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Effect of Anticoagulation Therapy on Clinical Outcomes in COVID-19 (COVID-PREVENT)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04416048
Recruitment Status : Not yet recruiting
First Posted : June 4, 2020
Last Update Posted : June 4, 2020
Sponsor:
Collaborators:
Deutsches Zentrum für Herz-Kreislauf-Forschung (DZHK)
Bayer
Information provided by (Responsible Party):
Ulf Landmesser, Charite University, Berlin, Germany

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 including low-molecular-weight heparin (LMWH) or unfractionated heparin (UFH) at prophylactic doses if applicable in the prevention of the composite of venous thromboembolism (deep vein thrombosis and/or fatal or non-fatal pulmonary embolism), arterial thromboembolism, new myocardial infarction, non-hemorrhagic stroke, all-cause mortality or progression to intubation and invasive ventilation 35 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 or no anticoagulation, if appropriate.

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.


Condition or disease Intervention/treatment Phase
COVID-19 Drug: Rivaroxaban Other: Standard Of Care (SOC) Phase 3

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 400 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: A multicenter, prospective, randomized, event-driven study.
Masking: None (Open Label)
Masking Description: Central randomization will be implemented in this study. Subjects will be randomly assigned to 1 of 2 treatment groups based on a computer-generated randomization schedule prepared before the study under the supervision of the sponsor. The randomization will be stratified by site, gender, age, kidney function (subjects with eGFR ≥30 mL/min/1.73m2 and <50 mL/min/1.73m2 versus subjects with eGFR ≥50 mL/min/1.73m2), history of CAD or heart failure and oxygen demand on admission to the hospital. The computer system will assign a unique treatment code, which will dictate the treatment assignment and study drug kits for the subject. The requestor must use his or her own user identification and personal identification number when contacting the system and will then give the relevant subject details to uniquely identify the subject.
Primary Purpose: Prevention
Official Title: Effect of Anticoagulation Therapy on Clinical Outcomes in Moderate to Severe Coronavirus Disease 2019 (COVID-19)
Estimated Study Start Date : June 15, 2020
Estimated Primary Completion Date : April 30, 2021
Estimated Study Completion Date : May 30, 2021

Resource links provided by the National Library of Medicine

Drug Information available for: Rivaroxaban

Arm Intervention/treatment
Experimental: Rivaroxaban
Subjects will receive treatment with rivaroxaban. (for more information see intervention description)
Drug: Rivaroxaban
Treatment with Rivaroxaban 20 mg (15 mg for subjects with an eGFR ≥30 mL/min/1.73m2 and <50 mL/min/1.73m2) once daily (OD) for at least 7 days. In case of hospitalization for more than 7 days, the therapeutic treatment with rivaroxaban will be continued for the duration of the hospital stay until discharge. After at least 7 days of therapeutic treatment with rivaroxaban or after hospital discharge, the study dose of rivaroxaban will be adjusted as follows. Patients randomized to the rivaroxaban study arm will reduce daily dosage to 10 mg OD, provided that they were not diagnosed with a condition requiring continued therapeutic anticoagulation. Thromboprophylaxis therapy will be given for 28 days up to day 35 post randomization or even longer. If the patient cannot be discharged from the hospital prior to day 35 post randomization, the thromboprophylaxis phase will also start upon hospital discharge, but is then shorter than 28 days, because the study ends at day 60 post randomization.
Other Name: XARELTO®

Standard of Care
Subjects will receive standard of care (SOC) treatment SOC including prophylactic LMWH or UFH, when considered appropriate according to the judgment of the treating physician.
Other: Standard Of Care (SOC)
Standard of care treatment




Primary Outcome Measures :
  1. Composite endpoint of venous thromboembolism (DVT and/or fatal or non-fatal PE), arterial thromboembolism, new myocardial infarction, non-hemorrhagic stroke, all-cause mortality or progression to intubation and invasive ventilation [ Time Frame: 35 days post randomization ]

Secondary Outcome Measures :
  1. Development of disseminated intravascular coagulation (DIC) according to the ISTH criteria [ Time Frame: 35 days post randomization ]
  2. Number of days requiring invasive ventilation [ Time Frame: 35 days post randomization ]
  3. Number of days requiring non-invasive ventilation [ Time Frame: 35 days post randomization ]
  4. Improvement on a seven-category ordinal scale recommended by the WHO as clinical improvement scale for patients with respiratory infections [ Time Frame: 35 days post randomization ]
    scale range from 1 to 7; improvement means a reduction in the scale number of at least one point



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04416048


Contacts
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Contact: Ulf Landmesser, Prof. Dr. +49 30 450 513 702 ulf.landmesser@charite.de
Contact: Ursula Rauch-Kroehnert, Prof. Dr. med. +49 30 450 513 794 ursula.rauch@charite.de

Locations
Show Show 27 study locations
Sponsors and Collaborators
Charite University, Berlin, Germany
Deutsches Zentrum für Herz-Kreislauf-Forschung (DZHK)
Bayer
Investigators
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Principal Investigator: Ulf Landmesser, Prof. Dr. Charite University, Berlin, Germany
Principal Investigator: Co-PI: Andreas M. Zeiher, Prof. Dr. Johann Wolfgang Goethe-University, Frankfurt am Main, Germany
Principal Investigator: Co-PI: Steffen Massberg, Prof. Dr. Ludwig-Maximilians - University of Munich
Principal Investigator: Co-PI: Ursula Rauch-Kröhnert, Prof. Dr. Charité University, Berlin, Germany
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Responsible Party: Ulf Landmesser, Prof. Dr., Charite University, Berlin, Germany
ClinicalTrials.gov Identifier: NCT04416048    
Other Study ID Numbers: COVID-PREVENT
2020-002282-33 ( EudraCT Number )
First Posted: June 4, 2020    Key Record Dates
Last Update Posted: June 4, 2020
Last Verified: June 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: after protection period

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Ulf Landmesser, Charite University, Berlin, Germany:
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
Additional relevant MeSH terms:
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Rivaroxaban
Factor Xa Inhibitors
Antithrombins
Serine Proteinase Inhibitors
Protease Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Anticoagulants