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COVID-19Phase 2COVID-PREVENTNCT04416048

Effect of Anticoagulation Therapy on Clinical Outcomes in COVID-19

A Phase 2 study testing Rivaroxaban in people with COVID-19, run by Charite University, Berlin, Germany at 24 sites in Germany.

Terminated

Stopped early. The study ended before it was planned to and will not resume.

Official record
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Trial 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… Read more about this study

Who is it for?
Ages 18 years and older
Conditions the study is for
COVID-19
What is being tested?
Rivaroxaban
Could I receive a placebo?
No, everyone receives an active treatment
How many people
111 participants
Where
24 sitesGermany
Study dates
30 Nov 2020to 20 Jul 2021
Phase
Phase 2
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • 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
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  • 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

Who cannot join

  • 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.
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  • 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.

Trial locations and contacts

24 sites in 1 country.

24 sites in 1 country

Germany24 sites
  • Department of Pneumology and Infectology Charité University Medicine Berlin, Campus Mitte

    Berlin, 10117

  • Department of Cardiology Charité University Medicine Berlin, Campus Benjamin Franklin

    Berlin, 12200

  • Internal Medicine/Cardiology department Unfallkrankenhaus Berlin

    Berlin, 12683

  • Pulmonary Clinic Berlin-Buch (Lungenklinik Berlin-Buch)

    Berlin, 13125

  • Department of Cardiology Charité University Medicine Berlin, Campus Virchow

    Berlin, 13353

  • Internal Medicine, Cardiology and Intensive Care Clinic Vivantes Humboldt Klinikum, Berlin

    Berlin, 13509

  • Berlin Vivantes Hospital Spandau Clinic for internal medicine, cardiology and conservative intensive care medicine

    Berlin, 13585

  • Internal Medicine Deparment Hospital Waldfriede, Berlin

    Berlin, 14163

  • Immanuel Klinikum Bernau Herzzentrum Brandenburg ( Immanuel Clinic Bernau Heart Center Brandenburg)

    Bernau bei Berlin, Brandenburg, 16321

  • Clinic for Cardiology and Intensive Care - Klinikum Bielefeld

    Bielefeld, North Rhine-Westphalia, 33604

  • Medical Clinic I. Universitätsklinikum Carl Gustav Carus, Dresden

    Dresden, Saxony, 01307

  • Westdeutsches Herz- und Gefäßzentrum Essen (West German Heart and Vascular Center Essen)

    Essen, North Rhine-Westphalia, 45147

  • Clinic for Cardiology, Angiology und Nephrology Universitätsklinikum Frankfurt, Goethe-Universität

    Frankfurt am Main, Hesse, 60590

  • Kardiologie und Angiologie I Universitätsherzzentrum Freiburg

    Freiburg im Breisgau, Baden-Wurttemberg, 79106

  • Friedrichshafen Hospital Clinic for cardiology, angiology, pneumology and internal intensive care medicine

    Friedrichshafen, Baden-Wurttemberg, 88048

  • Universitätsklinikum Halle (Saale) (University Hospital Halle (Saale))

    Halle, Saxony-Anhalt, 06120

  • Clinic for Gastroenterology, Infectology and Poisoning Universitäsklinikum Heidelberg

    Heidelberg, Baden-Wurttemberg, 69120

  • Internal Medicine and Cardiology Klinik Henningsdorf. Oberhavel Kliniken

    Hennigsdorf, Brandenburg, 16761

  • Medical Clinic I. Marien Hospital, Universitätsklinikum der Ruhr Universität Bochum, Herne

    Herne, North Rhine-Westphalia, 44625

  • Katholisches Klinikum Koblenz-Montabaur (Catholic Hospital Koblenz-Montabaur)

    Koblenz, Rhineland-Palatinate, 56073

  • Medical Clinic II, University Clinic Schleswig-Holstein - Campus Lübeck

    Lübeck, Schleswig-Holstein, 23538

  • Center for Cardiology, University Medicine Mainz

    Mainz, Rhineland-Palatinate, 55131

  • Medical Clinic and Polyclinic I. L. Ludwigs-Maximilians-University Clinic, Munich

    Munich, Bavaria, 81377

  • Pneumology, Allergology, Sleep-and Respiratory Medicine Clinic Helios Universitätsklinikum Wupperthal

    Wuppertal, North Rhine-Westphalia, 42283

Other trials in Germany

About this study

Official title: Effect of Anticoagulation Therapy on Clinical Outcomes in Moderate to Severe Coronavirus Disease 2019 (COVID-19)

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:

Read more

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.

Conditions
COVID-19
Being tested
Rivaroxaban, Standard Of Care (SOC)
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
Medical subject headings
COVID-19, Venous Thromboembolism, Venous Thrombosis, Pulmonary Embolism, Myocardial Infarction

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • RivaroxabanDrug

    Also called XARELTO®

    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.

  • Standard Of Care (SOC)Other

    Standard of care treatment

Study groups in NCT04416048
Study groupRoleWhat they receive
RivaroxabanExperimentalSubjects will receive treatment with rivaroxaban. (for more information see intervention description)
Receives: Drug: Rivaroxaban
Standard of CareOtherSubjects will receive standard of care (SOC) treatment SOC with prophylactic LMWH or UFH
Receives: Other: Standard Of Care (SOC)

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. D-dimer level

    Measured: 7 days post randomization

  2. Seven-category ordinal scale recommended by the WHO

    Measured: 7 days post randomization

Secondary outcomes (1)
  1. 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

    Measured: 35 days post randomization

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted4 Jun 2020
  2. Study start30 Nov 2020
  3. Primary completion20 Jul 2021
  4. Study completion20 Jul 2021

Why it stopped: Due to lower COVID-19 cases and therefore difficulties with the recruitment.

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 2
Primary purpose
Prevention
Allocation
Randomised
Intervention model
Parallel groups
Model description
A multicenter, prospective, randomized, event-driven study.
Masking
None (open label)
Enrolment
111 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT04416048
Sponsor's protocol ID
COVID-PREVENT
Other IDs
2020-002282-33
Acronym
COVID-PREVENT
Status last verified
Dec 2021
First submitted
2 Jun 2020
Last updated
12 Jan 2022
Results posted
No
Data monitoring committee
Yes
FDA-regulated drug
No
FDA-regulated device
No
Individual data sharing
Yes: after protection period

Publications

  • 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: a rapid review. Cochrane Database Syst Rev. 2022 Mar 4;3(3):CD013739. doi: 10.1002/14651858.CD013739.pub2.

    PubMed 35244208
  • 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.

    PubMed 33502773

Questions about this trial

What is this clinical trial studying?

A Phase 2 study testing Rivaroxaban in people with COVID-19, run by Charite University, Berlin, Germany at 24 sites in Germany.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 16 inclusion and 23 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: stopped early, as of the sponsor's last update on 12 Jan 2022. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 24 sites in Germany. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

The study was stopped early (reason given: Due to lower COVID-19 cases and therefore difficulties with the recruitment.). Results are not available in the source record.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

D-dimer level (time frame: 7 days post randomization). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT04416048, which also lists 2 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 12 Jan 2022.

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