Clinical trial NCT04416048: Effect of Anticoagulation Therapy on Clinical Outcomes in COVID-19
Official title: Effect of Anticoagulation Therapy on Clinical Outcomes in Moderate to Severe Coronavirus Disease 2019 (COVID-19)
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
Conditions: COVID-19
Keywords: COVID-19
therapeutic anticoagulation
thromboprophylaxis
anticoagulation
rivaroxaban
standard of care
prevention
venous thromboembolism
deep venous thrombosis
pulmonary embolism
arterial thromboembolism
myocardial infarction
non-hemorrhagic stroke
all-cause mortality
Lead sponsor: Charite University, Berlin, Germany
Sponsor class: OTHER
Collaborators: name: Deutsches Zentrum für Herz-Kreislauf-Forschung (DZHK)
name: Bayer
First posted: 2020-06-04
Enrollment: 111
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: A multicenter, prospective, randomized, event-driven study.
Primary purpose: PREVENTION

Brief summary: Patients with moderate to severe COVID-19 present a very high risk of thromboembolic disease.This multicenter, prospective, randomized, event-driven study evaluates rivaroxaban compared with standard of care with low-molecular-weight heparin (LMWH) or unfractionated heparin (UFH) at prophylactic doses comparing D-dimer levels and the seven-category ordinal scale recommended by the WHO 7 days post randomization in patients with moderate to severe COVID-19.

Experimental intervention/Index test:

Patients randomized into the rivaroxaban arm will receive rivaroxaban 20 mg once daily (OD) until day 7 post randomization or hospital discharge, whichever occurs later, followed by a 28-day-phase of prophylactic anticoagulation with rivaroxaban 10mg OD. Subjects with an eGFR between 30 and 50ml/min/1,73m2, will receive 15mg instead of 20mg OD.

Control intervention/Reference test:

The control group will receive standard of care including LMWH or UFH as thromboprophylaxis.

Duration of intervention per patient:

The total duration of the study treatment is flexible. For out-patients 7 days of therapeutic anticoagulation will be accompanied by 28 days-phase of prophylactic anticoagulation, summing up to 35 days. For subjects that require hospitalization, the duration of therapeutic anticoagulation will be at least 7 days or prolonged until discharge if hospitalized for more than 7 days post randomization.

After discharge from the hospital the subject receives 28 days of thromboprophylaxis with rivaroxaban. No study medication will be given past day 60 post randomization. This adds up to a study duration between 35 and 60 days depending on the duration of the hospital stay.

Follow-up per patient:

The study has a follow-up of 60 days.

Experimental and/or control off label or on label in Germany:

Rivaroxaban has been approved for multiple indications worldwide. Over 100,000 subjects have been studied from Phase 1 through multiple large Phase 4 studies in multiple settings, e.g. for the reduction in the risk of stroke and systemic embolism in arterial fibrillation, deep vein thrombosis and pulmonary embolism, major cardiovascular events. The drug had not been studied in patients with COVID-19 as an anticoagulant agent, yet.


Eligibility criteria: Inclusion Criteria:

* Subject must be willing, understanding and able to provide written informed consent
* Subject must be a man or a woman with age \> 18 years at screening
* Subject must have an active moderate to severe COVID-19 confirmed by

  o A positive SARS-CoV-2 PCR test in the last 14 days
* At least one of the following features should be present

  * D-Dimer elevation \> 1.5 ULN (age adjusted cut-offs) AND/OR
  * Cardiac injury reflected by an elevation in hs-cTnT \> 2.0 upper limit of normal (ULN) AND at least one of the following conditions:

    * Known coronary artery disease (CAD)
    * Known diabetes mellitus
    * Active smoking
* A woman of childbearing potential must have a negative serum or urine pregnancy test before randomization occurs. Before randomization, a woman must be either:

  * Postmenopausal, defined as \>45 years of age with amenorrhea for at least 18 months,
  * If menstruating:

    * If heterosexually active, practicing a highly effective method of birth control, including hormonal prescription oral contraceptives, contraceptive injections, contraceptive patch, intrauterine device, double-barrier method \[(e.g., condoms, diaphragm, or cervical cap, with spermicidal foam, cream, or gel)\], or male partner sterilization, consistent with local regulations regarding use of birth control methods for subjects participating in clinical studies, for the duration of their participation in the study, or
    * Surgically sterile (have had a hysterectomy or bilateral oophorectomy, tubal ligation, or otherwise be incapable of pregnancy), or
    * Not heterosexually active

Exclusion Criteria:

* Subject has a very high bleeding risk: Any condition that, in the opinion of the investigator, contraindicates anticoagulant therapy or would have an unacceptable risk of bleeding, such as, but not limited to, the following:

  * Any bleeding (defined as bleeding requiring hospitalization, transfusion, surgical intervention, invasive procedures, occurring in a critical anatomical site, or causing disability) within 1 months prior to randomization or occurring during index hospitalization.
  * Major surgery, biopsy of a parenchymal organ, ophthalmic surgery (excluding cataract surgery), or serious trauma (including head trauma) within 4 weeks before randomization.
  * A history of hemorrhagic stroke or any intracranial bleeding at any time in the past, evidence of primary intracranial hemorrhage on CT or magnetic resonance imaging scan of the brain, or clinical presentation consistent with intracranial hemorrhage. This applies as well to subjects hospitalized for ischemic stroke upon randomization.
  * Subject has a history of or current intracranial neoplasm (benign or malignant), cerebral metastases, arteriovenous (AV) malformation, or aneurysm.
  * Active gastroduodenal ulcer, defined as diagnosed within 1 months or currently symptomatic or known AV malformations of the gastrointestinal tract.
  * Platelet count \<90,000/μl at screening.
  * Patients with the diagnosis of bronchiectasis, that due to the investigator judgement are at an increased bleeding risk.
* Subject has any of the following diseases in the medical history:

  * Active cancer (excluding non-melanoma skin cancer) defined as cancer not in remission or requiring active chemotherapy or adjunctive therapies such as immunotherapy or radiotherapy. Chronic hormonal therapy (e.g. tamoxifen, anastrozole, leuprolide acetate) for cancer in remission is allowed.
  * Any medical condition (e.g. atrial fibrillation) that requires use of any therapeutic parenteral or oral anticoagulant(s) (e.g. warfarin sodium or other vitamin K antagonists, Factor IIa or FXa inhibitors, fibrinolytics) concomitantly with study medication.
  * Subject has known allergies, hypersensitivity, or intolerance to rivaroxaban or any of its excipients.
  * Baseline eGFR \<30 mL/min/1.73m2 calculated using CKD-EPI formula
  * Known significant liver disease (e.g. acute hepatitis, chronic active hepatitis, cirrhosis) which is associated with coagulopathy or moderate or severe hepatic impairment.
  * Known HIV infection.
* Subject has undergone any of the following procedures or received any of the following drugs:

  * Received fibrinolysis during index hospitalization.
  * Use of antiplatelet therapy with prasugrel or ticagrelor up to 7 days prior to randomization. Other P2Y12 antagonists can be given. However, the use of concomitant antiplatelet therapy should be carefully considered. ASS \> 100 mg/d and continuous NSAIDs should be avoided.
  * Use of dual antiplatelet therapy, such as aspirin plus clopidogrel during the study.
* Subject is a woman who is pregnant or breast-feeding.
* Known intolerance or history of hypersensitivity to the active substance or to any of the excipients of the Investigational Medicinal Product (IMP)
* Subjects who are legally detained in an official institution.
* Subjects who may be dependent on the sponsor, the investigator or the trial sites, are not eligible to enter the trial.

Primary outcomes:
measure: D-dimer level
timeFrame: 7 days post randomization
measure: Seven-category ordinal scale recommended by the WHO
timeFrame: 7 days post randomization
Secondary outcomes:
measure: Composite endpoint of venous thromboembolism (DVT and/or fatal or non-fatal PE), arterial thromboembolism, new myocardial infarction, non-hemorrhagic stroke, all-cause death or progression to intubation and invasive ventilation
timeFrame: 35 days post randomization
Other outcomes:
Locations:
city: Freiburg
country: Germany
facility: Kardiologie und Angiologie I Universitätsherzzentrum Freiburg
state: Baden-Württemberg
city: Friedrichshafen
country: Germany
facility: Friedrichshafen Hospital Clinic for cardiology, angiology, pneumology and internal intensive care medicine
state: Baden-Württemberg
city: Heidelberg
country: Germany
facility: Clinic for Gastroenterology, Infectology and Poisoning Universitäsklinikum Heidelberg
state: Baden-Württemberg
city: Munich
country: Germany
facility: Medical Clinic and Polyclinic I. L. Ludwigs-Maximilians-University Clinic, Munich
state: Bayern
city: Bernau
country: Germany
facility: Immanuel Klinikum Bernau Herzzentrum Brandenburg ( Immanuel Clinic Bernau Heart Center Brandenburg)
state: Brandenburg
city: Hennigsdorf
country: Germany
facility: Internal Medicine and Cardiology Klinik Henningsdorf. Oberhavel Kliniken
state: Brandenburg
city: Frankfurt am Main
country: Germany
facility: Clinic for Cardiology, Angiology und Nephrology Universitätsklinikum Frankfurt, Goethe-Universität
state: Hessen
city: Bielefeld
country: Germany
facility: Clinic for Cardiology and Intensive Care - Klinikum Bielefeld
state: Nordrhein-Westfalen
city: Essen
country: Germany
facility: Westdeutsches Herz- und Gefäßzentrum Essen (West German Heart and Vascular Center Essen)
state: Nordrhein-Westfalen
city: Herne
country: Germany
facility: Medical Clinic I. Marien Hospital, Universitätsklinikum der Ruhr Universität Bochum, Herne
state: Nordrhein-Westfalen
city: Wuppertal
country: Germany
facility: Pneumology, Allergology, Sleep-and Respiratory Medicine Clinic Helios Universitätsklinikum Wupperthal
state: Nordrhein-Westfalen
city: Koblenz
country: Germany
facility: Katholisches Klinikum Koblenz-Montabaur (Catholic Hospital Koblenz-Montabaur)
state: Rheinland-Pfalz
city: Mainz
country: Germany
facility: Center for Cardiology, University Medicine Mainz
state: Rheinland-Pfalz
city: Halle
country: Germany
facility: Universitätsklinikum Halle (Saale) (University Hospital Halle (Saale))
state: Sachsen-Anhalt
city: Dresden
country: Germany
facility: Medical Clinic I. Universitätsklinikum Carl Gustav Carus, Dresden
state: Sachsen
city: Lübeck
country: Germany
facility: Medical Clinic II, University Clinic Schleswig-Holstein - Campus Lübeck
state: Schleswig-Holstein
city: Berlin
country: Germany
facility: Department of Pneumology and Infectology Charité University Medicine Berlin, Campus Mitte
city: Berlin
country: Germany
facility: Department of Cardiology Charité University Medicine Berlin, Campus Benjamin Franklin
city: Berlin
country: Germany
facility: Internal Medicine/Cardiology department Unfallkrankenhaus Berlin
city: Berlin
country: Germany
facility: Pulmonary Clinic Berlin-Buch (Lungenklinik Berlin-Buch)
city: Berlin
country: Germany
facility: Department of Cardiology Charité University Medicine Berlin, Campus Virchow
city: Berlin
country: Germany
facility: Internal Medicine, Cardiology and Intensive Care Clinic Vivantes Humboldt Klinikum, Berlin
city: Berlin
country: Germany
facility: Berlin Vivantes Hospital Spandau Clinic for internal medicine, cardiology and conservative intensive care medicine
city: Berlin
country: Germany
facility: Internal Medicine Deparment Hospital Waldfriede, Berlin
Study officials:
affiliation: Charite University, Berlin, Germany
name: Ulf Landmesser, Prof. Dr.
role: PRINCIPAL_INVESTIGATOR
affiliation: Johann Wolfgang Goethe-University, Frankfurt am Main, Germany
name: Co-PI: Andreas M. Zeiher, Prof. Dr.
role: PRINCIPAL_INVESTIGATOR
affiliation: Ludwig-Maximilians - University of Munich
name: Co-PI: Steffen Massberg, Prof. Dr.
role: PRINCIPAL_INVESTIGATOR
affiliation: Charité University, Berlin, Germany
name: Co-PI: Ursula Rauch-Kröhnert, Prof. Dr.
role: PRINCIPAL_INVESTIGATOR
affiliation: University Hospital Carl Gustav Carus at the Technical University of Dresden
name: Co-PI: Jan Beyer-Westendorf, Prof. Dr.
role: PRINCIPAL_INVESTIGATOR
References:
citation: Flumignan RL, Civile VT, Tinoco JDS, Pascoal PI, Areias LL, Matar CF, Tendal B, Trevisani VF, Atallah AN, Nakano LC. Anticoagulants for people hospitalised with COVID-19. Cochrane Database Syst Rev. 2022 Mar 4;3(3):CD013739. doi: 10.1002/14651858.CD013739.pub2.
citation: Flumignan RL, Tinoco JDS, Pascoal PI, Areias LL, Cossi MS, Fernandes MI, Costa IK, Souza L, Matar CF, Tendal B, Trevisani VF, Atallah AN, Nakano LC. Prophylactic anticoagulants for people hospitalised with COVID-19. Cochrane Database Syst Rev. 2020 Oct 2;10(10):CD013739. doi: 10.1002/14651858.CD013739.