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    Summary
    EudraCT Number:2015-001785-26
    Sponsor's Protocol Code Number:14-505
    National Competent Authority:France - ANSM
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2015-12-07
    Trial results View 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 ConcernedFrance - ANSM
    A.2EudraCT number2015-001785-26
    A.3Full title of the trial
    Prospective, Open-label Study of Andexanet Alfa in Patients Receiving a Factor Xa Inhibitor who Have Acute Major Bleeding (ANNEXA-4).
    Étude prospective et ouverte sur l’andexanet alfa chez des patients recevant un inhibiteur du facteur Xa qui présentent une hémorragie aiguë majeure (ANNEXA-4).
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A study to confirm that andexanet alfa helps to stop severe/ life threatening bleeding in patients, taking a type of anticoagulants called Factor Xa inhibitors.
    Une étude pour confirmer que andexanet alfa aide à arrêter de hémorragies graves / mortelles chez les patients qui prennent un type d’anticoagulants appelés des inhibiteurs du facteur Xa.
    A.3.2Name or abbreviated title of the trial where available
    ANNEXA-4
    ANNEXA-4
    A.4.1Sponsor's protocol code number14-505
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT02329327
    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 SponsorPortola 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 supportPortola Pharmaceuticals, Inc.
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationPortola Pharmaceuticals, Inc.
    B.5.2Functional name of contact pointClinical Development
    B.5.3 Address:
    B.5.3.1Street Address270 East Grand Avenue,
    B.5.3.2Town/ citySouth San Francisco
    B.5.3.3Post codeCA 94080
    B.5.3.4CountryUnited States
    B.5.4Telephone number0016502467396
    B.5.6E-mailfdietrich@Portola.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 No
    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
    D.3.2Product code PRT064445
    D.3.4Pharmaceutical form Lyophilisate 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.3.9.2Current sponsor codePRT064445
    D.3.9.3Other descriptive nameRecombinant Factor Xa Inhibitor Antidote
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number50
    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
    Uncontrolled bleeding in patients who have taken either a direct factor Xa inhibitor (novel oral anticoagulants) or an indirect factor Xa inhibitor (low molecular weight heparins).
    Saignement incontrôlé pour des patients qui ont pris soit un inhibiteur du facteur Xa directe (nouvelles des anticoagulants oraux ) ou un inhibiteur du facteur Xa indirecte (HBPM).
    E.1.1.1Medical condition in easily understood language
    Serious bleeding complications in patients who have taken anticoagulant medicine, known as a factor Xa inhibitor.
    Complications hémorragiques graves pour des patients qui ont pris des médicaments anticoagulant , connu comme un inhibiteur du facteur Xa.
    E.1.1.2Therapeutic area Not possible to specify
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 18.1
    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
    Two Primary Objectives:
    1. To demonstrate the decrease in anti-fXa activity following andexanet treatment.
    The study will be considered to have met the first primary efficacy objective if there is a statistically significant (p<0.05) percent decrease in anti-fXa activity from the pre-treatment baseline to the evaluation period nadir (where the evaluation period starts 5 minutes following the end of the andexanet bolus and ends just prior to the end of the andexanet infusion).
    2. To evaluate the haemostatic efficacy of andexanet in patients receiving a fXa inhibitor who have acute major bleeding and reduced fXa activity.
    The study will be considered to have met the second primary efficacy objective if the proportion of patients with excellent or good haemostasis (as adjudicated by the independent Endpoint Adjudication Committeeis statistically significantly higher than 50% (p<0.05).
    1. Démontrer la diminution de l’activité anti-fXa après le traitement par andexanet. L’étude sera considérée comme ayant atteint le premier objectif principal d’efficacité si une diminution statistiquement significative en pourcentage (p < 0,05) de l’activité anti-fXa est observée entre l’évaluation initiale avant traitement et le creux de la période d’évaluation (où la période d’évaluation commence 5 minutes après la fin du bolus d’andexanet et se termine juste avant la fin de la perfusion d’andexanet).
    2. Évaluer l’efficacité hémostatique de l’andexanet chez les patients recevant un inhibiteur du fXa qui présentent une hémorragie aiguë majeure et une activité du fXa réduite.
    L’étude sera considérée comme ayant atteint le second objectif principal d’efficacité si la proportion de patients présentant une hémostase excellente ou bonne (telle qu’évaluée par le EAC) est de façon statistiquement significative supérieure à 50 % (p < 0,05).
    E.2.2Secondary objectives of the trial
    Secondary Objectives:
    To assess the relationship between decrease in anti-fXa activity and achievement of haemostatic efficacy in patients receiving a fXa inhibitor who have acute major bleeding and reduced fXa activity.

    Exploratory Objectives:
    • For patients receiving apixaban, edoxaban or rivaroxaban, to evaluate the decrease in the free fraction of the fXa inhibitor following andexanet treatment.
    • To evaluate the use of red blood cell transfusions.
    • To evaluate the use of other blood products and haemostatic agents.

    Safety Objectives:
    • To evaluate the overall safety of andexanet, including adjudicated thrombotic events (TEs) and antibodies to fX, fXa, and andexanet
    • To evaluate the 30-day all-cause mortality
    Objectif secondaire d’efficacité:
    Évaluer le lien entre une diminution de l’activité anti-fXa et l’obtention d’une efficacité hémostatique chez les patients recevant un inhibiteur du fXa qui présentent une hémorragie aiguë majeure et une activité du fXa réduite.

    Objectifs exploratoires:
    • Pour les patients recevant l’apixaban, l’edoxaban ou le rivaroxaban, évaluer la diminution de la fraction libre de l’inhibiteur du fXa après le traitement par andexanet
    • Évaluer l’utilisation de transfusions de globules rouges
    • Évaluer l’utilisation d’autres produits sanguins et agents hémostatiques
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1) Either the patient or his or her medical proxy has been adequately informed of the nature and risks of the study and has given written informed consent prior to Screening;
    2) The patient must be at least 18 years old at the time of Screening;
    3) The patient must have an acute overt major bleeding episode requiring urgent reversal of anticoagulation; Acute major bleeding requiring urgent reversal of anticoagulation is defined by at least ONE of the following:
    - Acute overt bleeding that is potentially life-threatening, e.g., with signs or symptoms of haemodynamic compromise, such as severe hypotension, poor skin perfusion, mental confusion, low urine output that cannot be otherwise explained;
    - Acute overt bleeding associated with a fall in haemoglobin level by ≥ 2 g/dL, OR a Hb ≤ 8 g/dL if no baseline Hb is available OR, in the opinion of the investigator that the patient’s haemoglobin will fall to ≤ 8 g/dL with resuscitation;
    - Acute symptomatic bleeding in a critical area or organ, such as, intra-spinal, retroperitoneal, intra-articular or pericardial, intracranial, or intramuscular with compartment syndrome.
    4) The patient, for whom the bleeding is intracranial must have undergone a head CT or MRI scan demonstrating the intracranial bleeding. Note: Patients with bleeding at non-intracranial locations do not require a head CT or MRI;
    5) Patient received or believed to have received one of the following within 18 hours prior to andexanet administration: apixaban, rivaroxaban, edoxaban or enoxaparin (dose of enoxaparin ≥1mg/kg/d).
    E.4Principal exclusion criteria
    1) The patient is scheduled to undergo surgery in less than 12 hours with the exception of minimally invasive surgery/procedures (e.g., endoscopy, bronchoscopy, central lines, Burr holes);
    2) A patient with ICH has any of the following:
    − Glasgow coma score < 7
    − Estimated intracerebral haematoma volume >60 cc as assessed by the CT or MRI.
    3) The patient has an expected survival of less than 1 month;
    4) The patient has a recent history (within 2 weeks) of a diagnosed thrombotic event (TE) as follows: myocardial infarction, disseminated intravascular coagulation (DIC), cerebral vascular accident, transient ischemic attack, unstable angina pectoris hospitalization, or severe peripheral vascular disease within 2 weeks prior to Screening;
    5) The patient has severe sepsis or septic shock at the time of Screening;
    6) The patient is pregnant or a lactating female;
    7) The patient has received any of the following drugs or blood products within 7 days or Screening:
    • Vitamin K antagonist (VKA) (e.g., warfarin);
    • Dabigatran;
    • Prothrombin Complex Concentrate products (PCC, e.g., Kcentra®) or recombinant factor VIIa (rfVIIa) (e.g., NovoSeven®);
    • Whole blood, plasma fractions
    Note: Administration of platelets or packed red blood cells (PRBCs) is not an exclusion criterion;
    8) The patient was treated with an investigational drug <30 days prior to Screening.
    Planned administration of PCC, fresh frozen plasma (FFP), or rfVIIa from Screening until within 12 hours after the end of the andexanet infusion;
    E.5 End points
    E.5.1Primary end point(s)
    The two primary endpoints are:
    1)The percent change from baseline (pre-treatment with andexanet) in anti-fXa activity to the nadir from the evaluation period (where the evaluation period starts 5 minutes following the end of the andexanet bolus and ends just prior to the end of the andexanet infusion).
    AND
    2) The achievement of haemostatic efficacy of stopping an ongoing major bleed at 12 hours from the end of the andexanet infusion, rated by the independent EAC as excellent or good.

    Haemostatic efficacy will be determined by the independent EAC as excellent, good, or poor/none, based on pre-specified definitions. These three categories will be collapsed to two categories for analysis (excellent/good vs. poor/none).
    E.5.1.1Timepoint(s) of evaluation of this end point
    Patients receive andexanet as an IV bolus administered over ~15–30 minutes, followed immediately by a continuous infusion administered over ~120 minutes.
    Primary endpoint 1:
    Sample for anti-fXa activity is drawn at 2 timepoints; one at (or within 30 minutes after) the end of the bolus, and another at (or within 30 minutes prior to) the end of the infusion.
    Primary Endpoint 2:
    Haemostatic efficacy: Evaluated through 12 hours from the end of the infusion with the following assessments: Visible, muscular, and skeletal bleeding evaluated at 1, 4, 8, and 12 hours following the end of infusion. ICH evaluated at 1 and 12 hours following the end of infusion. Haemoglobin and haematocrit will be measured during the infusion and at 1, 4, 8, and 12 hours following the end of infusion.
    E.5.2Secondary end point(s)
    Secondary Endpoints:
    The secondary efficacy objective is to assess the relationship between the two primary efficacy endpoints. No additional efficacy endpoint is defined to support the secondary efficacy objective.

    Exploratory Endpoints:
    -The achievement of haemostatic efficacy for visible and musculoskeletal non-visible bleeding at 1 hour and at 4 hours after the end of the andexanet infusion.
    -For patients receiving apixaban, edoxaban or rivaroxaban, to evaluate the decrease in free fraction of the fXa inhibitor following andexanet administration.
    -The number of patients receiving one or more red blood cell transfusions from the start of the andexanet bolus through 12 hours after the end of the andexanet infusion.
    -The number of red blood cell units transfused per patient from the start of the andexanet bolus through 12 hours after the end of the andexanet infusion.
    -The use of non-study-prescribed blood products and/or haemostatic agents.
    -The occurrence of all-cause mortality through Day 30.

    Safety Measurements:
    -Survival status, AEs, vital signs, and clinical laboratory measurements
    -Centrally-adjudicated Treatment-Emergent Adverse Events
    -Antibodies to andexanet, fX, and fXa
    E.5.2.1Timepoint(s) of evaluation of this end point
    Exploratory:
    - Haemostatic efficacy for visible and musculoskeletal non-visible bleeding: at 1 hour , 4 hours after the end of infusion.
    - Free fraction apixaban or rivaroxaban: 4, 8 and 12 hours after the end of infusion.
    - Number of patients receiving red blood cell transfusions and number of units: From the start of the bolus through 12 hours after the end of the infusion.
    - Use of non-study-prescribed blood products and/or haemostatic agents: 15mins prior to start of bolus through 12 hours after the end of the infusion.
    - All-cause mortality : through Day 30
    Safety:
    Adverse Events will be followed through Study Day 3 and related AEs and survival will be followed through the Day 30 post-treatment visit.
    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 No
    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) Yes
    E.7.4Therapeutic use (Phase IV) Yes
    E.8 Design of the trial
    E.8.1Controlled No
    E.8.1.1Randomised No
    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) No
    E.8.2.2Placebo No
    E.8.2.3Other No
    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 concerned10
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA30
    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
    Belgium
    Canada
    France
    Germany
    Netherlands
    Spain
    United Kingdom
    United States
    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 years8
    E.8.9.1In the Member State concerned months0
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years8
    E.8.9.2In all countries concerned by the trial months0
    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: 75
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 175
    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 For clinical trials recorded in the database before the 10th March 2011 this question read: "Women of childbearing potential" and did not include the words "not using contraception". An answer of yes could have included women of child bearing potential whether or not they would be using contraception. The answer should therefore be understood in that context. This trial was recorded in the database on 2015-12-07. Yes
    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 such as intracranial haemorrhage, pericardial and intra-spinal bleeding. 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 state40
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 125
    F.4.2.2In the whole clinical trial 250
    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.
    Après l'a realisation d'étude, la décision concernant le traitement du patient sera déterminé par son médecin en conformité avec tout traitement disponible selon la qualité des soins.
    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 Decision2015-11-19
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2015-12-22
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2020-09-24
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