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    Clinical Trial Results:
    AdreView™ Myocardial Imaging for Risk Evaluation – A Multicentre Trial to Guide ICD Implantation in NYHA class II & III Heart Failure Patients With 30%≤LVEF≤35% ADMIRE-ICD

    Summary
    EudraCT number
    		 2015-001464-19
    Trial protocol
    		 HU   ES   NL   CZ   DE   DK  
    Global end of trial date
    04 May 2018

    Results information
    Results version number
    		 v1(current)
    This version publication date
    27 Apr 2019
    First version publication date
    27 Apr 2019
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    GE-122-020
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02656329
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    GE Healthcare Ltd.
    Sponsor organisation address
    The Grove Centre, White Lion Road, Amersham, Buckinghamshire, United Kingdom, HP7 9LL
    Public contact
    Medical Director - Nuclear Medicine, GE Healthcare Ltd., info@ge.com
    Scientific contact
    Medical Director - Nuclear Medicine, GE Healthcare Ltd., info@ge.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    30 Aug 2018
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    04 May 2018
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    To demonstrate the efficacy of AdreView™ imaging for appropriately guiding the decision of ICD implantation in a population of New York Heart Association (NYHA) class II and III Heart Failure (HF) subjects with 25%≤left ventricular ejection fraction (LVEF) ≤35%. This will be achieved by comparing allcause mortality observed in the AdreView™-guided therapy group to that observed in subjects receiving the Standard of Care (SoC; defined as the medical care as recommended by internationally accepted HF guidelines), in whom no clinical decision will be made based upon AdreView™ scan results.
    Protection of trial subjects
    This study was conducted in full accordance with the Declaration of Helsinki, the Good Clinical Practice: Consolidated Guideline approved by the International Conference on Harmonisation (ICH), and any applicable national and local laws and regulations. The investigators were responsible for performing the study in accordance with the protocol and ICH E6-Good Clinical Practice (GCP), for collecting, recording, and reporting the data accurately and properly. The informed consent process was documented in the subject's medical record and the investigator signed, dated and timed the informed consent form after the subject had signed, dated and recorded the time. The study was designed and endorsed by a Steering/Scientific Committee composed of world leaders in heart failure (HF) and arrhythmia management.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    30 Dec 2015
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United States: 79
    Country: Number of subjects enrolled
    Canada: 16
    Country: Number of subjects enrolled
    European Union: 248
    Worldwide total number of subjects
    343
    EEA total number of subjects
    0
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    179
    From 65 to 84 years
    161
    85 years and over
    3

    Subject disposition

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    Recruitment
    Recruitment details
    		 The Study was conducted at 70 centers in United States of America, Canada and Europe between 30 December 2015 and 04 May 2018. A total of 395 subjects were enrolled in study, of which 52 were screen failures mainly due to exclusion criteria met.

    Pre-assignment
    Screening details
    		 Out of 343 subjects, 321 subjects with 25% <=left ventricular ejection fraction (LVEF) <=35% were randomized in a 1:1 ratio to the AdreView™ group or Standard of Care (SoC) group stratified by enrolling center via an interactive web response system and 22 subjects were not randomized but included in safety analysis set.

    Period 1
    Period 1 title
    Period 1 (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 AdreView™
    Arm description
    		 Subjects received 1 intravenous injection of 10 millicuries (mCi) (370 MBq) of AdreView™ (Iobenguane I-123 Injection). Subjects with AdreView™ Heart-to-Mediastinal ratio (H/M) <1.6 underwent Implantable Cardioverter Defibrillator (ICD) device implantation and H/M >= 1.6 continued to receive Guideline-Directed Optimal Medical Therapy (GDMT) according to clinical standard practice.
    Arm type
    		 Experimental

    Investigational medicinal product name
    AdreView™
    Investigational medicinal product code
    Other name
    Iobenguane I123 Injection
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    AdreView™ was administered in a volume of 5 mL (diluted using 0.9% sodium chloride as needed) and injected as a slow infusion over 1 to 2 minutes followed by 10 mL of saline flush injected over a maximum of 5 seconds.

    Arm title
    		 Standard of Care
    Arm description
    		 Subjects received 1 intravenous injection of 10 mCi (370 MBq) of AdreView™ (Iobenguane I-123 Injection) and underwent ICD implantation and were followed up in accordance with internationally accepted Heart Failure (HF) guidelines.
    Arm type
    		 Experimental

    Investigational medicinal product name
    AdreView™
    Investigational medicinal product code
    Other name
    Iobenguane I123 Injection
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    AdreView™ was administered in a volume of 5 mL (diluted using 0.9% sodium chloride as needed) and injected as a slow infusion over 1 to 2 minutes followed by 10 mL of saline flush injected over a maximum of 5 seconds.

    Number of subjects in period 1 [1]
    		AdreView™ Standard of Care
    Started
    164
    157
    Completed
    0
    0
    Not completed
    164
    157
         Other than specified above
    5
    6
         Consent withdrawn by subject
    7
    6
         Study terminated by sponsor
    150
    142
         Lost to follow-up
    2
    3
    Notes
    [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: A total of 343 subjects were included in study. Of which, 321 subjects were randomized in a 1:1 ratio to the AdreView™ group or Standard of Care (SoC) group stratified by enrolling center via an interactive web response system and 22 subjects were not randomized but included in safety analysis set.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    AdreView™
    Reporting group description
    		 Subjects received 1 intravenous injection of 10 millicuries (mCi) (370 MBq) of AdreView™ (Iobenguane I-123 Injection). Subjects with AdreView™ Heart-to-Mediastinal ratio (H/M) <1.6 underwent Implantable Cardioverter Defibrillator (ICD) device implantation and H/M >= 1.6 continued to receive Guideline-Directed Optimal Medical Therapy (GDMT) according to clinical standard practice.

    Reporting group title
    Standard of Care
    Reporting group description
    		 Subjects received 1 intravenous injection of 10 mCi (370 MBq) of AdreView™ (Iobenguane I-123 Injection) and underwent ICD implantation and were followed up in accordance with internationally accepted Heart Failure (HF) guidelines.

    Reporting group values
    		 AdreView™ Standard of Care Total
    Number of subjects
    		 164 157 321
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 64.1 ± 9.40 62.1 ± 10.05 -
    Gender categorical
    Units: Subjects
        Female
    		 35 22 57
        Male
    		 129 135 264
    Ethnicity
    Units: Subjects
        Hispanic or Latino
    		 17 9 26
        Not Hispanic or Latino
    		 142 140 282
        Unknown or Not Reported
    		 5 8 13
    Race
    Units: Subjects
        American Indian or Alaska Native
    		 0 0 0
        Asian
    		 0 3 3
        Native Hawaiian or Other Pacific Islander
    		 0 0 0
        Black or African American
    		 10 9 19
        White
    		 149 137 286
        More than one race
    		 0 0 0
        Unknown or Not Reported
    		 5 8 13

    End points

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    End points reporting groups
    Reporting group title
    AdreView™
    Reporting group description
    		 Subjects received 1 intravenous injection of 10 millicuries (mCi) (370 MBq) of AdreView™ (Iobenguane I-123 Injection). Subjects with AdreView™ Heart-to-Mediastinal ratio (H/M) <1.6 underwent Implantable Cardioverter Defibrillator (ICD) device implantation and H/M >= 1.6 continued to receive Guideline-Directed Optimal Medical Therapy (GDMT) according to clinical standard practice.

    Reporting group title
    Standard of Care
    Reporting group description
    		 Subjects received 1 intravenous injection of 10 mCi (370 MBq) of AdreView™ (Iobenguane I-123 Injection) and underwent ICD implantation and were followed up in accordance with internationally accepted Heart Failure (HF) guidelines.

    Primary: All-cause Mortality

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    End point title
    		 All-cause Mortality
    End point description
    All-cause mortality included deaths of subjects due to any cause. Percentage of subjects who died due to any cause were reported. Analysis was performed on full analysis set (FAS) that was defined as subjects included in the safety analysis set who were randomised to the AdreView™ group or the SoC group.
    End point type
    Primary
    End point timeframe
    From randomization until the end of the follow-up period (median 304 days)
    End point values
    		 AdreView™ Standard of Care
    Number of subjects analysed
    164
    157
    Units: percentage of subjects
        number (not applicable)
    3.0
    3.2
    Statistical analysis title
    		 AdreView™ vs. Standard of Care
    Statistical analysis description
    Analysis was performed using the Cox proportional hazards model stratified by enrolling center, with method of treatment guidance (SoC vs AdreView™ group) as the only covariate.
    Comparison groups
    AdreView™ v Standard of Care
    Number of subjects included in analysis
    321
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [1]
    P-value
    		 = 0.8459 [2]
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.047
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.295
         upper limit
    		 3.719
    Notes
    [1] - Non-inferiority of AdreView™ group over SoC group was demonstrated if upper bound of the 95% confidence interval (CI) for the hazard ratio (HR) (AdreView™ group / SoC) was equal to 1.20.
    [2] - Threshold for significance at 0.025 level.

    Secondary: Percentage of Subjects With Events of Complications of Device: H/M >=1.6 in Full Analysis Set

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    End point title
    		 Percentage of Subjects With Events of Complications of Device: H/M >=1.6 in Full Analysis Set
    End point description
    Composite of the percentage of subjects with events of hospitalization or death related to major complications of device implantation (i.e., need for thoracotomy, pericardiocentesis, or vascular surgery), complications of long-term device therapy (i.e., infection not leading to hospitalization, lead and/or generator removal/replacement, inappropriate shocks, explanation), and combined as ‘complications of device’ for subjects with H/M >=1.6. Subjects who were alive at time of database lock (DBL) were censored at the last known-alive date. Analysis was performed on FAS population. Here, number of subjects analysed = subjects with H/M >=1.6.
    End point type
    Secondary
    End point timeframe
    From randomization until the end of the follow-up period (median 304 days)
    End point values
    		 AdreView™ Standard of Care
    Number of subjects analysed
    26
    20
    Units: percentage of subjects
    number (not applicable)
        Hospitalisation/death
    3.8
    0
        Complications of long-term device therapy
    3.8
    15.0
        Complications of device
    3.8
    15.0
    No statistical analyses for this end point

    Secondary: Percentage of Subjects With Cardiac Death

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    End point title
    		 Percentage of Subjects With Cardiac Death
    End point description
    Cardiac death composed of sudden cardiac death, death due to cardiac arrhythmia, death due to heart failure, and death due to other cardiovascular causes. Analysis was performed on FAS population.
    End point type
    Secondary
    End point timeframe
    From randomization until the end of the follow-up period (median 304 days)
    End point values
    		 AdreView™ Standard of Care
    Number of subjects analysed
    164
    157
    Units: percentage of subjects
        number (not applicable)
    1.2
    0.6
    No statistical analyses for this end point

    Secondary: Percentage of Subjects With Hospitalization for Cardiovascular Cause

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    End point title
    		 Percentage of Subjects With Hospitalization for Cardiovascular Cause
    End point description
    Percentage of subjects who were hospitalised for cardiovascular cause were reported. Analysis was performed on FAS population.
    End point type
    Secondary
    End point timeframe
    From randomization until the end of the follow-up period (median 304 days)
    End point values
    		 AdreView™ Standard of Care
    Number of subjects analysed
    164
    157
    Units: percentage of subjects
        number (not applicable)
    7.3
    7.6
    No statistical analyses for this end point

    Secondary: Percentage of Subjects With All-Cause Hospitalization

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    End point title
    		 Percentage of Subjects With All-Cause Hospitalization
    End point description
    Percentage of subjects with all-cause hospitalization were reported. Analysis was performed on FAS population.
    End point type
    Secondary
    End point timeframe
    From randomization until the end of the follow-up period (median 304 days)
    End point values
    		 AdreView™ Standard of Care
    Number of subjects analysed
    164
    157
    Units: percentage of subjects
        number (not applicable)
    17.1
    22.3
    No statistical analyses for this end point

    Secondary: Percentage of Subjects With Events (Composite of the Occurrence of Resuscitated Life-Threatening Ventricular Tachycardia, Unstable Ventricular Tachyarrhythmias, Sudden Cardiac Death [SCD] and Resuscitated Cardiac Arrest)

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    End point title
    		 Percentage of Subjects With Events (Composite of the Occurrence of Resuscitated Life-Threatening Ventricular Tachycardia, Unstable Ventricular Tachyarrhythmias, Sudden Cardiac Death [SCD] and Resuscitated Cardiac Arrest)
    End point description
    Percentage of subjects with composite events i.e. occurrence of resuscitated life-threatening ventricular tachycardia, unstable ventricular tachy-arrhythmias, SCD and resuscitated cardiac arrest were reported. Subjects who were alive at time of database lock (DBL) were censored at the last known-alive date. Analysis was performed on FAS population.
    End point type
    Secondary
    End point timeframe
    From randomization until the end of the follow-up period (median 304 days)
    End point values
    		 AdreView™ Standard of Care
    Number of subjects analysed
    164
    157
    Units: percentage of subjects
        number (not applicable)
    1.2
    2.5
    No statistical analyses for this end point

    Secondary: Percentage of Subjects With Syncope

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    End point title
    		 Percentage of Subjects With Syncope
    End point description
    Percentage of subjects with Syncope were reported. Subjects who were alive at time of DBL were censored at the last known-alive date by date of DBL. Analysis was performed on FAS population.
    End point type
    Secondary
    End point timeframe
    From randomization until the end of the follow-up period (median 304 days)
    End point values
    		 AdreView™ Standard of Care
    Number of subjects analysed
    164
    157
    Units: percentage of subjects
        number (not applicable)
    2.4
    0
    No statistical analyses for this end point

    Secondary: Percentage of Subjects With Implantable Cardioverter Defibrillator (ICD) Implantation

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    End point title
    		 Percentage of Subjects With Implantable Cardioverter Defibrillator (ICD) Implantation
    End point description
    Percentage of subjects with ICD implantation were reported. Analysis was performed on FAS population.
    End point type
    Secondary
    End point timeframe
    From randomization until the end of the follow-up period (median 304 days)
    End point values
    		 AdreView™ Standard of Care
    Number of subjects analysed
    164
    157
    Units: percentage of subjects
        number (not applicable)
    73.2
    81.5
    No statistical analyses for this end point

    Secondary: Percentage of Subjects With Events of Complications of Device

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    End point title
    		 Percentage of Subjects With Events of Complications of Device
    End point description
    Composite of the percentage of subjects with events of hospitalization or death related to major complications of device implantation (i.e., need for thoracotomy, pericardiocentesis, or vascular surgery), complications of long-term device therapy (i.e., infection not leading to hospitalization, lead and/or generator removal/replacement, inappropriate shocks, explanation), and combined as ‘complications of device’. Analysis was performed on FAS population.
    End point type
    Secondary
    End point timeframe
    From randomization until the end of the follow-up period (median 304 days)
    End point values
    		 AdreView™ Standard of Care
    Number of subjects analysed
    164
    157
    Units: percentage of subjects
    number (not applicable)
        Hospitalization/death
    4.9
    3.8
        Complications of long-term device therapy
    4.3
    6.4
        Complications of device
    5.5
    6.4
    No statistical analyses for this end point

    Adverse events

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    Adverse events information [1]
    Timeframe for reporting adverse events
    All Adverse Events (AEs) were collected from randomization until the end of the follow-up period (median 304 days) regardless of seriousness or relationship to investigational product.
    Adverse event reporting additional description
    Reported AEs and deaths are study-emergent AEs that is AEs and deaths that developed/worsened during any time after randomization. Analysis was performed on safety population which included all subjects who signed the informed consent form and met all the inclusion criteria and none of the exclusion criteria.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    19.0
    Reporting groups
    Reporting group title
    AdreView™
    Reporting group description
    		 Subjects received 1 intravenous injection of 10 mCi (370 MBq) of AdreView™ (Iobenguane I-123 Injection). Subjects with AdreView™ H/M ratio <1.6 underwent ICD device implantation and H/M ratio >= 1.6 continued to receive GDMT according to clinical standard practice.

    Reporting group title
    Standard of Care
    Reporting group description
    		 Subjects received 1 intravenous injection of 10 mCi (370 MBq) of AdreView™ (Iobenguane I-123 Injection) and underwent ICD implantation and were followed up in accordance with internationally accepted HF guidelines.

    Reporting group title
    Total Subjects
    Reporting group description
    		 All subjects who were randomized in AdreView™ and Standard of Care group in addition with non-randomized subjects who signed informed consent form.

    Notes
    [1] - There are no non-serious adverse events recorded for these results. It is expected that there will be at least one non-serious adverse event reported.
    Justification: No non-serious adverse events were reported in this study.
    Serious adverse events
    		 AdreView™ Standard of Care Total Subjects
    Total subjects affected by serious adverse events
         subjects affected / exposed
    65 / 164 (39.63%)
    62 / 157 (39.49%)
    127 / 343 (37.03%)
         number of deaths (all causes)
    6
    5
    11
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Colon cancer
         subjects affected / exposed
    0 / 164 (0.00%)
    1 / 157 (0.64%)
    1 / 343 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    Gastrointestinal stromal cancer
         subjects affected / exposed
    0 / 164 (0.00%)
    1 / 157 (0.64%)
    1 / 343 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lung neoplasm
         subjects affected / exposed
    1 / 164 (0.61%)
    0 / 157 (0.00%)
    1 / 343 (0.29%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Neoplasm prostate
         subjects affected / exposed
    0 / 164 (0.00%)
    1 / 157 (0.64%)
    1 / 343 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Prostate cancer
         subjects affected / exposed
    0 / 164 (0.00%)
    1 / 157 (0.64%)
    1 / 343 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Aortic aneurysm
         subjects affected / exposed
    1 / 164 (0.61%)
    0 / 157 (0.00%)
    1 / 343 (0.29%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Aortic dissection
         subjects affected / exposed
    0 / 164 (0.00%)
    1 / 157 (0.64%)
    1 / 343 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Circulatory collapse
         subjects affected / exposed
    1 / 164 (0.61%)
    0 / 157 (0.00%)
    1 / 343 (0.29%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Deep vein thrombosis
         subjects affected / exposed
    1 / 164 (0.61%)
    0 / 157 (0.00%)
    1 / 343 (0.29%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypertension
         subjects affected / exposed
    0 / 164 (0.00%)
    1 / 157 (0.64%)
    1 / 343 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    2 / 164 (1.22%)
    1 / 157 (0.64%)
    3 / 343 (0.87%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Intermittent claudication
         subjects affected / exposed
    0 / 164 (0.00%)
    1 / 157 (0.64%)
    1 / 343 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lymphoedema
         subjects affected / exposed
    1 / 164 (0.61%)
    0 / 157 (0.00%)
    1 / 343 (0.29%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Orthostatic hypotension
         subjects affected / exposed
    0 / 164 (0.00%)
    1 / 157 (0.64%)
    1 / 343 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Peripheral artery stenosis
         subjects affected / exposed
    0 / 164 (0.00%)
    1 / 157 (0.64%)
    1 / 343 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Peripheral ischaemia
         subjects affected / exposed
    1 / 164 (0.61%)
    0 / 157 (0.00%)
    1 / 343 (0.29%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Phlebitis
         subjects affected / exposed
    1 / 164 (0.61%)
    0 / 157 (0.00%)
    1 / 343 (0.29%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Surgical and medical procedures
    Implantable defibrillator insertion
         subjects affected / exposed
    2 / 164 (1.22%)
    1 / 157 (0.64%)
    3 / 343 (0.87%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Chest discomfort
         subjects affected / exposed
    0 / 164 (0.00%)
    1 / 157 (0.64%)
    1 / 343 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Chest pain
         subjects affected / exposed
    1 / 164 (0.61%)
    0 / 157 (0.00%)
    1 / 343 (0.29%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Complication associated with device
         subjects affected / exposed
    1 / 164 (0.61%)
    1 / 157 (0.64%)
    2 / 343 (0.58%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Malaise
         subjects affected / exposed
    1 / 164 (0.61%)
    0 / 157 (0.00%)
    1 / 343 (0.29%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Medical device site irritation
         subjects affected / exposed
    0 / 164 (0.00%)
    1 / 157 (0.64%)
    1 / 343 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Non-cardiac chest pain
         subjects affected / exposed
    1 / 164 (0.61%)
    0 / 157 (0.00%)
    1 / 343 (0.29%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Oedema peripheral
         subjects affected / exposed
    1 / 164 (0.61%)
    1 / 157 (0.64%)
    2 / 343 (0.58%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pain
         subjects affected / exposed
    1 / 164 (0.61%)
    0 / 157 (0.00%)
    1 / 343 (0.29%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Polyp
         subjects affected / exposed
    1 / 164 (0.61%)
    0 / 157 (0.00%)
    1 / 343 (0.29%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Benign prostatic hyperplasia
         subjects affected / exposed
    0 / 164 (0.00%)
    1 / 157 (0.64%)
    1 / 343 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Prostatitis
         subjects affected / exposed
    1 / 164 (0.61%)
    0 / 157 (0.00%)
    1 / 343 (0.29%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute pulmonary oedema
         subjects affected / exposed
    0 / 164 (0.00%)
    1 / 157 (0.64%)
    1 / 343 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Asthma
         subjects affected / exposed
    1 / 164 (0.61%)
    1 / 157 (0.64%)
    2 / 343 (0.58%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bronchospasm
         subjects affected / exposed
    0 / 164 (0.00%)
    1 / 157 (0.64%)
    1 / 343 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    0 / 164 (0.00%)
    1 / 157 (0.64%)
    1 / 343 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cough
         subjects affected / exposed
    2 / 164 (1.22%)
    0 / 157 (0.00%)
    2 / 343 (0.58%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    2 / 164 (1.22%)
    0 / 157 (0.00%)
    2 / 343 (0.58%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dyspnoea paroxysmal nocturnal
         subjects affected / exposed
    0 / 164 (0.00%)
    1 / 157 (0.64%)
    1 / 343 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Epistaxis
         subjects affected / exposed
    1 / 164 (0.61%)
    1 / 157 (0.64%)
    2 / 343 (0.58%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypoxia
         subjects affected / exposed
    1 / 164 (0.61%)
    0 / 157 (0.00%)
    1 / 343 (0.29%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    1 / 164 (0.61%)
    0 / 157 (0.00%)
    1 / 343 (0.29%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    0 / 164 (0.00%)
    1 / 157 (0.64%)
    1 / 343 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pulmonary mass
         subjects affected / exposed
    1 / 164 (0.61%)
    0 / 157 (0.00%)
    1 / 343 (0.29%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pulmonary oedema
         subjects affected / exposed
    1 / 164 (0.61%)
    0 / 157 (0.00%)
    1 / 343 (0.29%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    2 / 164 (1.22%)
    1 / 157 (0.64%)
    3 / 343 (0.87%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    Sinus congestion
         subjects affected / exposed
    0 / 164 (0.00%)
    1 / 157 (0.64%)
    1 / 343 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Sleep apnoea syndrome
         subjects affected / exposed
    1 / 164 (0.61%)
    0 / 157 (0.00%)
    1 / 343 (0.29%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Tachypnoea
         subjects affected / exposed
    1 / 164 (0.61%)
    0 / 157 (0.00%)
    1 / 343 (0.29%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    1 / 164 (0.61%)
    0 / 157 (0.00%)
    1 / 343 (0.29%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Confusional state
         subjects affected / exposed
    1 / 164 (0.61%)
    0 / 157 (0.00%)
    1 / 343 (0.29%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Depression
         subjects affected / exposed
    1 / 164 (0.61%)
    1 / 157 (0.64%)
    2 / 343 (0.58%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Product issues
    Device inappropriate shock delivery
         subjects affected / exposed
    3 / 164 (1.83%)
    2 / 157 (1.27%)
    5 / 343 (1.46%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Device use issue
         subjects affected / exposed
    1 / 164 (0.61%)
    1 / 157 (0.64%)
    2 / 343 (0.58%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lead dislodgement
         subjects affected / exposed
    2 / 164 (1.22%)
    2 / 157 (1.27%)
    4 / 343 (1.17%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Blood cholesterol increased
         subjects affected / exposed
    1 / 164 (0.61%)
    0 / 157 (0.00%)
    1 / 343 (0.29%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood creatinine increased
         subjects affected / exposed
    1 / 164 (0.61%)
    0 / 157 (0.00%)
    1 / 343 (0.29%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood uric acid increased
         subjects affected / exposed
    2 / 164 (1.22%)
    0 / 157 (0.00%)
    2 / 343 (0.58%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    C-reactive protein increased
         subjects affected / exposed
    1 / 164 (0.61%)
    0 / 157 (0.00%)
    1 / 343 (0.29%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Weight decreased
         subjects affected / exposed
    0 / 164 (0.00%)
    1 / 157 (0.64%)
    1 / 343 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Humerus fracture
         subjects affected / exposed
    0 / 164 (0.00%)
    1 / 157 (0.64%)
    1 / 343 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Injury
         subjects affected / exposed
    1 / 164 (0.61%)
    0 / 157 (0.00%)
    1 / 343 (0.29%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lower limb fracture
         subjects affected / exposed
    1 / 164 (0.61%)
    0 / 157 (0.00%)
    1 / 343 (0.29%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Overdose
         subjects affected / exposed
    0 / 164 (0.00%)
    1 / 157 (0.64%)
    1 / 343 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Sternal fracture
         subjects affected / exposed
    1 / 164 (0.61%)
    0 / 157 (0.00%)
    1 / 343 (0.29%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Acute myocardial infarction
         subjects affected / exposed
    1 / 164 (0.61%)
    1 / 157 (0.64%)
    2 / 343 (0.58%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Angina pectoris
         subjects affected / exposed
    1 / 164 (0.61%)
    2 / 157 (1.27%)
    3 / 343 (0.87%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Angina unstable
         subjects affected / exposed
    0 / 164 (0.00%)
    1 / 157 (0.64%)
    1 / 343 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Arrhythmia
         subjects affected / exposed
    5 / 164 (3.05%)
    2 / 157 (1.27%)
    7 / 343 (2.04%)
         occurrences causally related to treatment / all
    0 / 11
    0 / 2
    0 / 13
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    3 / 164 (1.83%)
    3 / 157 (1.91%)
    7 / 343 (2.04%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 3
    0 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    3 / 164 (1.83%)
    1 / 157 (0.64%)
    4 / 343 (1.17%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorder
         subjects affected / exposed
    26 / 164 (15.85%)
    22 / 157 (14.01%)
    48 / 343 (13.99%)
         occurrences causally related to treatment / all
    0 / 38
    0 / 28
    0 / 68
         deaths causally related to treatment / all
    0 / 4
    0 / 2
    0 / 6
    Cardiac failure
         subjects affected / exposed
    8 / 164 (4.88%)
    5 / 157 (3.18%)
    13 / 343 (3.79%)
         occurrences causally related to treatment / all
    0 / 9
    0 / 8
    0 / 16
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac failure congestive
         subjects affected / exposed
    1 / 164 (0.61%)
    2 / 157 (1.27%)
    3 / 343 (0.87%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac perforation
         subjects affected / exposed
    2 / 164 (1.22%)
    0 / 157 (0.00%)
    2 / 343 (0.58%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac ventricular thrombosis
         subjects affected / exposed
    1 / 164 (0.61%)
    0 / 157 (0.00%)
    1 / 343 (0.29%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardio-respiratory arrest
         subjects affected / exposed
    1 / 164 (0.61%)
    0 / 157 (0.00%)
    1 / 343 (0.29%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Supraventricular tachycardia
         subjects affected / exposed
    0 / 164 (0.00%)
    2 / 157 (1.27%)
    2 / 343 (0.58%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Tachycardia
         subjects affected / exposed
    0 / 164 (0.00%)
    2 / 157 (1.27%)
    2 / 343 (0.58%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ventricular arrhythmia
         subjects affected / exposed
    0 / 164 (0.00%)
    1 / 157 (0.64%)
    1 / 343 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ventricular extrasystoles
         subjects affected / exposed
    2 / 164 (1.22%)
    0 / 157 (0.00%)
    2 / 343 (0.58%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ventricular tachycardia
         subjects affected / exposed
    1 / 164 (0.61%)
    4 / 157 (2.55%)
    5 / 343 (1.46%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 4
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Cerebrovascular accident
         subjects affected / exposed
    0 / 164 (0.00%)
    1 / 157 (0.64%)
    1 / 343 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dementia Alzheimer’s type
         subjects affected / exposed
    1 / 164 (0.61%)
    0 / 157 (0.00%)
    1 / 343 (0.29%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    Dizziness
         subjects affected / exposed
    2 / 164 (1.22%)
    0 / 157 (0.00%)
    2 / 343 (0.58%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Epilepsy
         subjects affected / exposed
    1 / 164 (0.61%)
    0 / 157 (0.00%)
    1 / 343 (0.29%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hemiplegia
         subjects affected / exposed
    1 / 164 (0.61%)
    0 / 157 (0.00%)
    1 / 343 (0.29%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Presyncope
         subjects affected / exposed
    1 / 164 (0.61%)
    0 / 157 (0.00%)
    1 / 343 (0.29%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Seizure
         subjects affected / exposed
    0 / 164 (0.00%)
    1 / 157 (0.64%)
    1 / 343 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    4 / 164 (2.44%)
    1 / 157 (0.64%)
    5 / 343 (1.46%)
         occurrences causally related to treatment / all
    0 / 7
    0 / 1
    0 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    0 / 164 (0.00%)
    1 / 157 (0.64%)
    1 / 343 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Iron deficiency anaemia
         subjects affected / exposed
    1 / 164 (0.61%)
    0 / 157 (0.00%)
    1 / 343 (0.29%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Leukocytosis
         subjects affected / exposed
    1 / 164 (0.61%)
    0 / 157 (0.00%)
    1 / 343 (0.29%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Normochromic normocytic anaemia
         subjects affected / exposed
    1 / 164 (0.61%)
    0 / 157 (0.00%)
    1 / 343 (0.29%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    2 / 164 (1.22%)
    0 / 157 (0.00%)
    2 / 343 (0.58%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    0 / 164 (0.00%)
    2 / 157 (1.27%)
    2 / 343 (0.58%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Abdominal pain upper
         subjects affected / exposed
    1 / 164 (0.61%)
    0 / 157 (0.00%)
    1 / 343 (0.29%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Chronic gastritis
         subjects affected / exposed
    1 / 164 (0.61%)
    0 / 157 (0.00%)
    1 / 343 (0.29%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    0 / 164 (0.00%)
    1 / 157 (0.64%)
    1 / 343 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dental caries
         subjects affected / exposed
    1 / 164 (0.61%)
    0 / 157 (0.00%)
    1 / 343 (0.29%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    1 / 164 (0.61%)
    0 / 157 (0.00%)
    1 / 343 (0.29%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diverticulum
         subjects affected / exposed
    1 / 164 (0.61%)
    0 / 157 (0.00%)
    1 / 343 (0.29%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dyspepsia
         subjects affected / exposed
    1 / 164 (0.61%)
    0 / 157 (0.00%)
    1 / 343 (0.29%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dysphagia
         subjects affected / exposed
    1 / 164 (0.61%)
    0 / 157 (0.00%)
    1 / 343 (0.29%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Enteritis
         subjects affected / exposed
    1 / 164 (0.61%)
    0 / 157 (0.00%)
    1 / 343 (0.29%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastroduodenal ulcer
         subjects affected / exposed
    1 / 164 (0.61%)
    0 / 157 (0.00%)
    1 / 343 (0.29%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    1 / 164 (0.61%)
    0 / 157 (0.00%)
    1 / 343 (0.29%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal ulcer haemorrhage
         subjects affected / exposed
    1 / 164 (0.61%)
    0 / 157 (0.00%)
    1 / 343 (0.29%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrooesophageal reflux disease
         subjects affected / exposed
    1 / 164 (0.61%)
    0 / 157 (0.00%)
    1 / 343 (0.29%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Haemorrhoids
         subjects affected / exposed
    0 / 164 (0.00%)
    1 / 157 (0.64%)
    1 / 343 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Incarcerated inguinal hernia
         subjects affected / exposed
    0 / 164 (0.00%)
    1 / 157 (0.64%)
    1 / 343 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    1 / 164 (0.61%)
    1 / 157 (0.64%)
    2 / 343 (0.58%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pancreatitis
         subjects affected / exposed
    1 / 164 (0.61%)
    0 / 157 (0.00%)
    1 / 343 (0.29%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Rectal haemorrhage
         subjects affected / exposed
    1 / 164 (0.61%)
    0 / 157 (0.00%)
    1 / 343 (0.29%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    0 / 164 (0.00%)
    2 / 157 (1.27%)
    2 / 343 (0.58%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholecystitis
         subjects affected / exposed
    1 / 164 (0.61%)
    0 / 157 (0.00%)
    1 / 343 (0.29%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    0 / 164 (0.00%)
    1 / 157 (0.64%)
    1 / 343 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    2 / 164 (1.22%)
    1 / 157 (0.64%)
    3 / 343 (0.87%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal impairment
         subjects affected / exposed
    1 / 164 (0.61%)
    0 / 157 (0.00%)
    1 / 343 (0.29%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urinary bladder haemorrhage
         subjects affected / exposed
    0 / 164 (0.00%)
    1 / 157 (0.64%)
    1 / 343 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Endocrine disorders
    Hyperthyroidism
         subjects affected / exposed
    0 / 164 (0.00%)
    1 / 157 (0.64%)
    1 / 343 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypothyroidism
         subjects affected / exposed
    1 / 164 (0.61%)
    1 / 157 (0.64%)
    2 / 343 (0.58%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    1 / 164 (0.61%)
    0 / 157 (0.00%)
    1 / 343 (0.29%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dupuytren’s contracture
         subjects affected / exposed
    1 / 164 (0.61%)
    0 / 157 (0.00%)
    1 / 343 (0.29%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Osteoarthritis
         subjects affected / exposed
    0 / 164 (0.00%)
    2 / 157 (1.27%)
    2 / 343 (0.58%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pain in extremity
         subjects affected / exposed
    2 / 164 (1.22%)
    0 / 157 (0.00%)
    2 / 343 (0.58%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Rhabdomyolysis
         subjects affected / exposed
    1 / 164 (0.61%)
    0 / 157 (0.00%)
    1 / 343 (0.29%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    3 / 164 (1.83%)
    0 / 157 (0.00%)
    3 / 343 (0.87%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    1 / 164 (0.61%)
    0 / 157 (0.00%)
    1 / 343 (0.29%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Device related infection
         subjects affected / exposed
    0 / 164 (0.00%)
    1 / 157 (0.64%)
    1 / 343 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Endocarditis
         subjects affected / exposed
    1 / 164 (0.61%)
    0 / 157 (0.00%)
    1 / 343 (0.29%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gangrene
         subjects affected / exposed
    0 / 164 (0.00%)
    1 / 157 (0.64%)
    1 / 343 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Helicobacter infection
         subjects affected / exposed
    0 / 164 (0.00%)
    1 / 157 (0.64%)
    1 / 343 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Implant site infection
         subjects affected / exposed
    0 / 164 (0.00%)
    1 / 157 (0.64%)
    1 / 343 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Incision site infection
         subjects affected / exposed
    1 / 164 (0.61%)
    0 / 157 (0.00%)
    1 / 343 (0.29%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infection
         subjects affected / exposed
    1 / 164 (0.61%)
    1 / 157 (0.64%)
    2 / 343 (0.58%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    2 / 164 (1.22%)
    3 / 157 (1.91%)
    5 / 343 (1.46%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nasopharyngitis
         subjects affected / exposed
    0 / 164 (0.00%)
    2 / 157 (1.27%)
    2 / 343 (0.58%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Otitis media
         subjects affected / exposed
    1 / 164 (0.61%)
    0 / 157 (0.00%)
    1 / 343 (0.29%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    4 / 164 (2.44%)
    1 / 157 (0.64%)
    5 / 343 (1.46%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 1
    0 / 5
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    Post procedural cellulitis
         subjects affected / exposed
    0 / 164 (0.00%)
    1 / 157 (0.64%)
    1 / 343 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    0 / 164 (0.00%)
    2 / 157 (1.27%)
    2 / 343 (0.58%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    2 / 164 (1.22%)
    0 / 157 (0.00%)
    2 / 343 (0.58%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Septic shock
         subjects affected / exposed
    0 / 164 (0.00%)
    1 / 157 (0.64%)
    1 / 343 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Streptococcal bacteraemia
         subjects affected / exposed
    0 / 164 (0.00%)
    1 / 157 (0.64%)
    1 / 343 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Subcutaneous abscess
         subjects affected / exposed
    1 / 164 (0.61%)
    0 / 157 (0.00%)
    1 / 343 (0.29%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 164 (0.00%)
    1 / 157 (0.64%)
    1 / 343 (0.29%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    2 / 164 (1.22%)
    0 / 157 (0.00%)
    2 / 343 (0.58%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Viral infection
         subjects affected / exposed
    1 / 164 (0.61%)
    0 / 157 (0.00%)
    1 / 343 (0.29%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Viral upper respiratory tract infection
         subjects affected / exposed
    1 / 164 (0.61%)
    0 / 157 (0.00%)
    1 / 343 (0.29%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Cachexia
         subjects affected / exposed
    0 / 164 (0.00%)
    1 / 157 (0.64%)
    1 / 343 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Decreased appetite
         subjects affected / exposed
    1 / 164 (0.61%)
    0 / 157 (0.00%)
    1 / 343 (0.29%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diabetes mellitus
         subjects affected / exposed
    2 / 164 (1.22%)
    0 / 157 (0.00%)
    2 / 343 (0.58%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diabetes mellitus inadequate control
         subjects affected / exposed
    0 / 164 (0.00%)
    1 / 157 (0.64%)
    1 / 343 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dyslipidaemia
         subjects affected / exposed
    1 / 164 (0.61%)
    1 / 157 (0.64%)
    2 / 343 (0.58%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gout
         subjects affected / exposed
    0 / 164 (0.00%)
    1 / 157 (0.64%)
    1 / 343 (0.29%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hyperglycaemia
         subjects affected / exposed
    1 / 164 (0.61%)
    1 / 157 (0.64%)
    2 / 343 (0.58%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hyperkalaemia
         subjects affected / exposed
    1 / 164 (0.61%)
    1 / 157 (0.64%)
    2 / 343 (0.58%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hyperuricaemia
         subjects affected / exposed
    1 / 164 (0.61%)
    1 / 157 (0.64%)
    2 / 343 (0.58%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    1 / 164 (0.61%)
    1 / 157 (0.64%)
    2 / 343 (0.58%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lactic acidosis
         subjects affected / exposed
    1 / 164 (0.61%)
    0 / 157 (0.00%)
    1 / 343 (0.29%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Type 2 diabetes mellitus
         subjects affected / exposed
    0 / 164 (0.00%)
    1 / 157 (0.64%)
    1 / 343 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vitamin D deficiency
         subjects affected / exposed
    0 / 164 (0.00%)
    1 / 157 (0.64%)
    1 / 343 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 AdreView™ Standard of Care Total Subjects
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    0 / 164 (0.00%)
    0 / 157 (0.00%)
    0 / 343 (0.00%)

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    03 Nov 2016
    Following amendments were made: - Inclusion criterion was revised to allow LVEF assessment performed within 3 months before or at the time of enrollment to be used. This change increased the flexibility of investigators to recruit subjects without having an impact on subject safety, scientific validity of the trial, or quality of the data. The amended criterion continued to adhere to international HF guidelines and additional wording stipulating a 40-day time lapse between hospitalization for HF or acute coronary syndrome ensured that inclusion criterion remained applicable in case the LVEF determination was made before the time of enrollment. - A blood sample for NT-proBNP was added as an alternative to BNP.
    11 May 2017
    The LVEF window was revised from 30%≤LVEF≤35% to 25%≤LVEF≤35%. As part of their remit, the Executive Steering Committee (ESC) continuously evaluated scientific data to ensure that trial integrity was aligned with up to date scientific evidence. Recent scientific evidence indicated that the benefits of additional risk stratification in subjects with HF and reduced ejection fraction with LVEF of 30 to 35% may be also applicable to subjects with lower LVEF values. Therefore, modification of the LVEF window from 30%≤LVEF≤35% to 25%≤LVEF≤35% was recommended by the ESC. The DSMB endorsed this change. The ESC discussed this amendment with the Data Safety Monitoring Board (DSMB) who noted that extending the study recruitment to LVEF values of 25 to 30% would still recruit subjects for whom good stratification was possible. The introduction and rationale were updated to support this. - The sample size was recalculated based on modification of the LVEF entry criteria. Minor clarifications to the primary and secondary efficacy analysis were included. - Investigators were reminded that subjects with HF were considered potential candidates for ICD implantation for primary prevention of SCD only after they had been under GDMT for at least 3 months. - Investigators were reminded that should any subjects not be receiving GDMT at target dose per local guidelines, the investigator must document the reason(s) why in the source documents. - The option to use an administration volume of up to 15 mL AdreView™ (to be achieved by combining the contents of up to 3 unit dose vials of IMP as necessary to obtain the correct amount of activity) was included to accommodate use in sites where there were logistical limitations to achieving delivery of IMP within the timelines required to meet the 370±10% MBq dose in a volume of 5 mL.

    Interruptions (globally)
    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    06 Mar 2018
    The study was early terminated by sponsor after enrollment of 395 participants due to very slow recruitment rates. Sample size was 395 participants instead of planned 2354 participants.
    -

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    Due to termination of the study by the Sponsor, the sample size was not sufficient for the hierarchical hypothesis testing.
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