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    Clinical Trial Results:
    A Randomized Clinical Trial of Andexanet Alfa in Acute Intracranial Hemorrhage in Patients Receiving an Oral Factor Xa Inhibitor

    Summary
    EudraCT number
    		 2018-002620-17
    Trial protocol
    		 FR   DE   GB   AT   BE   NL   ES   GR   CZ   LV   FI   NO   LT   PL   PT   DK   IT   HU  
    Global end of trial date
    09 Aug 2023

    Results information
    Results version number
    		 v1(current)
    This version publication date
    15 Aug 2024
    First version publication date
    15 Aug 2024
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    18-513
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03661528
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Alexion Pharmaceuticals, Inc.
    Sponsor organisation address
    121 Seaport Boulevard, Boston, MA, United States,
    Public contact
    European Clinical Trial Information, Alexion Pharmaceuticals, Inc., +35 3874162507, clinicaltrials.eu@alexion.com
    Scientific contact
    European Clinical Trial Information, Alexion Pharmaceuticals, Inc., +35  3874162507, clinicaltrials.eu@alexion.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
    09 Aug 2023
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    09 Aug 2023
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of this trial is to evaluate the effect of andexanet versus usual care on the rate of effective hemostasis.
    Protection of trial subjects
    This study was performed in accordance with the consensus ethical principles derived from international guidelines including the Declaration of Helsinki and Council for International Organizations of Medical Sciences (CIOMS) International Ethical Guidelines, applicable International Council for Harmonisation/GCP guidelines, and applicable laws and regulations.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    06 Jun 2019
    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
    Canada: 28
    Country: Number of subjects enrolled
    United States: 28
    Country: Number of subjects enrolled
    Germany: 186
    Country: Number of subjects enrolled
    Spain: 36
    Country: Number of subjects enrolled
    Italy: 35
    Country: Number of subjects enrolled
    France: 31
    Country: Number of subjects enrolled
    Israel: 30
    Country: Number of subjects enrolled
    Austria: 29
    Country: Number of subjects enrolled
    Belgium: 29
    Country: Number of subjects enrolled
    Netherlands: 24
    Country: Number of subjects enrolled
    United Kingdom: 13
    Country: Number of subjects enrolled
    Finland: 10
    Country: Number of subjects enrolled
    Denmark: 6
    Country: Number of subjects enrolled
    Greece: 6
    Country: Number of subjects enrolled
    Hungary: 6
    Country: Number of subjects enrolled
    Poland: 6
    Country: Number of subjects enrolled
    Switzerland: 6
    Country: Number of subjects enrolled
    Norway: 5
    Country: Number of subjects enrolled
    Czechia: 4
    Country: Number of subjects enrolled
    Latvia: 4
    Country: Number of subjects enrolled
    Lithuania: 3
    Country: Number of subjects enrolled
    Portugal: 3
    Country: Number of subjects enrolled
    Sweden: 2
    Worldwide total number of subjects
    530
    EEA total number of subjects
    425
    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)
    33
    From 65 to 84 years
    349
    85 years and over
    148

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 Data collected for the Andexanet Alfa arm were prespecified to be collected as a single Arm/Group regardless of the dose level the participant received.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Single blind
    Roles blinded
    		 Assessor [1]

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Andexanet Alfa
    Arm description
    		 Participants received a regimen of andexanet alfa administered as an intravenous (IV) bolus, immediately followed by a continuous infusion. Dosing regimen was based on which FXa inhibitor the participants received and the amount and timing of the most recent dose of treatment.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Andexanet
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Andexanet was received per dosage and administration details specified in the arm description.

    Arm title
    		 Usual Care
    Arm description
    		 Participants received usual care. Usual care consisted of any treatment(s) (including no treatment) other than andexanet alfa administered within 3 hours post-randomization that the Investigator and/or other treating physicians considered to be appropriate.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Usual care
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Usual care was received per dosage and administration details specified in the arm description.

    Notes
    [1] - The roles blinded appear inconsistent with a simple blinded trial.
    Justification: This is a randomized, open-label study with blinded adjudication on primary efficacy and safety outcomes, including death and thrombotic events.
    Number of subjects in period 1
    		Andexanet Alfa Usual Care
    Started
    263
    267
    Received at Least 1 Dose of Study Drug
    262
    265
    Completed
    180
    193
    Not completed
    83
    74
         Adverse event, serious fatal
    1
    -
         Physician decision
    3
    1
         Consent withdrawn by subject
    5
    3
         Adverse event, non-fatal
    61
    55
         Other than Specified
    5
    2
         Disease Progression
    8
    13

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Andexanet Alfa
    Reporting group description
    		 Participants received a regimen of andexanet alfa administered as an intravenous (IV) bolus, immediately followed by a continuous infusion. Dosing regimen was based on which FXa inhibitor the participants received and the amount and timing of the most recent dose of treatment.

    Reporting group title
    Usual Care
    Reporting group description
    		 Participants received usual care. Usual care consisted of any treatment(s) (including no treatment) other than andexanet alfa administered within 3 hours post-randomization that the Investigator and/or other treating physicians considered to be appropriate.

    Reporting group values
    		 Andexanet Alfa Usual Care Total
    Number of subjects
    		 263 267 530
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0
        Children (2-11 years)
    		 0 0 0
        Adolescents (12-17 years)
    		 0 0 0
        Adults (18-64 years)
    		 15 18 33
        From 65-84 years
    		 171 178 349
        85 years and over
    		 77 71 148
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 79.4 ( 8.51 ) 78.7 ( 8.61 ) -
    Sex: Female, Male
    Units: participants
        Female
    		 117 128 245
        Male
    		 146 139 285
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    		 0 0 0
        Asian
    		 3 4 7
        Native Hawaiian or Other Pacific Islander
    		 0 0 0
        Black or African American
    		 5 4 9
        White
    		 239 247 486
        More than one race
    		 0 0 0
        Unknown or Not Reported
    		 16 12 28
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    		 15 13 28
        Not Hispanic or Latino
    		 227 237 464
        Unknown or Not Reported
    		 21 17 38

    End points

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    End points reporting groups
    Reporting group title
    Andexanet Alfa
    Reporting group description
    		 Participants received a regimen of andexanet alfa administered as an intravenous (IV) bolus, immediately followed by a continuous infusion. Dosing regimen was based on which FXa inhibitor the participants received and the amount and timing of the most recent dose of treatment.

    Reporting group title
    Usual Care
    Reporting group description
    		 Participants received usual care. Usual care consisted of any treatment(s) (including no treatment) other than andexanet alfa administered within 3 hours post-randomization that the Investigator and/or other treating physicians considered to be appropriate.

    Primary: Number of Participants who Achieved Effective Hemostasis

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    End point title
    		 Number of Participants who Achieved Effective Hemostasis
    End point description
    Effective hemostasis was defined as change from baseline in National Institutes of Health Stroke Scale (NIHSS) of +6 or less at 12 hour timepoint and ≤35% increase in haematoma volume compared to baseline on a repeat computed tomography (CT) or magnetic resonance imaging (MRI) scan at 12 hours and no rescue therapies between 3-12 hours after randomization (defined as excellent or good hemostasis). The NIHSS is a validated quantitative assessment tool to measure stroke-related neurological deficits and ranges from 0 (no deficits) to 42 (very severe impairment). Data presented is number of participants with effective hemostasis (excellent or good hemostasis) adjudicated by the independent Endpoint Adjudication Committee (IEAC). Measured in the Intent-to-Treat Population (ITT), primary efficacy population, which included all participants randomized to treatment based on first data cut-off. Number of participants analyzed = participants evaluable for the endpoint.
    End point type
    Primary
    End point timeframe
    Baseline up to 12 hours
    End point values
    		 Andexanet Alfa Usual Care
    Number of subjects analysed
    224
    228
    Units: participants
    150
    121
    Statistical analysis title
    		 Andexanet Alfa vs Usual Care
    Comparison groups
    Andexanet Alfa v Usual Care
    Number of subjects included in analysis
    452
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.0032
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Percentage proportion difference
    Point estimate
    13.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 4.6
         upper limit
    		 22.2

    Secondary: Percentage Change from Baseline to Nadir in Anti-FXa Activity

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    End point title
    		 Percentage Change from Baseline to Nadir in Anti-FXa Activity
    End point description
    Anti-FXa activity was measured from plasma samples to assess the anticoagulant status of FXa inhibitors using a modified chromogenic assay performed at a Central Laboratory. Nadir was defined as the minimum anti-FXa activity post-randomization. Measured in the ITT set, primary efficacy population, which included all participants randomized to study intervention based on the first data cut-off. Here, 'Overall number of participants analyzed' = participants evaluable for this outcome measure.
    End point type
    Secondary
    End point timeframe
    Baseline up to 2 hours
    End point values
    		 Andexanet Alfa Usual Care
    Number of subjects analysed
    203
    199
    Units: Percent change
        median (full range (min-max))
    -94.41 (-99.1 to 1805.0)
    -27.46 (-97.9 to 416.0)
    Statistical analysis title
    		 Andexanet Alfa vs Usual Care
    Comparison groups
    Andexanet Alfa v Usual Care
    Number of subjects included in analysis
    402
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 < 0.0001
    Method
    		 ANCOVA
    Parameter type
    		 Difference in LS mean based on ranks
    Point estimate
    -185.99
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -199.93
         upper limit
    		 -172.05

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Up to approximately 30 days
    Adverse event reporting additional description
    Data are presented for randomized participants who received treatment and were analyzed according to treatment received. All cause mortality includes deaths due to AEs, initial intracranial hemorrhage, or participants who discontinued and died on, or after, the day of discontinuation.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    25.1
    Reporting groups
    Reporting group title
    Usual Care
    Reporting group description
    		 Participants received usual care. Usual care consisted of any treatment(s) (including no treatment) other than andexanet alfa administered within 3 hours post-randomization that the Investigator and/or other treating physicians considered to be appropriate.

    Reporting group title
    Andexanet Alfa
    Reporting group description
    		 Participants received a regimen of andexanet alfa administered as an IV bolus, immediately followed by a continuous infusion. Dosing regimen was based on which FXa inhibitor the participants received and the amount and timing of the most recent dose of treatment.

    Serious adverse events
    		 Usual Care Andexanet Alfa
    Total subjects affected by serious adverse events
         subjects affected / exposed
    96 / 265 (36.23%)
    120 / 262 (45.80%)
         number of deaths (all causes)
    70
    74
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Lung neoplasm malignant
         subjects affected / exposed
    2 / 265 (0.75%)
    0 / 262 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Brain cancer metastatic
         subjects affected / exposed
    1 / 265 (0.38%)
    0 / 262 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Arterial occlusive disease
         subjects affected / exposed
    1 / 265 (0.38%)
    0 / 262 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haematoma
         subjects affected / exposed
    1 / 265 (0.38%)
    1 / 262 (0.38%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Deep vein thrombosis
         subjects affected / exposed
    2 / 265 (0.75%)
    1 / 262 (0.38%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypertension
         subjects affected / exposed
    0 / 265 (0.00%)
    1 / 262 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Femoral artery embolism
         subjects affected / exposed
    0 / 265 (0.00%)
    1 / 262 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Embolism arterial
         subjects affected / exposed
    0 / 265 (0.00%)
    1 / 262 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Embolism
         subjects affected / exposed
    1 / 265 (0.38%)
    0 / 262 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral ischaemia
         subjects affected / exposed
    0 / 265 (0.00%)
    1 / 262 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    0 / 265 (0.00%)
    1 / 262 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    General physical health deterioration
         subjects affected / exposed
    0 / 265 (0.00%)
    1 / 262 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chest pain
         subjects affected / exposed
    1 / 265 (0.38%)
    0 / 262 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Multiple organ dysfunction syndrome
         subjects affected / exposed
    1 / 265 (0.38%)
    1 / 262 (0.38%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Sudden cardiac death
         subjects affected / exposed
    1 / 265 (0.38%)
    0 / 262 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Respiratory arrest
         subjects affected / exposed
    0 / 265 (0.00%)
    1 / 262 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Pulmonary embolism
         subjects affected / exposed
    7 / 265 (2.64%)
    2 / 262 (0.76%)
         occurrences causally related to treatment / all
    2 / 7
    0 / 2
         deaths causally related to treatment / all
    1 / 1
    0 / 1
    Respiratory failure
         subjects affected / exposed
    4 / 265 (1.51%)
    4 / 262 (1.53%)
         occurrences causally related to treatment / all
    0 / 4
    1 / 4
         deaths causally related to treatment / all
    0 / 4
    1 / 4
    Acute respiratory failure
         subjects affected / exposed
    1 / 265 (0.38%)
    3 / 262 (1.15%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Aspiration
         subjects affected / exposed
    1 / 265 (0.38%)
    1 / 262 (0.38%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Pulmonary oedema
         subjects affected / exposed
    0 / 265 (0.00%)
    2 / 262 (0.76%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Respiratory distress
         subjects affected / exposed
    0 / 265 (0.00%)
    2 / 262 (0.76%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    Acute respiratory distress syndrome
         subjects affected / exposed
    0 / 265 (0.00%)
    1 / 262 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atelectasis
         subjects affected / exposed
    0 / 265 (0.00%)
    1 / 262 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    0 / 265 (0.00%)
    1 / 262 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    1 / 265 (0.38%)
    0 / 262 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Delirium
         subjects affected / exposed
    3 / 265 (1.13%)
    2 / 262 (0.76%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    SARS-CoV-2 test positive
         subjects affected / exposed
    0 / 265 (0.00%)
    1 / 262 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Troponin increased
         subjects affected / exposed
    0 / 265 (0.00%)
    1 / 262 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Brain herniation
         subjects affected / exposed
    2 / 265 (0.75%)
    0 / 262 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    Subdural haematoma
         subjects affected / exposed
    2 / 265 (0.75%)
    1 / 262 (0.38%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Humerus fracture
         subjects affected / exposed
    0 / 265 (0.00%)
    1 / 262 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rib fracture
         subjects affected / exposed
    1 / 265 (0.38%)
    0 / 262 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Shunt thrombosis
         subjects affected / exposed
    0 / 265 (0.00%)
    1 / 262 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Atrioventricular block complete
         subjects affected / exposed
    0 / 265 (0.00%)
    1 / 262 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    0 / 265 (0.00%)
    1 / 262 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute cardiac event
         subjects affected / exposed
    1 / 265 (0.38%)
    0 / 262 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Cardiac failure
         subjects affected / exposed
    0 / 265 (0.00%)
    3 / 262 (1.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 3
    Acute myocardial infarction
         subjects affected / exposed
    2 / 265 (0.75%)
    3 / 262 (1.15%)
         occurrences causally related to treatment / all
    2 / 2
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    1 / 265 (0.38%)
    8 / 262 (3.05%)
         occurrences causally related to treatment / all
    0 / 1
    7 / 8
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Cardiac arrest
         subjects affected / exposed
    1 / 265 (0.38%)
    0 / 262 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Atrioventricular block second degree
         subjects affected / exposed
    1 / 265 (0.38%)
    0 / 262 (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 / 265 (0.00%)
    1 / 262 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Sinus node dysfunction
         subjects affected / exposed
    0 / 265 (0.00%)
    1 / 262 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulseless electrical activity
         subjects affected / exposed
    1 / 265 (0.38%)
    0 / 262 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiopulmonary failure
         subjects affected / exposed
    0 / 265 (0.00%)
    1 / 262 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Cardio-respiratory arrest
         subjects affected / exposed
    0 / 265 (0.00%)
    1 / 262 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Cardiac failure congestive
         subjects affected / exposed
    0 / 265 (0.00%)
    1 / 262 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Cardiac failure chronic
         subjects affected / exposed
    0 / 265 (0.00%)
    1 / 262 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac dysfunction
         subjects affected / exposed
    1 / 265 (0.38%)
    0 / 262 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Haemorrhage intracranial
         subjects affected / exposed
    11 / 265 (4.15%)
    8 / 262 (3.05%)
         occurrences causally related to treatment / all
    1 / 11
    0 / 8
         deaths causally related to treatment / all
    0 / 4
    0 / 5
    Cerebral haemorrhage
         subjects affected / exposed
    11 / 265 (4.15%)
    7 / 262 (2.67%)
         occurrences causally related to treatment / all
    0 / 11
    0 / 7
         deaths causally related to treatment / all
    0 / 9
    0 / 6
    Ischaemic stroke
         subjects affected / exposed
    2 / 265 (0.75%)
    13 / 262 (4.96%)
         occurrences causally related to treatment / all
    0 / 2
    10 / 13
         deaths causally related to treatment / all
    0 / 0
    0 / 3
    Hydrocephalus
         subjects affected / exposed
    4 / 265 (1.51%)
    7 / 262 (2.67%)
         occurrences causally related to treatment / all
    0 / 4
    1 / 7
         deaths causally related to treatment / all
    0 / 1
    0 / 2
    Neurological decompensation
         subjects affected / exposed
    7 / 265 (2.64%)
    2 / 262 (0.76%)
         occurrences causally related to treatment / all
    0 / 7
    0 / 2
         deaths causally related to treatment / all
    0 / 2
    0 / 1
    Cerebral haematoma
         subjects affected / exposed
    5 / 265 (1.89%)
    3 / 262 (1.15%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 3
         deaths causally related to treatment / all
    0 / 2
    0 / 2
    Epilepsy
         subjects affected / exposed
    2 / 265 (0.75%)
    1 / 262 (0.38%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Brain oedema
         subjects affected / exposed
    1 / 265 (0.38%)
    1 / 262 (0.38%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebral infarction
         subjects affected / exposed
    2 / 265 (0.75%)
    0 / 262 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    Cerebrospinal fluid circulation disorder
         subjects affected / exposed
    1 / 265 (0.38%)
    1 / 262 (0.38%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemorrhagic stroke
         subjects affected / exposed
    2 / 265 (0.75%)
    0 / 262 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    Somnolence
         subjects affected / exposed
    1 / 265 (0.38%)
    1 / 262 (0.38%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aphasia
         subjects affected / exposed
    0 / 265 (0.00%)
    1 / 262 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebellar stroke
         subjects affected / exposed
    0 / 265 (0.00%)
    1 / 262 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebral ischaemia
         subjects affected / exposed
    0 / 265 (0.00%)
    1 / 262 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Cerebral vasoconstriction
         subjects affected / exposed
    1 / 265 (0.38%)
    0 / 262 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Cerebral venous thrombosis
         subjects affected / exposed
    1 / 265 (0.38%)
    0 / 262 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    0 / 265 (0.00%)
    1 / 262 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Disturbance in attention
         subjects affected / exposed
    0 / 265 (0.00%)
    1 / 262 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemorrhagic transformation stroke
         subjects affected / exposed
    0 / 265 (0.00%)
    1 / 262 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic encephalopathy
         subjects affected / exposed
    0 / 265 (0.00%)
    1 / 262 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Intracranial haematoma
         subjects affected / exposed
    1 / 265 (0.38%)
    0 / 262 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Intraventricular haemorrhage
         subjects affected / exposed
    0 / 265 (0.00%)
    1 / 262 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Nervous system disorder
         subjects affected / exposed
    0 / 265 (0.00%)
    1 / 262 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Seizure
         subjects affected / exposed
    0 / 265 (0.00%)
    1 / 262 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Stroke in evolution
         subjects affected / exposed
    0 / 265 (0.00%)
    1 / 262 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Subarachnoid haemorrhage
         subjects affected / exposed
    1 / 265 (0.38%)
    0 / 262 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Subdural hygroma
         subjects affected / exposed
    1 / 265 (0.38%)
    0 / 262 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    0 / 265 (0.00%)
    1 / 262 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Status epilepticus
         subjects affected / exposed
    0 / 265 (0.00%)
    2 / 262 (0.76%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Intestinal obstruction
         subjects affected / exposed
    1 / 265 (0.38%)
    1 / 262 (0.38%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 265 (0.00%)
    2 / 262 (0.76%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dysphagia
         subjects affected / exposed
    0 / 265 (0.00%)
    1 / 262 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    1 / 265 (0.38%)
    0 / 262 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haematemesis
         subjects affected / exposed
    1 / 265 (0.38%)
    0 / 262 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal mass
         subjects affected / exposed
    1 / 265 (0.38%)
    0 / 262 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ischaemic enteritis
         subjects affected / exposed
    0 / 265 (0.00%)
    1 / 262 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholecystitis acute
         subjects affected / exposed
    0 / 265 (0.00%)
    1 / 262 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Chronic kidney disease
         subjects affected / exposed
    0 / 265 (0.00%)
    1 / 262 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute kidney injury
         subjects affected / exposed
    0 / 265 (0.00%)
    3 / 262 (1.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haematuria
         subjects affected / exposed
    0 / 265 (0.00%)
    1 / 262 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary bladder haemorrhage
         subjects affected / exposed
    0 / 265 (0.00%)
    1 / 262 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary bladder rupture
         subjects affected / exposed
    1 / 265 (0.38%)
    0 / 262 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    16 / 265 (6.04%)
    14 / 262 (5.34%)
         occurrences causally related to treatment / all
    0 / 16
    0 / 14
         deaths causally related to treatment / all
    0 / 6
    0 / 7
    Pneumonia aspiration
         subjects affected / exposed
    7 / 265 (2.64%)
    14 / 262 (5.34%)
         occurrences causally related to treatment / all
    0 / 7
    0 / 14
         deaths causally related to treatment / all
    0 / 5
    0 / 7
    Sepsis
         subjects affected / exposed
    2 / 265 (0.75%)
    6 / 262 (2.29%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 6
         deaths causally related to treatment / all
    0 / 1
    0 / 3
    Urinary tract infection
         subjects affected / exposed
    1 / 265 (0.38%)
    4 / 262 (1.53%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urosepsis
         subjects affected / exposed
    1 / 265 (0.38%)
    1 / 262 (0.38%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    COVID-19
         subjects affected / exposed
    0 / 265 (0.00%)
    1 / 262 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Clostridium difficile infection
         subjects affected / exposed
    0 / 265 (0.00%)
    1 / 262 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Escherichia bacteraemia
         subjects affected / exposed
    1 / 265 (0.38%)
    0 / 262 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Liver abscess
         subjects affected / exposed
    0 / 265 (0.00%)
    1 / 262 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Meningitis
         subjects affected / exposed
    0 / 265 (0.00%)
    1 / 262 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyelonephritis
         subjects affected / exposed
    0 / 265 (0.00%)
    1 / 262 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory syncytial virus infection
         subjects affected / exposed
    1 / 265 (0.38%)
    0 / 262 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Staphylococcal sepsis
         subjects affected / exposed
    0 / 265 (0.00%)
    1 / 262 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Septic shock
         subjects affected / exposed
    1 / 265 (0.38%)
    0 / 262 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    0 / 265 (0.00%)
    1 / 262 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Failure to thrive
         subjects affected / exposed
    1 / 265 (0.38%)
    0 / 262 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Usual Care Andexanet Alfa
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    200 / 265 (75.47%)
    198 / 262 (75.57%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    19 / 265 (7.17%)
    18 / 262 (6.87%)
         occurrences all number
    19
    18
    Nervous system disorders
    Headache
         subjects affected / exposed
    19 / 265 (7.17%)
    24 / 262 (9.16%)
         occurrences all number
    19
    24
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    22 / 265 (8.30%)
    23 / 262 (8.78%)
         occurrences all number
    23
    24
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    25 / 265 (9.43%)
    39 / 262 (14.89%)
         occurrences all number
    25
    40
    Nausea
         subjects affected / exposed
    17 / 265 (6.42%)
    23 / 262 (8.78%)
         occurrences all number
    17
    24
    Vomiting
         subjects affected / exposed
    14 / 265 (5.28%)
    9 / 262 (3.44%)
         occurrences all number
    14
    9
    Psychiatric disorders
    Delirium
         subjects affected / exposed
    26 / 265 (9.81%)
    20 / 262 (7.63%)
         occurrences all number
    26
    20
    Insomnia
         subjects affected / exposed
    9 / 265 (3.40%)
    14 / 262 (5.34%)
         occurrences all number
    10
    14
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    25 / 265 (9.43%)
    28 / 262 (10.69%)
         occurrences all number
    26
    30
    Pneumonia aspiration
         subjects affected / exposed
    16 / 265 (6.04%)
    19 / 262 (7.25%)
         occurrences all number
    17
    19
    Urinary tract infection
         subjects affected / exposed
    44 / 265 (16.60%)
    54 / 262 (20.61%)
         occurrences all number
    44
    59
    Metabolism and nutrition disorders
    Hypokalaemia
         subjects affected / exposed
    28 / 265 (10.57%)
    40 / 262 (15.27%)
         occurrences all number
    28
    42

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    15 Apr 2020
    - Inclusion/exclusion criteria revised - Objectives updated - Added section to clarify the population on which the primary and secondary endpoints were to be analyzed - Sample size increased from ~ 440 to ~ 900 participants and number of investigational sites from ~ 100 to ~ 200. - Added stratification factors of intended-usual-care-agent and time from symptom onset to baseline imaging scan, and removed stratification by site, to the randomization scheme.
    29 Jul 2021
    - Inclusion/exclusion criteria updated - The secondary efficacy objective related to percent change from baseline to nadir in anti-FXa activity was changed from 3 to 2 h post randomization. - Clarified use of hemostatic agents, procoagulant blood products, and other unplanned rescue procedures and surgeries within 3 h post randomization and adjudication by the Endpoint Adjudication Committee (EAC) - Added study-specific exceptions to AE and serious AE reporting - Updated instructions for reporting clinically significant laboratory abnormalities as AEs - Clarified scope of adjudication of primary endpoint by the EAC. - AE reporting revised. - Addition of section on potential risks to study participants posed by the coronavirus disease 2019 (COVID-19) pandemic.
    01 Dec 2022
    - Removal of enoxaparin eligible population (that had been added in CSP Amendment 2) based on Sponsor decision. - Deleted “stratification factor of intended-usual-care-agent.” from analyses. - Interim analysis stopping criteria based on primary efficacy endpoint were clarified.

    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
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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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