95 (4.21%)	0 / 3 (0.00%)	0 / 6 (0.00%)	3 / 80 (3.75%)	0 / 3 (0.00%)
occurrences all number	1	4	0	0	3	0
Cyst
subjects affected / exposed	0 / 3 (0.00%)	1 / 95 (1.05%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 80 (1.25%)	0 / 3 (0.00%)
occurrences all number	0	1	0	0	1	0
Facial pain
subjects affected / exposed	0 / 3 (0.00%)	1 / 95 (1.05%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 80 (1.25%)	0 / 3 (0.00%)
occurrences all number	0	1	0	0	1	0
Fatigue
subjects affected / exposed	3 / 3 (100.00%)	51 / 95 (53.68%)	2 / 3 (66.67%)	3 / 6 (50.00%)	41 / 80 (51.25%)	2 / 3 (66.67%)
occurrences all number	10	101	6	4	79	2
Feeling cold
subjects affected / exposed	0 / 3 (0.00%)	2 / 95 (2.11%)	0 / 3 (0.00%)	0 / 6 (0.00%)	2 / 80 (2.50%)	0 / 3 (0.00%)
occurrences all number	0	2	0	0	2	0
Gait disturbance
subjects affected / exposed	0 / 3 (0.00%)	2 / 95 (2.11%)	0 / 3 (0.00%)	0 / 6 (0.00%)	2 / 80 (2.50%)	0 / 3 (0.00%)
occurrences all number	0	2	0	0	2	0
Influenza like illness
subjects affected / exposed	0 / 3 (0.00%)	3 / 95 (3.16%)	0 / 3 (0.00%)	0 / 6 (0.00%)	3 / 80 (3.75%)	0 / 3 (0.00%)
occurrences all number	0	4	0	0	4	0
Infusion related reaction
subjects affected / exposed	0 / 3 (0.00%)	1 / 95 (1.05%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 80 (1.25%)	0 / 3 (0.00%)
occurrences all number	0	2	0	0	2	0
Infusion site haematoma
subjects affected / exposed	0 / 3 (0.00%)	1 / 95 (1.05%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 80 (1.25%)	0 / 3 (0.00%)
occurrences all number	0	1	0	0	1	0
Infusion site pain
subjects affected / exposed	0 / 3 (0.00%)	1 / 95 (1.05%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 80 (1.25%)	0 / 3 (0.00%)
occurrences all number	0	1	0	0	1	0
Injection site haematoma
subjects affected / exposed	0 / 3 (0.00%)	1 / 95 (1.05%)	0 / 3 (0.00%)	1 / 6 (16.67%)	0 / 80 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	1	0	1	0	0
Irritability
subjects affected / exposed	0 / 3 (0.00%)	1 / 95 (1.05%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 80 (1.25%)	0 / 3 (0.00%)
occurrences all number	0	1	0	0	1	0
Malaise
subjects affected / exposed	0 / 3 (0.00%)	4 / 95 (4.21%)	0 / 3 (0.00%)	0 / 6 (0.00%)	4 / 80 (5.00%)	0 / 3 (0.00%)
occurrences all number	0	6	0	0	6	0
Mass
subjects affected / exposed	0 / 3 (0.00%)	1 / 95 (1.05%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 80 (0.00%)	1 / 3 (33.33%)
occurrences all number	0	1	0	0	0	1
Mucosal inflammation
subjects affected / exposed	1 / 3 (33.33%)	4 / 95 (4.21%)	0 / 3 (0.00%)	1 / 6 (16.67%)	2 / 80 (2.50%)	0 / 3 (0.00%)
occurrences all number	1	4	0	1	2	0
Non-cardiac chest pain
subjects affected / exposed	1 / 3 (33.33%)	1 / 95 (1.05%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 80 (0.00%)	0 / 3 (0.00%)
occurrences all number	1	1	0	0	0	0
Oedema peripheral
subjects affected / exposed	1 / 3 (33.33%)	12 / 95 (12.63%)	1 / 3 (33.33%)	0 / 6 (0.00%)	9 / 80 (11.25%)	1 / 3 (33.33%)
occurrences all number	2	17	2	0	12	1
Pain
subjects affected / exposed	0 / 3 (0.00%)	4 / 95 (4.21%)	0 / 3 (0.00%)	0 / 6 (0.00%)	4 / 80 (5.00%)	0 / 3 (0.00%)
occurrences all number	0	4	0	0	4	0
Pyrexia
subjects affected / exposed	1 / 3 (33.33%)	12 / 95 (12.63%)	0 / 3 (0.00%)	0 / 6 (0.00%)	10 / 80 (12.50%)	1 / 3 (33.33%)
occurrences all number	2	15	0	0	11	2
Swelling
subjects affected / exposed	0 / 3 (0.00%)	1 / 95 (1.05%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 80 (1.25%)	0 / 3 (0.00%)
occurrences all number	0	1	0	0	1	0
Vessel puncture site haematoma
subjects affected / exposed	0 / 3 (0.00%)	1 / 95 (1.05%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 80 (1.25%)	0 / 3 (0.00%)
occurrences all number	0	1	0	0	1	0
Immune system disorders
Hypogammaglobulinaemia
subjects affected / exposed	0 / 3 (0.00%)	1 / 95 (1.05%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 80 (1.25%)	0 / 3 (0.00%)
occurrences all number	0	1	0	0	1	0
Reproductive system and breast disorders
Breast pain
subjects affected / exposed	0 / 3 (0.00%)	1 / 95 (1.05%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 80 (1.25%)	0 / 3 (0.00%)
occurrences all number	0	1	0	0	1	0
Epididymitis
subjects affected / exposed	0 / 3 (0.00%)	1 / 95 (1.05%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 80 (1.25%)	0 / 3 (0.00%)
occurrences all number	0	1	0	0	1	0
Genital pain
subjects affected / exposed	0 / 3 (0.00%)	1 / 95 (1.05%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 80 (1.25%)	0 / 3 (0.00%)
occurrences all number	0	1	0	0	1	0
Testicular cyst
subjects affected / exposed	0 / 3 (0.00%)	1 / 95 (1.05%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 80 (1.25%)	0 / 3 (0.00%)
occurrences all number	0	1	0	0	1	0
Testicular pain
subjects affected / exposed	0 / 3 (0.00%)	2 / 95 (2.11%)	0 / 3 (0.00%)	0 / 6 (0.00%)	2 / 80 (2.50%)	0 / 3 (0.00%)
occurrences all number	0	2	0	0	2	0
Respiratory, thoracic and mediastinal disorders
Atelectasis
subjects affected / exposed	0 / 3 (0.00%)	1 / 95 (1.05%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 80 (1.25%)	0 / 3 (0.00%)
occurrences all number	0	1	0	0	1	0
Cough
subjects affected / exposed	2 / 3 (66.67%)	21 / 95 (22.11%)	1 / 3 (33.33%)	1 / 6 (16.67%)	16 / 80 (20.00%)	1 / 3 (33.33%)
occurrences all number	2	29	1	1	23	2
Dry throat
subjects affected / exposed	1 / 3 (33.33%)	2 / 95 (2.11%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 80 (1.25%)	0 / 3 (0.00%)
occurrences all number	1	2	0	0	1	0
Dysphonia
subjects affected / exposed	0 / 3 (0.00%)	3 / 95 (3.16%)	0 / 3 (0.00%)	0 / 6 (0.00%)	3 / 80 (3.75%)	0 / 3 (0.00%)
occurrences all number	0	3	0	0	3	0
Dyspnoea
subjects affected / exposed	1 / 3 (33.33%)	19 / 95 (20.00%)	2 / 3 (66.67%)	1 / 6 (16.67%)	13 / 80 (16.25%)	2 / 3 (66.67%)
occurrences all number	5	25	2	2	14	2
Dyspnoea exertional
subjects affected / exposed	0 / 3 (0.00%)	6 / 95 (6.32%)	1 / 3 (33.33%)	0 / 6 (0.00%)	4 / 80 (5.00%)	1 / 3 (33.33%)
occurrences all number	0	9	2	0	6	1
Emphysema
subjects affected / exposed	0 / 3 (0.00%)	1 / 95 (1.05%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 80 (1.25%)	0 / 3 (0.00%)
occurrences all number	0	1	0	0	1	0
Epistaxis
subjects affected / exposed	0 / 3 (0.00%)	8 / 95 (8.42%)	0 / 3 (0.00%)	0 / 6 (0.00%)	8 / 80 (10.00%)	0 / 3 (0.00%)
occurrences all number	0	9	0	0	9	0
Haemoptysis
subjects affected / exposed	0 / 3 (0.00%)	1 / 95 (1.05%)	1 / 3 (33.33%)	0 / 6 (0.00%)	0 / 80 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	3	3	0	0	0
Hiccups
subjects affected / exposed	0 / 3 (0.00%)	3 / 95 (3.16%)	0 / 3 (0.00%)	0 / 6 (0.00%)	3 / 80 (3.75%)	0 / 3 (0.00%)
occurrences all number	0	3	0	0	3	0
Hypoxia
subjects affected / exposed	1 / 3 (33.33%)	1 / 95 (1.05%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 80 (0.00%)	0 / 3 (0.00%)
occurrences all number	1	1	0	0	0	0
Nasal congestion
subjects affected / exposed	0 / 3 (0.00%)	1 / 95 (1.05%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 80 (1.25%)	0 / 3 (0.00%)
occurrences all number	0	1	0	0	1	0
Oropharyngeal pain
subjects affected / exposed	1 / 3 (33.33%)	11 / 95 (11.58%)	1 / 3 (33.33%)	0 / 6 (0.00%)	9 / 80 (11.25%)	0 / 3 (0.00%)
occurrences all number	1	11	1	0	9	0
Pleural effusion
subjects affected / exposed	0 / 3 (0.00%)	1 / 95 (1.05%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 80 (1.25%)	0 / 3 (0.00%)
occurrences all number	0	1	0	0	1	0
Pneumothorax
subjects affected / exposed	0 / 3 (0.00%)	1 / 95 (1.05%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 80 (1.25%)	0 / 3 (0.00%)
occurrences all number	0	1	0	0	1	0
Productive cough
subjects affected / exposed	0 / 3 (0.00%)	6 / 95 (6.32%)	0 / 3 (0.00%)	0 / 6 (0.00%)	6 / 80 (7.50%)	0 / 3 (0.00%)
occurrences all number	0	7	0	0	7	0
Pulmonary oedema
subjects affected / exposed	0 / 3 (0.00%)	1 / 95 (1.05%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 80 (1.25%)	0 / 3 (0.00%)
occurrences all number	0	1	0	0	1	0
Rales
subjects affected / exposed	1 / 3 (33.33%)	3 / 95 (3.16%)	0 / 3 (0.00%)	0 / 6 (0.00%)	2 / 80 (2.50%)	0 / 3 (0.00%)
occurrences all number	1	3	0	0	2	0
Rhinorrhoea
subjects affected / exposed	1 / 3 (33.33%)	6 / 95 (6.32%)	0 / 3 (0.00%)	2 / 6 (33.33%)	3 / 80 (3.75%)	0 / 3 (0.00%)
occurrences all number	1	7	0	2	4	0
Sinus congestion
subjects affected / exposed	0 / 3 (0.00%)	1 / 95 (1.05%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 80 (1.25%)	0 / 3 (0.00%)
occurrences all number	0	1	0	0	1	0
Wheezing
subjects affected / exposed	1 / 3 (33.33%)	3 / 95 (3.16%)	0 / 3 (0.00%)	0 / 6 (0.00%)	2 / 80 (2.50%)	0 / 3 (0.00%)
occurrences all number	1	3	0	0	2	0
Psychiatric disorders
Abnormal dreams
subjects affected / exposed	0 / 3 (0.00%)	1 / 95 (1.05%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 80 (1.25%)	0 / 3 (0.00%)
occurrences all number	0	1	0	0	1	0
Anxiety
subjects affected / exposed	0 / 3 (0.00%)	5 / 95 (5.26%)	1 / 3 (33.33%)	0 / 6 (0.00%)	4 / 80 (5.00%)	0 / 3 (0.00%)
occurrences all number	0	5	1	0	4	0
Confusional state
subjects affected / exposed	0 / 3 (0.00%)	2 / 95 (2.11%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 80 (1.25%)	1 / 3 (33.33%)
occurrences all number	0	2	0	0	1	1
Depressed mood
subjects affected / exposed	0 / 3 (0.00%)	3 / 95 (3.16%)	0 / 3 (0.00%)	0 / 6 (0.00%)	3 / 80 (3.75%)	0 / 3 (0.00%)
occurrences all number	0	3	0	0	3	0
Depression
subjects affected / exposed	0 / 3 (0.00%)	3 / 95 (3.16%)	0 / 3 (0.00%)	0 / 6 (0.00%)	3 / 80 (3.75%)	0 / 3 (0.00%)
occurrences all number	0	3	0	0	3	0
Insomnia
subjects affected / exposed	1 / 3 (33.33%)	13 / 95 (13.68%)	0 / 3 (0.00%)	1 / 6 (16.67%)	10 / 80 (12.50%)	1 / 3 (33.33%)
occurrences all number	1	15	0	1	12	1
Libido decreased
subjects affected / exposed	0 / 3 (0.00%)	1 / 95 (1.05%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 80 (1.25%)	0 / 3 (0.00%)
occurrences all number	0	1	0	0	1	0
Mood altered
subjects affected / exposed	1 / 3 (33.33%)	2 / 95 (2.11%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 80 (1.25%)	0 / 3 (0.00%)
occurrences all number	1	2	0	0	1	0
Nightmare
subjects affected / exposed	0 / 3 (0.00%)	1 / 95 (1.05%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 80 (1.25%)	0 / 3 (0.00%)
occurrences all number	0	1	0	0	1	0
Investigations
Alanine aminotransferase increased
subjects affected / exposed	0 / 3 (0.00%)	3 / 95 (3.16%)	0 / 3 (0.00%)	0 / 6 (0.00%)	3 / 80 (3.75%)	0 / 3 (0.00%)
occurrences all number	0	3	0	0	3	0
Aspartate aminotransferase increased
subjects affected / exposed	0 / 3 (0.00%)	3 / 95 (3.16%)	0 / 3 (0.00%)	0 / 6 (0.00%)	3 / 80 (3.75%)	0 / 3 (0.00%)
occurrences all number	0	3	0	0	3	0
Blood alkaline phosphatase increased
subjects affected / exposed	0 / 3 (0.00%)	1 / 95 (1.05%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 80 (1.25%)	0 / 3 (0.00%)
occurrences all number	0	1	0	0	1	0
Blood creatinine increased
subjects affected / exposed	1 / 3 (33.33%)	3 / 95 (3.16%)	0 / 3 (0.00%)	0 / 6 (0.00%)	2 / 80 (2.50%)	0 / 3 (0.00%)
occurrences all number	1	4	0	0	3	0
Blood magnesium decreased
subjects affected / exposed	0 / 3 (0.00%)	2 / 95 (2.11%)	0 / 3 (0.00%)	0 / 6 (0.00%)	2 / 80 (2.50%)	0 / 3 (0.00%)
occurrences all number	0	2	0	0	2	0
Blood potassium decreased
subjects affected / exposed	1 / 3 (33.33%)	4 / 95 (4.21%)	0 / 3 (0.00%)	0 / 6 (0.00%)	3 / 80 (3.75%)	0 / 3 (0.00%)
occurrences all number	2	5	0	0	3	0
Blood pressure increased
subjects affected / exposed	0 / 3 (0.00%)	1 / 95 (1.05%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 80 (1.25%)	0 / 3 (0.00%)
occurrences all number	0	1	0	0	1	0
Blood sodium decreased
subjects affected / exposed	0 / 3 (0.00%)	1 / 95 (1.05%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 80 (1.25%)	0 / 3 (0.00%)
occurrences all number	0	1	0	0	1	0
Blood triglycerides increased
subjects affected / exposed	0 / 3 (0.00%)	1 / 95 (1.05%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 80 (1.25%)	0 / 3 (0.00%)
occurrences all number	0	1	0	0	1	0
Body temperature increased
subjects affected / exposed	0 / 3 (0.00%)	2 / 95 (2.11%)	0 / 3 (0.00%)	0 / 6 (0.00%)	2 / 80 (2.50%)	0 / 3 (0.00%)
occurrences all number	0	2	0	0	2	0
C-reactive protein increased
subjects affected / exposed	0 / 3 (0.00%)	1 / 95 (1.05%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 80 (1.25%)	0 / 3 (0.00%)
occurrences all number	0	1	0	0	1	0
Electrocardiogram QT prolonged
subjects affected / exposed	0 / 3 (0.00%)	3 / 95 (3.16%)	0 / 3 (0.00%)	0 / 6 (0.00%)	3 / 80 (3.75%)	0 / 3 (0.00%)
occurrences all number	0	3	0	0	3	0
Eosinophil count increased
subjects affected / exposed	0 / 3 (0.00%)	1 / 95 (1.05%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 80 (1.25%)	0 / 3 (0.00%)
occurrences all number	0	1	0	0	1	0
Gamma-glutamyltransferase increased
subjects affected / exposed	0 / 3 (0.00%)	1 / 95 (1.05%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 80 (1.25%)	0 / 3 (0.00%)
occurrences all number	0	1	0	0	1	0
Haemoglobin decreased
subjects affected / exposed	0 / 3 (0.00%)	2 / 95 (2.11%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 80 (1.25%)	1 / 3 (33.33%)
occurrences all number	0	3	0	0	1	2
Heart rate decreased
subjects affected / exposed	0 / 3 (0.00%)	1 / 95 (1.05%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 80 (1.25%)	0 / 3 (0.00%)
occurrences all number	0	1	0	0	1	0
Neutrophil count decreased
subjects affected / exposed	0 / 3 (0.00%)	5 / 95 (5.26%)	0 / 3 (0.00%)	0 / 6 (0.00%)	4 / 80 (5.00%)	1 / 3 (33.33%)
occurrences all number	0	11	0	0	10	1
Neutrophil count increased
subjects affected / exposed	0 / 3 (0.00%)	1 / 95 (1.05%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 80 (1.25%)	0 / 3 (0.00%)
occurrences all number	0	1	0	0	1	0
Platelet count decreased
subjects affected / exposed	0 / 3 (0.00%)	3 / 95 (3.16%)	0 / 3 (0.00%)	0 / 6 (0.00%)	3 / 80 (3.75%)	0 / 3 (0.00%)
occurrences all number	0	5	0	0	5	0
Protein total increased
subjects affected / exposed	0 / 3 (0.00%)	1 / 95 (1.05%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 80 (1.25%)	0 / 3 (0.00%)
occurrences all number	0	1	0	0	1	0
Weight decreased
subjects affected / exposed	1 / 3 (33.33%)	9 / 95 (9.47%)	0 / 3 (0.00%)	1 / 6 (16.67%)	7 / 80 (8.75%)	0 / 3 (0.00%)
occurrences all number	1	10	0	2	7	0
Weight increased
subjects affected / exposed	0 / 3 (0.00%)	1 / 95 (1.05%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 80 (1.25%)	0 / 3 (0.00%)
occurrences all number	0	1	0	0	1	0
White blood cell count decreased
subjects affected / exposed	0 / 3 (0.00%)	1 / 95 (1.05%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 80 (1.25%)	0 / 3 (0.00%)
occurrences all number	0	1	0	0	1	0
Injury, poisoning and procedural complications
Clavicle fracture
subjects affected / exposed	0 / 3 (0.00%)	1 / 95 (1.05%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 80 (1.25%)	0 / 3 (0.00%)
occurrences all number	0	1	0	0	1	0
Contusion
subjects affected / exposed	0 / 3 (0.00%)	4 / 95 (4.21%)	0 / 3 (0.00%)	0 / 6 (0.00%)	4 / 80 (5.00%)	0 / 3 (0.00%)
occurrences all number	0	4	0	0	4	0
Fall
subjects affected / exposed	0 / 3 (0.00%)	1 / 95 (1.05%)	0 / 3 (0.00%)	1 / 6 (16.67%)	0 / 80 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	1	0	1	0	0
Human bite
subjects affected / exposed	0 / 3 (0.00%)	1 / 95 (1.05%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 80 (1.25%)	0 / 3 (0.00%)
occurrences all number	0	1	0	0	1	0
Medical device site reaction
subjects affected / exposed	0 / 3 (0.00%)	1 / 95 (1.05%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 80 (1.25%)	0 / 3 (0.00%)
occurrences all number	0	1	0	0	1	0
Narcotic intoxication
subjects affected / exposed	0 / 3 (0.00%)	1 / 95 (1.05%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 80 (0.00%)	1 / 3 (33.33%)
occurrences all number	0	1	0	0	0	1
Post-traumatic pain
subjects affected / exposed	0 / 3 (0.00%)	1 / 95 (1.05%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 80 (1.25%)	0 / 3 (0.00%)
occurrences all number	0	1	0	0	1	0
Procedural pain
subjects affected / exposed	0 / 3 (0.00%)	1 / 95 (1.05%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 80 (1.25%)	0 / 3 (0.00%)
occurrences all number	0	1	0	0	1	0
Rib fracture
subjects affected / exposed	0 / 3 (0.00%)	1 / 95 (1.05%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 80 (1.25%)	0 / 3 (0.00%)
occurrences all number	0	1	0	0	1	0
Road traffic accident
subjects affected / exposed	0 / 3 (0.00%)	1 / 95 (1.05%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 80 (1.25%)	0 / 3 (0.00%)
occurrences all number	0	1	0	0	1	0
Thermal burn
subjects affected / exposed	0 / 3 (0.00%)	1 / 95 (1.05%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 80 (1.25%)	0 / 3 (0.00%)
occurrences all number	0	1	0	0	1	0
Tooth fracture
subjects affected / exposed	0 / 3 (0.00%)	1 / 95 (1.05%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 80 (1.25%)	0 / 3 (0.00%)
occurrences all number	0	1	0	0	1	0
Cardiac disorders
Angina pectoris
subjects affected / exposed	0 / 3 (0.00%)	1 / 95 (1.05%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 80 (1.25%)	0 / 3 (0.00%)
occurrences all number	0	1	0	0	1	0
Extrasystoles
subjects affected / exposed	0 / 3 (0.00%)	1 / 95 (1.05%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 80 (1.25%)	0 / 3 (0.00%)
occurrences all number	0	1	0	0	1	0
Palpitations
subjects affected / exposed	0 / 3 (0.00%)	1 / 95 (1.05%)	0 / 3 (0.00%)	1 / 6 (16.67%)	0 / 80 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	1	0	1	0	0
Tachycardia
subjects affected / exposed	0 / 3 (0.00%)	2 / 95 (2.11%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 80 (1.25%)	1 / 3 (33.33%)
occurrences all number	0	4	0	0	1	3
Ventricular extrasystoles
subjects affected / exposed	0 / 3 (0.00%)	1 / 95 (1.05%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 80 (1.25%)	0 / 3 (0.00%)
occurrences all number	0	2	0	0	2	0
Nervous system disorders
Ageusia
subjects affected / exposed	0 / 3 (0.00%)	1 / 95 (1.05%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 80 (1.25%)	0 / 3 (0.00%)
occurrences all number	0	1	0	0	1	0
Areflexia
subjects affected / exposed	0 / 3 (0.00%)	1 / 95 (1.05%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 80 (1.25%)	0 / 3 (0.00%)
occurrences all number	0	1	0	0	1	0
Balance disorder
subjects affected / exposed	0 / 3 (0.00%)	2 / 95 (2.11%)	0 / 3 (0.00%)	1 / 6 (16.67%)	1 / 80 (1.25%)	0 / 3 (0.00%)
occurrences all number	0	2	0	1	1	0
Burning sensation
subjects affected / exposed	0 / 3 (0.00%)	3 / 95 (3.16%)	0 / 3 (0.00%)	0 / 6 (0.00%)	3 / 80 (3.75%)	0 / 3 (0.00%)
occurrences all number	0	3	0	0	3	0
Depressed level of consciousness
subjects affected / exposed	1 / 3 (33.33%)	1 / 95 (1.05%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 80 (0.00%)	0 / 3 (0.00%)
occurrences all number	1	1	0	0	0	0
Dizziness
subjects affected / exposed	0 / 3 (0.00%)	25 / 95 (26.32%)	3 / 3 (100.00%)	3 / 6 (50.00%)	18 / 80 (22.50%)	1 / 3 (33.33%)
occurrences all number	0	33	8	3	21	1
Dizziness exertional
subjects affected / exposed	0 / 3 (0.00%)	2 / 95 (2.11%)	0 / 3 (0.00%)	0 / 6 (0.00%)	2 / 80 (2.50%)	0 / 3 (0.00%)
occurrences all number	0	2	0	0	2	0
Dysgeusia
subjects affected / exposed	1 / 3 (33.33%)	13 / 95 (13.68%)	2 / 3 (66.67%)	0 / 6 (0.00%)	10 / 80 (12.50%)	0 / 3 (0.00%)
occurrences all number	1	13	2	0	10	0
Head discomfort
subjects affected / exposed	0 / 3 (0.00%)	1 / 95 (1.05%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 80 (1.25%)	0 / 3 (0.00%)
occurrences all number	0	1	0	0	1	0
Headache
subjects affected / exposed	0 / 3 (0.00%)	23 / 95 (24.21%)	1 / 3 (33.33%)	2 / 6 (33.33%)	20 / 80 (25.00%)	0 / 3 (0.00%)
occurrences all number	0	41	1	2	38	0
Hyperaesthesia
subjects affected / exposed	0 / 3 (0.00%)	1 / 95 (1.05%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 80 (1.25%)	0 / 3 (0.00%)
occurrences all number	0	1	0	0	1	0
Hyperreflexia
subjects affected / exposed	0 / 3 (0.00%)	1 / 95 (1.05%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 80 (1.25%)	0 / 3 (0.00%)
occurrences all number	0	1	0	0	1	0
Hypoaesthesia
subjects affected / exposed	2 / 3 (66.67%)	8 / 95 (8.42%)	0 / 3 (0.00%)	1 / 6 (16.67%)	5 / 80 (6.25%)	0 / 3 (0.00%)
occurrences all number	3	11	0	1	7	0
Hypogeusia
subjects affected / exposed	0 / 3 (0.00%)	1 / 95 (1.05%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 80 (1.25%)	0 / 3 (0.00%)
occurrences all number	0	1	0	0	1	0
Hyporeflexia
subjects affected / exposed	1 / 3 (33.33%)	2 / 95 (2.11%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 80 (1.25%)	0 / 3 (0.00%)
occurrences all number	2	3	0	0	1	0
Lethargy
subjects affected / exposed	0 / 3 (0.00%)	6 / 95 (6.32%)	0 / 3 (0.00%)	0 / 6 (0.00%)	6 / 80 (7.50%)	0 / 3 (0.00%)
occurrences all number	0	8	0	0	8	0
Memory impairment
subjects affected / exposed	0 / 3 (0.00%)	1 / 95 (1.05%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 80 (1.25%)	0 / 3 (0.00%)
occurrences all number	0	1	0	0	1	0
Neuralgia
subjects affected / exposed	0 / 3 (0.00%)	8 / 95 (8.42%)	0 / 3 (0.00%)	0 / 6 (0.00%)	8 / 80 (10.00%)	0 / 3 (0.00%)
occurrences all number	0	13	0	0	13	0
Neuropathy peripheral
subjects affected / exposed	2 / 3 (66.67%)	28 / 95 (29.47%)	1 / 3 (33.33%)	0 / 6 (0.00%)	24 / 80 (30.00%)	1 / 3 (33.33%)
occurrences all number	3	48	1	0	42	2
Paraesthesia
subjects affected / exposed	2 / 3 (66.67%)	11 / 95 (11.58%)	0 / 3 (0.00%)	1 / 6 (16.67%)	7 / 80 (8.75%)	1 / 3 (33.33%)
occurrences all number	5	17	0	1	9	2
Peripheral sensory neuropathy
subjects affected / exposed	0 / 3 (0.00%)	15 / 95 (15.79%)	1 / 3 (33.33%)	0 / 6 (0.00%)	14 / 80 (17.50%)	0 / 3 (0.00%)
occurrences all number	0	36	1	0	35	0
Presyncope
subjects affected / exposed	0 / 3 (0.00%)	3 / 95 (3.16%)	0 / 3 (0.00%)	0 / 6 (0.00%)	3 / 80 (3.75%)	0 / 3 (0.00%)
occurrences all number	0	4	0	0	4	0
Sensory loss
subjects affected / exposed	1 / 3 (33.33%)	2 / 95 (2.11%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 80 (0.00%)	1 / 3 (33.33%)
occurrences all number	2	3	0	0	0	1
Somnolence
subjects affected / exposed	0 / 3 (0.00%)	1 / 95 (1.05%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 80 (1.25%)	0 / 3 (0.00%)
occurrences all number	0	1	0	0	1	0
Syncope
subjects affected / exposed	0 / 3 (0.00%)	3 / 95 (3.16%)	2 / 3 (66.67%)	0 / 6 (0.00%)	1 / 80 (1.25%)	0 / 3 (0.00%)
occurrences all number	0	4	3	0	1	0
Tremor
subjects affected / exposed	0 / 3 (0.00%)	2 / 95 (2.11%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 80 (1.25%)	1 / 3 (33.33%)
occurrences all number	0	2	0	0	1	1
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	0 / 3 (0.00%)	17 / 95 (17.89%)	0 / 3 (0.00%)	1 / 6 (16.67%)	14 / 80 (17.50%)	2 / 3 (66.67%)
occurrences all number	0	30	0	1	27	2
Febrile neutropenia
subjects affected / exposed	0 / 3 (0.00%)	2 / 95 (2.11%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 80 (1.25%)	1 / 3 (33.33%)
occurrences all number	0	2	0	0	1	1
Leukocytosis
subjects affected / exposed	0 / 3 (0.00%)	2 / 95 (2.11%)	0 / 3 (0.00%)	0 / 6 (0.00%)	2 / 80 (2.50%)	0 / 3 (0.00%)
occurrences all number	0	2	0	0	2	0
Leukopenia
subjects affected / exposed	0 / 3 (0.00%)	1 / 95 (1.05%)	0 / 3 (0.00%)	1 / 6 (16.67%)	0 / 80 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	1	0	1	0	0
Neutropenia
subjects affected / exposed	1 / 3 (33.33%)	15 / 95 (15.79%)	0 / 3 (0.00%)	0 / 6 (0.00%)	14 / 80 (17.50%)	0 / 3 (0.00%)
occurrences all number	1	37	0	0	36	0
Thrombocytopenia
subjects affected / exposed	0 / 3 (0.00%)	19 / 95 (20.00%)	0 / 3 (0.00%)	2 / 6 (33.33%)	17 / 80 (21.25%)	0 / 3 (0.00%)
occurrences all number	0	41	0	2	39	0
Ear and labyrinth disorders
Cerumen impaction
subjects affected / exposed	0 / 3 (0.00%)	1 / 95 (1.05%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 80 (1.25%)	0 / 3 (0.00%)
occurrences all number	0	1	0	0	1	0
Ear discomfort
subjects affected / exposed	0 / 3 (0.00%)	1 / 95 (1.05%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 80 (1.25%)	0 / 3 (0.00%)
occurrences all number	0	1	0	0	1	0
Ear pain
subjects affected / exposed	0 / 3 (0.00%)	1 / 95 (1.05%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 80 (1.25%)	0 / 3 (0.00%)
occurrences all number	0	1	0	0	1	0
Tinnitus
subjects affected / exposed	0 / 3 (0.00%)	1 / 95 (1.05%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 80 (1.25%)	0 / 3 (0.00%)
occurrences all number	0	1	0	0	1	0
Vertigo
subjects affected / exposed	1 / 3 (33.33%)	1 / 95 (1.05%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 80 (0.00%)	0 / 3 (0.00%)
occurrences all number	1	1	0	0	0	0
Eye disorders
Abnormal sensation in eye
subjects affected / exposed	0 / 3 (0.00%)	1 / 95 (1.05%)	1 / 3 (33.33%)	0 / 6 (0.00%)	0 / 80 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	1	1	0	0	0
Blepharitis
subjects affected / exposed	0 / 3 (0.00%)	1 / 95 (1.05%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 80 (1.25%)	0 / 3 (0.00%)
occurrences all number	0	1	0	0	1	0
Conjunctival hyperaemia
subjects affected / exposed	0 / 3 (0.00%)	1 / 95 (1.05%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 80 (1.25%)	0 / 3 (0.00%)
occurrences all number	0	1	0	0	1	0
Conjunctivitis
subjects affected / exposed	0 / 3 (0.00%)	4 / 95 (4.21%)	0 / 3 (0.00%)	0 / 6 (0.00%)	4 / 80 (5.00%)	0 / 3 (0.00%)
occurrences all number	0	4	0	0	4	0
Diplopia
subjects affected / exposed	0 / 3 (0.00%)	1 / 95 (1.05%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 80 (1.25%)	0 / 3 (0.00%)
occurrences all number	0	1	0	0	1	0
Dry eye
subjects affected / exposed	0 / 3 (0.00%)	4 / 95 (4.21%)	1 / 3 (33.33%)	0 / 6 (0.00%)	3 / 80 (3.75%)	0 / 3 (0.00%)
occurrences all number	0	4	1	0	3	0
Erythema of eyelid
subjects affected / exposed	0 / 3 (0.00%)	2 / 95 (2.11%)	0 / 3 (0.00%)	0 / 6 (0.00%)	2 / 80 (2.50%)	0 / 3 (0.00%)
occurrences all number	0	2	0	0	2	0
Eye discharge
subjects affected / exposed	0 / 3 (0.00%)	3 / 95 (3.16%)	1 / 3 (33.33%)	1 / 6 (16.67%)	1 / 80 (1.25%)	0 / 3 (0.00%)
occurrences all number	0	3	1	1	1	0
Eye irritation
subjects affected / exposed	0 / 3 (0.00%)	1 / 95 (1.05%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 80 (1.25%)	0 / 3 (0.00%)
occurrences all number	0	1	0	0	1	0
Eye pain
subjects affected / exposed	0 / 3 (0.00%)	4 / 95 (4.21%)	0 / 3 (0.00%)	0 / 6 (0.00%)	4 / 80 (5.00%)	0 / 3 (0.00%)
occurrences all number	0	4	0	0	4	0
Eye pruritus
subjects affected / exposed	0 / 3 (0.00%)	2 / 95 (2.11%)	1 / 3 (33.33%)	0 / 6 (0.00%)	1 / 80 (1.25%)	0 / 3 (0.00%)
occurrences all number	0	2	1	0	1	0
Eye swelling
subjects affected / exposed	0 / 3 (0.00%)	1 / 95 (1.05%)	0 / 3 (0.00%)	1 / 6 (16.67%)	0 / 80 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	1	0	1	0	0
Eyelid disorder
subjects affected / exposed	0 / 3 (0.00%)	1 / 95 (1.05%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 80 (1.25%)	0 / 3 (0.00%)
occurrences all number	0	1	0	0	1	0
Eyelid oedema
subjects affected / exposed	0 / 3 (0.00%)	1 / 95 (1.05%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 80 (1.25%)	0 / 3 (0.00%)
occurrences all number	0	1	0	0	1	0
Eyelids pruritus
subjects affected / exposed	0 / 3 (0.00%)	3 / 95 (3.16%)	0 / 3 (0.00%)	0 / 6 (0.00%)	3 / 80 (3.75%)	0 / 3 (0.00%)
occurrences all number	0	3	0	0	3	0
Foreign body sensation in eyes
subjects affected / exposed	0 / 3 (0.00%)	3 / 95 (3.16%)	0 / 3 (0.00%)	0 / 6 (0.00%)	2 / 80 (2.50%)	1 / 3 (33.33%)
occurrences all number	0	3	0	0	2	1
Lacrimation increased
subjects affected / exposed	0 / 3 (0.00%)	12 / 95 (12.63%)	1 / 3 (33.33%)	1 / 6 (16.67%)	8 / 80 (10.00%)	2 / 3 (66.67%)
occurrences all number	0	15	1	1	10	3
Macular degeneration
subjects affected / exposed	0 / 3 (0.00%)	1 / 95 (1.05%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 80 (1.25%)	0 / 3 (0.00%)
occurrences all number	0	1	0	0	1	0
Metamorphopsia
subjects affected / exposed	0 / 3 (0.00%)	1 / 95 (1.05%)	0 / 3 (0.00%)	1 / 6 (16.67%)	0 / 80 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	1	0	1	0	0
Ocular hyperaemia
subjects affected / exposed	0 / 3 (0.00%)	2 / 95 (2.11%)	1 / 3 (33.33%)	0 / 6 (0.00%)	1 / 80 (1.25%)	0 / 3 (0.00%)
occurrences all number	0	2	1	0	1	0
Photophobia
subjects affected / exposed	0 / 3 (0.00%)	1 / 95 (1.05%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 80 (1.25%)	0 / 3 (0.00%)
occurrences all number	0	2	0	0	2	0
Retinal disorder
subjects affected / exposed	0 / 3 (0.00%)	1 / 95 (1.05%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 80 (1.25%)	0 / 3 (0.00%)
occurrences all number	0	1	0	0	1	0
Vision blurred
subjects affected / exposed	0 / 3 (0.00%)	16 / 95 (16.84%)	1 / 3 (33.33%)	2 / 6 (33.33%)	12 / 80 (15.00%)	1 / 3 (33.33%)
occurrences all number	0	19	1	2	15	1
Visual acuity reduced
subjects affected / exposed	1 / 3 (33.33%)	4 / 95 (4.21%)	0 / 3 (0.00%)	0 / 6 (0.00%)	3 / 80 (3.75%)	0 / 3 (0.00%)
occurrences all number	1	5	0	0	4	0
Gastrointestinal disorders
Abdominal discomfort
subjects affected / exposed	0 / 3 (0.00%)	5 / 95 (5.26%)	0 / 3 (0.00%)	0 / 6 (0.00%)	5 / 80 (6.25%)	0 / 3 (0.00%)
occurrences all number	0	5	0	0	5	0
Abdominal distension
subjects affected / exposed	0 / 3 (0.00%)	13 / 95 (13.68%)	2 / 3 (66.67%)	0 / 6 (0.00%)	9 / 80 (11.25%)	2 / 3 (66.67%)
occurrences all number	0	19	6	0	11	2
Abdominal pain
subjects affected / exposed	0 / 3 (0.00%)	17 / 95 (17.89%)	2 / 3 (66.67%)	1 / 6 (16.67%)	13 / 80 (16.25%)	1 / 3 (33.33%)
occurrences all number	0	31	5	4	21	1
Abdominal pain lower
subjects affected / exposed	0 / 3 (0.00%)	1 / 95 (1.05%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 80 (1.25%)	0 / 3 (0.00%)
occurrences all number	0	1	0	0	1	0
Abdominal pain upper
subjects affected / exposed	0 / 3 (0.00%)	11 / 95 (11.58%)	3 / 3 (100.00%)	0 / 6 (0.00%)	8 / 80 (10.00%)	0 / 3 (0.00%)
occurrences all number	0	12	3	0	9	0
Abdominal tenderness
subjects affected / exposed	0 / 3 (0.00%)	1 / 95 (1.05%)	0 / 3 (0.00%)	1 / 6 (16.67%)	0 / 80 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	1	0	1	0	0
Anal haemorrhage
subjects affected / exposed	0 / 3 (0.00%)	1 / 95 (1.05%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 80 (1.25%)	0 / 3 (0.00%)
occurrences all number	0	1	0	0	1	0
Constipation
subjects affected / exposed	2 / 3 (66.67%)	42 / 95 (44.21%)	3 / 3 (100.00%)	2 / 6 (33.33%)	33 / 80 (41.25%)	2 / 3 (66.67%)
occurrences all number	4	71	8	3	54	2
Diarrhoea
subjects affected / exposed	2 / 3 (66.67%)	70 / 95 (73.68%)	3 / 3 (100.00%)	4 / 6 (66.67%)	58 / 80 (72.50%)	3 / 3 (100.00%)
occurrences all number	9	199	29	6	148	7
Dry mouth
subjects affected / exposed	1 / 3 (33.33%)	7 / 95 (7.37%)	0 / 3 (0.00%)	0 / 6 (0.00%)	6 / 80 (7.50%)	0 / 3 (0.00%)
occurrences all number	1	7	0	0	6	0
Dyspepsia
subjects affected / exposed	0 / 3 (0.00%)	13 / 95 (13.68%)	2 / 3 (66.67%)	0 / 6 (0.00%)	10 / 80 (12.50%)	1 / 3 (33.33%)
occurrences all number	0	20	3	0	16	1
Dysphagia
subjects affected / exposed	1 / 3 (33.33%)	1 / 95 (1.05%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 80 (0.00%)	0 / 3 (0.00%)
occurrences all number	1	1	0	0	0	0
Flatulence
subjects affected / exposed	0 / 3 (0.00%)	3 / 95 (3.16%)	1 / 3 (33.33%)	1 / 6 (16.67%)	1 / 80 (1.25%)	0 / 3 (0.00%)
occurrences all number	0	5	3	1	1	0
Frequent bowel movements
subjects affected / exposed	0 / 3 (0.00%)	1 / 95 (1.05%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 80 (1.25%)	0 / 3 (0.00%)
occurrences all number	0	1	0	0	1	0
Gastritis
subjects affected / exposed	0 / 3 (0.00%)	1 / 95 (1.05%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 80 (1.25%)	0 / 3 (0.00%)
occurrences all number	0	2	0	0	2	0
Gastrointestinal hypermotility
subjects affected / exposed	0 / 3 (0.00%)	1 / 95 (1.05%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 80 (1.25%)	0 / 3 (0.00%)
occurrences all number	0	1	0	0	1	0
Gastrooesophageal reflux disease
subjects affected / exposed	0 / 3 (0.00%)	3 / 95 (3.16%)	0 / 3 (0.00%)	0 / 6 (0.00%)	2 / 80 (2.50%)	1 / 3 (33.33%)
occurrences all number	0	3	0	0	2	1
Gingival pain
subjects affected / exposed	0 / 3 (0.00%)	1 / 95 (1.05%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 80 (1.25%)	0 / 3 (0.00%)
occurrences all number	0	1	0	0	1	0
Gingivitis
subjects affected / exposed	0 / 3 (0.00%)	1 / 95 (1.05%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 80 (1.25%)	0 / 3 (0.00%)
occurrences all number	0	1	0	0	1	0
Glossodynia
subjects affected / exposed	0 / 3 (0.00%)	2 / 95 (2.11%)	0 / 3 (0.00%)	0 / 6 (0.00%)	2 / 80 (2.50%)	0 / 3 (0.00%)
occurrences all number	0	2	0	0	2	0
Haematochezia
subjects affected / exposed	0 / 3 (0.00%)	1 / 95 (1.05%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 80 (1.25%)	0 / 3 (0.00%)
occurrences all number	0	3	0	0	3	0
Haemorrhoids
subjects affected / exposed	0 / 3 (0.00%)	1 / 95 (1.05%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 80 (1.25%)	0 / 3 (0.00%)
occurrences all number	0	1	0	0	1	0
Irritable bowel syndrome
subjects affected / exposed	0 / 3 (0.00%)	1 / 95 (1.05%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 80 (1.25%)	0 / 3 (0.00%)
occurrences all number	0	1	0	0	1	0
Mouth ulceration
subjects affected / exposed	0 / 3 (0.00%)	1 / 95 (1.05%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 80 (1.25%)	0 / 3 (0.00%)
occurrences all number	0	1	0	0	1	0
Nausea
subjects affected / exposed	1 / 3 (33.33%)	55 / 95 (57.89%)	3 / 3 (100.00%)	5 / 6 (83.33%)	45 / 80 (56.25%)	1 / 3 (33.33%)
occurrences all number	2	114	11	6	93	2
Oral pain
subjects affected / exposed	0 / 3 (0.00%)	2 / 95 (2.11%)	0 / 3 (0.00%)	0 / 6 (0.00%)	2 / 80 (2.50%)	0 / 3 (0.00%)
occurrences all number	0	2	0	0	2	0
Pneumatosis intestinalis
subjects affected / exposed	0 / 3 (0.00%)	1 / 95 (1.05%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 80 (1.25%)	0 / 3 (0.00%)
occurrences all number	0	1	0	0	1	0
Proctalgia
subjects affected / exposed	0 / 3 (0.00%)	1 / 95 (1.05%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 80 (1.25%)	0 / 3 (0.00%)
occurrences all number	0	1	0	0	1	0
Rectal haemorrhage
subjects affected / exposed	0 / 3 (0.00%)	1 / 95 (1.05%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 80 (1.25%)	0 / 3 (0.00%)
occurrences all number	0	1	0	0	1	0
Tongue coated
subjects affected / exposed	0 / 3 (0.00%)	1 / 95 (1.05%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 80 (1.25%)	0 / 3 (0.00%)
occurrences all number	0	1	0	0	1	0
Toothache
subjects affected / exposed	0 / 3 (0.00%)	1 / 95 (1.05%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 80 (1.25%)	0 / 3 (0.00%)
occurrences all number	0	1	0	0	1	0
Vomiting
subjects affected / exposed	1 / 3 (33.33%)	38 / 95 (40.00%)	1 / 3 (33.33%)	0 / 6 (0.00%)	35 / 80 (43.75%)	1 / 3 (33.33%)
occurrences all number	3	72	1	0	67	1
Skin and subcutaneous tissue disorders
Acne
subjects affected / exposed	0 / 3 (0.00%)	1 / 95 (1.05%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 80 (1.25%)	0 / 3 (0.00%)
occurrences all number	0	1	0	0	1	0
Alopecia
subjects affected / exposed	0 / 3 (0.00%)	1 / 95 (1.05%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 80 (1.25%)	0 / 3 (0.00%)
occurrences all number	0	1	0	0	1	0
Dermatitis allergic
subjects affected / exposed	0 / 3 (0.00%)	1 / 95 (1.05%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 80 (0.00%)	1 / 3 (33.33%)
occurrences all number	0	1	0	0	0	1
Dry skin
subjects affected / exposed	1 / 3 (33.33%)	7 / 95 (7.37%)	0 / 3 (0.00%)	0 / 6 (0.00%)	5 / 80 (6.25%)	1 / 3 (33.33%)
occurrences all number	1	7	0	0	5	1
Ecchymosis
subjects affected / exposed	0 / 3 (0.00%)	1 / 95 (1.05%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 80 (1.25%)	0 / 3 (0.00%)
occurrences all number	0	1	0	0	1	0
Erythema
subjects affected / exposed	0 / 3 (0.00%)	4 / 95 (4.21%)	0 / 3 (0.00%)	0 / 6 (0.00%)	3 / 80 (3.75%)	1 / 3 (33.33%)
occurrences all number	0	5	0	0	4	1
Exfoliative rash
subjects affected / exposed	0 / 3 (0.00%)	1 / 95 (1.05%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 80 (1.25%)	0 / 3 (0.00%)
occurrences all number	0	1	0	0	1	0
Hyperhidrosis
subjects affected / exposed	0 / 3 (0.00%)	1 / 95 (1.05%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 80 (1.25%)	0 / 3 (0.00%)
occurrences all number	0	1	0	0	1	0
Ingrowing nail
subjects affected / exposed	0 / 3 (0.00%)	1 / 95 (1.05%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 80 (1.25%)	0 / 3 (0.00%)
occurrences all number	0	1	0	0	1	0
Night sweats
subjects affected / exposed	0 / 3 (0.00%)	1 / 95 (1.05%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 80 (1.25%)	0 / 3 (0.00%)
occurrences all number	0	1	0	0	1	0
Pain of skin
subjects affected / exposed	0 / 3 (0.00%)	1 / 95 (1.05%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 80 (0.00%)	1 / 3 (33.33%)
occurrences all number	0	1	0	0	0	1
Pruritus
subjects affected / exposed	1 / 3 (33.33%)	8 / 95 (8.42%)	0 / 3 (0.00%)	0 / 6 (0.00%)	7 / 80 (8.75%)	0 / 3 (0.00%)
occurrences all number	1	9	0	0	8	0
Pruritus generalised
subjects affected / exposed	0 / 3 (0.00%)	1 / 95 (1.05%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 80 (1.25%)	0 / 3 (0.00%)
occurrences all number	0	1	0	0	1	0
Purpura
subjects affected / exposed	0 / 3 (0.00%)	1 / 95 (1.05%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 80 (1.25%)	0 / 3 (0.00%)
occurrences all number	0	1	0	0	1	0
Rash
subjects affected / exposed	0 / 3 (0.00%)	13 / 95 (13.68%)	0 / 3 (0.00%)	2 / 6 (33.33%)	11 / 80 (13.75%)	0 / 3 (0.00%)
occurrences all number	0	17	0	5	12	0
Rash erythematous
subjects affected / exposed	0 / 3 (0.00%)	4 / 95 (4.21%)	1 / 3 (33.33%)	0 / 6 (0.00%)	3 / 80 (3.75%)	0 / 3 (0.00%)
occurrences all number	0	4	1	0	3	0
Rash macular
subjects affected / exposed	0 / 3 (0.00%)	1 / 95 (1.05%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 80 (1.25%)	0 / 3 (0.00%)
occurrences all number	0	1	0	0	1	0
Rash maculo-papular
subjects affected / exposed	0 / 3 (0.00%)	1 / 95 (1.05%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 80 (1.25%)	0 / 3 (0.00%)
occurrences all number	0	1	0	0	1	0
Rash papular
subjects affected / exposed	0 / 3 (0.00%)	1 / 95 (1.05%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 80 (1.25%)	0 / 3 (0.00%)
occurrences all number	0	1	0	0	1	0
Rash pruritic
subjects affected / exposed	0 / 3 (0.00%)	2 / 95 (2.11%)	0 / 3 (0.00%)	0 / 6 (0.00%)	2 / 80 (2.50%)	0 / 3 (0.00%)
occurrences all number	0	2	0	0	2	0
Skin disorder
subjects affected / exposed	0 / 3 (0.00%)	1 / 95 (1.05%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 80 (1.25%)	0 / 3 (0.00%)
occurrences all number	0	1	0	0	1	0
Skin lesion
subjects affected / exposed	0 / 3 (0.00%)	1 / 95 (1.05%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 80 (1.25%)	0 / 3 (0.00%)
occurrences all number	0	2	0	0	2	0
Subcutaneous nodule
subjects affected / exposed	0 / 3 (0.00%)	1 / 95 (1.05%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 80 (1.25%)	0 / 3 (0.00%)
occurrences all number	0	1	0	0	1	0
Telangiectasia
subjects affected / exposed	1 / 3 (33.33%)	1 / 95 (1.05%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 80 (0.00%)	0 / 3 (0.00%)
occurrences all number	1	1	0	0	0	0
Renal and urinary disorders
Dysuria
subjects affected / exposed	0 / 3 (0.00%)	2 / 95 (2.11%)	0 / 3 (0.00%)	0 / 6 (0.00%)	2 / 80 (2.50%)	0 / 3 (0.00%)
occurrences all number	0	3	0	0	3	0
Haematuria
subjects affected / exposed	0 / 3 (0.00%)	1 / 95 (1.05%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 80 (1.25%)	0 / 3 (0.00%)
occurrences all number	0	2	0	0	2	0
Pollakiuria
subjects affected / exposed	0 / 3 (0.00%)	2 / 95 (2.11%)	0 / 3 (0.00%)	0 / 6 (0.00%)	2 / 80 (2.50%)	0 / 3 (0.00%)
occurrences all number	0	3	0	0	3	0
Proteinuria
subjects affected / exposed	0 / 3 (0.00%)	1 / 95 (1.05%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 80 (1.25%)	0 / 3 (0.00%)
occurrences all number	0	1	0	0	1	0
Renal failure
subjects affected / exposed	0 / 3 (0.00%)	1 / 95 (1.05%)	0 / 3 (0.00%)	1 / 6 (16.67%)	0 / 80 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	2	0	2	0	0
Renal impairment
subjects affected / exposed	1 / 3 (33.33%)	3 / 95 (3.16%)	0 / 3 (0.00%)	0 / 6 (0.00%)	2 / 80 (2.50%)	0 / 3 (0.00%)
occurrences all number	1	4	0	0	3	0
Musculoskeletal and connective tissue disorders
Arthralgia
subjects affected / exposed	0 / 3 (0.00%)	12 / 95 (12.63%)	0 / 3 (0.00%)	0 / 6 (0.00%)	11 / 80 (13.75%)	1 / 3 (33.33%)
occurrences all number	0	15	0	0	14	1
Back pain
subjects affected / exposed	1 / 3 (33.33%)	12 / 95 (12.63%)	0 / 3 (0.00%)	1 / 6 (16.67%)	10 / 80 (12.50%)	0 / 3 (0.00%)
occurrences all number	1	13	0	1	11	0
Bone disorder
subjects affected / exposed	0 / 3 (0.00%)	1 / 95 (1.05%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 80 (1.25%)	0 / 3 (0.00%)
occurrences all number	0	3	0	0	3	0
Bone pain
subjects affected / exposed	0 / 3 (0.00%)	5 / 95 (5.26%)	0 / 3 (0.00%)	0 / 6 (0.00%)	4 / 80 (5.00%)	1 / 3 (33.33%)
occurrences all number	0	6	0	0	4	2
Coccydynia
subjects affected / exposed	0 / 3 (0.00%)	1 / 95 (1.05%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 80 (1.25%)	0 / 3 (0.00%)
occurrences all number	0	1	0	0	1	0
Dactylitis
subjects affected / exposed	0 / 3 (0.00%)	1 / 95 (1.05%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 80 (1.25%)	0 / 3 (0.00%)
occurrences all number	0	1	0	0	1	0
Fasciitis
subjects affected / exposed	0 / 3 (0.00%)	1 / 95 (1.05%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 80 (1.25%)	0 / 3 (0.00%)
occurrences all number	0	1	0	0	1	0
Flank pain
subjects affected / exposed	0 / 3 (0.00%)	1 / 95 (1.05%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 80 (1.25%)	0 / 3 (0.00%)
occurrences all number	0	1	0	0	1	0
Groin pain
subjects affected / exposed	1 / 3 (33.33%)	1 / 95 (1.05%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 80 (0.00%)	0 / 3 (0.00%)
occurrences all number	1	1	0	0	0	0
Joint range of motion decreased
subjects affected / exposed	0 / 3 (0.00%)	1 / 95 (1.05%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 80 (1.25%)	0 / 3 (0.00%)
occurrences all number	0	1	0	0	1	0
Joint stiffness
subjects affected / exposed	0 / 3 (0.00%)	1 / 95 (1.05%)	1 / 3 (33.33%)	0 / 6 (0.00%)	0 / 80 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	1	1	0	0	0
Joint swelling
subjects affected / exposed	0 / 3 (0.00%)	1 / 95 (1.05%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 80 (1.25%)	0 / 3 (0.00%)
occurrences all number	0	1	0	0	1	0
Limb discomfort
subjects affected / exposed	0 / 3 (0.00%)	1 / 95 (1.05%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 80 (1.25%)	0 / 3 (0.00%)
occurrences all number	0	3	0	0	3	0
Mobility decreased
subjects affected / exposed	0 / 3 (0.00%)	1 / 95 (1.05%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 80 (1.25%)	0 / 3 (0.00%)
occurrences all number	0	1	0	0	1	0
Muscle spasms
subjects affected / exposed	0 / 3 (0.00%)	10 / 95 (10.53%)	0 / 3 (0.00%)	0 / 6 (0.00%)	10 / 80 (12.50%)	0 / 3 (0.00%)
occurrences all number	0	13	0	0	13	0
Muscle twitching
subjects affected / exposed	0 / 3 (0.00%)	1 / 95 (1.05%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 80 (1.25%)	0 / 3 (0.00%)
occurrences all number	0	1	0	0	1	0
Muscular weakness
subjects affected / exposed	0 / 3 (0.00%)	4 / 95 (4.21%)	0 / 3 (0.00%)	0 / 6 (0.00%)	4 / 80 (5.00%)	0 / 3 (0.00%)
occurrences all number	0	4	0	0	4	0
Musculoskeletal chest pain
subjects affected / exposed	1 / 3 (33.33%)	10 / 95 (10.53%)	0 / 3 (0.00%)	1 / 6 (16.67%)	7 / 80 (8.75%)	1 / 3 (33.33%)
occurrences all number	1	10	0	1	7	1
Musculoskeletal pain
subjects affected / exposed	1 / 3 (33.33%)	12 / 95 (12.63%)	0 / 3 (0.00%)	0 / 6 (0.00%)	10 / 80 (12.50%)	1 / 3 (33.33%)
occurrences all number	1	17	0	0	15	1
Musculoskeletal stiffness
subjects affected / exposed	0 / 3 (0.00%)	3 / 95 (3.16%)	0 / 3 (0.00%)	1 / 6 (16.67%)	1 / 80 (1.25%)	1 / 3 (33.33%)
occurrences all number	0	4	0	1	2	1
Myalgia
subjects affected / exposed	0 / 3 (0.00%)	5 / 95 (5.26%)	0 / 3 (0.00%)	0 / 6 (0.00%)	4 / 80 (5.00%)	1 / 3 (33.33%)
occurrences all number	0	6	0	0	4	2
Neck pain
subjects affected / exposed	0 / 3 (0.00%)	1 / 95 (1.05%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 80 (1.25%)	0 / 3 (0.00%)
occurrences all number	0	2	0	0	2	0
Pain in extremity
subjects affected / exposed	0 / 3 (0.00%)	15 / 95 (15.79%)	0 / 3 (0.00%)	1 / 6 (16.67%)	13 / 80 (16.25%)	1 / 3 (33.33%)
occurrences all number	0	19	0	1	17	1
Pain in jaw
subjects affected / exposed	1 / 3 (33.33%)	2 / 95 (2.11%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 80 (0.00%)	1 / 3 (33.33%)
occurrences all number	2	3	0	0	0	1
Rheumatoid arthritis
subjects affected / exposed	0 / 3 (0.00%)	1 / 95 (1.05%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 80 (1.25%)	0 / 3 (0.00%)
occurrences all number	0	1	0	0	1	0
Spinal osteoarthritis
subjects affected / exposed	0 / 3 (0.00%)	1 / 95 (1.05%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 80 (1.25%)	0 / 3 (0.00%)
occurrences all number	0	1	0	0	1	0
Infections and infestations
Bronchiectasis
subjects affected / exposed	1 / 3 (33.33%)	1 / 95 (1.05%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 80 (0.00%)	0 / 3 (0.00%)
occurrences all number	1	1	0	0	0	0
Bronchitis
subjects affected / exposed	0 / 3 (0.00%)	1 / 95 (1.05%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 80 (1.25%)	0 / 3 (0.00%)
occurrences all number	0	1	0	0	1	0
Cellulitis
subjects affected / exposed	0 / 3 (0.00%)	1 / 95 (1.05%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 80 (1.25%)	0 / 3 (0.00%)
occurrences all number	0	1	0	0	1	0
Clostridium difficile colitis
subjects affected / exposed	0 / 3 (0.00%)	1 / 95 (1.05%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 80 (1.25%)	0 / 3 (0.00%)
occurrences all number	0	1	0	0	1	0
Conjunctivitis infective
subjects affected / exposed	0 / 3 (0.00%)	1 / 95 (1.05%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 80 (1.25%)	0 / 3 (0.00%)
occurrences all number	0	1	0	0	1	0
Cystitis
subjects affected / exposed	0 / 3 (0.00%)	1 / 95 (1.05%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 80 (1.25%)	0 / 3 (0.00%)
occurrences all number	0	1	0	0	1	0
Enterocolitis infectious
subjects affected / exposed	0 / 3 (0.00%)	1 / 95 (1.05%)	1 / 3 (33.33%)	0 / 6 (0.00%)	0 / 80 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	1	1	0	0	0
Escherichia urinary tract infection
subjects affected / exposed	0 / 3 (0.00%)	1 / 95 (1.05%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 80 (1.25%)	0 / 3 (0.00%)
occurrences all number	0	1	0	0	1	0
Eye infection
subjects affected / exposed	0 / 3 (0.00%)	1 / 95 (1.05%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 80 (1.25%)	0 / 3 (0.00%)
occurrences all number	0	1	0	0	1	0
Eyelid infection
subjects affected / exposed	0 / 3 (0.00%)	1 / 95 (1.05%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 80 (1.25%)	0 / 3 (0.00%)
occurrences all number	0	1	0	0	1	0
Gastroenteritis
subjects affected / exposed	0 / 3 (0.00%)	1 / 95 (1.05%)	1 / 3 (33.33%)	0 / 6 (0.00%)	0 / 80 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	1	1	0	0	0
Gingival infection
subjects affected / exposed	0 / 3 (0.00%)	1 / 95 (1.05%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 80 (1.25%)	0 / 3 (0.00%)
occurrences all number	0	1	0	0	1	0
Herpes zoster
subjects affected / exposed	0 / 3 (0.00%)	2 / 95 (2.11%)	0 / 3 (0.00%)	0 / 6 (0.00%)	2 / 80 (2.50%)	0 / 3 (0.00%)
occurrences all number	0	2	0	0	2	0
Hordeolum
subjects affected / exposed	0 / 3 (0.00%)	1 / 95 (1.05%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 80 (1.25%)	0 / 3 (0.00%)
occurrences all number	0	1	0	0	1	0
Infection
subjects affected / exposed	0 / 3 (0.00%)	2 / 95 (2.11%)	1 / 3 (33.33%)	0 / 6 (0.00%)	1 / 80 (1.25%)	0 / 3 (0.00%)
occurrences all number	0	2	1	0	1	0
Influenza
subjects affected / exposed	0 / 3 (0.00%)	1 / 95 (1.05%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 80 (1.25%)	0 / 3 (0.00%)
occurrences all number	0	1	0	0	1	0
Localised infection
subjects affected / exposed	0 / 3 (0.00%)	1 / 95 (1.05%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 80 (1.25%)	0 / 3 (0.00%)
occurrences all number	0	1	0	0	1	0
Lower respiratory tract infection
subjects affected / exposed	1 / 3 (33.33%)	14 / 95 (14.74%)	2 / 3 (66.67%)	0 / 6 (0.00%)	11 / 80 (13.75%)	0 / 3 (0.00%)
occurrences all number	1	19	4	0	14	0
Lung infection
subjects affected / exposed	0 / 3 (0.00%)	1 / 95 (1.05%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 80 (1.25%)	0 / 3 (0.00%)
occurrences all number	0	1	0	0	1	0
Nasopharyngitis
subjects affected / exposed	0 / 3 (0.00%)	7 / 95 (7.37%)	0 / 3 (0.00%)	0 / 6 (0.00%)	7 / 80 (8.75%)	0 / 3 (0.00%)
occurrences all number	0	8	0	0	8	0
Onychomycosis
subjects affected / exposed	0 / 3 (0.00%)	1 / 95 (1.05%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 80 (1.25%)	0 / 3 (0.00%)
occurrences all number	0	1	0	0	1	0
Oral candidiasis
subjects affected / exposed	0 / 3 (0.00%)	3 / 95 (3.16%)	0 / 3 (0.00%)	1 / 6 (16.67%)	2 / 80 (2.50%)	0 / 3 (0.00%)
occurrences all number	0	3	0	1	2	0
Orchitis
subjects affected / exposed	0 / 3 (0.00%)	1 / 95 (1.05%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 80 (1.25%)	0 / 3 (0.00%)
occurrences all number	0	1	0	0	1	0
Pneumonia
subjects affected / exposed	0 / 3 (0.00%)	1 / 95 (1.05%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 80 (1.25%)	0 / 3 (0.00%)
occurrences all number	0	1	0	0	1	0
Respiratory tract infection
subjects affected / exposed	1 / 3 (33.33%)	3 / 95 (3.16%)	0 / 3 (0.00%)	0 / 6 (0.00%)	2 / 80 (2.50%)	0 / 3 (0.00%)
occurrences all number	1	4	0	0	3	0
Rhinitis
subjects affected / exposed	1 / 3 (33.33%)	7 / 95 (7.37%)	0 / 3 (0.00%)	0 / 6 (0.00%)	6 / 80 (7.50%)	0 / 3 (0.00%)
occurrences all number	3	13	0	0	10	0
Sepsis
subjects affected / exposed	0 / 3 (0.00%)	1 / 95 (1.05%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 80 (1.25%)	0 / 3 (0.00%)
occurrences all number	0	1	0	0	1	0
Sinusitis
subjects affected / exposed	0 / 3 (0.00%)	2 / 95 (2.11%)	0 / 3 (0.00%)	0 / 6 (0.00%)	2 / 80 (2.50%)	0 / 3 (0.00%)
occurrences all number	0	2	0	0	2	0
Skin candida
subjects affected / exposed	0 / 3 (0.00%)	1 / 95 (1.05%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 80 (1.25%)	0 / 3 (0.00%)
occurrences all number	0	1	0	0	1	0
Skin infection
subjects affected / exposed	0 / 3 (0.00%)	2 / 95 (2.11%)	0 / 3 (0.00%)	0 / 6 (0.00%)	2 / 80 (2.50%)	0 / 3 (0.00%)
occurrences all number	0	2	0	0	2	0
Upper respiratory tract infection
subjects affected / exposed	0 / 3 (0.00%)	14 / 95 (14.74%)	1 / 3 (33.33%)	0 / 6 (0.00%)	13 / 80 (16.25%)	0 / 3 (0.00%)
occurrences all number	0	15	1	0	14	0
Urinary tract infection
subjects affected / exposed	0 / 3 (0.00%)	6 / 95 (6.32%)	0 / 3 (0.00%)	0 / 6 (0.00%)	5 / 80 (6.25%)	1 / 3 (33.33%)
occurrences all number	0	7	0	0	6	1
Viral infection
subjects affected / exposed	0 / 3 (0.00%)	3 / 95 (3.16%)	0 / 3 (0.00%)	0 / 6 (0.00%)	3 / 80 (3.75%)	0 / 3 (0.00%)
occurrences all number	0	3	0	0	3	0
Metabolism and nutrition disorders
Decreased appetite
subjects affected / exposed	0 / 3 (0.00%)	28 / 95 (29.47%)	2 / 3 (66.67%)	1 / 6 (16.67%)	25 / 80 (31.25%)	0 / 3 (0.00%)
occurrences all number	0	44	4	2	38	0
Dehydration
subjects affected / exposed	0 / 3 (0.00%)	6 / 95 (6.32%)	1 / 3 (33.33%)	0 / 6 (0.00%)	5 / 80 (6.25%)	0 / 3 (0.00%)
occurrences all number	0	6	1	0	5	0
Diabetes mellitus
subjects affected / exposed	0 / 3 (0.00%)	1 / 95 (1.05%)	1 / 3 (33.33%)	0 / 6 (0.00%)	0 / 80 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	1	1	0	0	0
Fluid intake reduced
subjects affected / exposed	0 / 3 (0.00%)	1 / 95 (1.05%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 80 (1.25%)	0 / 3 (0.00%)
occurrences all number	0	2	0	0	2	0
Fluid overload
subjects affected / exposed	0 / 3 (0.00%)	1 / 95 (1.05%)	0 / 3 (0.00%)	1 / 6 (16.67%)	0 / 80 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	1	0	1	0	0
Gout
subjects affected / exposed	0 / 3 (0.00%)	1 / 95 (1.05%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 80 (1.25%)	0 / 3 (0.00%)
occurrences all number	0	1	0	0	1	0
Hypercalcaemia
subjects affected / exposed	0 / 3 (0.00%)	1 / 95 (1.05%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 80 (1.25%)	0 / 3 (0.00%)
occurrences all number	0	3	0	0	3	0
Hyperglycaemia
subjects affected / exposed	0 / 3 (0.00%)	1 / 95 (1.05%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 80 (1.25%)	0 / 3 (0.00%)
occurrences all number	0	1	0	0	1	0
Hyperphosphataemia
subjects affected / exposed	0 / 3 (0.00%)	1 / 95 (1.05%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 80 (1.25%)	0 / 3 (0.00%)
occurrences all number	0	2	0	0	2	0
Hyperuricaemia
subjects affected / exposed	0 / 3 (0.00%)	3 / 95 (3.16%)	0 / 3 (0.00%)	0 / 6 (0.00%)	3 / 80 (3.75%)	0 / 3 (0.00%)
occurrences all number	0	3	0	0	3	0
Hypoalbuminaemia
subjects affected / exposed	0 / 3 (0.00%)	1 / 95 (1.05%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 80 (1.25%)	0 / 3 (0.00%)
occurrences all number	0	1	0	0	1	0
Hypocalcaemia
subjects affected / exposed	0 / 3 (0.00%)	5 / 95 (5.26%)	0 / 3 (0.00%)	0 / 6 (0.00%)	5 / 80 (6.25%)	0 / 3 (0.00%)
occurrences all number	0	7	0	0	7	0
Hypoglycaemia
subjects affected / exposed	0 / 3 (0.00%)	1 / 95 (1.05%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 80 (1.25%)	0 / 3 (0.00%)
occurrences all number	0	1	0	0	1	0
Hypokalaemia
subjects affected / exposed	1 / 3 (33.33%)	8 / 95 (8.42%)	0 / 3 (0.00%)	0 / 6 (0.00%)	7 / 80 (8.75%)	0 / 3 (0.00%)
occurrences all number	1	13	0	0	12	0
Hypomagnesaemia
subjects affected / exposed	0 / 3 (0.00%)	4 / 95 (4.21%)	0 / 3 (0.00%)	0 / 6 (0.00%)	4 / 80 (5.00%)	0 / 3 (0.00%)
occurrences all number	0	5	0	0	5	0
Hyponatraemia
subjects affected / exposed	0 / 3 (0.00%)	3 / 95 (3.16%)	0 / 3 (0.00%)	0 / 6 (0.00%)	3 / 80 (3.75%)	0 / 3 (0.00%)
occurrences all number	0	4	0	0	4	0
Hypophosphataemia
subjects affected / exposed	0 / 3 (0.00%)	2 / 95 (2.11%)	0 / 3 (0.00%)	0 / 6 (0.00%)	2 / 80 (2.50%)	0 / 3 (0.00%)
occurrences all number	0	10	0	0	10	0
Vitamin B12 deficiency
subjects affected / exposed	0 / 3 (0.00%)	1 / 95 (1.05%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 80 (1.25%)	0 / 3 (0.00%)
occurrences all number	0	1	0	0	1	0

More information

Top of page

Were there any global substantial amendments to the protocol? Yes

21 Dec 2009

Operational and background information for the new sites in the Philippines.

21 Dec 2010

• Added investigational sites in the Philippines for the Phase 2 portion of the study. • Clarified the inclusion and exclusion criteria for the intended subject population. • Defined the period of time that subjects could continue to receive combination therapy with KW-2478 and BTZ and specified treatment with single-agent KW-2478 after discontinuation of BTZ. • Clarified wording for study drug administration and subsequent dose modifications. • Defined the Efficacy Analysis population. • Documented the change in sponsorship.

19 Apr 2012

• Clarified the inclusion and exclusion criteria for the intended subject population. • Clarified intended wording regarding the administration of the investigational products and subsequent dose modifications. • Clarified laboratory testing parameters and laboratory facilities responsible for the analysis of samples. • Clarified para proteins included in the quantitative determination of immunoglobulins for efficacy evaluation. • Clarified study procedures. • Clarified IMWG response criteria and criteria for progressive disease per current literature. • Updated study drug information relative to new formulation of investigational product.

Were there any global interruptions to the trial? No

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

None reported

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

Clinical trials

Clinical Trial Results:
An Open Label, Dose Escalation, Multicenter Phase 1/2 Study of KW-2478 in Combination with Bortezomib in Subjects with Relapsed and/or Refractory Multiple Myeloma

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: To establish the safety, tolerability, and RP2D (Phase 1); To assess the overall response rate in subjects with advanced Multiple Myeloma (Phase 2).

Primary: To establish the safety, tolerability, and RP2D (Phase 1); To assess the overall response rate in subjects with advanced Multiple Myeloma (Phase 2).

Secondary: Phase 1: PK Absorption tmax hr Day 11

Secondary: Phase 1: PK Absorption tmax hr Day 11

Secondary: Phase 1: PK Exposure Cmax ng/mL Day 11

Secondary: Phase 1: PK Exposure Cmax ng/mL Day 11

Secondary: Phase 1: PK Exposure AUC0-t hr*ng/mL Day 11

Secondary: Phase 1: PK Exposure AUC0-t hr*ng/mL Day 11

Secondary: Phase 1: PK Elimination t½ hr Day 11

Secondary: Phase 1: PK Elimination t½ hr Day 11

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information

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

Clinical trials

Clinical Trial Results: An Open Label, Dose Escalation, Multicenter Phase 1/2 Study of KW-2478 in Combination with Bortezomib in Subjects with Relapsed and/or Refractory Multiple Myeloma

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: To establish the safety, tolerability, and RP2D (Phase 1); To assess the overall response rate in subjects with advanced Multiple Myeloma (Phase 2).

Primary: To establish the safety, tolerability, and RP2D (Phase 1); To assess the overall response rate in subjects with advanced Multiple Myeloma (Phase 2).

Secondary: Phase 1: PK Absorption tmax hr Day 11

Secondary: Phase 1: PK Absorption tmax hr Day 11

Secondary: Phase 1: PK Exposure Cmax ng/mL Day 11

Secondary: Phase 1: PK Exposure Cmax ng/mL Day 11

Secondary: Phase 1: PK Exposure AUC0-t hr*ng/mL Day 11

Secondary: Phase 1: PK Exposure AUC0-t hr*ng/mL Day 11

Secondary: Phase 1: PK Elimination t½ hr Day 11

Secondary: Phase 1: PK Elimination t½ hr Day 11

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information

Clinical Trial Results:
An Open Label, Dose Escalation, Multicenter Phase 1/2 Study of KW-2478 in Combination with Bortezomib in Subjects with Relapsed and/or Refractory Multiple Myeloma