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Clinical Trial Results:
A Phase 1b/2, multi-center, double-blind (principal investigators and study subjects blinded, sponsor unblinded), placebo-controlled, randomized, single-ascending dose study to assess the safety, pharmacokinetics, and pharmacodynamics of DS-1040B in subjects with acute ischemic stroke.

Summary
EudraCT number	2015-001824-43
Trial protocol	DE FR GB CZ ES SK IT
Global end of trial date	13 Aug 2019

Results information
Results version number	v1(current)
This version publication date	17 Aug 2020
First version publication date	17 Aug 2020
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

DS1040-A-U103

ISRCTN number

-

US NCT number

NCT02586233

WHO universal trial number (UTN)

-

Sponsor organisation name

Daiichi Sankyo

Sponsor organisation address

211 Mt. Airy Road, Basking Ridge, United States, 07920

Public contact

Contact for Clinical Trial Information, Daiichi Sankyo Development Ltd, +1 908-992-6400, CTRinfo@dsi.com

Scientific contact

Contact for Clinical Trial Information, Daiichi Sankyo Development Ltd, +1 908-992-6400, CTRinfo@dsi.com

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

No

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

No

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

No

Analysis stage

Final

Date of interim/final analysis

13 Aug 2019

Is this the analysis of the primary completion data?

No

Global end of trial reached?

Yes

Global end of trial date

13 Aug 2019

Was the trial ended prematurely?

No

Main objective of the trial

To assess the safety and tolerability of DS-1040b (IV infusion over 6 hours) in subjects with AIS within 3 to 8 hours after stroke symptom onset

Protection of trial subjects

This study was conducted in compliance with the protocol, the ethical principles that have their origin in the Declaration of Helsinki, the International Council for Harmonisation consolidated Guideline E6 for Good Clinical Practice (GCP) (CPMP/International Council for Harmonisation/135/95), the United States Food and Drug Administration GCP Regulations: Code of Federal Regulations Title 21, Parts 11, 50, 54, 56, and 312 as appropriate and other applicable local regulations.

Background therapy

-

Evidence for comparator

-

Actual start date of recruitment

01 Sep 2015

Long term follow-up planned

No

Independent data monitoring committee (IDMC) involvement?

No

Number of subjects enrolled per country

Country: Number of subjects enrolled

Spain: 24

Country: Number of subjects enrolled

United Kingdom: 3

Country: Number of subjects enrolled

Czech Republic: 4

Country: Number of subjects enrolled

France: 1

Country: Number of subjects enrolled

Germany: 5

Country: Number of subjects enrolled

United States: 46

Country: Number of subjects enrolled

Taiwan: 13

Country: Number of subjects enrolled

Australia: 4

Country: Number of subjects enrolled

Korea, Republic of: 6

Worldwide total number of subjects

106

EEA total number of subjects

37

Number of subjects enrolled per age group

In utero

0

Preterm newborn - gestational age < 37 wk

0

Newborns (0-27 days)

0

Infants and toddlers (28 days-23 months)

0

Children (2-11 years)

0

Adolescents (12-17 years)

0

Adults (18-64 years)

55

From 65 to 84 years

49

85 years and over

2

Subject disposition

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Recruitment details

A total of 106 participants who met all inclusion criteria and no exclusion criteria were randomized to treatment at a total of 78 clinic sites (46 in Europe, 19 in the United States, 7 in Asia, 5 in Australia, and 1 in Canada). Of the 106 participants randomized, 101 participants received treatment.

Screening details

The study consisted of 6, sequential, ascending-dose cohorts. Participants were randomized to either DS-1040b or placebo in a 3:1 ratio.

Period 1 title

Overall Study (overall period)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator

Are arms mutually exclusive

Yes

Cohort 1: DS-1040b 0.6 mg

Arm description

Subjects who received a single intravenous infusion of DS-1040b 0.6 mg.

Arm type

Experimental

Investigational medicinal product name

DS-1040b

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Intravenous infusion of 0.6 mg to 9.6 mg over a 6-hour period

Cohort 2: DS-1040b 1.2 mg

Arm description

Subjects who received a single intravenous infusion of DS-1040b 1.2 mg.

Arm type

Experimental

Investigational medicinal product name

DS-1040b

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Intravenous infusion of 0.6 mg to 9.6 mg over a 6-hour period

Cohort 3: DS-1040b 2.4 mg

Arm description

Subjects who received a single intravenous infusion of DS-1040b 2.4 mg.

Arm type

Experimental

Investigational medicinal product name

DS-1040b

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Intravenous infusion of 0.6 mg to 9.6 mg over a 6-hour period

Cohort 4: DS-1040 4.8 mg

Arm description

Subjects who received a single intravenous infusion of DS-1040b 4.8 mg.

Arm type

Experimental

Investigational medicinal product name

DS-1040b

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Intravenous infusion of 0.6 mg to 9.6 mg over a 6-hour period

Cohort 5: DS-1040b 7.2 mg

Arm description

Subjects who received a single intravenous infusion of DS-1040b 7.2 mg.

Arm type

Experimental

Investigational medicinal product name

DS-1040b

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Intravenous infusion of 0.6 mg to 9.6 mg over a 6-hour period

Cohort 6: DS-1040b 9.6 mg

Arm description

Subjects who received a single intravenous infusion of DS-1040b 9.6 mg.

Arm type

Experimental

Investigational medicinal product name

DS-1040b

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Intravenous infusion of 0.6 mg to 9.6 mg over a 6-hour period

Placebo

Arm description

Subjects who received a single intravenous infusion of placebo.

Arm type

Placebo

Investigational medicinal product name

0.9% sodium chloride

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Intravenous infusion over 6-hour period

Number of subjects in period 1	Cohort 1: DS-1040b 0.6 mg	Cohort 2: DS-1040b 1.2 mg	Cohort 3: DS-1040b 2.4 mg	Cohort 4: DS-1040 4.8 mg	Cohort 5: DS-1040b 7.2 mg	Cohort 6: DS-1040b 9.6 mg	Placebo
Started	7	7	13	17	18	18	26
Completed	7	5	13	17	16	16	24
Not completed	0	2	0	0	2	2	2
Randomized, but did not receive treatment	-	1	-	-	-	2	2
Death	-	1	-	-	2	-	-

Baseline characteristics

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Reporting group title

Cohort 1: DS-1040b 0.6 mg

Reporting group description

Subjects who received a single intravenous infusion of DS-1040b 0.6 mg.

Reporting group title

Cohort 2: DS-1040b 1.2 mg

Reporting group description

Subjects who received a single intravenous infusion of DS-1040b 1.2 mg.

Reporting group title

Cohort 3: DS-1040b 2.4 mg

Reporting group description

Subjects who received a single intravenous infusion of DS-1040b 2.4 mg.

Reporting group title

Cohort 4: DS-1040 4.8 mg

Reporting group description

Subjects who received a single intravenous infusion of DS-1040b 4.8 mg.

Reporting group title

Cohort 5: DS-1040b 7.2 mg

Reporting group description

Subjects who received a single intravenous infusion of DS-1040b 7.2 mg.

Reporting group title

Cohort 6: DS-1040b 9.6 mg

Reporting group description

Subjects who received a single intravenous infusion of DS-1040b 9.6 mg.

Reporting group title

Placebo

Reporting group description

Subjects who received a single intravenous infusion of placebo.

Reporting group values	Cohort 1: DS-1040b 0.6 mg	Cohort 2: DS-1040b 1.2 mg	Cohort 3: DS-1040b 2.4 mg	Cohort 4: DS-1040 4.8 mg	Cohort 5: DS-1040b 7.2 mg	Cohort 6: DS-1040b 9.6 mg	Placebo	Total
Number of subjects	7	7	13	17	18	18	26	106
Age categorical
Based on Randomized Analysis Set
Units: Subjects
In utero	0	0	0	0	0	0	0	0
Preterm newborn infants (gestational age < 37 wks)	0	0	0	0	0	0	0	0
Newborns (0-27 days)	0	0	0	0	0	0	0	0
Infants and toddlers (28 days-23 months)	0	0	0	0	0	0	0	0
Children (2-11 years)	0	0	0	0	0	0	0	0
Adolescents (12-17 years)	0	0	0	0	0	0	0	0
Adults (18-64 years)	2	4	8	8	9	10	14	55
From 65-84 years	5	2	5	9	9	7	12	49
85 years and over	0	1	0	0	0	1	0	2
Age continuous
Based on Safety Analysis Set (N=101); age data were missing for participants in some cohorts.
Units: years
arithmetic mean (standard deviation)	68.2 ( 7.8 )	68.2 ( 10.2 )	62.7 ( 9.7 )	69.1 ( 11.1 )	65.8 ( 11.7 )	64.8 ( 12.8 )	62.2 ( 12.3 )	-
Gender categorical
Based on the Randomized Analysis Set
Units: Subjects
Female	3	2	5	6	8	7	11	42
Male	4	5	8	11	10	11	15	64

End points

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Reporting group title

Cohort 1: DS-1040b 0.6 mg

Reporting group description

Subjects who received a single intravenous infusion of DS-1040b 0.6 mg.

Reporting group title

Cohort 2: DS-1040b 1.2 mg

Reporting group description

Subjects who received a single intravenous infusion of DS-1040b 1.2 mg.

Reporting group title

Cohort 3: DS-1040b 2.4 mg

Reporting group description

Subjects who received a single intravenous infusion of DS-1040b 2.4 mg.

Reporting group title

Cohort 4: DS-1040 4.8 mg

Reporting group description

Subjects who received a single intravenous infusion of DS-1040b 4.8 mg.

Reporting group title

Cohort 5: DS-1040b 7.2 mg

Reporting group description

Subjects who received a single intravenous infusion of DS-1040b 7.2 mg.

Reporting group title

Cohort 6: DS-1040b 9.6 mg

Reporting group description

Subjects who received a single intravenous infusion of DS-1040b 9.6 mg.

Reporting group title

Placebo

Reporting group description

Subjects who received a single intravenous infusion of placebo.

Subject analysis set title

All DS-1040b

Subject analysis set type

Safety analysis

Subject analysis set description

All subjects who received a single intravenous infusion of DS-1040b.

Primary: Treatment-emergent Adverse Event Reported by >10% of Participants Following Ascending Doses of DS-1040b and a Placebo in Subjects With Acute Ischemic Stroke

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End point title

Treatment-emergent Adverse Event Reported by >10% of Participants Following Ascending Doses of DS-1040b and a Placebo in Subjects With Acute Ischemic Stroke ^[1]

End point description

Treatment-emergent adverse event (TEAE) is defined as an adverse event that emerges during the treatment period (from first dose date until 30 days after the last dosing date), having been absent at predose; or reemerges during treatment, having been present at baseline but stopped prior to treatment; or worsens in severity after starting treatment relative to the pre-dose state, when the adverse event is continuous.

End point type

Primary

End point timeframe

Baseline up to 90 days post last dose, up to 3 years 11 months

Notes
[1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Descriptive analyses were performed based on the study groups and study drugs administered for this outcome.

End point values	Cohort 1: DS-1040b 0.6 mg	Cohort 2: DS-1040b 1.2 mg	Cohort 3: DS-1040b 2.4 mg	Cohort 4: DS-1040 4.8 mg	Cohort 5: DS-1040b 7.2 mg	Cohort 6: DS-1040b 9.6 mg	Placebo	All DS-1040b
Number of subjects analysed	7	6	13	17	18	16	24	77
Units: Subjects
number (not applicable)
Any TEAE	5	5	10	15	14	14	18	63
Hypokalaemia	1	2	2	0	2	2	6	9
Constipation	1	2	3	1	5	2	5	14
Insomnia	0	0	1	0	1	3	5	5
Hypertension	0	0	1	3	1	0	3	5
Anxiety	0	1	0	0	0	2	3	3
Hyperglycaemia	0	0	0	1	1	0	3	2
Dyslipidaemia	0	0	0	0	1	1	3	2
Thrombocytopenia	0	1	0	0	0	0	3	1
Vomiting	0	1	0	0	0	0	3	1
Pyrexia	0	0	0	1	0	0	3	1
Vitamin B12 deficiency	0	0	0	0	0	0	3	0
Headache	3	1	2	2	1	4	2	13

No statistical analyses for this end point

Secondary: Pharmacokinetic Parameter Maximum (Peak) Observed Plasma Concentration (Cmax) of DS-1040b Following Ascending Doses in Subjects With Acute Ischemic Stroke

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End point title

Pharmacokinetic Parameter Maximum (Peak) Observed Plasma Concentration (Cmax) of DS-1040b Following Ascending Doses in Subjects With Acute Ischemic Stroke ^[2]

End point description

The PK parameter of Maximum (Peak) Observed Plasma Concentration (Cmax) of DS-1040b was calculated from the plasma concentrations of DS-1040b using non-compartmental analysis.

End point type

Secondary

End point timeframe

Predose, 0.5, 3, 6, 9, 12, 24, 48, 72, and 96 hours postdose

Notes
[2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Descriptive analyses were performed based on the study groups and study drugs administered for this outcome.

End point values	Cohort 1: DS-1040b 0.6 mg	Cohort 2: DS-1040b 1.2 mg	Cohort 3: DS-1040b 2.4 mg	Cohort 4: DS-1040 4.8 mg	Cohort 5: DS-1040b 7.2 mg	Cohort 6: DS-1040b 9.6 mg
Number of subjects analysed	5	6	13	16	17	10
Units: ng/mL
arithmetic mean (standard deviation)
Cmax	10.09 ( 3.26 )	26.95 ( 9.39 )	61.28 ( 35.67 )	729.76 ( 1661.06 )	191.06 ( 59.60 )	203.70 ( 41.49 )

No statistical analyses for this end point

Secondary: Pharmacokinetic Parameter Area Under the Concentration Versus Time Curve From Zero to Last Quantifiable Concentration Sampling Point (AUClast) of DS-1040b Following Ascending Doses in Subjects With Acute Ischemic Stroke

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End point title

Pharmacokinetic Parameter Area Under the Concentration Versus Time Curve From Zero to Last Quantifiable Concentration Sampling Point (AUClast) of DS-1040b Following Ascending Doses in Subjects With Acute Ischemic Stroke ^[3]

End point description

The PK parameter of Area Under the Concentration Versus Time Curve from Zero to Last Quantifiable Concentration Sampling Point of DS-1040b was calculated from the plasma concentrations of DS-1040b using non-compartmental analysis.

End point type

Secondary

End point timeframe

Pre-dose, 0.5, 3, 6, 9, 12, 24, 48, 72, and 96 hours post-dose

Notes
[3] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Descriptive analyses were performed based on the study groups and study drugs administered for this outcome.

End point values	Cohort 1: DS-1040b 0.6 mg	Cohort 2: DS-1040b 1.2 mg	Cohort 3: DS-1040b 2.4 mg	Cohort 4: DS-1040 4.8 mg	Cohort 5: DS-1040b 7.2 mg	Cohort 6: DS-1040b 9.6 mg
Number of subjects analysed	5	6	13	16	17	10
Units: ng*h/mL
arithmetic mean (standard deviation)
AUClast	69.74 ( 16.19 )	219.83 ( 95.16 )	447.75 ( 199.97 )	2611.87 ( 4471.65 )	1489.21 ( 460.78 )	1700.24 ( 346.43 )

No statistical analyses for this end point

Secondary: Pharmacokinetic Parameter Terminal Half-life (t1/2) of DS-1040b Following Ascending Doses in Subjects With Acute Ischemic Stroke

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End point title

Pharmacokinetic Parameter Terminal Half-life (t1/2) of DS-1040b Following Ascending Doses in Subjects With Acute Ischemic Stroke ^[4]

End point description

The PK parameter of Terminal Half-life of DS-1040b was calculated from the plasma concentrations of DS-1040b using non-compartmental analysis in patients with available sample for the analysis.

End point type

Secondary

End point timeframe

Pre-dose, 0.5, 3, 6, 9, 12, 24, 48, 72, and 96 hours post-dose

Notes
[4] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Descriptive analyses were performed based on the study groups and study drugs administered for this outcome.

End point values	Cohort 1: DS-1040b 0.6 mg	Cohort 2: DS-1040b 1.2 mg	Cohort 3: DS-1040b 2.4 mg	Cohort 4: DS-1040 4.8 mg	Cohort 5: DS-1040b 7.2 mg	Cohort 6: DS-1040b 9.6 mg
Number of subjects analysed	4	2	7	8	14	8
Units: hours
arithmetic mean (standard deviation)
Terminal half-life	2.59 ( 0.46 )	4.14 ( 0.17 )	10.50 ( 15.02 )	36.68 ( 25.94 )	33.37 ( 14.71 )	35.86 ( 10.98 )

No statistical analyses for this end point

Secondary: Activated Form of Thrombin-activatable Fibrinolysis Inhibitor (TAFIa) Following Ascending Doses of DS-1040b and a Placebo in Subjects With Acute Ischemic Stroke

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End point title

Activated Form of Thrombin-activatable Fibrinolysis Inhibitor (TAFIa) Following Ascending Doses of DS-1040b and a Placebo in Subjects With Acute Ischemic Stroke

End point description

The enzymatic activity of thrombin-activatable fibrinolysis inhibitor was assessed using the Stago Coagulation Analyzer.

End point type

Secondary

End point timeframe

Baseline and 6 hours postdose

End point values	Cohort 1: DS-1040b 0.6 mg	Cohort 2: DS-1040b 1.2 mg	Cohort 3: DS-1040b 2.4 mg	Cohort 4: DS-1040 4.8 mg	Cohort 5: DS-1040b 7.2 mg	Cohort 6: DS-1040b 9.6 mg	Placebo
Number of subjects analysed	7	6	13	17	18	10	24
Units: Mean percentage of TAFIa activity
arithmetic mean (standard deviation)
Baseline	96.7 ( 23.7 )	97.8 ( 17.5 )	100.4 ( 21.6 )	105.1 ( 23.4 )	108.1 ( 30.5 )	112.6 ( 27.2 )	100.9 ( 20.8 )
6 hours postdose	93.5 ( 26.6 )	98.8 ( 27.2 )	86.7 ( 16.7 )	75.9 ( 20.9 )	72.9 ( 22.6 )	73.9 ( 14.4 )	104.1 ( 24.7 )

No statistical analyses for this end point

Secondary: Change From Baseline at Day 30 in National Institute of Health Stroke Scale (NIHSS) Score Following Ascending Doses of DS-1040b and a Placebo in Subjects With Acute Ischemic Stroke

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End point title

Change From Baseline at Day 30 in National Institute of Health Stroke Scale (NIHSS) Score Following Ascending Doses of DS-1040b and a Placebo in Subjects With Acute Ischemic Stroke

End point description

The National Institute of Health Stroke Scale (NIHSS) quantifies stroke severity based on weighted evaluation findings. The score for each ability is a number between 0 and 4, with 0 being normal functioning and 4 being completely impaired. The patient's NIHSS score is calculated by adding the number for each element of the scale; 42 is the highest score possible. In the NIHSS, the higher the score indicates more impairment (worse outcome) in a stroke patient.

End point type

Secondary

End point timeframe

30 days postdose

End point values	Cohort 1: DS-1040b 0.6 mg	Cohort 2: DS-1040b 1.2 mg	Cohort 3: DS-1040b 2.4 mg	Cohort 4: DS-1040 4.8 mg	Cohort 5: DS-1040b 7.2 mg	Cohort 6: DS-1040b 9.6 mg	Placebo	All DS-1040b
Number of subjects analysed	7	6	13	17	18	16	24	77
Units: Units on a scale
arithmetic mean (standard deviation)
Change from baseline in NIHSS score	-3.7 ( 2.21 )	-3.0 ( 2.00 )	-3.5 ( 1.71 )	-2.06 ( 1.06 )	-3.4 ( 2.70 )	-6.2 ( 3.08 )	-3.6 ( 4.27 )	-3.9 ( 2.56 )

No statistical analyses for this end point

Secondary: Percentage of Participants With a Modified Rankin Scale (mRS) Score of 0 to 2 Following Ascending Doses of DS-1040b and a Placebo in Subjects With Acute Ischemic Stroke

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End point title

Percentage of Participants With a Modified Rankin Scale (mRS) Score of 0 to 2 Following Ascending Doses of DS-1040b and a Placebo in Subjects With Acute Ischemic Stroke

End point description

The modified Rankin scale (mRS) is a commonly used disability scale derived from the Rankin scale that is used to measure the degree of disability or dependence in the daily activities of people who have suffered a stroke or other causes of neurological disability. The level of disability following a stroke is assessed via a scale from 0 to 6, where 0 is no symptoms at all and 6 indicates death. Higher scores indicate worse outcome. The proportion (%) of participants with an mRS score of 0 to 2 at Day 5 (baseline) and Day 90 is being reported.

End point type

Secondary

End point timeframe

Day 5 (baseline) and Day 90 post dose

End point values	Cohort 1: DS-1040b 0.6 mg	Cohort 2: DS-1040b 1.2 mg	Cohort 3: DS-1040b 2.4 mg	Cohort 4: DS-1040 4.8 mg	Cohort 5: DS-1040b 7.2 mg	Cohort 6: DS-1040b 9.6 mg	Placebo	All DS-1040b
Number of subjects analysed	7	6	13	17	18	16	24	77
Units: Percentage of subjects
number (not applicable)
Day 5 (baseline)	66.7	40.0	76.9	82.4	72.2	53.3	54.2	68.9
Day 90 postdose	85.7	60.0	76.9	82.4	93.8	68.8	75.0	79.7

No statistical analyses for this end point

Adverse events

Top of page

Timeframe for reporting adverse events

Treatment-emergent adverse events (TEAEs) were collected from baseline up to 30 days post last dose, up to 3 years 11 months.

Adverse event reporting additional description

A TEAE is defined as an adverse event (AE) that emerges from first dose date until 30 days after the last dose, having been absent at predose; or reemerges during treatment, having been present at baseline but stopped prior to treatment; or worsens in severity after starting treatment relative to the pre-dose state, when the AE is continuous.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

17.1

Reporting group title

Cohort 1: DS-1040b 0.6 mg

Reporting group description

Subjects who received a single intravenous infusion of DS-1040b 0.6 mg.

Reporting group title

Cohort 2: DS-1040b 1.2 mg

Reporting group description

Subjects who received a single intravenous infusion of DS-1040b 1.2 mg.

Reporting group title

Cohort 3: DS-1040b 2.4 mg

Reporting group description

Subjects who received a single intravenous infusion of DS-1040b 2.4 mg.

Reporting group title

Cohort 4: DS-1040 4.8 mg

Reporting group description

Subjects who received a single intravenous infusion of DS-1040b 4.8 mg.

Reporting group title

Cohort 5: DS-1040b 7.2 mg

Reporting group description

Subjects who received a single intravenous infusion of DS-1040b 7.2 mg.

Reporting group title

Cohort 6: DS-1040b 9.6 mg

Reporting group description

Subjects who received a single intravenous infusion of DS-1040b 9.6 mg.

Reporting group title

Placebo

Reporting group description

Subjects who received a single intravenous infusion of placebo.

Reporting group title

All DS-1040b

Reporting group description

All subjects who received a single intravenous infusion of DS-1040b.

Serious adverse events	Cohort 1: DS-1040b 0.6 mg	Cohort 2: DS-1040b 1.2 mg	Cohort 3: DS-1040b 2.4 mg	Cohort 4: DS-1040 4.8 mg	Cohort 5: DS-1040b 7.2 mg	Cohort 6: DS-1040b 9.6 mg	Placebo	All DS-1040b
Total subjects affected by serious adverse events
subjects affected / exposed	1 / 7 (14.29%)	4 / 6 (66.67%)	0 / 13 (0.00%)	1 / 17 (5.88%)	2 / 18 (11.11%)	2 / 16 (12.50%)	4 / 24 (16.67%)	10 / 77 (12.99%)
number of deaths (all causes)	0	1	0	0	2	0	0	3
number of deaths resulting from adverse events	0	0	0	0	0	0	0	0
Vascular disorders
Haematoma
subjects affected / exposed	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 13 (0.00%)	1 / 17 (5.88%)	0 / 18 (0.00%)	0 / 16 (0.00%)	0 / 24 (0.00%)	1 / 77 (1.30%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cardiac disorders
Cardiac arrest
subjects affected / exposed	0 / 7 (0.00%)	1 / 6 (16.67%)	0 / 13 (0.00%)	0 / 17 (0.00%)	0 / 18 (0.00%)	0 / 16 (0.00%)	1 / 24 (4.17%)	1 / 77 (1.30%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
Nervous system disorders
Carotid arteriosclerosis
subjects affected / exposed	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 13 (0.00%)	0 / 17 (0.00%)	1 / 18 (5.56%)	0 / 16 (0.00%)	0 / 24 (0.00%)	1 / 77 (1.30%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Carotid artery stenosis
subjects affected / exposed	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 13 (0.00%)	0 / 17 (0.00%)	1 / 18 (5.56%)	0 / 16 (0.00%)	0 / 24 (0.00%)	1 / 77 (1.30%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cerebrovascular accident
subjects affected / exposed	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 13 (0.00%)	0 / 17 (0.00%)	0 / 18 (0.00%)	0 / 16 (0.00%)	1 / 24 (4.17%)	0 / 77 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Haemorrhage intracranial
subjects affected / exposed	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 13 (0.00%)	0 / 17 (0.00%)	0 / 18 (0.00%)	1 / 16 (6.25%)	0 / 24 (0.00%)	1 / 77 (1.30%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Simple partial seizures
subjects affected / exposed	1 / 7 (14.29%)	0 / 6 (0.00%)	0 / 13 (0.00%)	0 / 17 (0.00%)	0 / 18 (0.00%)	0 / 16 (0.00%)	0 / 24 (0.00%)	1 / 77 (1.30%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Spinal cord infarction
subjects affected / exposed	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 13 (0.00%)	0 / 17 (0.00%)	0 / 18 (0.00%)	0 / 16 (0.00%)	1 / 24 (4.17%)	0 / 77 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hepatobiliary disorders
Cholestasis
subjects affected / exposed	0 / 7 (0.00%)	1 / 6 (16.67%)	0 / 13 (0.00%)	0 / 17 (0.00%)	0 / 18 (0.00%)	0 / 16 (0.00%)	0 / 24 (0.00%)	1 / 77 (1.30%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hepatocellular injury
subjects affected / exposed	0 / 7 (0.00%)	1 / 6 (16.67%)	0 / 13 (0.00%)	0 / 17 (0.00%)	0 / 18 (0.00%)	0 / 16 (0.00%)	0 / 24 (0.00%)	1 / 77 (1.30%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Pulmonary embolism
subjects affected / exposed	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 13 (0.00%)	0 / 17 (0.00%)	0 / 18 (0.00%)	0 / 16 (0.00%)	1 / 24 (4.17%)	0 / 77 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Psychiatric disorders
Agitation
subjects affected / exposed	0 / 7 (0.00%)	1 / 6 (16.67%)	0 / 13 (0.00%)	0 / 17 (0.00%)	0 / 18 (0.00%)	0 / 16 (0.00%)	0 / 24 (0.00%)	1 / 77 (1.30%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Renal and urinary disorders
Renal failure acute
subjects affected / exposed	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 13 (0.00%)	0 / 17 (0.00%)	0 / 18 (0.00%)	1 / 16 (6.25%)	0 / 24 (0.00%)	1 / 77 (1.30%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Infections and infestations
Escherichia urinary tract infection
subjects affected / exposed	0 / 7 (0.00%)	1 / 6 (16.67%)	0 / 13 (0.00%)	0 / 17 (0.00%)	0 / 18 (0.00%)	0 / 16 (0.00%)	0 / 24 (0.00%)	1 / 77 (1.30%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pneumonia
subjects affected / exposed	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 13 (0.00%)	0 / 17 (0.00%)	0 / 18 (0.00%)	1 / 16 (6.25%)	0 / 24 (0.00%)	1 / 77 (1.30%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Urosepsis
subjects affected / exposed	0 / 7 (0.00%)	1 / 6 (16.67%)	0 / 13 (0.00%)	0 / 17 (0.00%)	0 / 18 (0.00%)	0 / 16 (0.00%)	0 / 24 (0.00%)	1 / 77 (1.30%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0

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

Non-serious adverse events	Cohort 1: DS-1040b 0.6 mg	Cohort 2: DS-1040b 1.2 mg	Cohort 3: DS-1040b 2.4 mg	Cohort 4: DS-1040 4.8 mg	Cohort 5: DS-1040b 7.2 mg	Cohort 6: DS-1040b 9.6 mg	Placebo	All DS-1040b
Total subjects affected by non serious adverse events
subjects affected / exposed	5 / 7 (71.43%)	5 / 6 (83.33%)	10 / 13 (76.92%)	15 / 17 (88.24%)	14 / 18 (77.78%)	14 / 16 (87.50%)	18 / 24 (75.00%)	63 / 77 (81.82%)
Vascular disorders
Arteriosclerosis
subjects affected / exposed	1 / 7 (14.29%)	0 / 6 (0.00%)	0 / 13 (0.00%)	0 / 17 (0.00%)	0 / 18 (0.00%)	0 / 16 (0.00%)	0 / 24 (0.00%)	1 / 77 (1.30%)
occurrences all number	1	0	0	0	0	0	0	1
Haematoma
subjects affected / exposed	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 13 (0.00%)	1 / 17 (5.88%)	0 / 18 (0.00%)	1 / 16 (6.25%)	0 / 24 (0.00%)	2 / 77 (2.60%)
occurrences all number	0	0	0	1	0	1	0	2
Hypertension
subjects affected / exposed	0 / 7 (0.00%)	0 / 6 (0.00%)	1 / 13 (7.69%)	3 / 17 (17.65%)	1 / 18 (5.56%)	0 / 16 (0.00%)	3 / 24 (12.50%)	5 / 77 (6.49%)
occurrences all number	0	0	1	3	1	0	3	5
Hypotension
subjects affected / exposed	0 / 7 (0.00%)	1 / 6 (16.67%)	0 / 13 (0.00%)	0 / 17 (0.00%)	0 / 18 (0.00%)	0 / 16 (0.00%)	1 / 24 (4.17%)	1 / 77 (1.30%)
occurrences all number	0	1	0	0	0	0	1	1
General disorders and administration site conditions
Asthenia
subjects affected / exposed	0 / 7 (0.00%)	1 / 6 (16.67%)	0 / 13 (0.00%)	0 / 17 (0.00%)	0 / 18 (0.00%)	0 / 16 (0.00%)	0 / 24 (0.00%)	1 / 77 (1.30%)
occurrences all number	0	1	0	0	0	0	0	1
Chest discomfort
subjects affected / exposed	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 13 (0.00%)	1 / 17 (5.88%)	0 / 18 (0.00%)	0 / 16 (0.00%)	0 / 24 (0.00%)	1 / 77 (1.30%)
occurrences all number	0	0	0	1	0	0	0	1
Chest pain
subjects affected / exposed	0 / 7 (0.00%)	1 / 6 (16.67%)	1 / 13 (7.69%)	0 / 17 (0.00%)	0 / 18 (0.00%)	0 / 16 (0.00%)	0 / 24 (0.00%)	2 / 77 (2.60%)
occurrences all number	0	1	1	0	0	0	0	2
Fatigue
subjects affected / exposed	1 / 7 (14.29%)	0 / 6 (0.00%)	0 / 13 (0.00%)	1 / 17 (5.88%)	1 / 18 (5.56%)	1 / 16 (6.25%)	0 / 24 (0.00%)	4 / 77 (5.19%)
occurrences all number	1	0	0	1	1	1	0	4
Inflammation
subjects affected / exposed	0 / 7 (0.00%)	0 / 6 (0.00%)	1 / 13 (7.69%)	0 / 17 (0.00%)	0 / 18 (0.00%)	0 / 16 (0.00%)	0 / 24 (0.00%)	1 / 77 (1.30%)
occurrences all number	0	0	1	0	0	0	0	1
Influenza like illness
subjects affected / exposed	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 13 (0.00%)	0 / 17 (0.00%)	0 / 18 (0.00%)	1 / 16 (6.25%)	0 / 24 (0.00%)	1 / 77 (1.30%)
occurrences all number	0	0	0	0	0	1	0	1
Infusion site phlebitis
subjects affected / exposed	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 13 (0.00%)	0 / 17 (0.00%)	0 / 18 (0.00%)	1 / 16 (6.25%)	0 / 24 (0.00%)	1 / 77 (1.30%)
occurrences all number	0	0	0	0	0	1	0	1
Pain
subjects affected / exposed	0 / 7 (0.00%)	1 / 6 (16.67%)	0 / 13 (0.00%)	1 / 17 (5.88%)	0 / 18 (0.00%)	0 / 16 (0.00%)	0 / 24 (0.00%)	2 / 77 (2.60%)
occurrences all number	0	1	0	1	0	0	0	2
Peripheral swelling
subjects affected / exposed	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 13 (0.00%)	1 / 17 (5.88%)	0 / 18 (0.00%)	0 / 16 (0.00%)	0 / 24 (0.00%)	1 / 77 (1.30%)
occurrences all number	0	0	0	1	0	0	0	1
Pyrexia
subjects affected / exposed	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 13 (0.00%)	1 / 17 (5.88%)	0 / 18 (0.00%)	0 / 16 (0.00%)	3 / 24 (12.50%)	1 / 77 (1.30%)
occurrences all number	0	0	0	1	0	0	3	1
Vessel puncture site pain
subjects affected / exposed	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 13 (0.00%)	1 / 17 (5.88%)	0 / 18 (0.00%)	0 / 16 (0.00%)	0 / 24 (0.00%)	1 / 77 (1.30%)
occurrences all number	0	0	0	1	0	0	0	1
Respiratory, thoracic and mediastinal disorders
Bronchiectasis
subjects affected / exposed	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 13 (0.00%)	0 / 17 (0.00%)	1 / 18 (5.56%)	0 / 16 (0.00%)	0 / 24 (0.00%)	1 / 77 (1.30%)
occurrences all number	0	0	0	0	1	0	0	1
Cough
subjects affected / exposed	1 / 7 (14.29%)	0 / 6 (0.00%)	0 / 13 (0.00%)	0 / 17 (0.00%)	2 / 18 (11.11%)	0 / 16 (0.00%)	1 / 24 (4.17%)	3 / 77 (3.90%)
occurrences all number	1	0	0	0	2	0	1	3
Dyspnoea
subjects affected / exposed	0 / 7 (0.00%)	0 / 6 (0.00%)	1 / 13 (7.69%)	0 / 17 (0.00%)	0 / 18 (0.00%)	0 / 16 (0.00%)	1 / 24 (4.17%)	1 / 77 (1.30%)
occurrences all number	0	0	1	0	0	0	1	1
Hypoxia
subjects affected / exposed	0 / 7 (0.00%)	1 / 6 (16.67%)	0 / 13 (0.00%)	0 / 17 (0.00%)	0 / 18 (0.00%)	0 / 16 (0.00%)	0 / 24 (0.00%)	1 / 77 (1.30%)
occurrences all number	0	1	0	0	0	0	0	1
Nasal obstruction
subjects affected / exposed	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 13 (0.00%)	0 / 17 (0.00%)	0 / 18 (0.00%)	1 / 16 (6.25%)	0 / 24 (0.00%)	1 / 77 (1.30%)
occurrences all number	0	0	0	0	0	1	0	1
Oropharyngeal pain
subjects affected / exposed	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 13 (0.00%)	0 / 17 (0.00%)	0 / 18 (0.00%)	1 / 16 (6.25%)	0 / 24 (0.00%)	1 / 77 (1.30%)
occurrences all number	0	0	0	0	0	1	0	1
Productive cough
subjects affected / exposed	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 13 (0.00%)	0 / 17 (0.00%)	1 / 18 (5.56%)	0 / 16 (0.00%)	0 / 24 (0.00%)	1 / 77 (1.30%)
occurrences all number	0	0	0	0	1	0	0	1
Pulmonary mass
subjects affected / exposed	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 13 (0.00%)	0 / 17 (0.00%)	0 / 18 (0.00%)	1 / 16 (6.25%)	0 / 24 (0.00%)	1 / 77 (1.30%)
occurrences all number	0	0	0	0	0	1	0	1
Pulmonary oedema
subjects affected / exposed	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 13 (0.00%)	1 / 17 (5.88%)	0 / 18 (0.00%)	0 / 16 (0.00%)	0 / 24 (0.00%)	1 / 77 (1.30%)
occurrences all number	0	0	0	1	0	0	0	1
Respiratory failure
subjects affected / exposed	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 13 (0.00%)	0 / 17 (0.00%)	1 / 18 (5.56%)	1 / 16 (6.25%)	0 / 24 (0.00%)	2 / 77 (2.60%)
occurrences all number	0	0	0	0	1	1	0	2
Rhinorrhoea
subjects affected / exposed	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 13 (0.00%)	0 / 17 (0.00%)	0 / 18 (0.00%)	0 / 16 (0.00%)	2 / 24 (8.33%)	0 / 77 (0.00%)
occurrences all number	0	0	0	0	0	0	2	0
Psychiatric disorders
Affective disorder
subjects affected / exposed	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 13 (0.00%)	1 / 17 (5.88%)	0 / 18 (0.00%)	0 / 16 (0.00%)	0 / 24 (0.00%)	1 / 77 (1.30%)
occurrences all number	0	0	0	1	0	0	0	1
Agitation
subjects affected / exposed	0 / 7 (0.00%)	1 / 6 (16.67%)	0 / 13 (0.00%)	0 / 17 (0.00%)	1 / 18 (5.56%)	1 / 16 (6.25%)	0 / 24 (0.00%)	3 / 77 (3.90%)
occurrences all number	0	1	0	0	1	1	0	3
Anxiety
subjects affected / exposed	0 / 7 (0.00%)	1 / 6 (16.67%)	0 / 13 (0.00%)	0 / 17 (0.00%)	0 / 18 (0.00%)	2 / 16 (12.50%)	3 / 24 (12.50%)	3 / 77 (3.90%)
occurrences all number	0	1	0	0	0	2	3	3
Confusional state
subjects affected / exposed	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 13 (0.00%)	1 / 17 (5.88%)	0 / 18 (0.00%)	1 / 16 (6.25%)	0 / 24 (0.00%)	2 / 77 (2.60%)
occurrences all number	0	0	0	1	0	1	0	2
Delirium
subjects affected / exposed	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 13 (0.00%)	0 / 17 (0.00%)	0 / 18 (0.00%)	0 / 16 (0.00%)	2 / 24 (8.33%)	0 / 77 (0.00%)
occurrences all number	0	0	0	0	0	0	2	0
Depressed mood
subjects affected / exposed	0 / 7 (0.00%)	0 / 6 (0.00%)	1 / 13 (7.69%)	1 / 17 (5.88%)	0 / 18 (0.00%)	0 / 16 (0.00%)	0 / 24 (0.00%)	2 / 77 (2.60%)
occurrences all number	0	0	1	1	0	0	0	2
Depression
subjects affected / exposed	0 / 7 (0.00%)	0 / 6 (0.00%)	1 / 13 (7.69%)	1 / 17 (5.88%)	0 / 18 (0.00%)	0 / 16 (0.00%)	2 / 24 (8.33%)	2 / 77 (2.60%)
occurrences all number	0	0	1	1	0	0	2	2
Hallucination
subjects affected / exposed	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 13 (0.00%)	0 / 17 (0.00%)	0 / 18 (0.00%)	1 / 16 (6.25%)	0 / 24 (0.00%)	1 / 77 (1.30%)
occurrences all number	0	0	0	0	0	1	0	1
Insomnia
subjects affected / exposed	0 / 7 (0.00%)	0 / 6 (0.00%)	1 / 13 (7.69%)	0 / 17 (0.00%)	1 / 18 (5.56%)	3 / 16 (18.75%)	5 / 24 (20.83%)	5 / 77 (6.49%)
occurrences all number	0	0	1	0	1	3	5	5
Mood altered
subjects affected / exposed	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 13 (0.00%)	1 / 17 (5.88%)	0 / 18 (0.00%)	0 / 16 (0.00%)	0 / 24 (0.00%)	1 / 77 (1.30%)
occurrences all number	0	0	0	1	0	0	0	1
Sleep disorder
subjects affected / exposed	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 13 (0.00%)	0 / 17 (0.00%)	1 / 18 (5.56%)	0 / 16 (0.00%)	1 / 24 (4.17%)	1 / 77 (1.30%)
occurrences all number	0	0	0	0	1	0	1	1
Investigations
Activated partial thromboplastin time prolonged
subjects affected / exposed	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 13 (0.00%)	0 / 17 (0.00%)	0 / 18 (0.00%)	0 / 16 (0.00%)	2 / 24 (8.33%)	0 / 77 (0.00%)
occurrences all number	0	0	0	0	0	0	2	0
Biopsy bone
subjects affected / exposed	0 / 7 (0.00%)	0 / 6 (0.00%)	1 / 13 (7.69%)	0 / 17 (0.00%)	0 / 18 (0.00%)	0 / 16 (0.00%)	0 / 24 (0.00%)	1 / 77 (1.30%)
occurrences all number	0	0	1	0	0	0	0	1
Blood albumin decreased
subjects affected / exposed	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 13 (0.00%)	0 / 17 (0.00%)	1 / 18 (5.56%)	0 / 16 (0.00%)	0 / 24 (0.00%)	1 / 77 (1.30%)
occurrences all number	0	0	0	0	1	0	0	1
Blood bicarbonate decreased
subjects affected / exposed	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 13 (0.00%)	0 / 17 (0.00%)	0 / 18 (0.00%)	0 / 16 (0.00%)	2 / 24 (8.33%)	0 / 77 (0.00%)
occurrences all number	0	0	0	0	0	0	2	0
Blood creatinine increased
subjects affected / exposed	1 / 7 (14.29%)	0 / 6 (0.00%)	0 / 13 (0.00%)	0 / 17 (0.00%)	0 / 18 (0.00%)	0 / 16 (0.00%)	0 / 24 (0.00%)	1 / 77 (1.30%)
occurrences all number	1	0	0	0	0	0	0	1
Blood fibrinogen increased
subjects affected / exposed	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 13 (0.00%)	1 / 17 (5.88%)	0 / 18 (0.00%)	0 / 16 (0.00%)	2 / 24 (8.33%)	1 / 77 (1.30%)
occurrences all number	0	0	0	1	0	0	2	1
Blood glucose increased
subjects affected / exposed	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 13 (0.00%)	1 / 17 (5.88%)	0 / 18 (0.00%)	0 / 16 (0.00%)	0 / 24 (0.00%)	1 / 77 (1.30%)
occurrences all number	0	0	0	1	0	0	0	1
Body temperature increased
subjects affected / exposed	1 / 7 (14.29%)	0 / 6 (0.00%)	0 / 13 (0.00%)	0 / 17 (0.00%)	0 / 18 (0.00%)	0 / 16 (0.00%)	0 / 24 (0.00%)	1 / 77 (1.30%)
occurrences all number	1	0	0	0	0	0	0	1
Ejection fraction decreased
subjects affected / exposed	1 / 7 (14.29%)	0 / 6 (0.00%)	0 / 13 (0.00%)	0 / 17 (0.00%)	0 / 18 (0.00%)	0 / 16 (0.00%)	0 / 24 (0.00%)	1 / 77 (1.30%)
occurrences all number	1	0	0	0	0	0	0	1
Electrocardiogram QT prolonged
subjects affected / exposed	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 13 (0.00%)	0 / 17 (0.00%)	1 / 18 (5.56%)	0 / 16 (0.00%)	0 / 24 (0.00%)	1 / 77 (1.30%)
occurrences all number	0	0	0	0	1	0	0	1
Red blood cell sedimentation rate increased
subjects affected / exposed	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 13 (0.00%)	1 / 17 (5.88%)	0 / 18 (0.00%)	0 / 16 (0.00%)	0 / 24 (0.00%)	1 / 77 (1.30%)
occurrences all number	0	0	0	1	0	0	0	1
Vitamin D decreased
subjects affected / exposed	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 13 (0.00%)	1 / 17 (5.88%)	0 / 18 (0.00%)	0 / 16 (0.00%)	0 / 24 (0.00%)	1 / 77 (1.30%)
occurrences all number	0	0	0	1	0	0	0	1
Injury, poisoning and procedural complications
Fall
subjects affected / exposed	1 / 7 (14.29%)	0 / 6 (0.00%)	1 / 13 (7.69%)	1 / 17 (5.88%)	0 / 18 (0.00%)	1 / 16 (6.25%)	1 / 24 (4.17%)	4 / 77 (5.19%)
occurrences all number	1	0	1	1	0	1	1	4
Joint injury
subjects affected / exposed	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 13 (0.00%)	0 / 17 (0.00%)	1 / 18 (5.56%)	0 / 16 (0.00%)	0 / 24 (0.00%)	1 / 77 (1.30%)
occurrences all number	0	0	0	0	1	0	0	1
Post procedural haematuria
subjects affected / exposed	0 / 7 (0.00%)	1 / 6 (16.67%)	0 / 13 (0.00%)	0 / 17 (0.00%)	0 / 18 (0.00%)	0 / 16 (0.00%)	0 / 24 (0.00%)	1 / 77 (1.30%)
occurrences all number	0	1	0	0	0	0	0	1
Wound
subjects affected / exposed	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 13 (0.00%)	0 / 17 (0.00%)	1 / 18 (5.56%)	0 / 16 (0.00%)	0 / 24 (0.00%)	1 / 77 (1.30%)
occurrences all number	0	0	0	0	1	0	0	1
Cardiac disorders
Atrial fibrillation
subjects affected / exposed	1 / 7 (14.29%)	0 / 6 (0.00%)	1 / 13 (7.69%)	0 / 17 (0.00%)	1 / 18 (5.56%)	1 / 16 (6.25%)	1 / 24 (4.17%)	4 / 77 (5.19%)
occurrences all number	1	0	1	0	1	1	1	4
Bradycardia
subjects affected / exposed	0 / 7 (0.00%)	1 / 6 (16.67%)	0 / 13 (0.00%)	0 / 17 (0.00%)	0 / 18 (0.00%)	1 / 16 (6.25%)	0 / 24 (0.00%)	2 / 77 (2.60%)
occurrences all number	0	1	0	0	0	1	0	2
Cardiac arrest
subjects affected / exposed	0 / 7 (0.00%)	1 / 6 (16.67%)	0 / 13 (0.00%)	0 / 17 (0.00%)	0 / 18 (0.00%)	0 / 16 (0.00%)	1 / 24 (4.17%)	1 / 77 (1.30%)
occurrences all number	0	1	0	0	0	0	1	1
Left ventricular dysfunction
subjects affected / exposed	1 / 7 (14.29%)	0 / 6 (0.00%)	1 / 13 (7.69%)	0 / 17 (0.00%)	0 / 18 (0.00%)	0 / 16 (0.00%)	0 / 24 (0.00%)	2 / 77 (2.60%)
occurrences all number	1	0	1	0	0	0	0	2
Sinus tachycardia
subjects affected / exposed	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 13 (0.00%)	0 / 17 (0.00%)	1 / 18 (5.56%)	0 / 16 (0.00%)	0 / 24 (0.00%)	1 / 77 (1.30%)
occurrences all number	0	0	0	0	1	0	0	1
Tachycardia
subjects affected / exposed	0 / 7 (0.00%)	1 / 6 (16.67%)	0 / 13 (0.00%)	0 / 17 (0.00%)	0 / 18 (0.00%)	0 / 16 (0.00%)	0 / 24 (0.00%)	1 / 77 (1.30%)
occurrences all number	0	1	0	0	0	0	0	1
Ventricular extrasystoles
subjects affected / exposed	1 / 7 (14.29%)	0 / 6 (0.00%)	0 / 13 (0.00%)	0 / 17 (0.00%)	0 / 18 (0.00%)	0 / 16 (0.00%)	0 / 24 (0.00%)	1 / 77 (1.30%)
occurrences all number	1	0	0	0	0	0	0	1
Nervous system disorders
Burning sensation
subjects affected / exposed	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 13 (0.00%)	0 / 17 (0.00%)	0 / 18 (0.00%)	1 / 16 (6.25%)	0 / 24 (0.00%)	1 / 77 (1.30%)
occurrences all number	0	0	0	0	0	1	0	1
Carotid arteriosclerosis
subjects affected / exposed	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 13 (0.00%)	0 / 17 (0.00%)	1 / 18 (5.56%)	0 / 16 (0.00%)	0 / 24 (0.00%)	1 / 77 (1.30%)
occurrences all number	0	0	0	0	1	0	0	1
Carotid artery stenosis
subjects affected / exposed	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 13 (0.00%)	0 / 17 (0.00%)	1 / 18 (5.56%)	0 / 16 (0.00%)	0 / 24 (0.00%)	1 / 77 (1.30%)
occurrences all number	0	0	0	0	1	0	0	1
Carpal tunnel syndrome
subjects affected / exposed	0 / 7 (0.00%)	0 / 6 (0.00%)	1 / 13 (7.69%)	0 / 17 (0.00%)	0 / 18 (0.00%)	0 / 16 (0.00%)	0 / 24 (0.00%)	1 / 77 (1.30%)
occurrences all number	0	0	1	0	0	0	0	1
Cerebral haemorrhage
subjects affected / exposed	1 / 7 (14.29%)	0 / 6 (0.00%)	0 / 13 (0.00%)	0 / 17 (0.00%)	0 / 18 (0.00%)	0 / 16 (0.00%)	0 / 24 (0.00%)	1 / 77 (1.30%)
occurrences all number	1	0	0	0	0	0	0	1
Cerebrovascular accident
subjects affected / exposed	1 / 7 (14.29%)	0 / 6 (0.00%)	1 / 13 (7.69%)	0 / 17 (0.00%)	0 / 18 (0.00%)	0 / 16 (0.00%)	1 / 24 (4.17%)	2 / 77 (2.60%)
occurrences all number	1	0	1	0	0	0	1	2
Circadian rhythm sleep disorder
subjects affected / exposed	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 13 (0.00%)	0 / 17 (0.00%)	1 / 18 (5.56%)	0 / 16 (0.00%)	0 / 24 (0.00%)	1 / 77 (1.30%)
occurrences all number	0	0	0	0	1	0	0	1
Dizziness
subjects affected / exposed	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 13 (0.00%)	0 / 17 (0.00%)	0 / 18 (0.00%)	1 / 16 (6.25%)	1 / 24 (4.17%)	1 / 77 (1.30%)
occurrences all number	0	0	0	0	0	1	1	1
Dysaesthesia
subjects affected / exposed	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 13 (0.00%)	1 / 17 (5.88%)	0 / 18 (0.00%)	0 / 16 (0.00%)	0 / 24 (0.00%)	1 / 77 (1.30%)
occurrences all number	0	0	0	1	0	0	0	1
Haemorrhage intracranial
subjects affected / exposed	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 13 (0.00%)	0 / 17 (0.00%)	0 / 18 (0.00%)	1 / 16 (6.25%)	1 / 24 (4.17%)	1 / 77 (1.30%)
occurrences all number	0	0	0	0	0	1	1	1
Haemorrhagic stroke
subjects affected / exposed	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 13 (0.00%)	0 / 17 (0.00%)	0 / 18 (0.00%)	1 / 16 (6.25%)	0 / 24 (0.00%)	1 / 77 (1.30%)
occurrences all number	0	0	0	0	0	1	0	1
Headache
subjects affected / exposed	3 / 7 (42.86%)	1 / 6 (16.67%)	2 / 13 (15.38%)	2 / 17 (11.76%)	1 / 18 (5.56%)	4 / 16 (25.00%)	2 / 24 (8.33%)	13 / 77 (16.88%)
occurrences all number	3	1	2	2	1	4	2	13
Memory impairment
subjects affected / exposed	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 13 (0.00%)	1 / 17 (5.88%)	1 / 18 (5.56%)	0 / 16 (0.00%)	0 / 24 (0.00%)	2 / 77 (2.60%)
occurrences all number	0	0	0	1	1	0	0	2
Partial seizures
subjects affected / exposed	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 13 (0.00%)	1 / 17 (5.88%)	0 / 18 (0.00%)	0 / 16 (0.00%)	0 / 24 (0.00%)	1 / 77 (1.30%)
occurrences all number	0	0	0	1	0	0	0	1
Psychomotor hyperactivity
subjects affected / exposed	0 / 7 (0.00%)	0 / 6 (0.00%)	1 / 13 (7.69%)	1 / 17 (5.88%)	0 / 18 (0.00%)	1 / 16 (6.25%)	0 / 24 (0.00%)	3 / 77 (3.90%)
occurrences all number	0	0	1	1	0	1	0	3
Sedation
subjects affected / exposed	0 / 7 (0.00%)	1 / 6 (16.67%)	0 / 13 (0.00%)	0 / 17 (0.00%)	0 / 18 (0.00%)	0 / 16 (0.00%)	0 / 24 (0.00%)	1 / 77 (1.30%)
occurrences all number	0	1	0	0	0	0	0	1
Simple partial seizures
subjects affected / exposed	1 / 7 (14.29%)	0 / 6 (0.00%)	0 / 13 (0.00%)	0 / 17 (0.00%)	0 / 18 (0.00%)	0 / 16 (0.00%)	0 / 24 (0.00%)	1 / 77 (1.30%)
occurrences all number	1	0	0	0	0	0	0	1
Somnolence
subjects affected / exposed	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 13 (0.00%)	0 / 17 (0.00%)	0 / 18 (0.00%)	1 / 16 (6.25%)	0 / 24 (0.00%)	1 / 77 (1.30%)
occurrences all number	0	0	0	0	0	1	0	1
Stroke in evolution
subjects affected / exposed	0 / 7 (0.00%)	1 / 6 (16.67%)	0 / 13 (0.00%)	0 / 17 (0.00%)	0 / 18 (0.00%)	0 / 16 (0.00%)	0 / 24 (0.00%)	1 / 77 (1.30%)
occurrences all number	0	1	0	0	0	0	0	1
Syncope
subjects affected / exposed	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 13 (0.00%)	0 / 17 (0.00%)	0 / 18 (0.00%)	1 / 16 (6.25%)	0 / 24 (0.00%)	1 / 77 (1.30%)
occurrences all number	0	0	0	0	0	1	0	1
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	0 / 7 (0.00%)	1 / 6 (16.67%)	2 / 13 (15.38%)	0 / 17 (0.00%)	1 / 18 (5.56%)	0 / 16 (0.00%)	2 / 24 (8.33%)	4 / 77 (5.19%)
occurrences all number	0	1	2	0	1	0	2	4
Hyperfibrinogenaemia
subjects affected / exposed	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 13 (0.00%)	0 / 17 (0.00%)	1 / 18 (5.56%)	0 / 16 (0.00%)	0 / 24 (0.00%)	1 / 77 (1.30%)
occurrences all number	0	0	0	0	1	0	0	1
Leukocytosis
subjects affected / exposed	1 / 7 (14.29%)	1 / 6 (16.67%)	1 / 13 (7.69%)	1 / 17 (5.88%)	2 / 18 (11.11%)	0 / 16 (0.00%)	2 / 24 (8.33%)	6 / 77 (7.79%)
occurrences all number	1	1	1	1	2	0	2	6
Thrombocytopenia
subjects affected / exposed	0 / 7 (0.00%)	1 / 6 (16.67%)	0 / 13 (0.00%)	0 / 17 (0.00%)	0 / 18 (0.00%)	0 / 16 (0.00%)	3 / 24 (12.50%)	1 / 77 (1.30%)
occurrences all number	0	1	0	0	0	0	3	1
Eye disorders
Conjunctival haemorrhage
subjects affected / exposed	0 / 7 (0.00%)	0 / 6 (0.00%)	1 / 13 (7.69%)	0 / 17 (0.00%)	0 / 18 (0.00%)	0 / 16 (0.00%)	0 / 24 (0.00%)	1 / 77 (1.30%)
occurrences all number	0	0	1	0	0	0	0	1
Dry eye
subjects affected / exposed	0 / 7 (0.00%)	0 / 6 (0.00%)	1 / 13 (7.69%)	0 / 17 (0.00%)	0 / 18 (0.00%)	0 / 16 (0.00%)	0 / 24 (0.00%)	1 / 77 (1.30%)
occurrences all number	0	0	1	0	0	0	0	1
Vision blurred
subjects affected / exposed	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 13 (0.00%)	0 / 17 (0.00%)	0 / 18 (0.00%)	1 / 16 (6.25%)	0 / 24 (0.00%)	1 / 77 (1.30%)
occurrences all number	0	0	0	0	0	1	0	1
Gastrointestinal disorders
Abdominal pain upper
subjects affected / exposed	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 13 (0.00%)	0 / 17 (0.00%)	1 / 18 (5.56%)	0 / 16 (0.00%)	1 / 24 (4.17%)	1 / 77 (1.30%)
occurrences all number	0	0	0	0	1	0	1	1
Constipation
subjects affected / exposed	1 / 7 (14.29%)	2 / 6 (33.33%)	3 / 13 (23.08%)	1 / 17 (5.88%)	5 / 18 (27.78%)	2 / 16 (12.50%)	5 / 24 (20.83%)	14 / 77 (18.18%)
occurrences all number	1	2	3	1	5	2	5	14
Diarrhoea
subjects affected / exposed	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 13 (0.00%)	0 / 17 (0.00%)	0 / 18 (0.00%)	2 / 16 (12.50%)	1 / 24 (4.17%)	2 / 77 (2.60%)
occurrences all number	0	0	0	0	0	2	1	2
Dyspepsia
subjects affected / exposed	0 / 7 (0.00%)	0 / 6 (0.00%)	1 / 13 (7.69%)	0 / 17 (0.00%)	0 / 18 (0.00%)	0 / 16 (0.00%)	0 / 24 (0.00%)	1 / 77 (1.30%)
occurrences all number	0	0	1	0	0	0	0	1
Dysphagia
subjects affected / exposed	0 / 7 (0.00%)	0 / 6 (0.00%)	1 / 13 (7.69%)	0 / 17 (0.00%)	0 / 18 (0.00%)	1 / 16 (6.25%)	1 / 24 (4.17%)	2 / 77 (2.60%)
occurrences all number	0	0	1	0	0	1	1	2
Nausea
subjects affected / exposed	0 / 7 (0.00%)	0 / 6 (0.00%)	2 / 13 (15.38%)	2 / 17 (11.76%)	0 / 18 (0.00%)	2 / 16 (12.50%)	2 / 24 (8.33%)	6 / 77 (7.79%)
occurrences all number	0	0	2	2	0	2	2	6
Toothache
subjects affected / exposed	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 13 (0.00%)	0 / 17 (0.00%)	1 / 18 (5.56%)	0 / 16 (0.00%)	0 / 24 (0.00%)	1 / 77 (1.30%)
occurrences all number	0	0	0	0	1	0	0	1
Vomiting
subjects affected / exposed	0 / 7 (0.00%)	1 / 6 (16.67%)	0 / 13 (0.00%)	0 / 17 (0.00%)	0 / 18 (0.00%)	0 / 16 (0.00%)	3 / 24 (12.50%)	1 / 77 (1.30%)
occurrences all number	0	1	0	0	0	0	3	1
Hepatobiliary disorders
Cholestasis
subjects affected / exposed	0 / 7 (0.00%)	1 / 6 (16.67%)	0 / 13 (0.00%)	0 / 17 (0.00%)	0 / 18 (0.00%)	0 / 16 (0.00%)	0 / 24 (0.00%)	1 / 77 (1.30%)
occurrences all number	0	1	0	0	0	0	0	1
Hepatocellular injury
subjects affected / exposed	0 / 7 (0.00%)	1 / 6 (16.67%)	0 / 13 (0.00%)	0 / 17 (0.00%)	0 / 18 (0.00%)	0 / 16 (0.00%)	0 / 24 (0.00%)	1 / 77 (1.30%)
occurrences all number	0	1	0	0	0	0	0	1
Skin and subcutaneous tissue disorders
Angioedema
subjects affected / exposed	1 / 7 (14.29%)	0 / 6 (0.00%)	0 / 13 (0.00%)	0 / 17 (0.00%)	0 / 18 (0.00%)	0 / 16 (0.00%)	0 / 24 (0.00%)	1 / 77 (1.30%)
occurrences all number	1	0	0	0	0	0	0	1
Decubitis ulcer
subjects affected / exposed	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 13 (0.00%)	0 / 17 (0.00%)	0 / 18 (0.00%)	0 / 16 (0.00%)	2 / 24 (8.33%)	0 / 77 (0.00%)
occurrences all number	0	0	0	0	0	0	2	0
Erythema
subjects affected / exposed	0 / 7 (0.00%)	0 / 6 (0.00%)	1 / 13 (7.69%)	1 / 17 (5.88%)	0 / 18 (0.00%)	0 / 16 (0.00%)	0 / 24 (0.00%)	2 / 77 (2.60%)
occurrences all number	0	0	1	1	0	0	0	2
Petechiae
subjects affected / exposed	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 13 (0.00%)	1 / 17 (5.88%)	1 / 18 (5.56%)	0 / 16 (0.00%)	0 / 24 (0.00%)	2 / 77 (2.60%)
occurrences all number	0	0	0	1	1	0	0	2
Psoriasis
subjects affected / exposed	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 13 (0.00%)	1 / 17 (5.88%)	0 / 18 (0.00%)	0 / 16 (0.00%)	0 / 24 (0.00%)	1 / 77 (1.30%)
occurrences all number	0	0	0	1	0	0	0	1
Swelling face
subjects affected / exposed	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 13 (0.00%)	1 / 17 (5.88%)	0 / 18 (0.00%)	0 / 16 (0.00%)	0 / 24 (0.00%)	1 / 77 (1.30%)
occurrences all number	0	0	0	1	0	0	0	1
Renal and urinary disorders
Dysuria
subjects affected / exposed	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 13 (0.00%)	1 / 17 (5.88%)	0 / 18 (0.00%)	0 / 16 (0.00%)	0 / 24 (0.00%)	1 / 77 (1.30%)
occurrences all number	0	0	0	1	0	0	0	1
Glycosuria
subjects affected / exposed	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 13 (0.00%)	0 / 17 (0.00%)	1 / 18 (5.56%)	0 / 16 (0.00%)	0 / 24 (0.00%)	1 / 77 (1.30%)
occurrences all number	0	0	0	0	1	0	0	1
Haematuria
subjects affected / exposed	0 / 7 (0.00%)	1 / 6 (16.67%)	1 / 13 (7.69%)	0 / 17 (0.00%)	0 / 18 (0.00%)	0 / 16 (0.00%)	2 / 24 (8.33%)	2 / 77 (2.60%)
occurrences all number	0	1	1	0	0	0	2	2
Neurogenic bladder
subjects affected / exposed	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 13 (0.00%)	0 / 17 (0.00%)	1 / 18 (5.56%)	0 / 16 (0.00%)	1 / 24 (4.17%)	1 / 77 (1.30%)
occurrences all number	0	0	0	0	1	0	1	1
Renal failure acute
subjects affected / exposed	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 13 (0.00%)	0 / 17 (0.00%)	0 / 18 (0.00%)	2 / 16 (12.50%)	0 / 24 (0.00%)	2 / 77 (2.60%)
occurrences all number	0	0	0	0	0	2	0	2
Urethral pain
subjects affected / exposed	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 13 (0.00%)	0 / 17 (0.00%)	0 / 18 (0.00%)	1 / 16 (6.25%)	0 / 24 (0.00%)	1 / 77 (1.30%)
occurrences all number	0	0	0	0	0	1	0	1
Urinary incontinence
subjects affected / exposed	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 13 (0.00%)	1 / 17 (5.88%)	0 / 18 (0.00%)	0 / 16 (0.00%)	1 / 24 (4.17%)	1 / 77 (1.30%)
occurrences all number	0	0	0	1	0	0	1	1
Urinary retention
subjects affected / exposed	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 13 (0.00%)	0 / 17 (0.00%)	1 / 18 (5.56%)	1 / 16 (6.25%)	0 / 24 (0.00%)	2 / 77 (2.60%)
occurrences all number	0	0	0	0	1	1	0	2
Musculoskeletal and connective tissue disorders
Arthralgia
subjects affected / exposed	0 / 7 (0.00%)	0 / 6 (0.00%)	2 / 13 (15.38%)	0 / 17 (0.00%)	1 / 18 (5.56%)	0 / 16 (0.00%)	2 / 24 (8.33%)	3 / 77 (3.90%)
occurrences all number	0	0	2	0	1	0	2	3
Arthritis
subjects affected / exposed	0 / 7 (0.00%)	0 / 6 (0.00%)	1 / 13 (7.69%)	0 / 17 (0.00%)	0 / 18 (0.00%)	0 / 16 (0.00%)	0 / 24 (0.00%)	1 / 77 (1.30%)
occurrences all number	0	0	1	0	0	0	0	1
Back pain
subjects affected / exposed	0 / 7 (0.00%)	1 / 6 (16.67%)	0 / 13 (0.00%)	0 / 17 (0.00%)	0 / 18 (0.00%)	1 / 16 (6.25%)	1 / 24 (4.17%)	2 / 77 (2.60%)
occurrences all number	0	1	0	0	0	1	1	2
Muscle spasms
subjects affected / exposed	0 / 7 (0.00%)	0 / 6 (0.00%)	1 / 13 (7.69%)	0 / 17 (0.00%)	0 / 18 (0.00%)	0 / 16 (0.00%)	0 / 24 (0.00%)	1 / 77 (1.30%)
occurrences all number	0	0	1	0	0	0	0	1
Muscle spasticity
subjects affected / exposed	0 / 7 (0.00%)	0 / 6 (0.00%)	1 / 13 (7.69%)	0 / 17 (0.00%)	0 / 18 (0.00%)	0 / 16 (0.00%)	0 / 24 (0.00%)	1 / 77 (1.30%)
occurrences all number	0	0	1	0	0	0	0	1
Muscular weakness
subjects affected / exposed	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 13 (0.00%)	2 / 17 (11.76%)	0 / 18 (0.00%)	0 / 16 (0.00%)	1 / 24 (4.17%)	2 / 77 (2.60%)
occurrences all number	0	0	0	2	0	0	1	2
Musculoskeletal pain
subjects affected / exposed	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 13 (0.00%)	1 / 17 (5.88%)	0 / 18 (0.00%)	0 / 16 (0.00%)	2 / 24 (8.33%)	1 / 77 (1.30%)
occurrences all number	0	0	0	1	0	0	2	1
Neurological decompensation
subjects affected / exposed	0 / 7 (0.00%)	1 / 6 (16.67%)	0 / 13 (0.00%)	0 / 17 (0.00%)	0 / 18 (0.00%)	0 / 16 (0.00%)	0 / 24 (0.00%)	1 / 77 (1.30%)
occurrences all number	0	1	0	0	0	0	0	1
Neurological symptom
subjects affected / exposed	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 13 (0.00%)	0 / 17 (0.00%)	0 / 18 (0.00%)	1 / 16 (6.25%)	0 / 24 (0.00%)	1 / 77 (1.30%)
occurrences all number	0	0	0	0	0	1	0	1
Osteoarthritis
subjects affected / exposed	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 13 (0.00%)	1 / 17 (5.88%)	0 / 18 (0.00%)	0 / 16 (0.00%)	0 / 24 (0.00%)	1 / 77 (1.30%)
occurrences all number	0	0	0	1	0	0	0	1
Paraesthesia
subjects affected / exposed	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 13 (0.00%)	0 / 17 (0.00%)	0 / 18 (0.00%)	1 / 16 (6.25%)	0 / 24 (0.00%)	1 / 77 (1.30%)
occurrences all number	0	0	0	0	0	1	0	1
Tendonitis
subjects affected / exposed	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 13 (0.00%)	0 / 17 (0.00%)	0 / 18 (0.00%)	1 / 16 (6.25%)	0 / 24 (0.00%)	1 / 77 (1.30%)
occurrences all number	0	0	0	0	0	1	0	1
Tenosynovitis
subjects affected / exposed	0 / 7 (0.00%)	0 / 6 (0.00%)	1 / 13 (7.69%)	0 / 17 (0.00%)	0 / 18 (0.00%)	0 / 16 (0.00%)	0 / 24 (0.00%)	1 / 77 (1.30%)
occurrences all number	0	0	1	0	0	0	0	1
Infections and infestations
Bacterial disease carrier
subjects affected / exposed	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 13 (0.00%)	0 / 17 (0.00%)	1 / 18 (5.56%)	0 / 16 (0.00%)	0 / 24 (0.00%)	1 / 77 (1.30%)
occurrences all number	0	0	0	0	1	0	0	1
Bronchitis
subjects affected / exposed	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 13 (0.00%)	1 / 17 (5.88%)	0 / 18 (0.00%)	0 / 16 (0.00%)	0 / 24 (0.00%)	1 / 77 (1.30%)
occurrences all number	0	0	0	1	0	0	0	1
Clostridium difficile colitis
subjects affected / exposed	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 13 (0.00%)	0 / 17 (0.00%)	1 / 18 (5.56%)	0 / 16 (0.00%)	0 / 24 (0.00%)	1 / 77 (1.30%)
occurrences all number	0	0	0	0	1	0	0	1
Conjunctivitis bacterial
subjects affected / exposed	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 13 (0.00%)	1 / 17 (5.88%)	0 / 18 (0.00%)	0 / 16 (0.00%)	0 / 24 (0.00%)	1 / 77 (1.30%)
occurrences all number	0	0	0	1	0	0	0	1
Escherichia urinary tract infection
subjects affected / exposed	0 / 7 (0.00%)	1 / 6 (16.67%)	0 / 13 (0.00%)	0 / 17 (0.00%)	0 / 18 (0.00%)	0 / 16 (0.00%)	0 / 24 (0.00%)	1 / 77 (1.30%)
occurrences all number	0	1	0	0	0	0	0	1
Hepatitis B
subjects affected / exposed	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 13 (0.00%)	0 / 17 (0.00%)	0 / 18 (0.00%)	1 / 16 (6.25%)	0 / 24 (0.00%)	1 / 77 (1.30%)
occurrences all number	0	0	0	0	0	1	0	1
Nasopharyngitis
subjects affected / exposed	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 13 (0.00%)	1 / 17 (5.88%)	1 / 18 (5.56%)	0 / 16 (0.00%)	0 / 24 (0.00%)	2 / 77 (2.60%)
occurrences all number	0	0	0	1	1	0	0	2
Pneumonia
subjects affected / exposed	1 / 7 (14.29%)	0 / 6 (0.00%)	0 / 13 (0.00%)	0 / 17 (0.00%)	2 / 18 (11.11%)	1 / 16 (6.25%)	1 / 24 (4.17%)	4 / 77 (5.19%)
occurrences all number	1	0	0	0	2	1	1	4
Postoperative wound infection
subjects affected / exposed	0 / 7 (0.00%)	0 / 6 (0.00%)	1 / 13 (7.69%)	0 / 17 (0.00%)	0 / 18 (0.00%)	0 / 16 (0.00%)	0 / 24 (0.00%)	1 / 77 (1.30%)
occurrences all number	0	0	1	0	0	0	0	1
Pyuria
subjects affected / exposed	0 / 7 (0.00%)	0 / 6 (0.00%)	1 / 13 (7.69%)	0 / 17 (0.00%)	0 / 18 (0.00%)	0 / 16 (0.00%)	0 / 24 (0.00%)	1 / 77 (1.30%)
occurrences all number	0	0	1	0	0	0	0	1
Respiratory tract infection
subjects affected / exposed	0 / 7 (0.00%)	0 / 6 (0.00%)	1 / 13 (7.69%)	0 / 17 (0.00%)	0 / 18 (0.00%)	0 / 16 (0.00%)	0 / 24 (0.00%)	1 / 77 (1.30%)
occurrences all number	0	0	1	0	0	0	0	1
Upper respiratory tract infection
subjects affected / exposed	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 13 (0.00%)	0 / 17 (0.00%)	2 / 18 (11.11%)	0 / 16 (0.00%)	0 / 24 (0.00%)	2 / 77 (2.60%)
occurrences all number	0	0	0	0	2	0	0	2
Urinary tract infection
subjects affected / exposed	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 13 (0.00%)	2 / 17 (11.76%)	3 / 18 (16.67%)	1 / 16 (6.25%)	1 / 24 (4.17%)	6 / 77 (7.79%)
occurrences all number	0	0	0	2	3	1	1	6
Urosepsis
subjects affected / exposed	0 / 7 (0.00%)	1 / 6 (16.67%)	0 / 13 (0.00%)	0 / 17 (0.00%)	0 / 18 (0.00%)	0 / 16 (0.00%)	1 / 24 (4.17%)	1 / 77 (1.30%)
occurrences all number	0	1	0	0	0	0	1	1
Metabolism and nutrition disorders
Diabetes mellitus
subjects affected / exposed	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 13 (0.00%)	1 / 17 (5.88%)	0 / 18 (0.00%)	0 / 16 (0.00%)	0 / 24 (0.00%)	1 / 77 (1.30%)
occurrences all number	0	0	0	1	0	0	0	1
Dyslipidaemia
subjects affected / exposed	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 13 (0.00%)	0 / 17 (0.00%)	1 / 18 (5.56%)	1 / 16 (6.25%)	3 / 24 (12.50%)	2 / 77 (2.60%)
occurrences all number	0	0	0	0	1	1	3	2
Electrolyte imbalance
subjects affected / exposed	0 / 7 (0.00%)	0 / 6 (0.00%)	1 / 13 (7.69%)	0 / 17 (0.00%)	0 / 18 (0.00%)	0 / 16 (0.00%)	0 / 24 (0.00%)	1 / 77 (1.30%)
occurrences all number	0	0	1	0	0	0	0	1
Fluid imbalance
subjects affected / exposed	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 13 (0.00%)	0 / 17 (0.00%)	1 / 18 (5.56%)	0 / 16 (0.00%)	0 / 24 (0.00%)	1 / 77 (1.30%)
occurrences all number	0	0	0	0	1	0	0	1
Hyperchloraemia
subjects affected / exposed	0 / 7 (0.00%)	1 / 6 (16.67%)	4 / 13 (30.77%)	0 / 17 (0.00%)	0 / 18 (0.00%)	0 / 16 (0.00%)	2 / 24 (8.33%)	5 / 77 (6.49%)
occurrences all number	0	1	4	0	0	0	2	5
Hypercholesterolaemia
subjects affected / exposed	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 13 (0.00%)	1 / 17 (5.88%)	0 / 18 (0.00%)	2 / 16 (12.50%)	0 / 24 (0.00%)	3 / 77 (3.90%)
occurrences all number	0	0	0	1	0	2	0	3
Hyperglycaemia
subjects affected / exposed	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 13 (0.00%)	1 / 17 (5.88%)	1 / 18 (5.56%)	0 / 16 (0.00%)	3 / 24 (12.50%)	2 / 77 (2.60%)
occurrences all number	0	0	0	1	1	0	3	2
Hyperlipidaemia
subjects affected / exposed	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 13 (0.00%)	0 / 17 (0.00%)	0 / 18 (0.00%)	1 / 16 (6.25%)	1 / 24 (4.17%)	1 / 77 (1.30%)
occurrences all number	0	0	0	0	0	1	1	1
Hyperuricaemia
subjects affected / exposed	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 13 (0.00%)	1 / 17 (5.88%)	0 / 18 (0.00%)	0 / 16 (0.00%)	0 / 24 (0.00%)	1 / 77 (1.30%)
occurrences all number	0	0	0	1	0	0	0	1
Hypoalbuminaemia
subjects affected / exposed	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 13 (0.00%)	0 / 17 (0.00%)	0 / 18 (0.00%)	1 / 16 (6.25%)	2 / 24 (8.33%)	1 / 77 (1.30%)
occurrences all number	0	0	0	0	0	1	2	1
Hypocalcaemia
subjects affected / exposed	1 / 7 (14.29%)	1 / 6 (16.67%)	2 / 13 (15.38%)	0 / 17 (0.00%)	0 / 18 (0.00%)	0 / 16 (0.00%)	2 / 24 (8.33%)	4 / 77 (5.19%)
occurrences all number	1	1	2	0	0	0	2	4
Hypoglycaemia
subjects affected / exposed	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 13 (0.00%)	1 / 17 (5.88%)	0 / 18 (0.00%)	0 / 16 (0.00%)	1 / 24 (4.17%)	1 / 77 (1.30%)
occurrences all number	0	0	0	1	0	0	1	1
Hypokalaemia
subjects affected / exposed	1 / 7 (14.29%)	2 / 6 (33.33%)	2 / 13 (15.38%)	0 / 17 (0.00%)	2 / 18 (11.11%)	2 / 16 (12.50%)	6 / 24 (25.00%)	9 / 77 (11.69%)
occurrences all number	1	2	2	0	2	2	6	9
Hypomagnesaemia
subjects affected / exposed	0 / 7 (0.00%)	1 / 6 (16.67%)	0 / 13 (0.00%)	0 / 17 (0.00%)	0 / 18 (0.00%)	0 / 16 (0.00%)	0 / 24 (0.00%)	1 / 77 (1.30%)
occurrences all number	0	1	0	0	0	0	0	1
Hyponatraemia
subjects affected / exposed	1 / 7 (14.29%)	1 / 6 (16.67%)	0 / 13 (0.00%)	0 / 17 (0.00%)	0 / 18 (0.00%)	1 / 16 (6.25%)	2 / 24 (8.33%)	3 / 77 (3.90%)
occurrences all number	1	1	0	0	0	1	2	3
Malnutrition
subjects affected / exposed	0 / 7 (0.00%)	1 / 6 (16.67%)	1 / 13 (7.69%)	0 / 17 (0.00%)	0 / 18 (0.00%)	1 / 16 (6.25%)	0 / 24 (0.00%)	3 / 77 (3.90%)
occurrences all number	0	1	1	0	0	1	0	3
Vitamin B12 deficiency
subjects affected / exposed	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 13 (0.00%)	0 / 17 (0.00%)	0 / 18 (0.00%)	0 / 16 (0.00%)	3 / 24 (12.50%)	0 / 77 (0.00%)
occurrences all number	0	0	0	0	0	0	3	0
Vitamin D deficiency
subjects affected / exposed	0 / 7 (0.00%)	0 / 6 (0.00%)	1 / 13 (7.69%)	0 / 17 (0.00%)	0 / 18 (0.00%)	0 / 16 (0.00%)	0 / 24 (0.00%)	1 / 77 (1.30%)
occurrences all number	0	0	1	0	0	0	0	1

More information

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Were there any global substantial amendments to the protocol? Yes

11 May 2015

Included an intermediate dose, updated number of sites, revised exclusion criteria, updated pharmacokinetics protocol, clarified dose escalation procedure, updated treatment details, and clarified purpose of assessments and details/timing of sample collection

01 Oct 2015

Updated secondary objectives, study duration, pharmacokinetic parameters, updated inclusion and exclusion criteria, and clarified rationale for assessments and details/timing of sample collection

12 Jul 2016

Revised inclusion and exclusion criteria, updated enrollment section and study duration, included exploratory assessments, updated primary objective, and clarified adverse event assessment

04 May 2018

Updated study rationale and number of subjects, revised cohort enrollment description, updated eligibility criteria, updated pharmacokinetic parameters, added exploratory assessments, extended study duration, clarified concomitant medications and procedures, and provided details of ECG assessment

Were there any global interruptions to the trial? No

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

None reported

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