Trial of Andexanet Alfa in ICrH Patients Receiving an Oral FXa Inhibitor

NCT03661528 | Completed Phase 4 Results DMC FDA Drug

• 2 other identifiers: 18-5132018-002620-17
• Study Type: interventional
• Target: 530
• Locations: 24 countries
• Sites: 142

Brief Summary

Randomized, controlled clinical trial evaluating the efficacy and safety of andexanet alfa versus usual care in patients with intracranial hemorrhage anticoagulated with a direct oral FXa anticoagulant

Conditions

Acute Intracranial Hemorrhage

Keywords

thrombosis; anticoagulant; acute intracranial hemorrhage; andexanet alfa

Outcome Measures

Primary Outcomes (1)

• Number of Participants Who Achieved Effective Hemostasis

  Effective hemostasis was defined as a change from baseline in National Institutes of Health Stroke Scale (NIHSS) of + 6 or less at the 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 administered between 3 hours and 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 neurological deficits) to a maximum of 42, indicative of a very severe level of impairment. Data presented is for the number of participants who achieved effective hemostasis (excellent or good hemostasis), as adjudicated by the independent Endpoint Adjudication Committee (IEAC).

  Baseline up to 12 hours

Secondary Outcomes (1)

• Percentage Change From Baseline to Nadir in Anti-FXa Activity

  Baseline up to 2 hours

Study Arms (2)

andexanet alfa

EXPERIMENTAL

Patients will receive one of two dosing regimens of andexanet alfa based on which FXa inhibitor they received and the amount and timing of the most recent dose.

Drug: andexanet alfa

Usual Care

OTHER

Usual care will consist 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 consider to be appropriate.

Drug: Usual Care

Interventions

andexanet alfa DRUG

Andexanet alfa is a recombinant version of human FXa

andexanet alfa

Usual Care DRUG

Usual care will consist 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 consider to be appropriate.

Usual Care

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Written informed consent. Either the patient or his or her medical proxy (or legally authorized representative 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.
• Age ≥ 18 years old at the time of consent.
• An acute intracerebral bleeding episode, defined as an estimated blood volume ≥ 0.5 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.
• Performance of a head CT or MRI scan demonstrating the intracerebral bleeding within 2 hours prior to randomization (the baseline scan may be repeated only once to meet this criterion).
• Treatment with an oral FXa inhibitor (apixaban \[last dose 2.5 mg or greater\], rivaroxaban \[last dose 10 mg or greater\], or edoxaban \[last dose 30 mg or greater\]):
• ≤ 15 hours prior to randomization.
• \> 15 hours prior to randomization or unknown time of last dose, if documented anti fXa activity is \> 100 ng/mL for direct fXa inhibitors (apixaban, rivaroxaban or edoxaban) may be enrolled, irrespective of the time of the last dose, and 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.
• 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.
• Have a negative pregnancy test documented prior to enrollment (for females of childbearing potential).
• NIHSS score ≤ 35 at the time of consent.

You may not qualify if:

• If a patient meets any of the following criteria, he or she is not eligible to participate in this trial:
• 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 hematoma volume are allowed (e.g., Burr holes for intracranial pressure monitoring, endoscopy, bronchoscopy, central lines.
• 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.
• Purposefully left blank.
• 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).
• Expected survival of less than 1 month (not related to the intracranial bleed).
• Recent history (within 2 weeks) of a diagnosed TE or clinically relevant symptoms of the following:
• ○ Venous Thromboembolism (VTE: e.g., deep venous thrombosis, 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.
• Acute decompensated heart failure or cardiogenic shock at the time of randomization.
• Severe sepsis or septic shock at the time of randomization.
• The patient is a pregnant or lactating female.
• Receipt of any of the following drugs or blood products within 7 days prior to consent:
• VKA (e.g., warfarin).
• Dabigatran.
• PCC (e.g., KCentra®) or rfVIIa (e.g., NovoSeven®), or anti-inhibitor coagulant complex (e.g., FEIBA®), FFP, and whole blood.

Sponsors & Collaborators

• Alexion Pharmaceuticals, Inc.: lead

Study Sites (142)

Research Site

Fort Lauderdale, Florida, 33308, United States

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Augusta, Georgia, 30905, United States

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Royal Oak, Michigan, 48073, United States

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Troy, Michigan, 48085, United States

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Albany, New York, 12208, United States

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Columbus, Ohio, 43210, United States

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Tulsa, Oklahoma, 74104, United States

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Allentown, Pennsylvania, 18103, United States

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Nashville, Tennessee, 37203, United States

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Austin, Texas, 78705, United States

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Austin, Texas, 78712, United States

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Innsbruck, 6020, Austria

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Klagenfurt, 9020, Austria

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Linz, 4020, Austria

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Salzburg, 5020, Austria

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Sankt Pölten, 3100, Austria

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Vienna, 1020, Austria

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Belgium, 1200, Belgium

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Genk, 3600, Belgium

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Ghent, 9000, Belgium

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Kortrijk, 8500, Belgium

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Leuven, 3000, Belgium

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Ottignies, 1340, Belgium

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Calgary, Alberta, T2N 2T9, Canada

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Edmonton, Alberta, T6G 2B7, Canada

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New Westminster, British Columbia, V3L 0E3, Canada

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Vancouver, British Columbia, V5Z 1M9, Canada

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Hamilton, Ontario, L8L 2X2, Canada

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London, Ontario, N6A 5A5, Canada

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Montreal, Quebec, H3A 2B4, Canada

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Montreal, Quebec, H3T 1E2, Canada

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Québec, Quebec, G1J 4Z1, Canada

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Brno, 656 91, Czechia

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Ostrava, 703 84, Czechia

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Prague, 150 06, Czechia

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Aalborg, 9100, Denmark

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Århus N, 8200, Denmark

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Copenhagen, DK-2400, Denmark

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Copenhagen Ø, 2100, Denmark

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Odense C, 5000, Denmark

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Helsinki, 00029, Finland

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Turku, FI-20521, Finland

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Angers, 49933, France

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Bordeaux, 33076, France

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Bourg-en-Bresse, 01012, France

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Clermont-Ferrand, 63003, France

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Lyon, 69437, France

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Montpellier, 34295, France

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Nancy, 54035, France

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Paris, 75014, France

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Paris, 75019, France

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Suresnes, 92151, France

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Toulouse, 31300, France

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Altenburg, 4600, Germany

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Augsburg, 86156, Germany

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Bad Neustadt an der Saale, 97616, Germany

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Bochum, 44892, Germany

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Bonn, 53127, Germany

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Bremen, 28755, Germany

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Chemnitz, 9116, Germany

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Dortmund, 44137, Germany

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Dresden, 1067, Germany

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Dresden, 1307, Germany

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Erlangen, 91054, Germany

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Essen, 45131, Germany

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Frankfurt, 65929, Germany

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Frankfurt am Main, 60528, Germany

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Giessen, 35392, Germany

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Göttingen, 37075, Germany

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Hamburg, 20246, Germany

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Hamburg, 22291, Germany

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Hanover, 30625, Germany

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Heidelberg, 69120, Germany

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Konstanz, 78464, Germany

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Lübeck, 23538, Germany

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Lünen, 44534, Germany

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Mannheim, 68135, Germany

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München, 81377, Germany

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Münster, 48149, Germany

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Osnabrück, 49076, Germany

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Sande, 26452, Germany

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Stuttgart, 70174, Germany

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Tübingen, 72076, Germany

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Ulm, 89081, Germany

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Alexandroupoli, 68100, Greece

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Athens, 12462, Greece

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Budapest, 1083, Hungary

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Budapest, 1106, Hungary

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Budapest, 1134, Hungary

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Debrecen, 4032, Hungary

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Pécs, 7623, Hungary

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Ashdod, 7747629, Israel

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Beersheba, 84101, Israel

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Haifa, 3109601, Israel

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Jerusalem, 91120, Israel

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Jerusalem, 9372212, Israel

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Petah Tikva, 4941492, Israel

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Tel Aviv, 6423906, Israel

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Bologna, 40133, Italy

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Genova, 16132, Italy

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Milan, 20132, Italy

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Perugia, 06156, Italy

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Roma, 00133, Italy

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Roma, 00168, Italy

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Rome, 152, Italy

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Rome, 161, Italy

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Riga, LV-1002, Latvia

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Vilnius, 4130, Lithuania

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Vilnius, LT-08661, Lithuania

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Amsterdam, 1061 AE, Netherlands

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Amsterdam, 1105 AZ, Netherlands

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Enschede, 7512 KZ, Netherlands

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Leiden, 2333 ZA, Netherlands

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Zwolle, 8025 AB, Netherlands

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Oslo, 450, Norway

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Krakow, 30-688, Poland

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Krakow, 31-913, Poland

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Lublin, 20-718, Poland

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Wejherowo, 84-200, Poland

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Coimbra, 3000-075, Portugal

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Vila Nova de Gaia, 4434-502, Portugal

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Arkhangelsk, 163045, Russia

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Novosibirsk, 630003, Russia

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Albacete, 02006, Spain

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Barcelona, 08035, Spain

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Barcelona, 08041, Spain

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L'Hospitalet de Llobregat, 08907, Spain

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Lleida, 25198, Spain

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Madrid, 28034, Spain

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Madrid, 28041, Spain

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Seville, 41009, Spain

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Seville, 41013, Spain

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Valencia, 46026, Spain

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Lund, SE-221 85, Sweden

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Uppsala, 751 85, Sweden

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Bern, 3010, Switzerland

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Cambridge, CB2 0QQ, United Kingdom

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Harrow, HA1 3UJ, United Kingdom

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Leeds, LS1 3EX, United Kingdom

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Leicester, LE1 5WW, United Kingdom

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London, SW17 0QT, United Kingdom

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Newcastle upon Tyne, NE1 4LP, United Kingdom

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Related Publications (3)

• Eikelboom JW, Sharma M, Xu L, Bamberg K, Beyer-Westendorf J, Falkenberg C, Ladenvall P, Narayan R, Penland RC, Verhamme P, Shoamanesh A. Association of Biomarkers With Intracerebral Hematoma Expansion and Arterial Thromboembolic Events in Patients With Acute Intracranial Hemorrhage: The ANNEXA-I Biomarker Substudy. Stroke. 2025 Jul;56(7):1807-1815. doi: 10.1161/STROKEAHA.124.049966. Epub 2025 Apr 28.

  PMID: 40289797 DERIVED

• Shoamanesh A, Sharma M. Andexanet for Factor Xa Inhibitor-Associated Acute Intracerebral Hemorrhage. Reply. N Engl J Med. 2024 Aug 22;391(8):10.1056/NEJMc2407378#sa4. doi: 10.1056/NEJMc2407378. No abstract available.

  PMID: 39167819 DERIVED

• Connolly SJ, Sharma M, Cohen AT, Demchuk AM, Czlonkowska A, Lindgren AG, Molina CA, Bereczki D, Toni D, Seiffge DJ, Tanne D, Sandset EC, Tsivgoulis G, Christensen H, Beyer-Westendorf J, Coutinho JM, Crowther M, Verhamme P, Amarenco P, Roine RO, Mikulik R, Lemmens R, Veltkamp R, Middeldorp S, Robinson TG, Milling TJ Jr, Tedim-Cruz V, Lang W, Himmelmann A, Ladenvall P, Knutsson M, Ekholm E, Law A, Taylor A, Karyakina T, Xu L, Tsiplova K, Poli S, Kallmunzer B, Gumbinger C, Shoamanesh A; ANNEXA-I Investigators. Andexanet for Factor Xa Inhibitor-Associated Acute Intracerebral Hemorrhage. N Engl J Med. 2024 May 16;390(19):1745-1755. doi: 10.1056/NEJMoa2313040.

  PMID: 38749032 DERIVED

Related Links

• Related Info

MeSH Terms

Conditions

Thrombosis

Interventions

PRT064445

Condition Hierarchy (Ancestors)

Embolism and Thrombosis; Vascular Diseases; Cardiovascular Diseases

Results Point of Contact

• Title: Alexion Pharmaceuticals, Inc.
• Organization: Alexion Pharmaceuticals, Inc.

clinicaltrials@alexion.com

+1.855.752.2356

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: SINGLE
• Who Masked: OUTCOMES ASSESSOR
• Masking Details: ANNEXA-I is a randomized, open-label study with blinded adjudication on primary efficacy and safety outcomes, including death and thrombotic events.
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: August 30, 2018
• First Posted: September 7, 2018
• Study Start: June 6, 2019
• Primary Completion: May 27, 2023
• Study Completion: August 9, 2023
• Last Updated: July 3, 2024
• Results First Posted: July 3, 2024

Record last verified: 2024-07

Locations

US (11); LA (1); DE (31); IT (8); AU (6); CZ (3); CA (9); BE (6); HU (5); GR (2); RU (2); NO (1); ES (10); SE (2); PL (4); LI (2); PT (2); FI (2); CH (1); GB (6); FR (11); DK (5); IL (7); NL (5)