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    Clinical Trial Results:
    Start or STop Anticoagulants Randomised Trial (SoSTART) after spontaneous intracranial haemorrhage

    Summary
    EudraCT number
    		 2016-004121-16
    Trial protocol
    		 GB  
    Global end of trial date
    31 Mar 2021

    Results information
    Results version number
    		 v1(current)
    This version publication date
    01 Oct 2021
    First version publication date
    01 Oct 2021
    Other versions
    Summary report(s)
    		 Published results of SoSTART

    Trial information

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    Trial identification
    Sponsor protocol code
    AC16141
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03153150
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 ClinicalTrials.gov Identifier: NCT03153150
    Sponsors
    Sponsor organisation name
    Academic and Clinical Central Office for Research and Development (ACCORD)
    Sponsor organisation address
    47 Little France Crescent, Edinburgh, United Kingdom, EH16 4TJ
    Public contact
    Professor Rustam Al-Shahi Salman, University of Edinburgh, +44 0131 242 7014, rustam.al-shahi@ed.ac.uk
    Scientific contact
    Head of Research Governance, Academic and Clinical Central Office for Research and Development (ACCORD), +44 0131 242 3330, enquiries@accord.scot
    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
    16 Jul 2021
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    26 Feb 2021
    Global end of trial reached?
    Yes
    Global end of trial date
    31 Mar 2021
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    SoSTART aims to study at least 190 people aged ≥18 years, >24 hours after onset of spontaneous symptomatic intracranial haemorrhage, with AF and CHA2DS2VASc score ≥2 to determine the safety of starting full treatment dose OAC compared to not starting OAC for the prevention of the primary outcome of recurrent symptomatic intracranial haemorrhage over ≥1 year after randomisation.
    Protection of trial subjects
    SoSTART was conducted in accordance with all relevant data protection, ethical and regulatory requirements to ensure the privacy and security of patient information and to ensure the rights, safety and well-being of the patients and the quality of the research data. We sought support and advice from members of the patient reference group for the Research to Understand Stroke due to Haemorrhage (RUSH) programme for ongoing review of our study materials and on trial progress. We also included a member of this group as part of our Trial Steering Committee. We sought to minimise risk and the burden to the patient without compromising the scientific rigour of the trial. Annual follow-up questionnaires were kept to a minumum to avoid burden and a central helpline was available to support participants, families, GPs and research staff.
    Background therapy
    		 Any background therapy in standard clinical practice for this patient population (e.g. antihypertensive drugs) was determined for participants by the clinical teams at each of our 67 hospital sites.
    Evidence for comparator
    		 Standard clinical practice for patients with atrial fibrillation after intracranial haemorrhage, who do not start oral anticoagulation, is either complete avoidance of antithrombotic drugs or the use of an antiplatelet drug (used either for secondary prevention following vaso-occlusive comorbidites, or for reduction of systemic embolism in AF based on existing data [Hart RG, Pearce LA, Aguilar MI. Meta-analysis: antithrombotic therapy to prevent stroke in patients who have nonvalvular atrial fibrillation. Ann Intern Med 2007;146:857-67]).
    Actual start date of recruitment
    28 Mar 2018
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety, Efficacy, Scientific research
    Long term follow-up duration
    		 2 Years
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United Kingdom: 203
    Worldwide total number of subjects
    203
    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)
    7
    From 65 to 84 years
    147
    85 years and over
    49

    Subject disposition

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    Recruitment
    Recruitment details
    		 Between March 28, 2018 and February 27, 2020, consent was obtained at 61 sites for 218 people to participate, of whom 203 (93%) were randomised a median of 115 days (IQR 49–265) after intracranial haemorrhage onset. 15 were not enrolled; 5 were ineligible, 2 had deterioration of health condition, and 8 were uncertain about oral anticoagulation.

    Pre-assignment
    Screening details
    		 During the feasibility phase only, sites were required to provide screening log data on all potentially eligible patients at each site, which patients were recruited, and reasons why the others were not. These data helped confirm the suitability of the eligibility criteria, understand recruitment, and inform the feasibility of a definitive trial.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Start
    Arm description
    		 Start long-term (≥1y) full treatment dose open-label oral anticoagulation.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Apixaban
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    As prescribed by randomising clinician.

    Investigational medicinal product name
    Rivaroxaban
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    As prescribed by randomising clinician.

    Investigational medicinal product name
    Edoxaban
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    As prescribed by randomising clinician.

    Investigational medicinal product name
    Dabigatran etexilate
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    As prescribed by randomising clinician.

    Investigational medicinal product name
    Warfarin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet, Concentrate for oral suspension
    Routes of administration
    Oral use
    Dosage and administration details
    As prescribed by randomising clinician.

    Investigational medicinal product name
    Acenocoumarol
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    As prescribed by randomising clinician.

    Investigational medicinal product name
    Phenindione
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    As prescribed by randomising clinician.

    Arm title
    		 Avoid
    Arm description
    		 Avoid long-term (≥1y) full treatment dose open-label oral anticoagulation.
    Arm type
    		 No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Number of subjects in period 1
    		Start Avoid
    Started
    101
    102
    Completed
    101
    102

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Start
    Reporting group description
    		 Start long-term (≥1y) full treatment dose open-label oral anticoagulation.

    Reporting group title
    Avoid
    Reporting group description
    		 Avoid long-term (≥1y) full treatment dose open-label oral anticoagulation.

    Reporting group values
    		 Start Avoid Total
    Number of subjects
    		 101 102 203
    Age categorical
    Units: Subjects
    Age continuous
    At randomisation, participants in the two treatment groups were on average 79 years old.
    Units: years
        median (inter-quartile range (Q1-Q3))
    		 79 (74 to 85) 79 (74 to 84) -
    Gender categorical
    Units: Subjects
        Female
    		 39 37 76
        Male
    		 62 65 127
    Ethnicity
    Units: Subjects
        White
    		 92 96 188
        Asian
    		 7 4 11
        Black
    		 1 1 2
        Mixed
    		 0 1 1
        Other
    		 1 0 1
    Type of qualifying spontaneous intracranial haemorrhage
    Units: Subjects
        Lobar intracerebral haemorrhage
    		 35 38 73
        Non-lobar intracerebral haemorrhage
    		 58 56 114
        Other
    		 8 8 16
    Time since qualifying intracranial haemorrhage symptom onset
    Units: Subjects
        <10 weeks
    		 37 38 75
        >=10 weeks
    		 64 64 128
    Probability of good 6-month outcome
    Units: Subjects
        <0·15
    		 21 22 43
        ≥0·15
    		 80 80 160
    Type of atrial arrhythmia
    Units: Subjects
        Persistent atrial fibrillation
    		 28 24 52
        Permanent atrial fibrillation
    		 51 51 102
        Paroxysmal atrial fibrillation
    		 22 26 48
        Atrial flutter
    		 0 1 1
    Detection of atrial arrhythmia
    Units: Subjects
        Before intracranial haemorrhage
    		 92 95 187
        After intracranial haemorrhage
    		 9 7 16
    CHA2DS2-VASc score
    The CHA2DS2-VASc score to predict the risk of ischaemic stroke or systemic embolism for patients with atrial fibrillation ranges from 0-9 and is based on the sum of individual scores for: congestive heart failure or left ventricular dysfunction (1); systemic arterial hypertension (1); age ≥75 years (2); diabetes mellitus (1); stroke or transient ischaemic attack or other thromboembolism (2); vascular disease (prior myocardial infarction, peripheral artery disease, or aortic plaque) (1); age 65-74 years (1); female sex (1).
    Units: Subjects
        Two
    		 14 18 32
        Three
    		 22 20 42
        Four
    		 32 26 58
        Five
    		 21 15 36
        Six
    		 9 17 26
        Seven
    		 3 6 9
    Use of oral anticoagulation before qualifying intracranial haemorrhage
    Units: Subjects
        Yes
    		 84 86 170
        No
    		 17 16 33
    HAS-BLED score
    The HAS-BLED score to predict the risk of major bleeding for patients with atrial fibrillation ranges from 0-9 and is based on the sum of the individual scores for: hypertension (1); abnormal renal and liver function (1 point each); stroke (1); bleeding history or disposition (1), labile international normalised ratio (1); elderly i.e. age >65 years (1); drugs or alcohol concomitantly (1 point each).
    Units: Subjects
        Zero
    		 3 0 3
        One
    		 48 46 94
        Two
    		 34 31 65
        Three
    		 12 20 32
        Four
    		 4 5 9
    Intended type of oral anticoagulation (if allocated to start)
    Units: Subjects
        Direct oral anticoagulant
    		 97 101 198
        Other
    		 4 1 5
    Intended comparator (if allocated to avoid)
    Units: Subjects
        No antithrombotic agents
    		 77 70 147
        Antiplatelet agent
    		 24 32 56
    Time since qualifying intracranial haemorrhage symptom onset
    Units: day
        median (inter-quartile range (Q1-Q3))
    		 104 (44 to 244) 115 (51 to 288) -

    End points

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    End points reporting groups
    Reporting group title
    Start
    Reporting group description
    		 Start long-term (≥1y) full treatment dose open-label oral anticoagulation.

    Reporting group title
    Avoid
    Reporting group description
    		 Avoid long-term (≥1y) full treatment dose open-label oral anticoagulation.

    Primary: Recurrent symptomatic spontaneous intracranial haemorrhage

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    End point title
    		 Recurrent symptomatic spontaneous intracranial haemorrhage
    End point description
    End point type
    Primary
    End point timeframe
    First event after randomisation and before death or most recent follow up.
    End point values
    		 Start Avoid
    Number of subjects analysed
    101
    102
    Units: Events
        Recurrent symptomatic spontaneous intracranial hae
    8
    4
    Statistical analysis title
    		 Adjusted Cox proportional hazards analysis
    Statistical analysis description
    Cox proportional hazards models were adjusted for two of the six minimisation variables: time since intracranial haemorrhage symptom onset (<10 weeks [reference] vs ≥10 weeks) and type of qualifying intracranial haemorrhage (lobar intracerebral haemorrhage vs non-lobar intracerebral haemorrhage and lobar intracerebral haemorrhage vs other); model non-convergence due to the low number of events prevented the inclusion of any more minimisation variables.
    Comparison groups
    Start v Avoid
    Number of subjects included in analysis
    203
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 = 0.152 [1]
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    2.42
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.72
         upper limit
    		 8.09
    Notes
    [1] - Our prespecified margin for declaring non-inferiority was not met.

    Secondary: Composite secondary outcome - Any symptomatic major vascular event

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    End point title
    		 Composite secondary outcome - Any symptomatic major vascular event
    End point description
    Myocardial infarction; symptomatic spontaneous intracerebral, subarachnoid, intraventricular or subdural haemorrhage; ischaemic stroke; death within 30 days of recurrent symptomatic spontaneous intracranial haemorrhage, ischaemic stroke, myocardial infarction, or symptomatic deep vein thrombosis; sudden cardiac death; death from another vascular cause (i.e. not within 30 days of an outcome event); death of an unknown cause.
    End point type
    Secondary
    End point timeframe
    First event after randomisation and before death or most recent follow up.
    End point values
    		 Start Avoid
    Number of subjects analysed
    101
    102
    Units: Events
        Any symptomatic major vascular event
    12
    24
    Statistical analysis title
    		 Adjusted Cox proportional hazards analysis
    Statistical analysis description
    Cox proportional hazards models were adjusted for two of the six minimisation variables time since intracranial haemorrhage symptom onset (<10 weeks [reference] vs ≥10 weeks) and type of qualifying intracranial haemorrhage (lobar intracerebral haemorrhage vs non-lobar intracerebral haemorrhage and lobar intracerebral haemorrhage vs other); model non-convergence due to the low number of events prevented the inclusion of any more minimisation variables.
    Comparison groups
    Start v Avoid
    Number of subjects included in analysis
    203
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.06
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.51
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.26
         upper limit
    		 1.03

    Secondary: Composite secondary outcome - Any stroke

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    End point title
    		 Composite secondary outcome - Any stroke
    End point description
    End point type
    Secondary
    End point timeframe
    First event after randomisation and before death or most recent follow up.
    End point values
    		 Start Avoid
    Number of subjects analysed
    101
    102
    Units: Events
        Any stroke
    11
    22
    Statistical analysis title
    		 Adjusted Cox proportional hazards analysis
    Statistical analysis description
    Cox proportional hazards models were adjusted for two of the six minimisation variables time since intracranial haemorrhage symptom onset (<10 weeks [reference] vs ≥10 weeks) and type of qualifying intracranial haemorrhage (lobar intracerebral haemorrhage vs non-lobar intracerebral haemorrhage and lobar intracerebral haemorrhage vs other); model non-convergence due to the low number of events prevented the inclusion of any more minimisation variables.
    Comparison groups
    Avoid v Start
    Number of subjects included in analysis
    203
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.084
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.53
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.25
         upper limit
    		 1.09

    Secondary: Composite secondary outcomes - Any stroke or vascular death

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    End point title
    		 Composite secondary outcomes - Any stroke or vascular death
    End point description
    End point type
    Secondary
    End point timeframe
    First event after randomisation and before death or most recent follow up.
    End point values
    		 Start Avoid
    Number of subjects analysed
    101
    102
    Units: Events
        Any stroke or vascular death
    12
    23
    Statistical analysis title
    		 Adjusted Cox proportional hazards analysis
    Statistical analysis description
    Cox proportional hazards models were adjusted for two of the six minimisation variables time since intracranial haemorrhage symptom onset (<10 weeks [reference] vs ≥10 weeks) and type of qualifying intracranial haemorrhage (lobar intracerebral haemorrhage vs non-lobar intracerebral haemorrhage and lobar intracerebral haemorrhage vs other); model non-convergence due to the low number of events prevented the inclusion of any more minimisation variables.
    Comparison groups
    Avoid v Start
    Number of subjects included in analysis
    203
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.09
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.55
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.27
         upper limit
    		 1.1

    Adverse events

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    Adverse events information [1]
    Timeframe for reporting adverse events
    Serious adverse events in the SoSTART trial were collected for all participants from the period between randomisation and the end of the trial (unless they withdrew).
    Adverse event reporting additional description
    Only serious adverse events were required to be reported by the protocol.
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    23.1
    Reporting groups
    Reporting group title
    Start
    Reporting group description
    		 Start long-term (≥1y) full treatment dose open-label oral anticoagulation.

    Reporting group title
    Avoid
    Reporting group description
    		 Avoid long-term (≥1y) full treatment dose open-label oral anticoagulation.

    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: Section 16.6 of the protocol states, "safety assessments in SoSTART are focussed on detecting: primary and secondary outcomes (all of which relate to the safety of antithrombotic drugs in this patient group) and any SAEs and SUSARs that may occur after randomisation."
    Serious adverse events
    		 Start Avoid
    Total subjects affected by serious adverse events
         subjects affected / exposed
    25 / 101 (24.75%)
    25 / 102 (24.51%)
         number of deaths (all causes)
    15
    11
         number of deaths resulting from adverse events
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Prostate cancer
         subjects affected / exposed
    1 / 101 (0.99%)
    0 / 102 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Aortic stenosis
         subjects affected / exposed
    3 / 101 (2.97%)
    0 / 102 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Orthostatic hypotension
         subjects affected / exposed
    0 / 101 (0.00%)
    1 / 102 (0.98%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Surgical and medical procedures
    Bladder neoplasm surgery
         subjects affected / exposed
    1 / 101 (0.99%)
    0 / 102 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebral endovascular aneurysm repair
         subjects affected / exposed
    0 / 101 (0.00%)
    1 / 102 (0.98%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Chest pain
         subjects affected / exposed
    1 / 101 (0.99%)
    1 / 102 (0.98%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Asthma
         subjects affected / exposed
    1 / 101 (0.99%)
    0 / 102 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Interstitial lung disease
         subjects affected / exposed
    1 / 101 (0.99%)
    0 / 102 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Subdural haematoma
         subjects affected / exposed
    1 / 101 (0.99%)
    0 / 102 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fall
         subjects affected / exposed
    2 / 101 (1.98%)
    1 / 102 (0.98%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Bradycardia
         subjects affected / exposed
    1 / 101 (0.99%)
    0 / 102 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial flutter
         subjects affected / exposed
    1 / 101 (0.99%)
    0 / 102 (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 / 101 (1.98%)
    2 / 102 (1.96%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Palpitations
         subjects affected / exposed
    1 / 101 (0.99%)
    0 / 102 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    1 / 101 (0.99%)
    0 / 102 (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
    0 / 101 (0.00%)
    1 / 102 (0.98%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Angina pectoris
         subjects affected / exposed
    0 / 101 (0.00%)
    1 / 102 (0.98%)
         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 / 101 (0.00%)
    1 / 102 (0.98%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Spinal cord compression
         subjects affected / exposed
    1 / 101 (0.99%)
    0 / 102 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Normal pressure hydrocephalus
         subjects affected / exposed
    0 / 101 (0.00%)
    1 / 102 (0.98%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Splenic infarction
         subjects affected / exposed
    0 / 101 (0.00%)
    1 / 102 (0.98%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    1 / 101 (0.99%)
    1 / 102 (0.98%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal perforation
         subjects affected / exposed
    1 / 101 (0.99%)
    0 / 102 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholecystectomy
         subjects affected / exposed
    0 / 101 (0.00%)
    1 / 102 (0.98%)
         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
    0 / 101 (0.00%)
    1 / 102 (0.98%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Sepsis
         subjects affected / exposed
    1 / 101 (0.99%)
    0 / 102 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    1 / 101 (0.99%)
    2 / 102 (1.96%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    COVID-19 pneumonia
         subjects affected / exposed
    1 / 101 (0.99%)
    1 / 102 (0.98%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    0 / 101 (0.00%)
    2 / 102 (1.96%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infective exacerbation of chronic obstructive airways disease
         subjects affected / exposed
    0 / 101 (0.00%)
    1 / 102 (0.98%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infective exacerbation of bronchiectasis
         subjects affected / exposed
    0 / 101 (0.00%)
    1 / 102 (0.98%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea infectious
         subjects affected / exposed
    0 / 101 (0.00%)
    1 / 102 (0.98%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diabetes mellitus inadequate control
         subjects affected / exposed
    0 / 101 (0.00%)
    1 / 102 (0.98%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gangrene
         subjects affected / exposed
    0 / 101 (0.00%)
    1 / 102 (0.98%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    0 / 101 (0.00%)
    1 / 102 (0.98%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    1 / 101 (0.99%)
    0 / 102 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypercalcaemia
         subjects affected / exposed
    1 / 101 (0.99%)
    0 / 102 (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
    		 Start Avoid
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    0 / 101 (0.00%)
    0 / 102 (0.00%)

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    07 Jun 2018
    An update to the Reference Safety Information (RSI)
    29 Aug 2018
    - Addition of 30 sites - Change of PI
    06 Sep 2018
    - Inclusion of a safety phase in the study between the pilot and main phases of the study; - Addition of spontaneous haemorrhage as a primary outcome in the protocol; - Inclusion of the EQ-5D-5L to the annual questionnaire which contributes to the secondary objectives of the main phase
    29 Nov 2018
    - Addition of 9 sites - 2 Change of PIs
    08 Jan 2019
    Change of PI
    05 Feb 2019
    2 Change of PIs
    25 Apr 2019
    Change of PI
    28 Jun 2019
    2 Change of PIs
    14 Aug 2019
    Change of PI
    07 Oct 2019
    Change of PI
    04 Nov 2019
    - Protocol: outcome definition clarification - GP annual questionnaire: outcome wording changed as per new version of the protocol - GP letter changes to include a Professional Summary from a new version of the protocol - Change of PI
    12 Dec 2019
    2 Change of PIs
    12 Feb 2020
    - Protocol: main phase removal - Change of PI
    29 Apr 2020
    SmPC update
    29 Jul 2020
    2 Change of PIs

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/33598560
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