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Clinical Trial Results:
A multicenter, randomized, double-blind, placebo-controlled study to demonstrate that digitoxin reduces a composite of overall mortality and hospitalization for worsening heart failure in patients with chronic heart failure and reduced ejection fraction

Summary
EudraCT number	2013-005326-38
Trial protocol	DE AT
Global end of trial date	29 Nov 2024

Results information
Results version number	v1(current)
This version publication date	26 Feb 2026
First version publication date	26 Feb 2026
Other versions

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

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Trial information

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Sponsor protocol code

DIGIT-HF

ISRCTN number

US NCT number

WHO universal trial number (UTN)

Sponsor organisation name

Hannover Medical School

Sponsor organisation address

Carl-Neuberg-Str. 1, Hannover, Germany, 30625

Public contact

Stabsstelle Zentrum für Klinische Studien, Hannover Medical School, EudraCT@mh-hannover.de

Scientific contact

Stabsstelle Zentrum für Klinische Studien, Hannover Medical School, EudraCT@mh-hannover.de

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

24 Nov 2025

Is this the analysis of the primary completion data?

Yes

Primary completion date

29 Nov 2024

Global end of trial reached?

Yes

Global end of trial date

29 Nov 2024

Was the trial ended prematurely?

Main objective of the trial

To demonstrate in a large and simple clinical trial-approach that digitoxin (target serum concentrations preferably 8 - 18 ng/ml (10.5 – 23.6 nmol/l)) on top of standard of care is superior in reducing a composite of all-cause mortality and hospitalization for worsening heart failure (whichever occurs first) in patients with advanced systolic chronic heart failure (NYHA class III-IV and EF ≤ 40% or NYHA class II and ≤ 30%) to a greater extent compared to standard care plus placebo.

Protection of trial subjects

Measurement of digitoxin serum concentration at dose titration six weeks after randomisation (and 12 weeks after randomization, only if dose was increased at six weeks), and of digitoxin serum concentration at 12 months after randomisation.

Background therapy

guideline-directed medical therapy for patients with chronic heart failure and a left ventricular ejection fraction ≤40% and New York Heart Association [NYHA] functional class ≥III or a left ventricular ejection fraction ≤30% and NYHA functional class II

Evidence for comparator

Actual start date of recruitment

01 Apr 2015

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

Austria: 33

Country: Number of subjects enrolled

Germany: 1078

Country: Number of subjects enrolled

Serbia: 101

Worldwide total number of subjects

1212

EEA total number of subjects

1111

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)

521

From 65 to 84 years

671

85 years and over

Subject disposition

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Recruitment details

Start of recruitment: 04.05.2015 Randomization of last patient: 29.09.2023 Recruitment in Germany, Austria, Serbia

Screening details

Patients with advanced systolic chronic heart failure NYHA class III-IV and ejection fraction ≤ 40 % or NYHA class II and ejection fraction ≤ 30% who are at least 18 years of age will be screened. They will be recruited from the clinics of the participating centers.

Period 1 title

overall trial (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

Digitoxin

Arm description

Arm type

Experimental

Investigational medicinal product name

Digitoxin AWD 0 07

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

One tablet (0,07 mg Digitoxin) per os daily

Placebo

Arm description

Arm type

Placebo

Investigational medicinal product name

Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Placebo per os daily (0,05 mg or 0,07 mg or 0,1mg)

Number of subjects in period 1	Digitoxin	Placebo
Started	613	599
Completed	596	591
Not completed	17	8
Lost to follow-up	17	8

Baseline characteristics

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Reporting group title

Digitoxin

Reporting group description

Reporting group title

Placebo

Reporting group description

Reporting group values	Digitoxin	Placebo	Total
Number of subjects	613	599	1212
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)	266	255	521
From 65-84 years	336	335	671
85 years and over	11	9	20
Gender categorical
Units: Subjects
Female	122	125	247
Male	491	474	965

End points

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Reporting group title

Digitoxin

Reporting group description

Reporting group title

Placebo

Reporting group description

Primary: Composite endpoint of time to all-cause mortalitiy /heart failure hospitalisation (whichever occurs first)

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End point title

Composite endpoint of time to all-cause mortalitiy /heart failure hospitalisation (whichever occurs first)

End point description

End point type

Primary

End point timeframe

individual study start to individual event

End point values	Digitoxin	Placebo
Number of subjects analysed	613	599
Units: events / 100 patient years
number (not applicable)	12.8	15.7

ITT

Comparison groups

Digitoxin v Placebo

Number of subjects included in analysis

1212

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.05

Method

Regression, Cox

Parameter type

Hazard ratio (HR)

Point estimate

0.82

Confidence interval

level

95%

sides

2-sided

lower limit

0.69

upper limit

0.98

Primary: Time to all-cause death

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End point title

Time to all-cause death

End point description

End point type

Primary

End point timeframe

individual study start to indiviual event

End point values	Digitoxin	Placebo
Number of subjects analysed	613	599
Units: events / 100 patient years
number (not applicable)	7.8	8.9

ITT

Comparison groups

Digitoxin v Placebo

Number of subjects included in analysis

1212

Analysis specification

Pre-specified

Analysis type

non-inferiority

P-value

< 0.05

Method

Regression, Cox

Parameter type

Hazard ratio (HR)

Point estimate

0.86

Confidence interval

level

95%

sides

2-sided

lower limit

0.69

upper limit

1.07

Primary: Time to first heart failure hospitalisation

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End point title

Time to first heart failure hospitalisation

End point description

End point type

Primary

End point timeframe

individual study start to individual event

End point values	Digitoxin	Placebo
Number of subjects analysed	613	599
Units: events / 100 patient years
number (not applicable)	9.1	10.8

ITT

Comparison groups

Digitoxin v Placebo

Number of subjects included in analysis

1212

Analysis specification

Pre-specified

Analysis type

non-inferiority

P-value

< 0.05

Method

Regression, Cox

Parameter type

Hazard ratio (HR)

Point estimate

0.85

Confidence interval

level

95%

sides

2-sided

lower limit

0.69

upper limit

1.05

Secondary: All-cause death and total heart failure hospitalisations

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End point title

All-cause death and total heart failure hospitalisations

End point description

End point type

Secondary

End point timeframe

individual study start to individual event

End point values	Digitoxin	Placebo
Number of subjects analysed	613	599
Units: events / 100 patient years
number (not applicable)	25.1	26.6

ITT

Comparison groups

Digitoxin v Placebo

Number of subjects included in analysis

1212

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.05

Method

adjusted negative binomial model

Parameter type

rate ratio

Point estimate

0.85

Confidence interval

level

95%

sides

2-sided

lower limit

0.67

upper limit

1.09

Adverse events

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Timeframe for reporting adverse events

The AE documentation period The documentation period of these events begin upon first administration of the IMP (after baseline visit) and ends at the end of the study.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

27.1

Reporting group title

Digitoxin

Reporting group description

Reporting group title

Placebo

Reporting group description

Serious adverse events	Digitoxin	Placebo
Total subjects affected by serious adverse events
subjects affected / exposed	29 / 613 (4.73%)	17 / 599 (2.84%)
number of deaths (all causes)	0	0
number of deaths resulting from adverse events
Injury, poisoning and procedural complications
Toxicity to various agents
subjects affected / exposed	1 / 613 (0.16%)	0 / 599 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Vascular disorders
Myocardial infarction
subjects affected / exposed	0 / 613 (0.00%)	1 / 599 (0.17%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Gangrene
subjects affected / exposed	1 / 613 (0.16%)	0 / 599 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Syncope
subjects affected / exposed	0 / 613 (0.00%)	1 / 599 (0.17%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Cardiac disorders
Acute myocardial infarction
subjects affected / exposed	1 / 613 (0.16%)	0 / 599 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Pulseless electrical activity
subjects affected / exposed	0 / 613 (0.00%)	1 / 599 (0.17%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Myocardial infarction
subjects affected / exposed	1 / 613 (0.16%)	0 / 599 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Arrhythmic storm
subjects affected / exposed	1 / 613 (0.16%)	0 / 599 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Atrial fibrillation
subjects affected / exposed	2 / 613 (0.33%)	0 / 599 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Cardiac arrest
subjects affected / exposed	0 / 613 (0.00%)	1 / 599 (0.17%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Cardiac failure
subjects affected / exposed	0 / 613 (0.00%)	1 / 599 (0.17%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Cardiac failure chronic
subjects affected / exposed	1 / 613 (0.16%)	0 / 599 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Cardiac tamponade
subjects affected / exposed	1 / 613 (0.16%)	0 / 599 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Cardiogenic shock
subjects affected / exposed	0 / 613 (0.00%)	1 / 599 (0.17%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Cardiorenal syndrome
subjects affected / exposed	1 / 613 (0.16%)	0 / 599 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Ventricular fibrillation
subjects affected / exposed	10 / 613 (1.63%)	3 / 599 (0.50%)
occurrences causally related to treatment / all	0 / 11	0 / 6
deaths causally related to treatment / all	0 / 0	0 / 0
Surgical and medical procedures
Ventricular assist device insertion
subjects affected / exposed	0 / 613 (0.00%)	1 / 599 (0.17%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Nervous system disorders
Cerebral haemorrhage
subjects affected / exposed	0 / 613 (0.00%)	1 / 599 (0.17%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Cerebrovascular accident
subjects affected / exposed	1 / 613 (0.16%)	0 / 599 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Dizziness
subjects affected / exposed	1 / 613 (0.16%)	0 / 599 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Epilepsy
subjects affected / exposed	1 / 613 (0.16%)	0 / 599 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Hepatobiliary disorders
Cholelithiasis
subjects affected / exposed	0 / 613 (0.00%)	1 / 599 (0.17%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Renal and urinary disorders
Acute kidney injury
subjects affected / exposed	1 / 613 (0.16%)	0 / 599 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Bursitis
subjects affected / exposed	1 / 613 (0.16%)	0 / 599 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Infections and infestations
Pneumonia klebsiella
subjects affected / exposed	1 / 613 (0.16%)	0 / 599 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Pneumonia
subjects affected / exposed	1 / 613 (0.16%)	0 / 599 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Gastroenteritis clostridial
subjects affected / exposed	1 / 613 (0.16%)	0 / 599 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Respiratory tract infection
subjects affected / exposed	0 / 613 (0.00%)	1 / 599 (0.17%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Staphylococcal sepsis
subjects affected / exposed	1 / 613 (0.16%)	0 / 599 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Metabolism and nutrition disorders
Hyperglycaemia
subjects affected / exposed	1 / 613 (0.16%)	0 / 599 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Respiratory acidosis
subjects affected / exposed	1 / 613 (0.16%)	0 / 599 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0

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

Non-serious adverse events	Digitoxin	Placebo
Total subjects affected by non serious adverse events
subjects affected / exposed	369 / 613 (60.20%)	341 / 599 (56.93%)
Vascular disorders
Arteriovenous fistula
subjects affected / exposed	1 / 613 (0.16%)	0 / 599 (0.00%)
occurrences all number	1	0
Achenbach syndrome
subjects affected / exposed	0 / 613 (0.00%)	1 / 599 (0.17%)
occurrences all number	0	1
Aneurysm
subjects affected / exposed	0 / 613 (0.00%)	1 / 599 (0.17%)
occurrences all number	0	1
Aortic stenosis
subjects affected / exposed	0 / 613 (0.00%)	1 / 599 (0.17%)
occurrences all number	0	1
Blood pressure fluctuation
subjects affected / exposed	0 / 613 (0.00%)	2 / 599 (0.33%)
occurrences all number	0	2
Circulatory collapse
subjects affected / exposed	3 / 613 (0.49%)	2 / 599 (0.33%)
occurrences all number	3	2
Deep vein thrombosis
subjects affected / exposed	0 / 613 (0.00%)	1 / 599 (0.17%)
occurrences all number	0	1
Extremity necrosis
subjects affected / exposed	0 / 613 (0.00%)	1 / 599 (0.17%)
occurrences all number	0	1
Haemorrhage
subjects affected / exposed	1 / 613 (0.16%)	0 / 599 (0.00%)
occurrences all number	1	0
Hot flush
subjects affected / exposed	1 / 613 (0.16%)	0 / 599 (0.00%)
occurrences all number	1	0
Hypertension
subjects affected / exposed	4 / 613 (0.65%)	3 / 599 (0.50%)
occurrences all number	4	3
Hypertensive crisis
subjects affected / exposed	0 / 613 (0.00%)	2 / 599 (0.33%)
occurrences all number	0	2
Hypotension
subjects affected / exposed	18 / 613 (2.94%)	10 / 599 (1.67%)
occurrences all number	18	11
Iliac artery stenosis
subjects affected / exposed	1 / 613 (0.16%)	0 / 599 (0.00%)
occurrences all number	1	0
Ischaemia
subjects affected / exposed	0 / 613 (0.00%)	1 / 599 (0.17%)
occurrences all number	0	1
Jugular vein occlusion
subjects affected / exposed	0 / 613 (0.00%)	1 / 599 (0.17%)
occurrences all number	0	1
Lymphatic fistula
subjects affected / exposed	0 / 613 (0.00%)	1 / 599 (0.17%)
occurrences all number	0	1
Orthostatic hypotension
subjects affected / exposed	1 / 613 (0.16%)	0 / 599 (0.00%)
occurrences all number	1	0
Peripheral arterial occlusive disease
subjects affected / exposed	2 / 613 (0.33%)	1 / 599 (0.17%)
occurrences all number	2	1
Peripheral artery stenosis
subjects affected / exposed	1 / 613 (0.16%)	0 / 599 (0.00%)
occurrences all number	1	0
Peripheral venous disease
subjects affected / exposed	0 / 613 (0.00%)	1 / 599 (0.17%)
occurrences all number	0	1
Phlebitis
subjects affected / exposed	0 / 613 (0.00%)	1 / 599 (0.17%)
occurrences all number	0	1
Scalp haematoma
subjects affected / exposed	1 / 613 (0.16%)	0 / 599 (0.00%)
occurrences all number	1	0
Thrombophlebitis
subjects affected / exposed	0 / 613 (0.00%)	1 / 599 (0.17%)
occurrences all number	0	1
Thrombosis
subjects affected / exposed	1 / 613 (0.16%)	0 / 599 (0.00%)
occurrences all number	1	0
Venous occlusion
subjects affected / exposed	0 / 613 (0.00%)	1 / 599 (0.17%)
occurrences all number	0	1
Bleeding varicose vein
subjects affected / exposed	1 / 613 (0.16%)	0 / 599 (0.00%)
occurrences all number	3	0
Surgical and medical procedures
Cardiac resynchronisation therapy
subjects affected / exposed	3 / 613 (0.49%)	1 / 599 (0.17%)
occurrences all number	3	1
Cardioversion
subjects affected / exposed	4 / 613 (0.65%)	6 / 599 (1.00%)
occurrences all number	4	8
Carotid endarterectomy
subjects affected / exposed	0 / 613 (0.00%)	1 / 599 (0.17%)
occurrences all number	0	1
Cataract operation
subjects affected / exposed	5 / 613 (0.82%)	0 / 599 (0.00%)
occurrences all number	6	0
Cerebrospinal fluid drainage
subjects affected / exposed	0 / 613 (0.00%)	1 / 599 (0.17%)
occurrences all number	0	1
Fistula repair
subjects affected / exposed	0 / 613 (0.00%)	1 / 599 (0.17%)
occurrences all number	0	1
Implantable defibrillator insertion
subjects affected / exposed	1 / 613 (0.16%)	0 / 599 (0.00%)
occurrences all number	1	0
Implantable defibrillator replacement
subjects affected / exposed	1 / 613 (0.16%)	0 / 599 (0.00%)
occurrences all number	1	0
Large intestinal polypectomy
subjects affected / exposed	1 / 613 (0.16%)	0 / 599 (0.00%)
occurrences all number	1	0
Mitral valve repair
subjects affected / exposed	0 / 613 (0.00%)	1 / 599 (0.17%)
occurrences all number	0	1
Salpingo-oophorectomy bilateral
subjects affected / exposed	0 / 613 (0.00%)	1 / 599 (0.17%)
occurrences all number	0	1
Skin cyst excision
subjects affected / exposed	0 / 613 (0.00%)	1 / 599 (0.17%)
occurrences all number	0	1
Skin lesion removal
subjects affected / exposed	0 / 613 (0.00%)	1 / 599 (0.17%)
occurrences all number	0	1
Tooth extraction
subjects affected / exposed	0 / 613 (0.00%)	2 / 599 (0.33%)
occurrences all number	0	5
Ventricular assist device insertion
subjects affected / exposed	0 / 613 (0.00%)	1 / 599 (0.17%)
occurrences all number	0	1
Wrist surgery
subjects affected / exposed	1 / 613 (0.16%)	0 / 599 (0.00%)
occurrences all number	1	0
General disorders and administration site conditions
Adverse drug reaction
subjects affected / exposed	1 / 613 (0.16%)	0 / 599 (0.00%)
occurrences all number	1	0
Fatigue
subjects affected / exposed	21 / 613 (3.43%)	12 / 599 (2.00%)
occurrences all number	21	12
Asthenia
subjects affected / exposed	4 / 613 (0.65%)	1 / 599 (0.17%)
occurrences all number	5	1
Chest discomfort
subjects affected / exposed	6 / 613 (0.98%)	3 / 599 (0.50%)
occurrences all number	6	3
Chest pain
subjects affected / exposed	7 / 613 (1.14%)	13 / 599 (2.17%)
occurrences all number	8	14
Chills
subjects affected / exposed	1 / 613 (0.16%)	1 / 599 (0.17%)
occurrences all number	1	1
Condition aggravated
subjects affected / exposed	1 / 613 (0.16%)	0 / 599 (0.00%)
occurrences all number	1	0
Cyst
subjects affected / exposed	0 / 613 (0.00%)	1 / 599 (0.17%)
occurrences all number	0	1
Drug intolerance
subjects affected / exposed	3 / 613 (0.49%)	2 / 599 (0.33%)
occurrences all number	4	2
Exercise tolerance decreased
subjects affected / exposed	2 / 613 (0.33%)	0 / 599 (0.00%)
occurrences all number	2	0
Foreign body reaction
subjects affected / exposed	0 / 613 (0.00%)	1 / 599 (0.17%)
occurrences all number	0	1
General physical health deterioration
subjects affected / exposed	2 / 613 (0.33%)	0 / 599 (0.00%)
occurrences all number	2	0
Generalised oedema
subjects affected / exposed	0 / 613 (0.00%)	1 / 599 (0.17%)
occurrences all number	0	1
Illness
subjects affected / exposed	1 / 613 (0.16%)	0 / 599 (0.00%)
occurrences all number	1	0
Impaired healing
subjects affected / exposed	1 / 613 (0.16%)	0 / 599 (0.00%)
occurrences all number	1	0
Implant site pain
subjects affected / exposed	0 / 613 (0.00%)	1 / 599 (0.17%)
occurrences all number	0	1
Inflammation
subjects affected / exposed	1 / 613 (0.16%)	1 / 599 (0.17%)
occurrences all number	1	1
Influenza like illness
subjects affected / exposed	16 / 613 (2.61%)	18 / 599 (3.01%)
occurrences all number	16	26
Localised oedema
subjects affected / exposed	1 / 613 (0.16%)	1 / 599 (0.17%)
occurrences all number	1	1
Malaise
subjects affected / exposed	5 / 613 (0.82%)	1 / 599 (0.17%)
occurrences all number	5	1
Medical device site discomfort
subjects affected / exposed	1 / 613 (0.16%)	0 / 599 (0.00%)
occurrences all number	1	0
Medical device site fistula
subjects affected / exposed	1 / 613 (0.16%)	0 / 599 (0.00%)
occurrences all number	1	0
Medical device site haemorrhage
subjects affected / exposed	0 / 613 (0.00%)	1 / 599 (0.17%)
occurrences all number	0	1
Non-cardiac chest pain
subjects affected / exposed	0 / 613 (0.00%)	1 / 599 (0.17%)
occurrences all number	0	1
Oedema
subjects affected / exposed	3 / 613 (0.49%)	2 / 599 (0.33%)
occurrences all number	3	3
Oedema peripheral
subjects affected / exposed	16 / 613 (2.61%)	8 / 599 (1.34%)
occurrences all number	18	8
Pain
subjects affected / exposed	5 / 613 (0.82%)	2 / 599 (0.33%)
occurrences all number	6	2
Peripheral swelling
subjects affected / exposed	4 / 613 (0.65%)	6 / 599 (1.00%)
occurrences all number	4	6
Pyrexia
subjects affected / exposed	1 / 613 (0.16%)	3 / 599 (0.50%)
occurrences all number	1	3
Swelling
subjects affected / exposed	1 / 613 (0.16%)	0 / 599 (0.00%)
occurrences all number	1	0
Thirst
subjects affected / exposed	1 / 613 (0.16%)	0 / 599 (0.00%)
occurrences all number	1	0
Gait disturbance
subjects affected / exposed	1 / 613 (0.16%)	0 / 599 (0.00%)
occurrences all number	1	0
Immune system disorders
Allergy to arthropod sting
subjects affected / exposed	0 / 613 (0.00%)	1 / 599 (0.17%)
occurrences all number	0	1
Amyloidosis
subjects affected / exposed	1 / 613 (0.16%)	0 / 599 (0.00%)
occurrences all number	1	0
Drug hypersensitivity
subjects affected / exposed	1 / 613 (0.16%)	1 / 599 (0.17%)
occurrences all number	1	1
Rubber sensitivity
subjects affected / exposed	1 / 613 (0.16%)	0 / 599 (0.00%)
occurrences all number	1	0
Reproductive system and breast disorders
Benign prostatic hyperplasia
subjects affected / exposed	5 / 613 (0.82%)	2 / 599 (0.33%)
occurrences all number	5	2
Breast engorgement
subjects affected / exposed	1 / 613 (0.16%)	0 / 599 (0.00%)
occurrences all number	1	0
Erectile dysfunction
subjects affected / exposed	1 / 613 (0.16%)	2 / 599 (0.33%)
occurrences all number	1	2
Gynaecomastia
subjects affected / exposed	8 / 613 (1.31%)	3 / 599 (0.50%)
occurrences all number	8	3
Haematospermia
subjects affected / exposed	1 / 613 (0.16%)	0 / 599 (0.00%)
occurrences all number	1	0
Nipple pain
subjects affected / exposed	2 / 613 (0.33%)	1 / 599 (0.17%)
occurrences all number	2	1
Penile swelling
subjects affected / exposed	1 / 613 (0.16%)	0 / 599 (0.00%)
occurrences all number	1	0
Peyronie's disease
subjects affected / exposed	1 / 613 (0.16%)	0 / 599 (0.00%)
occurrences all number	1	0
Postmenopausal haemorrhage
subjects affected / exposed	1 / 613 (0.16%)	0 / 599 (0.00%)
occurrences all number	2	0
Prostatic disorder
subjects affected / exposed	1 / 613 (0.16%)	0 / 599 (0.00%)
occurrences all number	1	0
Prostatitis
subjects affected / exposed	1 / 613 (0.16%)	0 / 599 (0.00%)
occurrences all number	1	0
Uterine polyp
subjects affected / exposed	1 / 613 (0.16%)	0 / 599 (0.00%)
occurrences all number	1	0
Respiratory, thoracic and mediastinal disorders
Haemoptysis
subjects affected / exposed	2 / 613 (0.33%)	1 / 599 (0.17%)
occurrences all number	2	1
Asthma
subjects affected / exposed	1 / 613 (0.16%)	0 / 599 (0.00%)
occurrences all number	1	0
Chronic obstructive pulmonary disease
subjects affected / exposed	3 / 613 (0.49%)	0 / 599 (0.00%)
occurrences all number	3	0
Cough
subjects affected / exposed	6 / 613 (0.98%)	8 / 599 (1.34%)
occurrences all number	6	9
Diaphragmatic spasm
subjects affected / exposed	1 / 613 (0.16%)	1 / 599 (0.17%)
occurrences all number	1	1
Dysphonia
subjects affected / exposed	2 / 613 (0.33%)	1 / 599 (0.17%)
occurrences all number	2	1
Dyspnoea
subjects affected / exposed	18 / 613 (2.94%)	23 / 599 (3.84%)
occurrences all number	23	28
Dyspnoea at rest
subjects affected / exposed	1 / 613 (0.16%)	1 / 599 (0.17%)
occurrences all number	1	1
Dyspnoea exertional
subjects affected / exposed	7 / 613 (1.14%)	4 / 599 (0.67%)
occurrences all number	9	4
Dyspnoea paroxysmal nocturnal
subjects affected / exposed	1 / 613 (0.16%)	1 / 599 (0.17%)
occurrences all number	1	1
Epistaxis
subjects affected / exposed	6 / 613 (0.98%)	7 / 599 (1.17%)
occurrences all number	8	7
Nasal septum deviation
subjects affected / exposed	1 / 613 (0.16%)	0 / 599 (0.00%)
occurrences all number	1	0
Lung infiltration
subjects affected / exposed	1 / 613 (0.16%)	0 / 599 (0.00%)
occurrences all number	1	0
Nocturnal dyspnoea
subjects affected / exposed	2 / 613 (0.33%)	1 / 599 (0.17%)
occurrences all number	2	1
Obstructive airways disorder
subjects affected / exposed	1 / 613 (0.16%)	0 / 599 (0.00%)
occurrences all number	1	0
Obstructive sleep apnoea syndrome
subjects affected / exposed	1 / 613 (0.16%)	1 / 599 (0.17%)
occurrences all number	1	1
Oropharyngeal pain
subjects affected / exposed	0 / 613 (0.00%)	1 / 599 (0.17%)
occurrences all number	0	1
Orthopnoea
subjects affected / exposed	0 / 613 (0.00%)	2 / 599 (0.33%)
occurrences all number	0	2
Pharyngeal inflammation
subjects affected / exposed	2 / 613 (0.33%)	0 / 599 (0.00%)
occurrences all number	2	0
Pleural effusion
subjects affected / exposed	2 / 613 (0.33%)	5 / 599 (0.83%)
occurrences all number	2	5
Pleurisy
subjects affected / exposed	1 / 613 (0.16%)	0 / 599 (0.00%)
occurrences all number	1	0
Pneumonitis
subjects affected / exposed	0 / 613 (0.00%)	2 / 599 (0.33%)
occurrences all number	0	2
Pneumothorax
subjects affected / exposed	0 / 613 (0.00%)	1 / 599 (0.17%)
occurrences all number	0	2
Productive cough
subjects affected / exposed	3 / 613 (0.49%)	1 / 599 (0.17%)
occurrences all number	3	1
Pulmonary congestion
subjects affected / exposed	1 / 613 (0.16%)	0 / 599 (0.00%)
occurrences all number	1	0
Pulmonary embolism
subjects affected / exposed	0 / 613 (0.00%)	1 / 599 (0.17%)
occurrences all number	0	1
Pulmonary fibrosis
subjects affected / exposed	1 / 613 (0.16%)	0 / 599 (0.00%)
occurrences all number	1	0
Pulmonary hypertension
subjects affected / exposed	0 / 613 (0.00%)	1 / 599 (0.17%)
occurrences all number	0	1
Pulmonary oedema
subjects affected / exposed	1 / 613 (0.16%)	0 / 599 (0.00%)
occurrences all number	1	0
Respiratory acidosis
subjects affected / exposed	1 / 613 (0.16%)	0 / 599 (0.00%)
occurrences all number	1	0
Respiratory disorder
subjects affected / exposed	0 / 613 (0.00%)	1 / 599 (0.17%)
occurrences all number	0	1
Respiratory failure
subjects affected / exposed	3 / 613 (0.49%)	0 / 599 (0.00%)
occurrences all number	3	0
Rhinorrhoea
subjects affected / exposed	1 / 613 (0.16%)	0 / 599 (0.00%)
occurrences all number	1	0
Rhonchi
subjects affected / exposed	0 / 613 (0.00%)	2 / 599 (0.33%)
occurrences all number	0	2
Sleep apnoea syndrome
subjects affected / exposed	4 / 613 (0.65%)	2 / 599 (0.33%)
occurrences all number	5	2
Tracheal pain
subjects affected / exposed	1 / 613 (0.16%)	0 / 599 (0.00%)
occurrences all number	1	0
Vocal cord erythema
subjects affected / exposed	0 / 613 (0.00%)	1 / 599 (0.17%)
occurrences all number	0	1
Vocal cord inflammation
subjects affected / exposed	1 / 613 (0.16%)	0 / 599 (0.00%)
occurrences all number	1	0
Hypersensitivity pneumonitis
subjects affected / exposed	1 / 613 (0.16%)	0 / 599 (0.00%)
occurrences all number	1	0
Nasal turbinate hypertrophy
subjects affected / exposed	1 / 613 (0.16%)	0 / 599 (0.00%)
occurrences all number	1	0
Psychiatric disorders
Nervousness
subjects affected / exposed	1 / 613 (0.16%)	0 / 599 (0.00%)
occurrences all number	1	0
Aggression
subjects affected / exposed	0 / 613 (0.00%)	1 / 599 (0.17%)
occurrences all number	0	1
Anxiety
subjects affected / exposed	2 / 613 (0.33%)	1 / 599 (0.17%)
occurrences all number	2	1
Apathy
subjects affected / exposed	0 / 613 (0.00%)	1 / 599 (0.17%)
occurrences all number	0	1
Confusional state
subjects affected / exposed	1 / 613 (0.16%)	1 / 599 (0.17%)
occurrences all number	1	1
Delirium
subjects affected / exposed	1 / 613 (0.16%)	0 / 599 (0.00%)
occurrences all number	1	0
Depressed mood
subjects affected / exposed	0 / 613 (0.00%)	1 / 599 (0.17%)
occurrences all number	0	1
Depression
subjects affected / exposed	2 / 613 (0.33%)	3 / 599 (0.50%)
occurrences all number	2	3
Disorientation
subjects affected / exposed	0 / 613 (0.00%)	1 / 599 (0.17%)
occurrences all number	0	1
Hallucination
subjects affected / exposed	1 / 613 (0.16%)	0 / 599 (0.00%)
occurrences all number	1	0
Initial insomnia
subjects affected / exposed	1 / 613 (0.16%)	0 / 599 (0.00%)
occurrences all number	1	0
Insomnia
subjects affected / exposed	0 / 613 (0.00%)	3 / 599 (0.50%)
occurrences all number	0	3
Intensive care unit delirium
subjects affected / exposed	1 / 613 (0.16%)	0 / 599 (0.00%)
occurrences all number	1	0
Middle insomnia
subjects affected / exposed	1 / 613 (0.16%)	3 / 599 (0.50%)
occurrences all number	1	4
Mood swings
subjects affected / exposed	1 / 613 (0.16%)	0 / 599 (0.00%)
occurrences all number	1	0
Nightmare
subjects affected / exposed	0 / 613 (0.00%)	2 / 599 (0.33%)
occurrences all number	0	2
Panic attack
subjects affected / exposed	1 / 613 (0.16%)	0 / 599 (0.00%)
occurrences all number	1	0
Restlessness
subjects affected / exposed	4 / 613 (0.65%)	3 / 599 (0.50%)
occurrences all number	4	3
Sleep disorder
subjects affected / exposed	6 / 613 (0.98%)	3 / 599 (0.50%)
occurrences all number	6	3
Product issues
Device pacing issue
subjects affected / exposed	1 / 613 (0.16%)	0 / 599 (0.00%)
occurrences all number	1	0
Device dislocation
subjects affected / exposed	0 / 613 (0.00%)	1 / 599 (0.17%)
occurrences all number	0	1
Device malfunction
subjects affected / exposed	3 / 613 (0.49%)	2 / 599 (0.33%)
occurrences all number	3	2
Investigations
Arthroscopy
subjects affected / exposed	1 / 613 (0.16%)	0 / 599 (0.00%)
occurrences all number	1	0
Catheterisation cardiac
subjects affected / exposed	1 / 613 (0.16%)	0 / 599 (0.00%)
occurrences all number	1	0
Blood bilirubin increased
subjects affected / exposed	1 / 613 (0.16%)	0 / 599 (0.00%)
occurrences all number	1	0
Blood creatine phosphokinase increased
subjects affected / exposed	2 / 613 (0.33%)	0 / 599 (0.00%)
occurrences all number	2	0
Blood creatinine increased
subjects affected / exposed	3 / 613 (0.49%)	0 / 599 (0.00%)
occurrences all number	3	0
Blood glucose fluctuation
subjects affected / exposed	0 / 613 (0.00%)	1 / 599 (0.17%)
occurrences all number	0	1
Blood glucose increased
subjects affected / exposed	2 / 613 (0.33%)	0 / 599 (0.00%)
occurrences all number	2	0
Blood potassium decreased
subjects affected / exposed	1 / 613 (0.16%)	0 / 599 (0.00%)
occurrences all number	1	0
Blood potassium increased
subjects affected / exposed	4 / 613 (0.65%)	1 / 599 (0.17%)
occurrences all number	4	1
Blood pressure abnormal
subjects affected / exposed	0 / 613 (0.00%)	2 / 599 (0.33%)
occurrences all number	0	2
Blood pressure increased
subjects affected / exposed	1 / 613 (0.16%)	0 / 599 (0.00%)
occurrences all number	1	0
Blood thyroid stimulating hormone decreased
subjects affected / exposed	0 / 613 (0.00%)	1 / 599 (0.17%)
occurrences all number	0	1
Blood triglycerides increased
subjects affected / exposed	5 / 613 (0.82%)	0 / 599 (0.00%)
occurrences all number	5	0
Blood uric acid increased
subjects affected / exposed	1 / 613 (0.16%)	2 / 599 (0.33%)
occurrences all number	1	2
Blood urine
subjects affected / exposed	1 / 613 (0.16%)	0 / 599 (0.00%)
occurrences all number	1	0
Blood urine present
subjects affected / exposed	0 / 613 (0.00%)	2 / 599 (0.33%)
occurrences all number	0	2
C-reactive protein increased
subjects affected / exposed	1 / 613 (0.16%)	1 / 599 (0.17%)
occurrences all number	2	1
Cardiac murmur
subjects affected / exposed	0 / 613 (0.00%)	2 / 599 (0.33%)
occurrences all number	0	2
Cardioactive drug level above therapeutic
subjects affected / exposed	2 / 613 (0.33%)	1 / 599 (0.17%)
occurrences all number	2	1
Cardioactive drug level increased
subjects affected / exposed	2 / 613 (0.33%)	0 / 599 (0.00%)
occurrences all number	2	0
Biopsy heart
subjects affected / exposed	0 / 613 (0.00%)	1 / 599 (0.17%)
occurrences all number	0	8
Glomerular filtration rate decreased
subjects affected / exposed	0 / 613 (0.00%)	1 / 599 (0.17%)
occurrences all number	0	1
Glomerular filtration rate abnormal
subjects affected / exposed	4 / 613 (0.65%)	1 / 599 (0.17%)
occurrences all number	4	1
Heart rate decreased
subjects affected / exposed	2 / 613 (0.33%)	0 / 599 (0.00%)
occurrences all number	2	0
Heart rate increased
subjects affected / exposed	0 / 613 (0.00%)	2 / 599 (0.33%)
occurrences all number	0	2
Hepatic enzyme increased
subjects affected / exposed	0 / 613 (0.00%)	1 / 599 (0.17%)
occurrences all number	0	1
Inflammatory marker increased
subjects affected / exposed	1 / 613 (0.16%)	0 / 599 (0.00%)
occurrences all number	1	0
International normalised ratio abnormal
subjects affected / exposed	1 / 613 (0.16%)	0 / 599 (0.00%)
occurrences all number	1	0
International normalised ratio increased
subjects affected / exposed	2 / 613 (0.33%)	0 / 599 (0.00%)
occurrences all number	2	0
Intraocular pressure increased
subjects affected / exposed	0 / 613 (0.00%)	1 / 599 (0.17%)
occurrences all number	0	1
Liver function test abnormal
subjects affected / exposed	1 / 613 (0.16%)	1 / 599 (0.17%)
occurrences all number	1	1
Liver function test increased
subjects affected / exposed	4 / 613 (0.65%)	1 / 599 (0.17%)
occurrences all number	4	1
N-terminal prohormone brain natriuretic peptide increased
subjects affected / exposed	1 / 613 (0.16%)	2 / 599 (0.33%)
occurrences all number	1	2
Renal function test abnormal
subjects affected / exposed	3 / 613 (0.49%)	0 / 599 (0.00%)
occurrences all number	3	0
Coronavirus test positive
subjects affected / exposed	1 / 613 (0.16%)	0 / 599 (0.00%)
occurrences all number	1	0
Device function test
subjects affected / exposed	2 / 613 (0.33%)	2 / 599 (0.33%)
occurrences all number	4	2
Ejection fraction decreased
subjects affected / exposed	0 / 613 (0.00%)	1 / 599 (0.17%)
occurrences all number	0	1
Electrocardiogram PR prolongation
subjects affected / exposed	1 / 613 (0.16%)	1 / 599 (0.17%)
occurrences all number	1	1
Electrocardiogram QRS complex abnormal
subjects affected / exposed	0 / 613 (0.00%)	1 / 599 (0.17%)
occurrences all number	0	1
Electrocardiogram QT prolonged
subjects affected / exposed	0 / 613 (0.00%)	3 / 599 (0.50%)
occurrences all number	0	3
Electrocardiogram ST segment depression
subjects affected / exposed	2 / 613 (0.33%)	0 / 599 (0.00%)
occurrences all number	2	0
Electrocardiogram T wave inversion
subjects affected / exposed	1 / 613 (0.16%)	0 / 599 (0.00%)
occurrences all number	1	0
Electrocardiogram change
subjects affected / exposed	1 / 613 (0.16%)	0 / 599 (0.00%)
occurrences all number	1	0
Gamma-glutamyltransferase increased
subjects affected / exposed	6 / 613 (0.98%)	0 / 599 (0.00%)
occurrences all number	7	0
General physical condition abnormal
subjects affected / exposed	1 / 613 (0.16%)	0 / 599 (0.00%)
occurrences all number	1	0
Glycosylated haemoglobin increased
subjects affected / exposed	3 / 613 (0.49%)	0 / 599 (0.00%)
occurrences all number	3	0
Sensory level abnormal
subjects affected / exposed	1 / 613 (0.16%)	1 / 599 (0.17%)
occurrences all number	1	1
Transaminases increased
subjects affected / exposed	1 / 613 (0.16%)	0 / 599 (0.00%)
occurrences all number	1	0
Transferrin saturation decreased
subjects affected / exposed	0 / 613 (0.00%)	1 / 599 (0.17%)
occurrences all number	0	1
Transplant evaluation
subjects affected / exposed	1 / 613 (0.16%)	0 / 599 (0.00%)
occurrences all number	1	0
Troponin T increased
subjects affected / exposed	1 / 613 (0.16%)	1 / 599 (0.17%)
occurrences all number	1	1
Troponin increased
subjects affected / exposed	2 / 613 (0.33%)	1 / 599 (0.17%)
occurrences all number	2	1
Vascular resistance pulmonary increased
subjects affected / exposed	1 / 613 (0.16%)	0 / 599 (0.00%)
occurrences all number	1	0
Venous pressure jugular
subjects affected / exposed	0 / 613 (0.00%)	1 / 599 (0.17%)
occurrences all number	0	1
Weight decreased
subjects affected / exposed	6 / 613 (0.98%)	3 / 599 (0.50%)
occurrences all number	7	3
Weight increased
subjects affected / exposed	3 / 613 (0.49%)	2 / 599 (0.33%)
occurrences all number	3	2
White blood cell count increased
subjects affected / exposed	0 / 613 (0.00%)	1 / 599 (0.17%)
occurrences all number	0	1
Serum ferritin increased
subjects affected / exposed	1 / 613 (0.16%)	0 / 599 (0.00%)
occurrences all number	1	0
Injury, poisoning and procedural complications
Arthropod sting
subjects affected / exposed	0 / 613 (0.00%)	1 / 599 (0.17%)
occurrences all number	0	1
Anaemia postoperative
subjects affected / exposed	1 / 613 (0.16%)	0 / 599 (0.00%)
occurrences all number	1	0
Animal bite
subjects affected / exposed	0 / 613 (0.00%)	1 / 599 (0.17%)
occurrences all number	0	1
Arthropod bite
subjects affected / exposed	0 / 613 (0.00%)	2 / 599 (0.33%)
occurrences all number	0	2
Cervical vertebral fracture
subjects affected / exposed	1 / 613 (0.16%)	0 / 599 (0.00%)
occurrences all number	1	0
Rib fracture
subjects affected / exposed	2 / 613 (0.33%)	1 / 599 (0.17%)
occurrences all number	2	1
Contusion
subjects affected / exposed	4 / 613 (0.65%)	4 / 599 (0.67%)
occurrences all number	4	4
Coronary artery restenosis
subjects affected / exposed	0 / 613 (0.00%)	1 / 599 (0.17%)
occurrences all number	0	1
Craniofacial fracture
subjects affected / exposed	2 / 613 (0.33%)	0 / 599 (0.00%)
occurrences all number	2	0
Electric injury
subjects affected / exposed	0 / 613 (0.00%)	3 / 599 (0.50%)
occurrences all number	0	3
Epicondylitis
subjects affected / exposed	0 / 613 (0.00%)	1 / 599 (0.17%)
occurrences all number	0	1
Fall
subjects affected / exposed	4 / 613 (0.65%)	6 / 599 (1.00%)
occurrences all number	5	7
Femur fracture
subjects affected / exposed	0 / 613 (0.00%)	1 / 599 (0.17%)
occurrences all number	0	2
Fibula fracture
subjects affected / exposed	1 / 613 (0.16%)	1 / 599 (0.17%)
occurrences all number	1	1
Foot fracture
subjects affected / exposed	1 / 613 (0.16%)	1 / 599 (0.17%)
occurrences all number	1	1
Fracture
subjects affected / exposed	1 / 613 (0.16%)	0 / 599 (0.00%)
occurrences all number	1	0
Head injury
subjects affected / exposed	0 / 613 (0.00%)	1 / 599 (0.17%)
occurrences all number	0	1
Immunisation reaction
subjects affected / exposed	1 / 613 (0.16%)	1 / 599 (0.17%)
occurrences all number	2	2
Joint injury
subjects affected / exposed	0 / 613 (0.00%)	1 / 599 (0.17%)
occurrences all number	0	1
Ligament sprain
subjects affected / exposed	0 / 613 (0.00%)	1 / 599 (0.17%)
occurrences all number	0	1
Limb crushing injury
subjects affected / exposed	0 / 613 (0.00%)	1 / 599 (0.17%)
occurrences all number	0	1
Limb injury
subjects affected / exposed	2 / 613 (0.33%)	1 / 599 (0.17%)
occurrences all number	2	1
Lip injury
subjects affected / exposed	1 / 613 (0.16%)	1 / 599 (0.17%)
occurrences all number	1	1
Lumbar vertebral fracture
subjects affected / exposed	1 / 613 (0.16%)	0 / 599 (0.00%)
occurrences all number	1	0
Medication error
subjects affected / exposed	1 / 613 (0.16%)	1 / 599 (0.17%)
occurrences all number	1	1
Meniscus injury
subjects affected / exposed	0 / 613 (0.00%)	1 / 599 (0.17%)
occurrences all number	0	1
Muscle strain
subjects affected / exposed	1 / 613 (0.16%)	0 / 599 (0.00%)
occurrences all number	1	0
Nasal injury
subjects affected / exposed	1 / 613 (0.16%)	0 / 599 (0.00%)
occurrences all number	1	0
Overdose
subjects affected / exposed	3 / 613 (0.49%)	1 / 599 (0.17%)
occurrences all number	3	1
Poisoning
subjects affected / exposed	1 / 613 (0.16%)	0 / 599 (0.00%)
occurrences all number	1	0
Post procedural complication
subjects affected / exposed	1 / 613 (0.16%)	0 / 599 (0.00%)
occurrences all number	1	0
Post procedural haemorrhage
subjects affected / exposed	1 / 613 (0.16%)	0 / 599 (0.00%)
occurrences all number	1	0
Psychosis postoperative
subjects affected / exposed	1 / 613 (0.16%)	0 / 599 (0.00%)
occurrences all number	1	0
Radial nerve injury
subjects affected / exposed	0 / 613 (0.00%)	1 / 599 (0.17%)
occurrences all number	0	1
Clavicle fracture
subjects affected / exposed	1 / 613 (0.16%)	1 / 599 (0.17%)
occurrences all number	1	1
Skin laceration
subjects affected / exposed	1 / 613 (0.16%)	0 / 599 (0.00%)
occurrences all number	1	0
Tendon injury
subjects affected / exposed	1 / 613 (0.16%)	0 / 599 (0.00%)
occurrences all number	1	0
Tendon rupture
subjects affected / exposed	1 / 613 (0.16%)	0 / 599 (0.00%)
occurrences all number	1	0
Tooth fracture
subjects affected / exposed	0 / 613 (0.00%)	1 / 599 (0.17%)
occurrences all number	0	1
Traumatic haematoma
subjects affected / exposed	0 / 613 (0.00%)	1 / 599 (0.17%)
occurrences all number	0	1
Traumatic intracranial haemorrhage
subjects affected / exposed	1 / 613 (0.16%)	0 / 599 (0.00%)
occurrences all number	1	0
Upper limb fracture
subjects affected / exposed	1 / 613 (0.16%)	0 / 599 (0.00%)
occurrences all number	1	0
Vascular graft stenosis
subjects affected / exposed	0 / 613 (0.00%)	1 / 599 (0.17%)
occurrences all number	0	1
Wound
subjects affected / exposed	3 / 613 (0.49%)	3 / 599 (0.50%)
occurrences all number	3	3
Wrist fracture
subjects affected / exposed	1 / 613 (0.16%)	1 / 599 (0.17%)
occurrences all number	1	1
Spinal fracture
subjects affected / exposed	0 / 613 (0.00%)	1 / 599 (0.17%)
occurrences all number	0	1
Cardiac disorders
Arteriosclerosis coronary artery
subjects affected / exposed	1 / 613 (0.16%)	0 / 599 (0.00%)
occurrences all number	1	0
Acute coronary syndrome
subjects affected / exposed	0 / 613 (0.00%)	2 / 599 (0.33%)
occurrences all number	0	2
Acute myocardial infarction
subjects affected / exposed	2 / 613 (0.33%)	1 / 599 (0.17%)
occurrences all number	2	1
Angina pectoris
subjects affected / exposed	12 / 613 (1.96%)	9 / 599 (1.50%)
occurrences all number	14	10
Angina unstable
subjects affected / exposed	2 / 613 (0.33%)	0 / 599 (0.00%)
occurrences all number	2	0
Anophthalmos
subjects affected / exposed	0 / 613 (0.00%)	1 / 599 (0.17%)
occurrences all number	0	1
Aortic valve stenosis
subjects affected / exposed	1 / 613 (0.16%)	0 / 599 (0.00%)
occurrences all number	1	0
Arrhythmia
subjects affected / exposed	6 / 613 (0.98%)	2 / 599 (0.33%)
occurrences all number	7	3
Arrhythmia supraventricular
subjects affected / exposed	0 / 613 (0.00%)	1 / 599 (0.17%)
occurrences all number	0	1
Atrial fibrillation
subjects affected / exposed	33 / 613 (5.38%)	31 / 599 (5.18%)
occurrences all number	39	34
Congenital, familial and genetic disorders
subjects affected / exposed	0 / 613 (0.00%)	1 / 599 (0.17%)
occurrences all number	0	1
Atrial tachycardia
subjects affected / exposed	3 / 613 (0.49%)	5 / 599 (0.83%)
occurrences all number	3	5
Atrial thrombosis
subjects affected / exposed	1 / 613 (0.16%)	0 / 599 (0.00%)
occurrences all number	1	0
Atrioventricular block
subjects affected / exposed	3 / 613 (0.49%)	5 / 599 (0.83%)
occurrences all number	3	5
Atrioventricular block first degree
subjects affected / exposed	3 / 613 (0.49%)	5 / 599 (0.83%)
occurrences all number	3	5
Atrioventricular block second degree
subjects affected / exposed	1 / 613 (0.16%)	0 / 599 (0.00%)
occurrences all number	1	0
Bradyarrhythmia
subjects affected / exposed	5 / 613 (0.82%)	0 / 599 (0.00%)
occurrences all number	5	0
Bradycardia
subjects affected / exposed	10 / 613 (1.63%)	3 / 599 (0.50%)
occurrences all number	10	3
Bundle branch block left
subjects affected / exposed	4 / 613 (0.65%)	2 / 599 (0.33%)
occurrences all number	4	2
Bundle branch block right
subjects affected / exposed	0 / 613 (0.00%)	4 / 599 (0.67%)
occurrences all number	0	4
Cardiac aneurysm
subjects affected / exposed	0 / 613 (0.00%)	1 / 599 (0.17%)
occurrences all number	0	1
Cardiac arrest
subjects affected / exposed	0 / 613 (0.00%)	1 / 599 (0.17%)
occurrences all number	0	1
Cardiac discomfort
subjects affected / exposed	0 / 613 (0.00%)	1 / 599 (0.17%)
occurrences all number	0	1
Cardiac failure
subjects affected / exposed	29 / 613 (4.73%)	26 / 599 (4.34%)
occurrences all number	43	36
Cardiac failure chronic
subjects affected / exposed	2 / 613 (0.33%)	1 / 599 (0.17%)
occurrences all number	2	2
Cardiac failure congestive
subjects affected / exposed	0 / 613 (0.00%)	1 / 599 (0.17%)
occurrences all number	0	1
Cardiac fibrillation
subjects affected / exposed	1 / 613 (0.16%)	1 / 599 (0.17%)
occurrences all number	1	1
Cardiac tamponade
subjects affected / exposed	1 / 613 (0.16%)	0 / 599 (0.00%)
occurrences all number	1	0
Cardiac ventricular thrombosis
subjects affected / exposed	0 / 613 (0.00%)	2 / 599 (0.33%)
occurrences all number	0	2
Cardiogenic shock
subjects affected / exposed	0 / 613 (0.00%)	1 / 599 (0.17%)
occurrences all number	0	1
Cardiorenal syndrome
subjects affected / exposed	1 / 613 (0.16%)	1 / 599 (0.17%)
occurrences all number	1	1
Cardiovascular disorder
subjects affected / exposed	1 / 613 (0.16%)	1 / 599 (0.17%)
occurrences all number	1	1
Atrial flutter
subjects affected / exposed	2 / 613 (0.33%)	4 / 599 (0.67%)
occurrences all number	2	4
Myocardial infarction
subjects affected / exposed	1 / 613 (0.16%)	1 / 599 (0.17%)
occurrences all number	1	1
Mitral valve incompetence
subjects affected / exposed	1 / 613 (0.16%)	2 / 599 (0.33%)
occurrences all number	1	2
Palpitations
subjects affected / exposed	9 / 613 (1.47%)	2 / 599 (0.33%)
occurrences all number	9	2
Pericarditis
subjects affected / exposed	1 / 613 (0.16%)	0 / 599 (0.00%)
occurrences all number	1	0
Pulseless electrical activity
subjects affected / exposed	0 / 613 (0.00%)	1 / 599 (0.17%)
occurrences all number	0	1
Sinus bradycardia
subjects affected / exposed	1 / 613 (0.16%)	3 / 599 (0.50%)
occurrences all number	1	3
Sinus node dysfunction
subjects affected / exposed	1 / 613 (0.16%)	0 / 599 (0.00%)
occurrences all number	1	0
Sinus tachycardia
subjects affected / exposed	4 / 613 (0.65%)	5 / 599 (0.83%)
occurrences all number	4	5
Supraventricular tachycardia
subjects affected / exposed	5 / 613 (0.82%)	2 / 599 (0.33%)
occurrences all number	5	2
Tachyarrhythmia
subjects affected / exposed	0 / 613 (0.00%)	3 / 599 (0.50%)
occurrences all number	0	3
Tachycardia
subjects affected / exposed	4 / 613 (0.65%)	7 / 599 (1.17%)
occurrences all number	4	8
Tricuspid valve incompetence
subjects affected / exposed	0 / 613 (0.00%)	1 / 599 (0.17%)
occurrences all number	0	1
Ventricular extrasystoles
subjects affected / exposed	6 / 613 (0.98%)	9 / 599 (1.50%)
occurrences all number	6	9
Ventricular fibrillation
subjects affected / exposed	13 / 613 (2.12%)	5 / 599 (0.83%)
occurrences all number	16	8
Ventricular tachycardia
subjects affected / exposed	36 / 613 (5.87%)	38 / 599 (6.34%)
occurrences all number	58	82
Coronary artery disease
subjects affected / exposed	5 / 613 (0.82%)	1 / 599 (0.17%)
occurrences all number	5	1
Coronary artery stenosis
subjects affected / exposed	3 / 613 (0.49%)	1 / 599 (0.17%)
occurrences all number	3	1
Extrasystoles
subjects affected / exposed	0 / 613 (0.00%)	2 / 599 (0.33%)
occurrences all number	0	2
Left ventricular dysfunction
subjects affected / exposed	1 / 613 (0.16%)	0 / 599 (0.00%)
occurrences all number	1	0
Left ventricular failure
subjects affected / exposed	0 / 613 (0.00%)	1 / 599 (0.17%)
occurrences all number	0	1
Myocardial ischaemia
subjects affected / exposed	2 / 613 (0.33%)	0 / 599 (0.00%)
occurrences all number	2	0
Nervous system disorders
Ageusia
subjects affected / exposed	0 / 613 (0.00%)	1 / 599 (0.17%)
occurrences all number	0	2
Aphasia
subjects affected / exposed	2 / 613 (0.33%)	0 / 599 (0.00%)
occurrences all number	2	0
Carotid artery stenosis
subjects affected / exposed	2 / 613 (0.33%)	0 / 599 (0.00%)
occurrences all number	2	0
Carpal tunnel syndrome
subjects affected / exposed	0 / 613 (0.00%)	1 / 599 (0.17%)
occurrences all number	0	1
Cerebral haemorrhage
subjects affected / exposed	0 / 613 (0.00%)	1 / 599 (0.17%)
occurrences all number	0	1
Cerebral infarction
subjects affected / exposed	1 / 613 (0.16%)	1 / 599 (0.17%)
occurrences all number	1	1
Cerebrovascular accident
subjects affected / exposed	1 / 613 (0.16%)	0 / 599 (0.00%)
occurrences all number	1	0
Chronic inflammatory demyelinating polyradiculoneuropathy
subjects affected / exposed	1 / 613 (0.16%)	0 / 599 (0.00%)
occurrences all number	1	0
Cognitive disorder
subjects affected / exposed	1 / 613 (0.16%)	0 / 599 (0.00%)
occurrences all number	1	0
Cold dysaesthesia
subjects affected / exposed	1 / 613 (0.16%)	0 / 599 (0.00%)
occurrences all number	1	0
Diabetic neuropathy
subjects affected / exposed	1 / 613 (0.16%)	1 / 599 (0.17%)
occurrences all number	1	1
Dizziness
subjects affected / exposed	47 / 613 (7.67%)	39 / 599 (6.51%)
occurrences all number	52	43
Dizziness exertional
subjects affected / exposed	0 / 613 (0.00%)	1 / 599 (0.17%)
occurrences all number	0	1
Dizziness postural
subjects affected / exposed	1 / 613 (0.16%)	3 / 599 (0.50%)
occurrences all number	1	3
Epilepsy
subjects affected / exposed	1 / 613 (0.16%)	1 / 599 (0.17%)
occurrences all number	4	1
Headache
subjects affected / exposed	5 / 613 (0.82%)	12 / 599 (2.00%)
occurrences all number	5	13
Hypersomnia
subjects affected / exposed	0 / 613 (0.00%)	1 / 599 (0.17%)
occurrences all number	0	1
Hypoaesthesia
subjects affected / exposed	2 / 613 (0.33%)	1 / 599 (0.17%)
occurrences all number	2	1
Hypoglycaemic unconsciousness
subjects affected / exposed	0 / 613 (0.00%)	1 / 599 (0.17%)
occurrences all number	0	1
Loss of consciousness
subjects affected / exposed	1 / 613 (0.16%)	0 / 599 (0.00%)
occurrences all number	2	0
Lumbosacral radiculopathy
subjects affected / exposed	1 / 613 (0.16%)	0 / 599 (0.00%)
occurrences all number	1	0
Memory impairment
subjects affected / exposed	1 / 613 (0.16%)	0 / 599 (0.00%)
occurrences all number	1	0
Migraine
subjects affected / exposed	1 / 613 (0.16%)	0 / 599 (0.00%)
occurrences all number	1	0
Migraine with aura
subjects affected / exposed	0 / 613 (0.00%)	1 / 599 (0.17%)
occurrences all number	0	1
Neuralgia
subjects affected / exposed	1 / 613 (0.16%)	0 / 599 (0.00%)
occurrences all number	1	0
Neuromyopathy
subjects affected / exposed	1 / 613 (0.16%)	0 / 599 (0.00%)
occurrences all number	1	0
Nystagmus
subjects affected / exposed	1 / 613 (0.16%)	0 / 599 (0.00%)
occurrences all number	1	0
Paraesthesia
subjects affected / exposed	6 / 613 (0.98%)	5 / 599 (0.83%)
occurrences all number	7	5
Parkinson's disease
subjects affected / exposed	1 / 613 (0.16%)	3 / 599 (0.50%)
occurrences all number	1	3
Parkinsonism
subjects affected / exposed	1 / 613 (0.16%)	0 / 599 (0.00%)
occurrences all number	1	0
Polyneuropathy
subjects affected / exposed	3 / 613 (0.49%)	2 / 599 (0.33%)
occurrences all number	4	2
Poor quality sleep
subjects affected / exposed	1 / 613 (0.16%)	0 / 599 (0.00%)
occurrences all number	1	0
Sciatica
subjects affected / exposed	2 / 613 (0.33%)	1 / 599 (0.17%)
occurrences all number	2	1
Seizure
subjects affected / exposed	0 / 613 (0.00%)	1 / 599 (0.17%)
occurrences all number	0	1
Sensory disturbance
subjects affected / exposed	0 / 613 (0.00%)	1 / 599 (0.17%)
occurrences all number	0	1
Somnolence
subjects affected / exposed	0 / 613 (0.00%)	1 / 599 (0.17%)
occurrences all number	0	1
Syncope
subjects affected / exposed	22 / 613 (3.59%)	13 / 599 (2.17%)
occurrences all number	23	15
Taste disorder
subjects affected / exposed	1 / 613 (0.16%)	0 / 599 (0.00%)
occurrences all number	1	0
Tongue biting
subjects affected / exposed	0 / 613 (0.00%)	1 / 599 (0.17%)
occurrences all number	0	1
Tremor
subjects affected / exposed	3 / 613 (0.49%)	2 / 599 (0.33%)
occurrences all number	3	2
Vertebral artery occlusion
subjects affected / exposed	0 / 613 (0.00%)	1 / 599 (0.17%)
occurrences all number	0	1
Visual field defect
subjects affected / exposed	1 / 613 (0.16%)	0 / 599 (0.00%)
occurrences all number	1	0
Presyncope
subjects affected / exposed	2 / 613 (0.33%)	3 / 599 (0.50%)
occurrences all number	2	3
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	8 / 613 (1.31%)	3 / 599 (0.50%)
occurrences all number	9	3
Coagulopathy
subjects affected / exposed	0 / 613 (0.00%)	1 / 599 (0.17%)
occurrences all number	0	1
Haemorrhagic diathesis
subjects affected / exposed	1 / 613 (0.16%)	0 / 599 (0.00%)
occurrences all number	1	0
Iron deficiency anaemia
subjects affected / exposed	3 / 613 (0.49%)	3 / 599 (0.50%)
occurrences all number	5	3
Leukocytosis
subjects affected / exposed	0 / 613 (0.00%)	1 / 599 (0.17%)
occurrences all number	0	1
Lymphadenopathy
subjects affected / exposed	1 / 613 (0.16%)	1 / 599 (0.17%)
occurrences all number	1	1
Macrocytosis
subjects affected / exposed	0 / 613 (0.00%)	1 / 599 (0.17%)
occurrences all number	0	1
Microcytic anaemia
subjects affected / exposed	0 / 613 (0.00%)	1 / 599 (0.17%)
occurrences all number	0	1
Pancytopenia
subjects affected / exposed	1 / 613 (0.16%)	0 / 599 (0.00%)
occurrences all number	1	0
Polycythaemia
subjects affected / exposed	0 / 613 (0.00%)	1 / 599 (0.17%)
occurrences all number	0	1
Thrombocytopenia
subjects affected / exposed	2 / 613 (0.33%)	2 / 599 (0.33%)
occurrences all number	3	2
Ear and labyrinth disorders
Ear discomfort
subjects affected / exposed	1 / 613 (0.16%)	0 / 599 (0.00%)
occurrences all number	1	0
Ear pain
subjects affected / exposed	2 / 613 (0.33%)	0 / 599 (0.00%)
occurrences all number	2	0
Hypoacusis
subjects affected / exposed	0 / 613 (0.00%)	1 / 599 (0.17%)
occurrences all number	0	1
Middle ear effusion
subjects affected / exposed	0 / 613 (0.00%)	1 / 599 (0.17%)
occurrences all number	0	1
Middle ear inflammation
subjects affected / exposed	1 / 613 (0.16%)	0 / 599 (0.00%)
occurrences all number	1	0
Sudden hearing loss
subjects affected / exposed	1 / 613 (0.16%)	0 / 599 (0.00%)
occurrences all number	1	0
Tinnitus
subjects affected / exposed	3 / 613 (0.49%)	1 / 599 (0.17%)
occurrences all number	3	1
Vertigo
subjects affected / exposed	12 / 613 (1.96%)	8 / 599 (1.34%)
occurrences all number	15	10
Vertigo positional
subjects affected / exposed	1 / 613 (0.16%)	0 / 599 (0.00%)
occurrences all number	1	0
Eye disorders
Glaucoma
subjects affected / exposed	1 / 613 (0.16%)	0 / 599 (0.00%)
occurrences all number	1	0
Amaurosis fugax
subjects affected / exposed	0 / 613 (0.00%)	1 / 599 (0.17%)
occurrences all number	0	2
Blepharitis
subjects affected / exposed	1 / 613 (0.16%)	0 / 599 (0.00%)
occurrences all number	1	0
Cataract
subjects affected / exposed	5 / 613 (0.82%)	4 / 599 (0.67%)
occurrences all number	6	4
Chromatopsia
subjects affected / exposed	1 / 613 (0.16%)	1 / 599 (0.17%)
occurrences all number	2	1
Corneal deposits
subjects affected / exposed	1 / 613 (0.16%)	0 / 599 (0.00%)
occurrences all number	1	0
Endocrine ophthalmopathy
subjects affected / exposed	0 / 613 (0.00%)	1 / 599 (0.17%)
occurrences all number	0	1
Eye haematoma
subjects affected / exposed	0 / 613 (0.00%)	1 / 599 (0.17%)
occurrences all number	0	1
Eye haemorrhage
subjects affected / exposed	1 / 613 (0.16%)	0 / 599 (0.00%)
occurrences all number	1	0
Lacrimation increased
subjects affected / exposed	1 / 613 (0.16%)	0 / 599 (0.00%)
occurrences all number	1	0
Optic atrophy
subjects affected / exposed	1 / 613 (0.16%)	0 / 599 (0.00%)
occurrences all number	1	0
Photophobia
subjects affected / exposed	1 / 613 (0.16%)	1 / 599 (0.17%)
occurrences all number	1	1
Pseudophakia
subjects affected / exposed	1 / 613 (0.16%)	0 / 599 (0.00%)
occurrences all number	1	0
Retinopathy
subjects affected / exposed	1 / 613 (0.16%)	0 / 599 (0.00%)
occurrences all number	1	0
Vision blurred
subjects affected / exposed	1 / 613 (0.16%)	1 / 599 (0.17%)
occurrences all number	1	1
Visual acuity reduced
subjects affected / exposed	1 / 613 (0.16%)	0 / 599 (0.00%)
occurrences all number	1	0
Visual field defect
subjects affected / exposed	1 / 613 (0.16%)	0 / 599 (0.00%)
occurrences all number	1	0
Visual impairment
subjects affected / exposed	3 / 613 (0.49%)	10 / 599 (1.67%)
occurrences all number	3	10
Vitreous detachment
subjects affected / exposed	0 / 613 (0.00%)	1 / 599 (0.17%)
occurrences all number	0	1
Vitreous haemorrhage
subjects affected / exposed	1 / 613 (0.16%)	0 / 599 (0.00%)
occurrences all number	1	0
Myopia
subjects affected / exposed	1 / 613 (0.16%)	0 / 599 (0.00%)
occurrences all number	1	0
Gastrointestinal disorders
Abdominal discomfort
subjects affected / exposed	2 / 613 (0.33%)	7 / 599 (1.17%)
occurrences all number	2	7
Abdominal distension
subjects affected / exposed	2 / 613 (0.33%)	3 / 599 (0.50%)
occurrences all number	2	3
Abdominal hernia
subjects affected / exposed	1 / 613 (0.16%)	0 / 599 (0.00%)
occurrences all number	1	0
Abdominal pain
subjects affected / exposed	1 / 613 (0.16%)	5 / 599 (0.83%)
occurrences all number	1	5
Abdominal pain lower
subjects affected / exposed	2 / 613 (0.33%)	1 / 599 (0.17%)
occurrences all number	2	1
Abdominal pain upper
subjects affected / exposed	5 / 613 (0.82%)	5 / 599 (0.83%)
occurrences all number	5	7
Pancreatitis acute
subjects affected / exposed	1 / 613 (0.16%)	0 / 599 (0.00%)
occurrences all number	1	0
Oesophagitis
subjects affected / exposed	0 / 613 (0.00%)	1 / 599 (0.17%)
occurrences all number	0	1
Nausea
subjects affected / exposed	29 / 613 (4.73%)	22 / 599 (3.67%)
occurrences all number	33	23
Mouth haemorrhage
subjects affected / exposed	1 / 613 (0.16%)	0 / 599 (0.00%)
occurrences all number	1	0
Melaena
subjects affected / exposed	1 / 613 (0.16%)	0 / 599 (0.00%)
occurrences all number	1	0
Large intestine polyp
subjects affected / exposed	1 / 613 (0.16%)	0 / 599 (0.00%)
occurrences all number	1	0
Intestinal polyp
subjects affected / exposed	1 / 613 (0.16%)	0 / 599 (0.00%)
occurrences all number	1	0
Inguinal hernia
subjects affected / exposed	2 / 613 (0.33%)	0 / 599 (0.00%)
occurrences all number	2	0
Hiatus hernia
subjects affected / exposed	2 / 613 (0.33%)	0 / 599 (0.00%)
occurrences all number	2	0
Haemorrhoids
subjects affected / exposed	0 / 613 (0.00%)	1 / 599 (0.17%)
occurrences all number	0	1
Haemorrhagic erosive gastritis
subjects affected / exposed	0 / 613 (0.00%)	1 / 599 (0.17%)
occurrences all number	0	1
Haematochezia
subjects affected / exposed	1 / 613 (0.16%)	3 / 599 (0.50%)
occurrences all number	1	4
Gastrooesophageal reflux disease
subjects affected / exposed	3 / 613 (0.49%)	2 / 599 (0.33%)
occurrences all number	3	2
Gastrointestinal inflammation
subjects affected / exposed	0 / 613 (0.00%)	1 / 599 (0.17%)
occurrences all number	0	1
Gastrointestinal haemorrhage
subjects affected / exposed	3 / 613 (0.49%)	1 / 599 (0.17%)
occurrences all number	3	1
Gastritis haemorrhagic
subjects affected / exposed	1 / 613 (0.16%)	0 / 599 (0.00%)
occurrences all number	1	0
Gastritis
subjects affected / exposed	3 / 613 (0.49%)	5 / 599 (0.83%)
occurrences all number	3	5
Flatulence
subjects affected / exposed	1 / 613 (0.16%)	0 / 599 (0.00%)
occurrences all number	1	0
Enterocolitis haemorrhagic
subjects affected / exposed	0 / 613 (0.00%)	1 / 599 (0.17%)
occurrences all number	0	1
Dysphagia
subjects affected / exposed	2 / 613 (0.33%)	1 / 599 (0.17%)
occurrences all number	2	1
Dyspepsia
subjects affected / exposed	3 / 613 (0.49%)	6 / 599 (1.00%)
occurrences all number	3	6
Duodenitis
subjects affected / exposed	2 / 613 (0.33%)	0 / 599 (0.00%)
occurrences all number	2	0
Diverticulum intestinal
subjects affected / exposed	0 / 613 (0.00%)	1 / 599 (0.17%)
occurrences all number	0	1
Diarrhoea
subjects affected / exposed	37 / 613 (6.04%)	18 / 599 (3.01%)
occurrences all number	44	18
Constipation
subjects affected / exposed	6 / 613 (0.98%)	2 / 599 (0.33%)
occurrences all number	6	2
Colitis
subjects affected / exposed	1 / 613 (0.16%)	0 / 599 (0.00%)
occurrences all number	1	0
Chronic gastrointestinal bleeding
subjects affected / exposed	1 / 613 (0.16%)	0 / 599 (0.00%)
occurrences all number	1	0
Chronic gastritis
subjects affected / exposed	2 / 613 (0.33%)	1 / 599 (0.17%)
occurrences all number	2	1
Ascites
subjects affected / exposed	1 / 613 (0.16%)	3 / 599 (0.50%)
occurrences all number	2	3
Anal fissure
subjects affected / exposed	0 / 613 (0.00%)	2 / 599 (0.33%)
occurrences all number	0	2
Anal incontinence
subjects affected / exposed	1 / 613 (0.16%)	0 / 599 (0.00%)
occurrences all number	1	0
Vomiting
subjects affected / exposed	8 / 613 (1.31%)	5 / 599 (0.83%)
occurrences all number	11	5
Umbilical hernia
subjects affected / exposed	1 / 613 (0.16%)	0 / 599 (0.00%)
occurrences all number	1	0
Toothache
subjects affected / exposed	0 / 613 (0.00%)	1 / 599 (0.17%)
occurrences all number	0	1
Swollen tongue
subjects affected / exposed	1 / 613 (0.16%)	0 / 599 (0.00%)
occurrences all number	1	0
Salivary hypersecretion
subjects affected / exposed	0 / 613 (0.00%)	1 / 599 (0.17%)
occurrences all number	0	1
Salivary gland calculus
subjects affected / exposed	1 / 613 (0.16%)	0 / 599 (0.00%)
occurrences all number	2	0
Retching
subjects affected / exposed	2 / 613 (0.33%)	0 / 599 (0.00%)
occurrences all number	2	0
Proctalgia
subjects affected / exposed	1 / 613 (0.16%)	0 / 599 (0.00%)
occurrences all number	1	0
Hepatobiliary disorders
Hepatic lesion
subjects affected / exposed	1 / 613 (0.16%)	0 / 599 (0.00%)
occurrences all number	1	0
Bile duct stone
subjects affected / exposed	0 / 613 (0.00%)	1 / 599 (0.17%)
occurrences all number	0	1
Cholecystitis
subjects affected / exposed	0 / 613 (0.00%)	1 / 599 (0.17%)
occurrences all number	0	1
Cholecystitis chronic
subjects affected / exposed	0 / 613 (0.00%)	1 / 599 (0.17%)
occurrences all number	0	1
Congestive hepatopathy
subjects affected / exposed	1 / 613 (0.16%)	0 / 599 (0.00%)
occurrences all number	1	0
Hepatic failure
subjects affected / exposed	0 / 613 (0.00%)	1 / 599 (0.17%)
occurrences all number	0	1
Hepatic steatosis
subjects affected / exposed	0 / 613 (0.00%)	1 / 599 (0.17%)
occurrences all number	0	1
Jaundice
subjects affected / exposed	1 / 613 (0.16%)	0 / 599 (0.00%)
occurrences all number	1	0
Hepatomegaly
subjects affected / exposed	1 / 613 (0.16%)	0 / 599 (0.00%)
occurrences all number	1	0
Skin and subcutaneous tissue disorders
Acne
subjects affected / exposed	1 / 613 (0.16%)	0 / 599 (0.00%)
occurrences all number	1	0
Actinic keratosis
subjects affected / exposed	2 / 613 (0.33%)	4 / 599 (0.67%)
occurrences all number	2	4
Blister
subjects affected / exposed	1 / 613 (0.16%)	0 / 599 (0.00%)
occurrences all number	1	0
Decubitus ulcer
subjects affected / exposed	1 / 613 (0.16%)	0 / 599 (0.00%)
occurrences all number	1	0
Dermal cyst
subjects affected / exposed	1 / 613 (0.16%)	0 / 599 (0.00%)
occurrences all number	1	0
Dermatitis allergic
subjects affected / exposed	1 / 613 (0.16%)	0 / 599 (0.00%)
occurrences all number	1	0
Diabetic foot
subjects affected / exposed	1 / 613 (0.16%)	1 / 599 (0.17%)
occurrences all number	1	1
Ecchymosis
subjects affected / exposed	0 / 613 (0.00%)	1 / 599 (0.17%)
occurrences all number	0	1
Eczema
subjects affected / exposed	1 / 613 (0.16%)	1 / 599 (0.17%)
occurrences all number	1	1
Erythema
subjects affected / exposed	3 / 613 (0.49%)	1 / 599 (0.17%)
occurrences all number	3	1
Hirsutism
subjects affected / exposed	0 / 613 (0.00%)	1 / 599 (0.17%)
occurrences all number	0	1
Hyperhidrosis
subjects affected / exposed	5 / 613 (0.82%)	7 / 599 (1.17%)
occurrences all number	6	8
Ingrowing nail
subjects affected / exposed	0 / 613 (0.00%)	1 / 599 (0.17%)
occurrences all number	0	1
Nail psoriasis
subjects affected / exposed	1 / 613 (0.16%)	0 / 599 (0.00%)
occurrences all number	1	0
Night sweats
subjects affected / exposed	2 / 613 (0.33%)	1 / 599 (0.17%)
occurrences all number	2	1
Onychoclasis
subjects affected / exposed	1 / 613 (0.16%)	0 / 599 (0.00%)
occurrences all number	1	0
Pigmentation disorder
subjects affected / exposed	0 / 613 (0.00%)	1 / 599 (0.17%)
occurrences all number	0	1
Pruritus
subjects affected / exposed	7 / 613 (1.14%)	10 / 599 (1.67%)
occurrences all number	7	10
Psoriasis
subjects affected / exposed	1 / 613 (0.16%)	0 / 599 (0.00%)
occurrences all number	1	0
Pyoderma gangrenosum
subjects affected / exposed	1 / 613 (0.16%)	0 / 599 (0.00%)
occurrences all number	1	0
Rash
subjects affected / exposed	5 / 613 (0.82%)	5 / 599 (0.83%)
occurrences all number	6	5
Skin disorder
subjects affected / exposed	2 / 613 (0.33%)	0 / 599 (0.00%)
occurrences all number	2	0
Skin erosion
subjects affected / exposed	1 / 613 (0.16%)	0 / 599 (0.00%)
occurrences all number	1	0
Skin haemorrhage
subjects affected / exposed	1 / 613 (0.16%)	0 / 599 (0.00%)
occurrences all number	1	0
Skin induration
subjects affected / exposed	1 / 613 (0.16%)	0 / 599 (0.00%)
occurrences all number	1	0
Skin irritation
subjects affected / exposed	1 / 613 (0.16%)	0 / 599 (0.00%)
occurrences all number	1	0
Skin ulcer
subjects affected / exposed	3 / 613 (0.49%)	0 / 599 (0.00%)
occurrences all number	3	0
Stasis dermatitis
subjects affected / exposed	1 / 613 (0.16%)	0 / 599 (0.00%)
occurrences all number	1	0
Swelling face
subjects affected / exposed	0 / 613 (0.00%)	1 / 599 (0.17%)
occurrences all number	0	1
Urticaria
subjects affected / exposed	2 / 613 (0.33%)	0 / 599 (0.00%)
occurrences all number	2	0
Renal and urinary disorders
Ureteric stenosis
subjects affected / exposed	1 / 613 (0.16%)	0 / 599 (0.00%)
occurrences all number	1	0
Urethral stenosis
subjects affected / exposed	1 / 613 (0.16%)	0 / 599 (0.00%)
occurrences all number	1	0
Renal impairment
subjects affected / exposed	5 / 613 (0.82%)	2 / 599 (0.33%)
occurrences all number	5	2
Renal failure
subjects affected / exposed	6 / 613 (0.98%)	2 / 599 (0.33%)
occurrences all number	6	2
Renal cyst
subjects affected / exposed	1 / 613 (0.16%)	1 / 599 (0.17%)
occurrences all number	1	1
Prerenal failure
subjects affected / exposed	0 / 613 (0.00%)	1 / 599 (0.17%)
occurrences all number	0	1
Pollakiuria
subjects affected / exposed	1 / 613 (0.16%)	1 / 599 (0.17%)
occurrences all number	1	1
Oliguria
subjects affected / exposed	0 / 613 (0.00%)	1 / 599 (0.17%)
occurrences all number	0	1
Nocturia
subjects affected / exposed	2 / 613 (0.33%)	0 / 599 (0.00%)
occurrences all number	2	0
Nephrolithiasis
subjects affected / exposed	1 / 613 (0.16%)	0 / 599 (0.00%)
occurrences all number	1	0
Leukocyturia
subjects affected / exposed	1 / 613 (0.16%)	0 / 599 (0.00%)
occurrences all number	1	0
Incontinence
subjects affected / exposed	1 / 613 (0.16%)	0 / 599 (0.00%)
occurrences all number	1	0
Haematuria
subjects affected / exposed	2 / 613 (0.33%)	3 / 599 (0.50%)
occurrences all number	2	3
Dysuria
subjects affected / exposed	0 / 613 (0.00%)	1 / 599 (0.17%)
occurrences all number	0	1
Cystitis noninfective
subjects affected / exposed	4 / 613 (0.65%)	1 / 599 (0.17%)
occurrences all number	4	1
Cystitis haemorrhagic
subjects affected / exposed	1 / 613 (0.16%)	0 / 599 (0.00%)
occurrences all number	1	0
Chronic kidney disease
subjects affected / exposed	2 / 613 (0.33%)	1 / 599 (0.17%)
occurrences all number	2	1
Azotaemia
subjects affected / exposed	1 / 613 (0.16%)	0 / 599 (0.00%)
occurrences all number	1	0
Acute kidney injury
subjects affected / exposed	10 / 613 (1.63%)	12 / 599 (2.00%)
occurrences all number	15	12
Urethral obstruction
subjects affected / exposed	0 / 613 (0.00%)	1 / 599 (0.17%)
occurrences all number	0	1
Urethral haemorrhage
subjects affected / exposed	1 / 613 (0.16%)	0 / 599 (0.00%)
occurrences all number	1	0
Renal mass
subjects affected / exposed	1 / 613 (0.16%)	0 / 599 (0.00%)
occurrences all number	1	0
Urinary incontinence
subjects affected / exposed	1 / 613 (0.16%)	0 / 599 (0.00%)
occurrences all number	1	0
Urinary tract inflammation
subjects affected / exposed	0 / 613 (0.00%)	1 / 599 (0.17%)
occurrences all number	0	1
Urinary hesitation
subjects affected / exposed	3 / 613 (0.49%)	2 / 599 (0.33%)
occurrences all number	3	2
Endocrine disorders
Goitre
subjects affected / exposed	1 / 613 (0.16%)	0 / 599 (0.00%)
occurrences all number	1	0
Hyperthyroidism
subjects affected / exposed	1 / 613 (0.16%)	1 / 599 (0.17%)
occurrences all number	2	1
Hypothyroidism
subjects affected / exposed	4 / 613 (0.65%)	1 / 599 (0.17%)
occurrences all number	4	1
Toxic nodular goitre
subjects affected / exposed	0 / 613 (0.00%)	1 / 599 (0.17%)
occurrences all number	0	1
Musculoskeletal and connective tissue disorders
Adenocarcinoma of colon
subjects affected / exposed	2 / 613 (0.33%)	0 / 599 (0.00%)
occurrences all number	2	0
Arthralgia
subjects affected / exposed	5 / 613 (0.82%)	9 / 599 (1.50%)
occurrences all number	5	11
Arthritis
subjects affected / exposed	1 / 613 (0.16%)	1 / 599 (0.17%)
occurrences all number	1	1
Arthropathy
subjects affected / exposed	1 / 613 (0.16%)	0 / 599 (0.00%)
occurrences all number	1	0
Back pain
subjects affected / exposed	11 / 613 (1.79%)	6 / 599 (1.00%)
occurrences all number	11	6
Basal cell carcinoma
subjects affected / exposed	2 / 613 (0.33%)	0 / 599 (0.00%)
occurrences all number	2	0
Bladder cancer
subjects affected / exposed	0 / 613 (0.00%)	1 / 599 (0.17%)
occurrences all number	0	2
Bowen's disease
subjects affected / exposed	0 / 613 (0.00%)	1 / 599 (0.17%)
occurrences all number	0	1
Bursa disorder
subjects affected / exposed	1 / 613 (0.16%)	1 / 599 (0.17%)
occurrences all number	2	1
Bursitis
subjects affected / exposed	2 / 613 (0.33%)	1 / 599 (0.17%)
occurrences all number	2	1
Coccydynia
subjects affected / exposed	0 / 613 (0.00%)	1 / 599 (0.17%)
occurrences all number	0	1
Colorectal adenoma
subjects affected / exposed	1 / 613 (0.16%)	0 / 599 (0.00%)
occurrences all number	1	0
Diffuse large B-cell lymphoma recurrent
subjects affected / exposed	1 / 613 (0.16%)	0 / 599 (0.00%)
occurrences all number	1	0
Exostosis
subjects affected / exposed	1 / 613 (0.16%)	0 / 599 (0.00%)
occurrences all number	1	0
Gouty arthritis
subjects affected / exposed	2 / 613 (0.33%)	3 / 599 (0.50%)
occurrences all number	2	3
Haemarthrosis
subjects affected / exposed	0 / 613 (0.00%)	1 / 599 (0.17%)
occurrences all number	0	1
Intervertebral disc protrusion
subjects affected / exposed	0 / 613 (0.00%)	2 / 599 (0.33%)
occurrences all number	0	2
Joint effusion
subjects affected / exposed	1 / 613 (0.16%)	0 / 599 (0.00%)
occurrences all number	1	0
Joint impingement
subjects affected / exposed	1 / 613 (0.16%)	0 / 599 (0.00%)
occurrences all number	1	0
Joint range of motion decreased
subjects affected / exposed	0 / 613 (0.00%)	1 / 599 (0.17%)
occurrences all number	0	1
Joint swelling
subjects affected / exposed	1 / 613 (0.16%)	1 / 599 (0.17%)
occurrences all number	1	3
Lung neoplasm malignant
subjects affected / exposed	1 / 613 (0.16%)	1 / 599 (0.17%)
occurrences all number	1	1
Meniscal degeneration
subjects affected / exposed	1 / 613 (0.16%)	0 / 599 (0.00%)
occurrences all number	1	0
Metastases to bone
subjects affected / exposed	0 / 613 (0.00%)	1 / 599 (0.17%)
occurrences all number	0	1
Muscle discomfort
subjects affected / exposed	1 / 613 (0.16%)	0 / 599 (0.00%)
occurrences all number	1	0
Muscle spasms
subjects affected / exposed	9 / 613 (1.47%)	4 / 599 (0.67%)
occurrences all number	10	4
Muscular weakness
subjects affected / exposed	1 / 613 (0.16%)	0 / 599 (0.00%)
occurrences all number	1	0
Musculoskeletal chest pain
subjects affected / exposed	0 / 613 (0.00%)	2 / 599 (0.33%)
occurrences all number	0	2
Musculoskeletal discomfort
subjects affected / exposed	4 / 613 (0.65%)	3 / 599 (0.50%)
occurrences all number	5	3
Musculoskeletal stiffness
subjects affected / exposed	1 / 613 (0.16%)	0 / 599 (0.00%)
occurrences all number	1	0
Myalgia
subjects affected / exposed	2 / 613 (0.33%)	4 / 599 (0.67%)
occurrences all number	3	5
Myeloproliferative neoplasm
subjects affected / exposed	1 / 613 (0.16%)	0 / 599 (0.00%)
occurrences all number	1	0
Myopathy
subjects affected / exposed	1 / 613 (0.16%)	0 / 599 (0.00%)
occurrences all number	1	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
subjects affected / exposed	9 / 613 (1.47%)	9 / 599 (1.50%)
occurrences all number	10	14
Oesophageal carcinoma
subjects affected / exposed	1 / 613 (0.16%)	0 / 599 (0.00%)
occurrences all number	1	0
Osteoarthritis
subjects affected / exposed	3 / 613 (0.49%)	7 / 599 (1.17%)
occurrences all number	5	12
Osteochondrosis
subjects affected / exposed	1 / 613 (0.16%)	1 / 599 (0.17%)
occurrences all number	1	1
Osteolysis
subjects affected / exposed	1 / 613 (0.16%)	1 / 599 (0.17%)
occurrences all number	1	1
Osteopenia
subjects affected / exposed	1 / 613 (0.16%)	0 / 599 (0.00%)
occurrences all number	2	0
Pain in extremity
subjects affected / exposed	10 / 613 (1.63%)	4 / 599 (0.67%)
occurrences all number	11	4
Pain in jaw
subjects affected / exposed	1 / 613 (0.16%)	0 / 599 (0.00%)
occurrences all number	1	0
Plantar fasciitis
subjects affected / exposed	1 / 613 (0.16%)	0 / 599 (0.00%)
occurrences all number	1	0
Polyarthritis
subjects affected / exposed	0 / 613 (0.00%)	1 / 599 (0.17%)
occurrences all number	0	1
Polymyalgia rheumatica
subjects affected / exposed	1 / 613 (0.16%)	0 / 599 (0.00%)
occurrences all number	1	0
Prostate cancer
subjects affected / exposed	1 / 613 (0.16%)	3 / 599 (0.50%)
occurrences all number	1	3
Rhabdomyolysis
subjects affected / exposed	0 / 613 (0.00%)	1 / 599 (0.17%)
occurrences all number	0	1
Rheumatoid arthritis
subjects affected / exposed	0 / 613 (0.00%)	1 / 599 (0.17%)
occurrences all number	0	1
Rotator cuff syndrome
subjects affected / exposed	0 / 613 (0.00%)	1 / 599 (0.17%)
occurrences all number	0	1
Skin papilloma
subjects affected / exposed	0 / 613 (0.00%)	1 / 599 (0.17%)
occurrences all number	0	1
Spinal osteoarthritis
subjects affected / exposed	0 / 613 (0.00%)	2 / 599 (0.33%)
occurrences all number	0	2
Spinal pain
subjects affected / exposed	2 / 613 (0.33%)	3 / 599 (0.50%)
occurrences all number	2	3
Spondylitis
subjects affected / exposed	0 / 613 (0.00%)	1 / 599 (0.17%)
occurrences all number	0	1
Squamous cell carcinoma
subjects affected / exposed	0 / 613 (0.00%)	1 / 599 (0.17%)
occurrences all number	0	2
Squamous cell carcinoma of skin
subjects affected / exposed	0 / 613 (0.00%)	1 / 599 (0.17%)
occurrences all number	0	1
Synovial cyst
subjects affected / exposed	1 / 613 (0.16%)	0 / 599 (0.00%)
occurrences all number	1	0
Tendon pain
subjects affected / exposed	1 / 613 (0.16%)	0 / 599 (0.00%)
occurrences all number	1	0
Thymoma malignant recurrent
subjects affected / exposed	0 / 613 (0.00%)	1 / 599 (0.17%)
occurrences all number	0	1
Tongue neoplasm
subjects affected / exposed	0 / 613 (0.00%)	1 / 599 (0.17%)
occurrences all number	0	1
Weight bearing difficulty
subjects affected / exposed	0 / 613 (0.00%)	1 / 599 (0.17%)
occurrences all number	0	1
Neck mass
subjects affected / exposed	1 / 613 (0.16%)	0 / 599 (0.00%)
occurrences all number	1	0
Infections and infestations
Arthritis infective
subjects affected / exposed	1 / 613 (0.16%)	1 / 599 (0.17%)
occurrences all number	1	1
Abscess of external ear
subjects affected / exposed	0 / 613 (0.00%)	1 / 599 (0.17%)
occurrences all number	0	1
Abscess oral
subjects affected / exposed	0 / 613 (0.00%)	1 / 599 (0.17%)
occurrences all number	0	1
Acarodermatitis
subjects affected / exposed	0 / 613 (0.00%)	1 / 599 (0.17%)
occurrences all number	0	1
Atypical pneumonia
subjects affected / exposed	1 / 613 (0.16%)	0 / 599 (0.00%)
occurrences all number	1	0
Nasopharyngitis
subjects affected / exposed	25 / 613 (4.08%)	21 / 599 (3.51%)
occurrences all number	31	25
Bacterial disease carrier
subjects affected / exposed	1 / 613 (0.16%)	2 / 599 (0.33%)
occurrences all number	1	2
Bacterial infection
subjects affected / exposed	0 / 613 (0.00%)	1 / 599 (0.17%)
occurrences all number	0	1
Bronchitis
subjects affected / exposed	11 / 613 (1.79%)	15 / 599 (2.50%)
occurrences all number	13	15
COVID-19
subjects affected / exposed	31 / 613 (5.06%)	28 / 599 (4.67%)
occurrences all number	32	29
COVID-19 pneumonia
subjects affected / exposed	0 / 613 (0.00%)	1 / 599 (0.17%)
occurrences all number	0	1
Coronavirus infection
subjects affected / exposed	7 / 613 (1.14%)	13 / 599 (2.17%)
occurrences all number	7	14
Cystitis
subjects affected / exposed	1 / 613 (0.16%)	1 / 599 (0.17%)
occurrences all number	1	1
Diabetic foot infection
subjects affected / exposed	1 / 613 (0.16%)	0 / 599 (0.00%)
occurrences all number	1	0
Enterococcal infection
subjects affected / exposed	1 / 613 (0.16%)	0 / 599 (0.00%)
occurrences all number	1	0
Enterocolitis bacterial
subjects affected / exposed	0 / 613 (0.00%)	1 / 599 (0.17%)
occurrences all number	0	1
Erysipelas
subjects affected / exposed	4 / 613 (0.65%)	2 / 599 (0.33%)
occurrences all number	4	2
Febrile infection
subjects affected / exposed	2 / 613 (0.33%)	1 / 599 (0.17%)
occurrences all number	2	1
Furuncle
subjects affected / exposed	0 / 613 (0.00%)	1 / 599 (0.17%)
occurrences all number	0	1
Gangrene
subjects affected / exposed	1 / 613 (0.16%)	0 / 599 (0.00%)
occurrences all number	1	0
Gastroenteritis
subjects affected / exposed	7 / 613 (1.14%)	9 / 599 (1.50%)
occurrences all number	7	10
Gastroenteritis clostridial
subjects affected / exposed	1 / 613 (0.16%)	0 / 599 (0.00%)
occurrences all number	1	0
Gastrointestinal infection
subjects affected / exposed	0 / 613 (0.00%)	1 / 599 (0.17%)
occurrences all number	0	1
Gingivitis
subjects affected / exposed	2 / 613 (0.33%)	0 / 599 (0.00%)
occurrences all number	2	0
Groin abscess
subjects affected / exposed	1 / 613 (0.16%)	0 / 599 (0.00%)
occurrences all number	1	0
Herpes zoster
subjects affected / exposed	6 / 613 (0.98%)	2 / 599 (0.33%)
occurrences all number	6	2
Hordeolum
subjects affected / exposed	0 / 613 (0.00%)	1 / 599 (0.17%)
occurrences all number	0	1
Impetigo
subjects affected / exposed	0 / 613 (0.00%)	1 / 599 (0.17%)
occurrences all number	0	1
Implant site infection
subjects affected / exposed	1 / 613 (0.16%)	0 / 599 (0.00%)
occurrences all number	1	0
Infection
subjects affected / exposed	3 / 613 (0.49%)	2 / 599 (0.33%)
occurrences all number	3	2
Influenza
subjects affected / exposed	3 / 613 (0.49%)	5 / 599 (0.83%)
occurrences all number	3	5
Klebsiella infection
subjects affected / exposed	1 / 613 (0.16%)	0 / 599 (0.00%)
occurrences all number	1	0
Laryngitis
subjects affected / exposed	0 / 613 (0.00%)	1 / 599 (0.17%)
occurrences all number	0	1
Localised infection
subjects affected / exposed	1 / 613 (0.16%)	1 / 599 (0.17%)
occurrences all number	1	1
Lower respiratory tract infection
subjects affected / exposed	1 / 613 (0.16%)	1 / 599 (0.17%)
occurrences all number	1	1
Mastitis
subjects affected / exposed	0 / 613 (0.00%)	1 / 599 (0.17%)
occurrences all number	0	1
Bacteraemia
subjects affected / exposed	1 / 613 (0.16%)	0 / 599 (0.00%)
occurrences all number	1	0
Onychomycosis
subjects affected / exposed	1 / 613 (0.16%)	0 / 599 (0.00%)
occurrences all number	1	0
Oral fungal infection
subjects affected / exposed	1 / 613 (0.16%)	0 / 599 (0.00%)
occurrences all number	1	0
Oral herpes
subjects affected / exposed	1 / 613 (0.16%)	0 / 599 (0.00%)
occurrences all number	1	0
Orchitis
subjects affected / exposed	1 / 613 (0.16%)	0 / 599 (0.00%)
occurrences all number	1	0
Otitis media
subjects affected / exposed	0 / 613 (0.00%)	1 / 599 (0.17%)
occurrences all number	0	1
Penile infection
subjects affected / exposed	1 / 613 (0.16%)	0 / 599 (0.00%)
occurrences all number	1	0
Periodontitis
subjects affected / exposed	2 / 613 (0.33%)	0 / 599 (0.00%)
occurrences all number	2	0
Pharyngitis
subjects affected / exposed	1 / 613 (0.16%)	0 / 599 (0.00%)
occurrences all number	1	0
Pneumonia
subjects affected / exposed	6 / 613 (0.98%)	17 / 599 (2.84%)
occurrences all number	7	18
Pneumonia aspiration
subjects affected / exposed	1 / 613 (0.16%)	0 / 599 (0.00%)
occurrences all number	1	0
Pneumonia klebsiella
subjects affected / exposed	1 / 613 (0.16%)	0 / 599 (0.00%)
occurrences all number	1	0
Post-acute COVID-19 syndrome
subjects affected / exposed	0 / 613 (0.00%)	1 / 599 (0.17%)
occurrences all number	0	1
Pulpitis dental
subjects affected / exposed	0 / 613 (0.00%)	1 / 599 (0.17%)
occurrences all number	0	1
Respiratory tract infection
subjects affected / exposed	12 / 613 (1.96%)	9 / 599 (1.50%)
occurrences all number	13	9
Respiratory tract infection viral
subjects affected / exposed	0 / 613 (0.00%)	1 / 599 (0.17%)
occurrences all number	0	1
Severe acute respiratory syndrome
subjects affected / exposed	1 / 613 (0.16%)	0 / 599 (0.00%)
occurrences all number	1	0
Sialoadenitis
subjects affected / exposed	1 / 613 (0.16%)	0 / 599 (0.00%)
occurrences all number	1	0
Sinusitis
subjects affected / exposed	1 / 613 (0.16%)	1 / 599 (0.17%)
occurrences all number	1	1
Staphylococcal infection
subjects affected / exposed	1 / 613 (0.16%)	2 / 599 (0.33%)
occurrences all number	1	2
Staphylococcal sepsis
subjects affected / exposed	1 / 613 (0.16%)	0 / 599 (0.00%)
occurrences all number	1	0
Superinfection
subjects affected / exposed	1 / 613 (0.16%)	0 / 599 (0.00%)
occurrences all number	1	0
Tinea pedis
subjects affected / exposed	0 / 613 (0.00%)	1 / 599 (0.17%)
occurrences all number	0	1
Upper respiratory tract infection
subjects affected / exposed	5 / 613 (0.82%)	3 / 599 (0.50%)
occurrences all number	5	3
Urinary tract infection
subjects affected / exposed	9 / 613 (1.47%)	9 / 599 (1.50%)
occurrences all number	9	13
Urinary tract infection bacterial
subjects affected / exposed	2 / 613 (0.33%)	0 / 599 (0.00%)
occurrences all number	2	0
Viral infection
subjects affected / exposed	1 / 613 (0.16%)	1 / 599 (0.17%)
occurrences all number	1	1
Vulvovaginal mycotic infection
subjects affected / exposed	1 / 613 (0.16%)	0 / 599 (0.00%)
occurrences all number	1	0
Wound infection
subjects affected / exposed	1 / 613 (0.16%)	0 / 599 (0.00%)
occurrences all number	1	0
Oral candidiasis
subjects affected / exposed	1 / 613 (0.16%)	0 / 599 (0.00%)
occurrences all number	1	0
Metabolism and nutrition disorders
Abnormal loss of weight
subjects affected / exposed	0 / 613 (0.00%)	1 / 599 (0.17%)
occurrences all number	0	1
Cachexia
subjects affected / exposed	1 / 613 (0.16%)	0 / 599 (0.00%)
occurrences all number	1	0
Dehydration
subjects affected / exposed	2 / 613 (0.33%)	2 / 599 (0.33%)
occurrences all number	2	2
Diabetes mellitus
subjects affected / exposed	9 / 613 (1.47%)	8 / 599 (1.34%)
occurrences all number	9	8
Diabetes mellitus inadequate control
subjects affected / exposed	7 / 613 (1.14%)	5 / 599 (0.83%)
occurrences all number	7	5
Folate deficiency
subjects affected / exposed	1 / 613 (0.16%)	0 / 599 (0.00%)
occurrences all number	1	0
Food aversion
subjects affected / exposed	0 / 613 (0.00%)	1 / 599 (0.17%)
occurrences all number	0	1
Food craving
subjects affected / exposed	0 / 613 (0.00%)	1 / 599 (0.17%)
occurrences all number	0	1
Glucose tolerance impaired
subjects affected / exposed	0 / 613 (0.00%)	2 / 599 (0.33%)
occurrences all number	0	2
Gout
subjects affected / exposed	19 / 613 (3.10%)	10 / 599 (1.67%)
occurrences all number	29	13
Hypercholesterolaemia
subjects affected / exposed	1 / 613 (0.16%)	1 / 599 (0.17%)
occurrences all number	1	1
Hyperglycaemia
subjects affected / exposed	3 / 613 (0.49%)	2 / 599 (0.33%)
occurrences all number	3	2
Hyperkalaemia
subjects affected / exposed	22 / 613 (3.59%)	25 / 599 (4.17%)
occurrences all number	24	26
Hyperlipidaemia
subjects affected / exposed	0 / 613 (0.00%)	1 / 599 (0.17%)
occurrences all number	0	1
Hypernatraemia
subjects affected / exposed	1 / 613 (0.16%)	0 / 599 (0.00%)
occurrences all number	1	0
Hyperphosphataemia
subjects affected / exposed	1 / 613 (0.16%)	0 / 599 (0.00%)
occurrences all number	1	0
Hypertriglyceridaemia
subjects affected / exposed	1 / 613 (0.16%)	0 / 599 (0.00%)
occurrences all number	1	0
Hyperuricaemia
subjects affected / exposed	2 / 613 (0.33%)	1 / 599 (0.17%)
occurrences all number	2	1
Hypocalcaemia
subjects affected / exposed	1 / 613 (0.16%)	0 / 599 (0.00%)
occurrences all number	1	0
Hypoglycaemia
subjects affected / exposed	4 / 613 (0.65%)	1 / 599 (0.17%)
occurrences all number	4	1
Hypokalaemia
subjects affected / exposed	9 / 613 (1.47%)	12 / 599 (2.00%)
occurrences all number	10	12
Hyponatraemia
subjects affected / exposed	2 / 613 (0.33%)	1 / 599 (0.17%)
occurrences all number	2	1
Iron deficiency
subjects affected / exposed	5 / 613 (0.82%)	0 / 599 (0.00%)
occurrences all number	5	0
Metabolic acidosis
subjects affected / exposed	1 / 613 (0.16%)	1 / 599 (0.17%)
occurrences all number	1	1
Type 1 diabetes mellitus
subjects affected / exposed	1 / 613 (0.16%)	0 / 599 (0.00%)
occurrences all number	1	0
Type 2 diabetes mellitus
subjects affected / exposed	6 / 613 (0.98%)	4 / 599 (0.67%)
occurrences all number	6	4
Vitamin B12 deficiency
subjects affected / exposed	2 / 613 (0.33%)	0 / 599 (0.00%)
occurrences all number	2	0
Vitamin D deficiency
subjects affected / exposed	1 / 613 (0.16%)	2 / 599 (0.33%)
occurrences all number	1	2
Decreased appetite
subjects affected / exposed	8 / 613 (1.31%)	3 / 599 (0.50%)
occurrences all number	8	3

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Were there any global substantial amendments to the protocol? Yes

23 Feb 2016

SA No. 1: Protocol Vs. 2.0 dated 26.01.2016 Change Inclusion Criteria 4 (Patients with chronic heart failure NYHA class III-IV and aventricular ejection fraction of EF ≤ 40%* or patients with heart failure NYHA class II and EF ≤ 30 %* (* % (determined at screening by echocardiography or cardiac magnetic resonance tomography or within 8 weeks prior to study inclusion by left-ventricular angiography, echocardiography, radionuclide ventriculography, cardiac magnetic resonance tomography AND an evidence based heart failure therapy at least for six months upon discretion of the treating physician) Change Exclusion Criteria 1 (Recent (< 2 months ago): myocardial infarction, coronary revascularization, acute coronary syndrome, stroke or cerebral ischemia and start of heart failure device therapy potentially improving left ventricular ejection fraction or heart failure symptoms (e.g. cardiac resynchronization therapy (CRT), cardiac contractility modulation (CCM), baroreflex-activation therapy (BAT)) Change Exclusion Criteria 2 Scheduled surgery or catheter intervention for valvular heart disease or scheduled coronary revascularization) Change Exclusion Criteria 4 (Complex congenital heart disease; this does not include: mild-moderate valve disease, uncomplicated shunts (isolated patent foramen ovale, small atrial 3 or ventricular septum defects without associated lesions), repaired secundum or sinus venosus atrial septal defects and ventricular septal defects without residua, previously ligated or occluded ductus arteriosus) Change Exclusion Criteria 5 (High-urgency listing for heart transplantation or scheduled therapy with left ventricular assist device (LVAD)) Change of Exclusion Criteria 14 (Thoracic aortic aneurysm (defined as diameter ≥ 45 mm)) Change of Exclusion Criteria 18 and Exclusion Criteria 26 Clarification of the possible administration of amiodarone Addition of an additional digitoxin determination after 1 year

08 Mar 2017

SA No. 2: Protocol Vs. 3.0 dated 06.02.2017 Approval Germany 08.03.2017 (BfArM) and 16.03.2017 (IEC MHH) - Change/specification of the exclusion criterion 1 (Recent (< 2 months ago): myocardial infarction, coronary revascularization, surgery or catheter intervention for valvular heart disease, acute coronary syndrome, stroke or cerebral ischemia and start of heart failure device therapy potentially improving left ventricular ejection fraction or heart failure symptoms (e.g. cardiac resynchronization therapy (CRT), cardiac contractility modulation (CCM), baroreflexactivation therapy (BAT))) - Change/specification of the exclusion criterion 6 (Heart rate < 60 b.p.m. (except if ffunctional CRT in place)). - Change/specification of the exclusion criterion 20 (Presence of both treatment with cardiac glycosides and atrial fibrillation). - Addition of the exclusion criterion 27 (Life expectancy < 12 month (e.g. due to active cancer)).

09 Mar 2018

SA No. 3: Protocol Vs. 4.1 dated 06.02.2018 Clarification of inclusion criteria 2 (Male or female patients age ≥ 18 years at day of iinclusion) Change/specification inclusion criterion 5 (Women without childbearing potential defined as one or more of following: * Women at least 6 weeks after surgical sterilization by bilateral tubal ligation or bilateral oophorectomy with or without hysterectomy, * Women ≥ 50 years of age at the day of inclusion who have been postmenopausal since at least 1 year, * Women < 50 years and in postmenopausal state ≥ 1 year with serum FSH > 40 IU/l OR Women of childbearing potential who have a negative hCG pregnancy test and agree to meet one of the following criteria from the time of screening/baseline, during the study and for a period of 40 days following the last administration of study medication: * Correct use of reliable contraception methods. This includes hormonal contraceptive or an intrauterine device or a barrier method of contraception such as condom or occlusive cap with spermicide, * True abstinence, * Sexual relationship only with female partners and/or sterile male partners OR Men Clarification of exclusion criteria 1 (Recent: myocardial infarction, coronary revascularization, surgery or catheter intervention for valvular heart disease, acute coronary syndrome, stroke or cerebral ischema ... Clarification of exclusion criteria 4 Recruitment period extension (ca72 months in total) Clarification of time frame (event-driven) Addition of 2 substudies (effect of digitoxin on arrhythmia burden / endothelial function) Dose adjustment for digitoxin serum concentrations (25 ng/ml (33 nmol/l) Introduction of telephone FU visits for participants who are no longer taking IMP Change in procedure for endpoint adjudication No determination of digitoxin serum conc. if study medication is not taken Introduction of the option to query health insurance companies Change AE documentation Data management and monitoring

02 May 2019

SA No. 4: Protocol Vs. 5.0 dated 06.02.2019 Approval Germany 02.05.2019 (BfArM) and 22.05.2019 (IEC MHH) Approval Austria: 14.05.2019 (BASG) and 29.05.2019 (IEC Wien) Approval Serbia: 21.10.2020 (Serbian Agency for Medicines and Medical Devices) and 08.07.2019 (Ethical Board of CHC "Bežanijska kosa", Belgrade) - Addition of two substudies on the effect of digitoxin on exercise capacity and echocardiographic remodeling - Specification/supplement to the exclusion criterion 2 (Scheduled surgery or catheter intervention for valvular heart disease, scheduled coronary revascularization, scheduled heart ffailure device therapy potentially improving left ventricular ejection fraction or heart failure symptoms (e.g. cardiac resynchronization therapy (CRT), cardiac contractility modulation (CCM), baroreflex-activation therapy (BAT))) - Additions to the procedure for adjusting the dose of the IMP - Change of sponsor contact person - Change in the legal form of the CRO

14 Aug 2020

SA No. 5: Protocol Vs. 6.0 dated 16.07.2020 Approval Germany 14.08.2020 (BfArM) and 05.10.2020 (IEC MHH) Approval Austria: 23.12.2020 (BASG) and 20.11.2020 (IEC Wien) Approval Serbia: 08.04.2022 (Serbian Agency for Medicines and Medical Devices, including IEC) Intermittend measures due to Covid-19/Corona pandemic for recruitment, IMP allocation, drug accountability, trial visits, collection of blood samples, monitoring

20 Apr 2022

SA No. 6: Protocol Vs. 7.0 dated 14.12.2021 Approval Germany 20.04.2022 (BfArM) and 19.05.2022 (IEC MHH) Approval Austria: 31.05.2022 (BASG) and 17.05.2022 (IEC Wien) Approval Serbia: 24.08.2023 (Serbian Agency for Medicines and Medical Devices, including IEC) - Adjustment of recruitment and study duration - Adjustment to the updated guideline (addition of Sodium-Glucose-Transporter-2-Inhibitor) - Addition of subgroup analysis for regions ((EU versus Serbia), supplement quadruple therapy in statistical analysis - Clarification: Hospital stay overnight = date change - Removal of SF-12 as an appendix to the protocol due to possible copyright infringement upon publication of the protocol

05 Sep 2023

SA No. 7: Protocol Vs. 8.0 dated 20.07.2023 Approval Germany 05.09.2023 (BfArM) und 06.09.2023 (IEC MHH) Approval Austria: 14.09.2023 (BASG) und 10.10.2023 (IEC Wien) Approval Serbia: 14.02.2025 (Serbian Agency for Medicines and Medical Devices, including IEC) • Adjustment of recruitment period and study duration • Non-implementation of interim evaluation • Change in key secondary endpoints (and the resulting change in the evaluation method) • Change to the Reference Safety Information (the existing Digimerck® product information will no longer be updated)

Were there any global interruptions to the trial? No

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

None reported

http://www.ncbi.nlm.nih.gov/pubmed/40389288
http://www.ncbi.nlm.nih.gov/pubmed/37087503
http://www.ncbi.nlm.nih.gov/pubmed/39838553
http://www.ncbi.nlm.nih.gov/pubmed/40879434
http://www.ncbi.nlm.nih.gov/pubmed/30892806

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Clinical trials

Clinical Trial Results:
A multicenter, randomized, double-blind, placebo-controlled study to demonstrate that digitoxin reduces a composite of overall mortality and hospitalization for worsening heart failure in patients with chronic heart failure and reduced ejection fraction

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Primary: Composite endpoint of time to all-cause mortalitiy /heart failure hospitalisation (whichever occurs first)

Primary: Composite endpoint of time to all-cause mortalitiy /heart failure hospitalisation (whichever occurs first)

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Primary: Time to all-cause death

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Primary: Time to first heart failure hospitalisation

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Clinical trials

Clinical Trial Results: A multicenter, randomized, double-blind, placebo-controlled study to demonstrate that digitoxin reduces a composite of overall mortality and hospitalization for worsening heart failure in patients with chronic heart failure and reduced ejection fraction

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Composite endpoint of time to all-cause mortalitiy /heart failure hospitalisation (whichever occurs first)

Primary: Composite endpoint of time to all-cause mortalitiy /heart failure hospitalisation (whichever occurs first)

Primary: Time to all-cause death

Primary: Time to all-cause death

Primary: Time to first heart failure hospitalisation

Primary: Time to first heart failure hospitalisation

Secondary: All-cause death and total heart failure hospitalisations

Secondary: All-cause death and total heart failure hospitalisations

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

Online references

More information

Clinical Trial Results:
A multicenter, randomized, double-blind, placebo-controlled study to demonstrate that digitoxin reduces a composite of overall mortality and hospitalization for worsening heart failure in patients with chronic heart failure and reduced ejection fraction