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Anti-thrombotics for Adults Hospitalized With COVID-19

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: NCT04505774
Recruitment Status : Recruiting
First Posted : August 10, 2020
Last Update Posted : September 10, 2020
Sponsor:
Collaborator:
National Heart, Lung, and Blood Institute (NHLBI)
Information provided by (Responsible Party):
Matthew Neal MD, University of Pittsburgh

Brief Summary:
This is a randomized, open label, adaptive platform trial to compare the effectiveness of antithrombotic strategies for prevention of adverse outcomes in COVID-19 positive inpatients

Condition or disease Intervention/treatment Phase
Covid19 Drug: theraputic heparin Drug: prophylactic heparin Phase 4

Detailed Description:

The severe acute respiratory syndrome coronavirus 2, which causes the highly contagious coronavirus disease 2019 (COVID-19), has resulted in a global pandemic.

The clinical spectrum of COVID-19 infection is broad, encompassing asymptomatic infection, mild upper respiratory tract illness, and severe viral pneumonia with respiratory failure and death. The risk of thrombotic complications is increased, even as compared to other viral respiratory illnesses, such as influenza. A pro-inflammatory cytokine response as well as induction of procoagulant factors associated with COVID-19 has been proposed to contribute to thrombosis as well as plaque rupture through local inflammation. Patients with COVID-19 are at increased risk for arterial and vein thromboembolism, with high rates observed despite thromboprophylaxis. Autopsy reports have noted micro and macro vascular thrombosis across multiple organ beds consistent with an early hypercoagulable state.

Notably, in COVID-19, data in the U.K. and U.S. document that infection and outcomes of infection are worse in African and Hispanic descent persons than in other groups. The reasons for this are uncertain.

Viral Infection and Thrombosis A large body of literature links inflammation and coagulation; altered hemostasis is a known complication of respiratory viral infections. Procoagulant markers are severely elevated in viral infections. Specifically, proinflammatory cytokines in viral infections upregulate expression of tissue factor, markers of thrombin generation, platelet activation, and down-regulate natural anticoagulant proteins C and S.

Studies have demonstrated significant risk of deep venous thrombosis (DVT), pulmonary embolism (PE), and myocardial infarction (MI) associated with viral respiratory infections. In a series of patients with fatal influenza H1N1, 75% had pulmonary thrombi on autopsy (a rate considerably higher than reported on autopsy studies among the general intensive care unit population). Incidence ratio for acute myocardial infarction in the context of Influenza A is over 10. Severe acute respiratory syndrome coronavirus-1 (SARS CoV-1) and influenza have been associated with disseminated intravascular coagulation (DIC), endothelial damage, DVT, PE, and large artery ischemic stroke. Patients with Influenza H1N1 and acute respiratory distress syndrome (ARDS) had a 23.3-fold higher risk for pulmonary embolism, and a 17.9-fold increased risk for deep vein thrombosis. Compared to those treated with systemic anticoagulation, those without treatment were 33 times more likely to suffer a VTE.

Thrombosis, both microvascular and macrovascular, is a prominent feature in multiple organs at autopsy in fatal cases of COVID-19. Thrombosis may thus contribute to respiratory failure, renal failure, and hepatic injury in COVID-19. The number of megakaryocytes in tissues is higher than in other forms of ARDS, and thrombi are platelet-rich based on specific staining. Thrombotic stroke has been reported in young COVID-19 patients with no cardiovascular risk factors. Both arterial and venous thrombotic events have been seen in increasing numbers of hospitalized patients infected with COVID-19. The incidence of thrombosis has ranged from 10 to 30% in hospitalized patients; however, this varies by type of thrombosis captured (arterial or vein) and severity of illness (ICU level care, requiring mechanical ventilation, etc.).

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 2000 participants
Allocation: Randomized
Intervention Model: Single Group Assignment
Intervention Model Description: This is an adaptive design
Masking: None (Open Label)
Masking Description: There will be independent masked adjudicators.
Primary Purpose: Treatment
Official Title: A Multicenter, Adaptive, Randomized Controlled Platform Trial of the Safety and Efficacy of Antithrombotic Strategies in Hospitalized Adults With COVID-19
Actual Study Start Date : September 4, 2020
Estimated Primary Completion Date : March 2021
Estimated Study Completion Date : December 2021

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Blood Thinners

Arm Intervention/treatment
Therapeutic Dose Anticoagulation
increased dose of heparin above standard of care.
Drug: theraputic heparin
increased dose of heparin above standard of care.
Other Names:
  • unfractionated heparin
  • Enoxaparin
  • Dalteparin
  • Tinzaparin
  • Heparin

Prophylactic Dose Anticoagulation
Heparin standard of care
Drug: prophylactic heparin
standard of care dose of heparin
Other Names:
  • enoxaparin
  • dalteparin
  • Tinzaparin
  • Fondparinux
  • Heparin




Primary Outcome Measures :
  1. 21 Day Organ Support (respiratory or vasopressor) Free Days [ Time Frame: 21 days from study enrollment ]
    which is defined as the number of days that a patient is alive and free of organ support through the first 21 days after trial entry. Organ Support is defined as receipt of non-invasive mechanical ventilation, high flow nasal canula oxygen, mechanical ventilation, or vasopressor therapy, with death at any time during the index hospitalization assigned -1 days.


Secondary Outcome Measures :
  1. Key Platform Secondary Thrombotic Endpoint [ Time Frame: 28 days from study enrollment ]
    Composite endpoint of death, pulmonary embolism, systemic arterial thromboembolism, myocardial infarction, or ischemic stroke at hospital discharge or 28 days, whichever occurs first

  2. Other Platform Secondary Endpoints of Morbidity and Hospitalization [ Time Frame: 28 days from study enrollment ]
    Acute kidney injury defined by KDIGO criteria, Individual endpoints comprising the key secondary endpoint, death during hospitalization, 28 Day Ventilator-Free Days, 28 Day Vasopressor Free Days, 28 Day Renal Replacement Free Days, WHO clinical scale, 28 Day Hospital Free Days, 28 day organ support free days.

  3. All cause mortality [ Time Frame: 90 days from enrollment ]
    Any mortality of patients enrolled within 90 days.


Other Outcome Measures:
  1. Primary Safety Endpoint of Major Bleeding [ Time Frame: 28 days from study enrollment ]
    Major bleeding (as defined by the ISTH)

  2. Secondary Safety Endpoint of HIT [ Time Frame: 28 days from study enrollment ]
    Confirmed heparin induced thrombocytopenia (HIT)



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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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:

  • ≥ 18 years of age
  • Hospitalized for COVID-19
  • Enrolled within 72 hours of hospital admittance or 72 hours of positive COVID test
  • Expected to require hospitalization for > 72 hours

Exclusion Criteria:

  • Imminent death
  • Requirement for chronic mechanical ventilation via tracheostomy prior to hospitalization
  • Pregnancy

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): NCT04505774


Contacts
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Contact: Judith Hochman, MD 212-236-6927 Judith.Hochman@nyulangone.org
Contact: Matthew Neal, MD 412-692-2850 nealm2@upmc.edu

Locations
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United States, New York
NYU Langone Recruiting
New York, New York, United States, 10016
Contact: Jeffrey Berger, MD    212-263-0855    Jeffrey.Berger@nyulangone.org   
Sponsors and Collaborators
Matthew Neal MD
National Heart, Lung, and Blood Institute (NHLBI)
Investigators
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Study Chair: Judith Hochman, MD New York University - Grossman School of Medicine
Publications:
Bikdeli B, Madhavan MV, Jimenez D, Chuich T, Dreyfus I, Driggin E, Nigoghossian C, Ageno W, Madjid M, Guo Y, Tang LV, Hu Y, Giri J, Cushman M, Quéré I, Dimakakos EP, Gibson CM, Lippi G, Favaloro EJ, Fareed J, Caprini JA, Tafur AJ, Burton JR, Francese DP, Wang EY, Falanga A, McLintock C, Hunt BJ, Spyropoulos AC, Barnes GD, Eikelboom JW, Weinberg I, Schulman S, Carrier M, Piazza G, Beckman JA, Steg PG, Stone GW, Rosenkranz S, Goldhaber SZ, Parikh SA, Monreal M, Krumholz HM, Konstantinides SV, Weitz JI, Lip GYH; Global COVID-19 Thrombosis Collaborative Group, Endorsed by the ISTH, NATF, ESVM, and the IUA, Supported by the ESC Working Group on Pulmonary Circulation and Right Ventricular Function. COVID-19 and Thrombotic or Thromboembolic Disease: Implications for Prevention, Antithrombotic Therapy, and Follow-Up: JACC State-of-the-Art Review. J Am Coll Cardiol. 2020 Jun 16;75(23):2950-2973. doi: 10.1016/j.jacc.2020.04.031. Epub 2020 Apr 17. Review.
Xu J, W.L., Zhao L, et al. , Risk assessment of venous thromboembolism and bleeding in COVID-19 patients. BMC Pulmonary Medicine 2020.
Xie Y, W.X., Yang P, Zhang S, COVID-19 complicated by Acute Pulmonary Embolism. Radiology: Cardiothoracic Imaging, 2020. 2(2):e200067
Centers for Disease Control and Prevention. COVID-19 in Racial and Ethnic Minority Groups. 2020.
Kamin-Mukaz D, Gergi M, Koh I, Zakai NA, Judd SE, Sholzberg M, Bauman Kreuziger L, Freeman K, Colovos C, Cushman M. Biomarkers of COVID-19 coagulopathy and D-dimer in a biracial cohort study [abstract]. Res Pract Thromb Haemost 2020;4:Suppl2.

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Responsible Party: Matthew Neal MD, MD, University of Pittsburgh
ClinicalTrials.gov Identifier: NCT04505774    
Other Study ID Numbers: ACTIV-4 ACUTE
First Posted: August 10, 2020    Key Record Dates
Last Update Posted: September 10, 2020
Last Verified: September 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: Data will be shared as per NIH guidelines.
Supporting Materials: Study Protocol
Statistical Analysis Plan (SAP)
Informed Consent Form (ICF)
Clinical Study Report (CSR)
Analytic Code

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
Keywords provided by Matthew Neal MD, University of Pittsburgh:
anti-coagulation
antithrombosis
anticoagulation
ACTIV
inpatient
heparin
Additional relevant MeSH terms:
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Heparin
Calcium heparin
Enoxaparin
Dalteparin
Tinzaparin
Heparin, Low-Molecular-Weight
Anticoagulants
Fibrinolytic Agents
Fibrin Modulating Agents
Molecular Mechanisms of Pharmacological Action