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    Summary
    EudraCT Number:2018-002620-17
    Sponsor's Protocol Code Number:18-513
    National Competent Authority:Finland - Fimea
    Clinical Trial Type:EEA CTA
    Trial Status:Prematurely Ended
    Date on which this record was first entered in the EudraCT database:2020-06-17
    Trial results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedFinland - Fimea
    A.2EudraCT number2018-002620-17
    A.3Full title of the trial
    A RANDOMIZED CLINICAL TRIAL OF ANDEXANET ALFA IN ACUTE INTRACRANIAL HEMORRHAGE IN PATIENTS RECEIVING AN ORAL FACTOR XA INHIBITOR
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A clinical trial to study the effect of andexanet alfa compared to the usual care with regards to stopping severe/life threatening bleeding in patients with bleeding inside the skull.
    A.4.1Sponsor's protocol code number18-513
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorAlexion Pharmaceuticals, Inc
    B.1.3.4CountryUnited States
    B.3.1 and B.3.2Status of the sponsorCommercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportAlexion Pharmaceuticals, Inc.
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationAlexion Europe SAS
    B.5.2Functional name of contact pointEuropean Clinical Trial Information
    B.5.3 Address:
    B.5.3.1Street Address103-105 Rue Anatole France
    B.5.3.2Town/ cityLevallois-Perret
    B.5.3.3Post code92300
    B.5.3.4CountryFrance
    B.5.4Telephone number+33147100615
    B.5.5Fax number+33147100611
    B.5.6E-mailclinicaltrials.eu@alexion.com
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name Ondexxya(R)
    D.2.1.1.2Name of the Marketing Authorisation holderAlexion Europe SAS
    D.2.1.2Country which granted the Marketing AuthorisationEuropean Union
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameandexanet alfa 200 mg vial
    D.3.2Product code ALXN2070
    D.3.4Pharmaceutical form Powder for solution for infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNANDEXANET ALFA
    D.3.9.1CAS number 1262449-58-0
    D.3.9.2Current sponsor codeALXN2070
    D.3.9.3Other descriptive nameRecombinant Factor Xa Inhibitor Antidote
    D.3.9.4EV Substance CodeSUB181082
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number10
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin No
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) Yes
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product Yes
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Oral FXa inhibitor-treated patients with acute intracranial bleeding.
    E.1.1.1Medical condition in easily understood language
    Serious bleeding complications inside skull of patients who have taken anticoagulant medicine, known as a factor Xa inhibitor.
    E.1.1.2Therapeutic area Not possible to specify
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level LLT
    E.1.2Classification code 10075279
    E.1.2Term Anticoagulant reversal therapy
    E.1.2System Organ Class 100000004865
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    • To evaluate the effect of andexanet versus usual care on the rate of effective hemostasis.
    E.2.2Secondary objectives of the trial
    • To evaluate the effect of andexanet versus usual care on anti-fXa activity.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1.Written informed consent. Either the patient or his or her legally acceptable representative (LAR) if permissible by local or regional laws and regulations has been adequately informed of the nature and risks of the study and has given written informed consent prior to Screening.

    -Deferred consent procedure is allowed where approved by local ethics committees. In cases of deferred consent, the time of the study
    physician's documented decision to include the patient into the study will serve as "time of consent" with respect to protocol specific procedures.
    -In all cases where the patient does not sign informed consent prior to study entry, informed consent from the patient (or LAR) will be obtained as soon as realistically possible after inclusion in Study 18-513 and in accordance with the Declaration of Helsinki, International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) Good Clinical Practice (GCP), the EU General Data Protection Regulation (GDPR) and national and local regulations.

    2. Age ≥ 18 years old at the time of consent.

    3. An acute intracranial bleeding episode, defined as an estimated blood volume of ≥0.5 mL to ≤60 mL acutely observed radiographically within the cerebrum. Patients may have extracerebral (e.g., subdural, subarachnoid, epidural) or extracranial (e.g., gastrointestinal, intraspinal) bleeding additionally, but the intracerebral hemorrhage must be considered the most clinically significant bleed at the time of enrollment.

    4. Performance of a head CT or MRI scan demonstrating the intracranial bleeding within 2 hours prior to randomization (the baseline scan may be repeated only once to meet this criterion).

    5. Treatment with an oral FXa inhibitor (apixaban [last dose 2.5 mg or greater], rivaroxaban [last dose 10 mg or greater] or edoxaban [last dose
    30 mg or greater]:
    o≤15 hours prior to randomization.
    o > 15 hours prior to randomization or unknown time of last dose, only if 1) the local anti -fXa activity > 100 ng/mL (for direct fXa inhibitors (apixaban, rivaroxaban or edoxaban) or > 0.5 IU/mL for enoxaparin, and 2) the local anti-fXa activity level is obtained within 2 hours prior to consent, performed as per standard of care. Note: Patients enrolled in this manner should receive a high andexanet dosing regimen.

    6. Time from bleeding symptom onset < 6 hours prior to the baseline imaging scan. Time of trauma (if applicable) or time last seen normal may be used as surrogates for time of symptom onset. (If the baseline scan is repeated to meet Inclusion Criterion #4, the time from bleeding symptom onset must be < 6 hours prior to the repeat baseline imaging scan.)

    7. Female patients of childbearing potential and male patients with female partners of childbearing potential must follow protocol-specified guidance for avoiding pregnancy for 30 days after the last dose of study drug.

    8.Have a negative pregnancy test documented prior to enrollment (for females of childbearing potential).

    9.NIHSS score ≤ 35 at the time of consent.
    E.4Principal exclusion criteria
    1.Planned surgery, including Burr holes for hematoma drainage, within 12 hours after randomization. Minimally invasive surgery/procedures not directly related to the treatment of intracranial bleeding and that are not expected to significantly affect haematoma volume are allowed (e.g., Burr holes for intracranial pressure monitoring, endoscopy, bronchoscopy, central lines—Sections 7.2, 7.3 and Appendix G).

    2.Glasgow Coma Scale (GCS) score < 7 at the time of consent. If a patient is intubated and/or sedated at the time of consent, they may be enrolled if it can be documented that they were intubated/sedated for non neurologic reasons within 2 hours prior to consent.

    3. Purposefully left blank to align with the programmed database.

    4. Anticipation that the baseline and follow up brain scans will not be able to use the same imaging modalities (i.e., patients with a baseline CT scan should have a CT scan in follow upÍž similarly for MRI).

    5. Expected survival of less than 1 month (not related to intracranial bleed).

    6. Recent history (within 2 weeks) of a diagnosed TE or clinically relevant symptoms of the following:

    -Venous Thromboembolism (VTE: e.g., deep venous thrombosis, pulmonary embolism[PE], cerebral venous thrombosis), myocardial infarction (MI), Disseminated Intravascular Coagulation (DIC), cerebral vascular accident, transient ischemic attack (TIA), acute coronary syndrome, or arterial systemic embolism (see Appendix H for DIC scoring algorithm).

    7. Acute decompensated heart failure or cardiogenic shock at the time of randomization (see Appendix H for cardiogenic shock definition).

    8. Severe sepsis or septic shock at the time of randomization (see Appendix H for sepsis definition).

    9. The patient is a pregnant or lactating female.

    10. Receipt of any of the following drugs or blood products within 7 days prior to consent:
    a. Vitamin K Antagonist (VKA) (e.g., warfarin).
    b. Dabigatran.
    c. Prothrombin Complex Concentrate products (PCC, e.g., Kcentra®) or recombinant factor VIIa (rfVIIa) (e.g., NovoSeven®), or anti-inhibitor coagulant complex (e.g., FEIBA®), FFP, and whole blood.

    11. Past use of andexanet (or planned use of commercial andexanet).

    12. Treatment with an investigational drug < 30 days prior to consent.

    13. Any tumor-related bleeding.

    14. Known hypersensitivity to any component of andexanet.

    15. National Institutes of Health Stroke Scale (NIHSS) score >35 at the time of consent
    E.5 End points
    E.5.1Primary end point(s)
    • Effective hemostasis 12 hours post-randomisation as determined by the blinded EAC, based on pre-specified criteria documented in the Adjudication Charter (see Appendix B).

    Effective hemostasis is defined as:
    1=for patients with hemostatic efficacy rated by the EAC as excellent or
    good, and
    0=for patients with hemostatic efficacy rated by the EAC as poor/none.
    E.5.1.1Timepoint(s) of evaluation of this end point
    12 Hours post randomizarion
    E.5.2Secondary end point(s)
    • Percent change from baseline to nadir in anti-fXa activity during the first 2 hours post-randomization.
    E.5.2.1Timepoint(s) of evaluation of this end point
    30 days and up to 120 days for patients with positive anti-andexanet antibody response.
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy Yes
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic No
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) No
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) Yes
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group No
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) Yes
    E.8.2.2Placebo No
    E.8.2.3Other Yes
    E.8.2.3.1Comparator description
    Standard of Care
    E.8.2.4Number of treatment arms in the trial2
    E.8.3 The trial involves single site in the Member State concerned No
    E.8.4 The trial involves multiple sites in the Member State concerned Yes
    E.8.4.1Number of sites anticipated in Member State concerned13
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA172
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA Yes
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    Canada
    Israel
    United States
    Switzerland
    Russian Federation
    Austria
    Belgium
    Czechia
    Denmark
    Estonia
    Finland
    France
    Germany
    Greece
    Hungary
    Italy
    Latvia
    Lithuania
    Netherlands
    Poland
    Portugal
    Spain
    Sweden
    United Kingdom
    E.8.7Trial has a data monitoring committee Yes
    E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial
    LVLS
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years4
    E.8.9.1In the Member State concerned months5
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years4
    E.8.9.2In all countries concerned by the trial months5
    E.8.9.2In all countries concerned by the trial days0
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) No
    F.1.1.6Adolescents (12-17 years) No
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 190
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 1010
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations Yes
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception Yes
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation Yes
    F.3.3.6Subjects incapable of giving consent personally Yes
    F.3.3.6.1Details of subjects incapable of giving consent
    Patients are experiencing serious/life-threatening bleeding (intracranial haemorrhage). Due to the critical nature of the illness some patients will be unable to provide their own consent.
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state8
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 794
    F.4.2.2In the whole clinical trial 1200
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    Following study completion the decision regarding the patient's
    treatment will be determined by his/her physician in accordance to any
    available treatment as per the standard of care.
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2020-08-11
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2020-06-16
    P. End of Trial
    P.End of Trial StatusPrematurely Ended
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