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    Summary
    EudraCT Number:2018-002620-17
    Sponsor's Protocol Code Number:18-513
    National Competent Authority:Italy - Italian Medicines Agency
    Clinical Trial Type:EEA CTA
    Trial Status:Prematurely Ended
    Date on which this record was first entered in the EudraCT database:2021-06-17
    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 ConcernedItaly - Italian Medicines Agency
    A.2EudraCT number2018-002620-17
    A.3Full title of the trial
    A PHASE 4 RANDOMIZED CLINICAL TRIAL OF ANDEXANET ALFA [ANDEXANET ALFA FOR INJECTION] IN ACUTE INTRACRANIAL HEMORRHAGE IN PATIENTS RECEIVING AN ORAL FACTOR XA INHIBITOR
    Studio clinico di fase 4 randomizzato di Andexanet Alfa [Andexanet Alfa per iniezione] in emorragia intracranica acuta in pazienti trattati con inibitore orale del fattore Xa
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A phase 4 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.
    Una sperimentazione clinica di fase 4 per studiare l'effetto di andexanet alfa rispetto alla cura standard per quanto riguarda l'arresto del sanguinamento grave / potenzialmente letale nei pazienti con sanguinamento all'interno del cranio.
    A.3.2Name or abbreviated title of the trial where available
    Andexanet
    Andexanet
    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 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 Trials
    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 number0016502467039
    B.5.5Fax number0016502467039
    B.5.6E-mailclinicaltrials@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 nameANDEXXA
    D.3.2Product code [PRT064445]
    D.3.4Pharmaceutical form Lyophilisate for solution for injection
    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 codePRT064445
    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 milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number200
    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 Information not present in EudraCT
    D.3.11.3.2Gene therapy medical product Information not present in EudraCT
    D.3.11.3.3Tissue Engineered Product Information not present in EudraCT
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) Information not present in EudraCT
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product Information not present in EudraCT
    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
    Pazienti trattati con inibitori FXa orali con emorragia intracranica acuta
    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.
    Gravi complicanze emorragiche all'interno del cranio di pazienti che hanno assunto farmaci anticoagulanti, noti come inibitori del fattore Xa.
    E.1.1.2Therapeutic area Body processes [G] - Circulatory and Respiratory Physiological Phenomena [G09]
    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
    Valutare l'effetto di andexanet rispetto alle cure standard sul tasso di emostasi efficace
    E.2.2Secondary objectives of the trial
    To evaluate the effect of andexanet versus usual care on anti-fXa activity
    Valutare l'effetto di andexanet rispetto alle cure standard sull'attività anti-fXa
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Written informed consent. Either the patient or his or her medical proxy (or legally acceptable designee) has been adequately informed of the nature and risks of the study and has given written informed consent prior to Screening.
    2. Age 18 years old or greater at the time of consent.
    3. An acute intracranial bleeding episode, defined as any amount of blood acutely observed radiographically within the cranium. Patients may have extracranial bleeding (e.g., gastrointestinal, intraspinal) additionally, but the intracranial hemorrhage must be considered the primary bleed.
    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 to meet this criterion).
    5. Treatment with an oral FXa inhibitor (apixaban, rivaroxaban, or edoxaban) within 15 hours prior to randomization. If the time of last dose is unknown, the patient is not eligible for the study. If a patient is documented to have an anti-fXa activity > 100 ng/mL within 2 hours prior to consent, they may be enrolled irrespective of the time since last dose (as long as it is known).
    6. Time from bleeding symptom onset < 12 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.
    1. Sottoscrizione del modulo di consenso informato. Il/la paziente o il suo rappresentante medico (o designato in virtù della legge) è stato adeguatamente informato sulla natura e dei rischi dello studio e ha dato il consenso informato scritto prima dello screening.
    2. Età 18 anni o più al momento di sottoscrizione del consenso.
    3. Evento di sanguinamento intracranico acuto inteso come qualsiasi quantità di sangue all'interno del cranio osservata radiograficamente. Nei pazienti si può manifestare anche un'emorragia extracranica (ad es., gastrointestinale, intraspinale), ma l'emorragia intracranica deve essere considerata l'emorragia primaria.
    4. Una scansione TAC o RM che dimostri l’esistenza del sanguinamento intracranico entro 2 ore prima della randomizzazione (la scansione basale può essere ripetuta per soddisfare questo criterio).
    5. Trattamento con un inibitore orale del FXa (apixaban, rivaroxaban o edoxaban) entro
    15 ore prima della randomizzazione. Se il tempo dell’ultima dose è sconosciuto, il paziente non viene considerato idoneo per lo studio. Se è documentato che il/la paziente aveva un'attività anti-fXa > 100 ng/mL entro 2 ore prima del consenso,
    può essere arruolato/a indipendentemente dal tempo trascorso dall'ultima dose (purché sia noto).
    6. Tempo di insorgenza dei sintomi emorragici <12 ore prima della scansione basale. Tempo del trauma (se applicabile) o il tempo in cui il paziente è stato osservato nello stato normale l'ultima volta possono essere usati come surrogati per determinazione del tempo di insorgenza dei sintomi.
    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 are allowed (e.g., Burr holes for intracranial pressure monitoring, endoscopy, bronchoscopy, central lines—see Section 7.3 and Appendix F).
    2. Glasgow Coma 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. Estimated intracerebral hematoma volume > 60 mL assessed by the baseline CT or MRI.
    4. Any bleeding into the (intracranial) epidural space.
    5. 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 up; similarly for MRI).
    6. Expected survival of less than 1 month.
    7. Recent history (within 2 weeks) of a diagnosed Thrombotic Event (TE) or clinically relevant symptoms of the following: Venous Thromboembolism (VTE: e.g., deep venous thrombosis, pulmonary embolism, cerebral venous thrombosis), myocardial
    infarction, Disseminated Intravascular Coagulation (DIC), cerebral vascular accident, transient ischemic attack, acute coronary syndrome, or arterial systemic embolism within 2 weeks prior to Screening (see Appendix G for DIC scoring algorithm).
    8. Acute decompensated heart failure or cardiogenic shock at the time of randomization (see Appendix H for cardiogenic shock definition).
    9. Severe sepsis or septic shock at the time of randomization (see
    Appendix H for sepsis definition).
    10. Pregnant or lactating.
    11. 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®).
    12. Past or planned use of andexanet.
    13. Treatment with an investigational drug < 30 days prior to consent.
    Se il/la paziente soddisfa uno dei seguenti criteri, non è idoneo/a a partecipare allo studio.
    1. Interventi chirurgici programmati, compresa trapanazione del cranio per il drenaggio dell'ematoma, entro 12 ore dopo la randomizzazione. Sono consentiti interventi chirurgici mini-invasivi o procedure mini-invasive non direttamente correlate al trattamento del sanguinamento intracranico (ad es., perforazioni nel cranio per il monitoraggio della pressione intracranica, endoscopia, broncoscopia, catetere centrale, (vedi Sezione 7.3 e l'Appendice F).
    2. Punteggio <7 sulla scala di Glasgow Coma. Se un/una paziente è intubato/a e/o sottoposto/a a trattamento con sedativi al momento del consenso, può essere arruolato/a solo se è possibile documentare che è stato intubato/a-sedato/a per ragioni non neurologiche entro 2 ore prima del consenso.
    3. Volume stimato di ematoma intracerebrale >60 mL rilevato dalla TAC o dalla RM basale.
    4. Qualsiasi sanguinamento nello spazio epidurale (intracranico).
    5. L'ipotesi che le scansioni cerebrali basali e quelle di follow-up non potranno essere eseguite utilizzando la stessa modalità di imaging (cioè pazienti con una TAC basale dovrebbe avere una TAC in follow-up; analogamente per la RM).
    6. Sopravvivenza attesa inferiore a 1 mese.
    7. Storia recente (entro 2 settimane) di un evento trombotico diagnosticato (TE) o sintomi clinicamente rilevanti di: Tromboembolismo venoso (VTE: ad es., trombosi venosa profonda, embolia polmonare, trombosi venosa cerebrale), infarto miocardico, coagulazione intravascolare disseminata (DIC), disturbo acuto della circolazione cerebrale, attacco ischemico transitorio, sindrome coronarica acuta o embolia sistemica arteriosa entro 2 settimane prima dello screening (vedi Appendice G per l'algoritmo di punteggio DIC).
    8. Insufficienza cardiaca scompensata acuta o shock cardiogeno al momento della randomizzazione (vedi Appendice H per la definizione di shock cardiogeno).
    9. Grave sepsi o shock settico al momento della randomizzazione (vedi Appendice H per la definizione di sepsi).
    10. Gravidanza o allattamento.
    11. Somministrazione di uno qualsiasi dei seguenti farmaci o emoderivati entro 7 giorni prima del consenso:
    a. Antagonisti della vitamina K (VKA) (ad es., warfarin).
    b. Dabigatran.
    c. Complessi protrombinici concentrati (PCC, ad es., Kcentra®) o fattore ricombinante VIIa (rfVIIa) (ad es., NovoSeven®) o complesso coagulante
    (ad es., FEIBA®).
    12. Uso passato o programmato di andexanet.
    13. Trattamento con un farmaco sperimentale <30 giorni prima del consenso.
    E.5 End points
    E.5.1Primary end point(s)
    Effective hemostasis as determined by the blinded EAC.
    Effective hemostasis is defined as no greater than a 35% increase from baseline in hematoma volume/thickness at 12 hours post randomization, AND less than a 7 point increase from baseline NIHSS score at 12 hours post randomization (see Section 11.4.2).
    Efficacia dell'emostasi determinata dall’EAC in cieco.
    Per emostasi efficace si intende quella che evidenzia un aumento del volume/spessore dell’ematoma a 12 ore dopo la randomizzazione non superiore a 35% rispetto al basale e un aumento inferiore a 7 punti rispetto al basale secondo il punteggio NIHSS
    E.5.1.1Timepoint(s) of evaluation of this end point
    12 Hours post randomizarion
    12 ore dopo la randomizzazione
    E.5.2Secondary end point(s)
    - Maximum reduction in anti-fXa activity.
    - Minimum value of anti-fXa activity post randomization
    • Riduzione massima dell'attività anti-fXa.
    • Valore minimo di attività anti-fXa dopo la randomizzazione
    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
    30 giorni e fino a 120 giorni per i pazienti con risposta anticorpale anti-andexanet positiva
    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) No
    E.8.2.2Placebo No
    E.8.2.3Other Yes
    E.8.2.3.1Comparator description
    Terapia standard
    Standard care
    E.8.2.4Number of treatment arms in the trial1
    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 concerned9
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA46
    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 Information not present in EudraCT
    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
    United States
    Belgium
    France
    Germany
    Netherlands
    Spain
    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
    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: 40
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 400
    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 2021-06-17. 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 (intracranial haemorrhage). Due to the critical nature of the illness some patients will be unable to provide their own consent
    I pazienti hanno un sanguinamento grave / potenzialmente letale (emorragia intracranica). A causa della natura critica della malattia alcuni pazienti non saranno in grado di fornire il proprio consenso
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state55
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 249
    F.4.2.2In the whole clinical trial 439
    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
    A seguito del completamento dello studio, la decisione relativa al trattamento del paziente sarà determinata dal proprio medico in accordo con qualsiasi trattamento disponibile secondo lo standard di cura
    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 Decision2019-05-22
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2019-03-07
    P. End of Trial
    P.End of Trial StatusPrematurely Ended
    P.Date of the global end of the trial2023-06-05
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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
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