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Anti-thrombotics for Adults Hospitalized With COVID-19 (ACTIV-4)

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ClinicalTrials.gov Identifier: NCT04505774
Recruitment Status : Recruiting
First Posted : August 10, 2020
Last Update Posted : March 2, 2021
Sponsor:
Collaborator:
National Heart, Lung, and Blood Institute (NHLBI)
Information provided by (Responsible Party):
Matthew Neal MD, University of Pittsburgh

Tracking Information
First Submitted Date  ICMJE August 6, 2020
First Posted Date  ICMJE August 10, 2020
Last Update Posted Date March 2, 2021
Actual Study Start Date  ICMJE September 4, 2020
Estimated Primary Completion Date September 2021   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: August 7, 2020)
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.
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: August 10, 2020)
  • 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
  • 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.
  • All cause mortality [ Time Frame: 90 days from enrollment ]
    Any mortality of patients enrolled within 90 days.
Original Secondary Outcome Measures  ICMJE
 (submitted: August 7, 2020)
  • Key Platform Secondary Thrombotic Endpoint [ Time Frame: 28 days from study enrollment ]
    Composite endpoint of death, deep vein thrombosis, pulmonary embolism, systemic arterial thromboembolism, myocardial infarction, or ischemic stroke at hospital discharge or 28 days, whichever occurs first
  • 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.
Current Other Pre-specified Outcome Measures
 (submitted: August 7, 2020)
  • Primary Safety Endpoint of Major Bleeding [ Time Frame: 28 days from study enrollment ]
    Major bleeding (as defined by the ISTH)
  • Secondary Safety Endpoint of HIT [ Time Frame: 28 days from study enrollment ]
    Confirmed heparin induced thrombocytopenia (HIT)
Original Other Pre-specified Outcome Measures Same as current
 
Descriptive Information
Brief Title  ICMJE Anti-thrombotics for Adults Hospitalized With COVID-19 (ACTIV-4)
Official Title  ICMJE A Multicenter, Adaptive, Randomized Controlled Platform Trial of the Safety and Efficacy of Antithrombotic Strategies in Hospitalized Adults With COVID-19
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
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.).

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 4
Study Design  ICMJE Allocation: Randomized
Intervention Model: Sequential Assignment
Intervention Model Description:
This is an adaptive design
Masking: None (Open Label)
Masking Description:
There will be independent masked adjudicators.
Primary Purpose: Treatment
Condition  ICMJE Covid19
Intervention  ICMJE
  • Drug: theraputic heparin
    increased dose of heparin above standard of care.
    Other Names:
    • unfractionated heparin
    • Enoxaparin
    • Dalteparin
    • Tinzaparin
    • Heparin
  • Drug: prophylactic heparin
    standard of care dose of heparin
    Other Names:
    • enoxaparin
    • dalteparin
    • Tinzaparin
    • Fondparinux
    • Heparin
  • Drug: P2Y12
    added P2Y12 inhibitor
    Other Names:
    • Ticagrelor
    • Prasugrel
    • Clopidogrel
Study Arms  ICMJE
  • Therapeutic Dose Anticoagulation

    increased dose of heparin above standard of care.

    This arm was stopped Jan 21, 2021

    Intervention: Drug: theraputic heparin
  • Prophylactic Dose Anticoagulation

    Heparin standard of care

    This arm was stopped Jan 21, 2021

    Intervention: Drug: prophylactic heparin
  • Therapeutic Dose Anticoagulation + P2Y12 inhibitor
    increased dose of heparin above standard of care with an added P2Y12 inhibitor
    Interventions:
    • Drug: theraputic heparin
    • Drug: P2Y12
  • Prophylactic Dose Anticoagulation + P2Y12 inhibitor
    Heparin standard of care with an added P2Y12 inhibitor
    Interventions:
    • Drug: prophylactic heparin
    • Drug: P2Y12
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: August 7, 2020)
2000
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE December 2021
Estimated Primary Completion Date September 2021   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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

    • Based on a recommendation from the ACTIV4 DSMB on December 19, 2020, enrollment of patients requiring ICU level of care into the therapeutic anti-coagulation arm was stopped due to meeting a futility threshold and a potential for harm for this sub-group could not be excluded. Enrollment continues for moderately ill hospitalized COVID-19 patients.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Judith Hochman, MD 212-263-6927 Judith.Hochman@nyulangone.org
Contact: Matthew Neal, MD 412-692-2850 nealm2@upmc.edu
Listed Location Countries  ICMJE Spain,   United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT04505774
Other Study ID Numbers  ICMJE ACTIV-4 ACUTE
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
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
IPD Sharing Statement  ICMJE
Plan to Share IPD: Yes
Plan Description: Data will be shared as per NIH guidelines.
Supporting Materials: Study Protocol
Supporting Materials: Statistical Analysis Plan (SAP)
Supporting Materials: Informed Consent Form (ICF)
Supporting Materials: Clinical Study Report (CSR)
Supporting Materials: Analytic Code
Responsible Party Matthew Neal MD, University of Pittsburgh
Study Sponsor  ICMJE Matthew Neal MD
Collaborators  ICMJE National Heart, Lung, and Blood Institute (NHLBI)
Investigators  ICMJE
Study Chair: Judith Hochman, MD New York University - Grossman School of Medicine
PRS Account University of Pittsburgh
Verification Date February 2021

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP