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Accelerating COVID-19 Therapeutic Interventions and Vaccines 4 ACUTE (ACTIV-4A)

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 : October 29, 2021
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 and additional strategies for prevention of adverse outcomes in COVID-19 positive inpatients

Condition or disease Intervention/treatment Phase
Covid19 Drug: theraputic heparin Drug: prophylactic heparin Drug: P2Y12 Drug: Crizanlizumab Injection Drug: SGLT2 inhibitor Phase 4

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 3000 participants
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
Official Title: A Multicenter, Adaptive, Randomized Controlled Platform Trial of the Safety and Efficacy of Antithrombotic and Additional Strategies in Hospitalized Adults With COVID-19
Actual Study Start Date : September 4, 2020
Estimated Primary Completion Date : September 2022
Estimated Study Completion Date : December 2022

Arm Intervention/treatment
Therapeutic Dose Anticoagulation

increased dose of heparin above standard of care.

1.0 - This arm was stopped in severe patients in December 2020 1.1 - this arm was stopped for moderate patients in June 2021

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

1.0 - this arm was stopped for all patients in January, 2021. 1.1 - this arm was reinstated for severe patients.

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

Therapeutic Dose Anticoagulation + P2Y12 inhibitor

increased dose of heparin above standard of care with an added P2Y12 inhibitor

This Arm enrolled moderate illness patients only. Enrollment of moderate illness patients in the trial was ended per DSMB on June 19, 2021.

Drug: theraputic heparin
increased dose of heparin above standard of care.
Other Names:
  • unfractionated heparin
  • Enoxaparin
  • Dalteparin
  • Tinzaparin
  • Heparin

Drug: P2Y12
added P2Y12 inhibitor
Other Names:
  • Ticagrelor
  • Prasugrel
  • Clopidogrel

Prophylactic Dose Anticoagulation + P2Y12 inhibitor

Heparin standard of care with an added P2Y12 inhibitor

This Arm enrolled severe illness patients only.

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

Standard of Care + Crizanlizumab

Standard of care plus crizanlizumab infusion

This arm will enroll moderate and severe illness patients

Drug: Crizanlizumab Injection
crizanlizumab injection

Standard of Care + SGLT2 inhibitor

Standard of care plus SGLT2 inhibitor

This arm will enroll moderate and severe illness patients

Drug: SGLT2 inhibitor
sglt2 inhibitor
Other Names:
  • dapagliflozin
  • empagliflozin
  • canagliflozin
  • ertugliflozin




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. Secondary Endpoint all cause mortality [ Time Frame: 28 days from study enrollment ]
    Categorization of the primary endpoint into a three-level ordinal outcome (Death, invasive mechanical ventilation without death, neither invasive mechanical ventilation nor death)

  2. Other Platform Secondary Endpoints of Morbidity and Hospitalization [ Time Frame: 28 days from study enrollment ]
    Categorization of the primary endpoint into a three-level ordinal outcome (Death, organ support (any respiratory or cardiovascular) without death, neither organ support nor death) (for moderate illness severity at enrollment)

  3. Days free of death [ Time Frame: 28 days from enrollment ]
    Days free of death and respiratory and cardiovascular organ support and renal replacement therapy (RRT) during Index Hospitalization through Day 28.

  4. Death Composite [ Time Frame: 28 days from enrollment ]
    Composite endpoint of death, pulmonary embolism, systemic arterial thromboembolism, myocardial infarction, or ischemic stroke at hospital discharge or 28 days, whichever occurs first.

  5. Acute kidney injury [ Time Frame: 90 days from enrollment ]
    Individual endpoints comprising the primary and secondary endpoint components; death during hospitalization, WHO clinical scale and 90 day mortality


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

Inclusion Criteria for Arm E

Inclusion criteria contained in the master protocol in addition to the following:

Moderate illness severity - defined as non-ICU level of care at the time of randomization (not receiving high flow nasal oxygen (HFNO), non-invasive ventilation (NIV), invasive ventilation (IV), vasopressors or inotropes, or extracorporeal membrane oxygenation (ECMO) OR Severe illness severity - defined as ICU level of care at the time of randomization (receiving HFNO, NIV, IV, vasopressors or inotropes, or ECMO)

For moderate illness severity, participants are required to meet one or more of the following risk criteria:

  1. Age ≥ 65 years or
  2. ≥2 of the following -

    • O2 supplementation > 2 liters per minute
    • BMI ≥ 35
    • GFR ≤ 60
    • History of Type 2 diabetes
    • History of heart failure (regardless of ejection fraction)
    • D dimer ≥ 2x the site's upper limit of normal (ULN)
    • Troponin ≥ 2x the site's ULN
    • BNP≥100 pg/mL or NT-proBNP≥300 pg/mL
    • CRP ≥50 mg/L

Exclusion Criteria for Arm E

  • Exclusion criteria contained in the master protocol, and
  • Any condition that, in the opinion of the investigator, precludes the use of crizanlizumab such as uncontrolled bleeding or severe anemia (hemoglobin<4 g/dL)
  • Open label treatment with crizanlizumab within the past three months

Inclusion Criteria for Arm F

Inclusion criteria contained in the master protocol in addition to the following:

Moderate illness severity - defined as non-ICU level of care at the time of randomization (not receiving high flow nasal oxygen (HFNO), non-invasive ventilation (NIV), invasive ventilation (IV), vasopressors or inotropes, or extracorporeal membrane oxygenation (ECMO)) OR Severe illness severity - defined as ICU level of care at the time of randomization (receiving HFNO, NIV, IV, vasopressors or inotropes, or ECMO)

For moderate illness severity, participants are required to meet one or more of the following risk criteria:

  1. Age ≥ 65 years or
  2. ≥2 of the following-

    • O2 supplementation > 2 liters per minute
    • BMI ≥ 35
    • GFR ≤ 60
    • History of Type 2 diabetes
    • History of heart failure (regardless of ejection fraction)
    • D dimer ≥ 2x the site's upper limit of normal (ULN)
    • Troponin ≥ 2x the site's ULN
    • BNP≥100 pg/mL or NT-proBNP≥300 pg/mL
    • CRP ≥50 mg/L

Exclusion Criteria for Arm F

In addition to the exclusion criteria noted in the master protocol, arm-specific exclusion criteria are as follows:

  • Known hypersensitivity to any SGLT2 inhibitors
  • Type 1 diabetes
  • History of diabetic ketoacidosis
  • eGFR <20 and/or requirement for renal replacement therapy
  • Open label treatment with any SGLT2 inhibitor

    • 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.
    • Based on a recommendation from the ACTIV4 DSMB on June 18, 2021, enrollment of patients not requiring ICU level of care and randomized to P2Y12 or standard care was stopped due to meeting a futility threshold. Enrollment continues for severely ill (ICU level of care) hospitalized COVID-19 patients.

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 212-263-6927 Judith.Hochman@nyulangone.org
Contact: Matthew Neal, MD 412-692-2850 nealm2@upmc.edu

Locations
Show Show 102 study locations
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
Principal Investigator: Scott Solomon, MD Brigham and Women's Hospital
Principal Investigator: Mikhail Kosiborod, MD Saint Lukes
Principal Investigator: Jeffrey Berger, 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.
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.
Leucker TM, Osburn WO, Reventum P, Smith K, Claggett B, Kirwan BA, de Brouwer S, Williams MS, Gerstenblith G, Hager DN, Streiff MB, Solomon SD, Lowenstein CJ. Effect of crizanlizumab, a P-selectin inhibitor, in COVID-19: A randomized controlled trial. JACC Basic Trans Sci. In Press

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
REMAP-CAP Investigators; ACTIV-4a Investigators; ATTACC Investigators, Goligher EC, Bradbury CA, McVerry BJ, Lawler PR, Berger JS, Gong MN, Carrier M, Reynolds HR, Kumar A, Turgeon AF, Kornblith LZ, Kahn SR, Marshall JC, Kim KS, Houston BL, Derde LPG, Cushman M, Tritschler T, Angus DC, Godoy LC, McQuilten Z, Kirwan BA, Farkouh ME, Brooks MM, Lewis RJ, Berry LR, Lorenzi E, Gordon AC, Ahuja T, Al-Beidh F, Annane D, Arabi YM, Aryal D, Baumann Kreuziger L, Beane A, Bhimani Z, Bihari S, Billett HH, Bond L, Bonten M, Brunkhorst F, Buxton M, Buzgau A, Castellucci LA, Chekuri S, Chen JT, Cheng AC, Chkhikvadze T, Coiffard B, Contreras A, Costantini TW, de Brouwer S, Detry MA, Duggal A, Džavík V, Effron MB, Eng HF, Escobedo J, Estcourt LJ, Everett BM, Fergusson DA, Fitzgerald M, Fowler RA, Froess JD, Fu Z, Galanaud JP, Galen BT, Gandotra S, Girard TD, Goodman AL, Goossens H, Green C, Greenstein YY, Gross PL, Haniffa R, Hegde SM, Hendrickson CM, Higgins AM, Hindenburg AA, Hope AA, Horowitz JM, Horvat CM, Huang DT, Hudock K, Hunt BJ, Husain M, Hyzy RC, Jacobson JR, Jayakumar D, Keller NM, Khan A, Kim Y, Kindzelski A, King AJ, Knudson MM, Kornblith AE, Kutcher ME, Laffan MA, Lamontagne F, Le Gal G, Leeper CM, Leifer ES, Lim G, Gallego Lima F, Linstrum K, Litton E, Lopez-Sendon J, Lother SA, Marten N, Saud Marinez A, Martinez M, Mateos Garcia E, Mavromichalis S, McAuley DF, McDonald EG, McGlothlin A, McGuinness SP, Middeldorp S, Montgomery SK, Mouncey PR, Murthy S, Nair GB, Nair R, Nichol AD, Nicolau JC, Nunez-Garcia B, Park JJ, Park PK, Parke RL, Parker JC, Parnia S, Paul JD, Pompilio M, Quigley JG, Rosenson RS, Rost NS, Rowan K, Santos FO, Santos M, Santos MO, Satterwhite L, Saunders CT, Schreiber J, Schutgens REG, Seymour CW, Siegal DM, Silva DG Jr, Singhal AB, Slutsky AS, Solvason D, Stanworth SJ, Turner AM, van Bentum-Puijk W, van de Veerdonk FL, van Diepen S, Vazquez-Grande G, Wahid L, Wareham V, Widmer RJ, Wilson JG, Yuriditsky E, Zhong Y, Berry SM, McArthur CJ, Neal MD, Hochman JS, Webb SA, Zarychanski R. Therapeutic Anticoagulation with Heparin in Critically Ill Patients with Covid-19. N Engl J Med. 2021 Aug 26;385(9):777-789. doi: 10.1056/NEJMoa2103417. Epub 2021 Aug 4.
ATTACC Investigators; ACTIV-4a Investigators; REMAP-CAP Investigators, Lawler PR, Goligher EC, Berger JS, Neal MD, McVerry BJ, Nicolau JC, Gong MN, Carrier M, Rosenson RS, Reynolds HR, Turgeon AF, Escobedo J, Huang DT, Bradbury CA, Houston BL, Kornblith LZ, Kumar A, Kahn SR, Cushman M, McQuilten Z, Slutsky AS, Kim KS, Gordon AC, Kirwan BA, Brooks MM, Higgins AM, Lewis RJ, Lorenzi E, Berry SM, Berry LR, Aday AW, Al-Beidh F, Annane D, Arabi YM, Aryal D, Baumann Kreuziger L, Beane A, Bhimani Z, Bihari S, Billett HH, Bond L, Bonten M, Brunkhorst F, Buxton M, Buzgau A, Castellucci LA, Chekuri S, Chen JT, Cheng AC, Chkhikvadze T, Coiffard B, Costantini TW, de Brouwer S, Derde LPG, Detry MA, Duggal A, Džavík V, Effron MB, Estcourt LJ, Everett BM, Fergusson DA, Fitzgerald M, Fowler RA, Galanaud JP, Galen BT, Gandotra S, García-Madrona S, Girard TD, Godoy LC, Goodman AL, Goossens H, Green C, Greenstein YY, Gross PL, Hamburg NM, Haniffa R, Hanna G, Hanna N, Hegde SM, Hendrickson CM, Hite RD, Hindenburg AA, Hope AA, Horowitz JM, Horvat CM, Hudock K, Hunt BJ, Husain M, Hyzy RC, Iyer VN, Jacobson JR, Jayakumar D, Keller NM, Khan A, Kim Y, Kindzelski AL, King AJ, Knudson MM, Kornblith AE, Krishnan V, Kutcher ME, Laffan MA, Lamontagne F, Le Gal G, Leeper CM, Leifer ES, Lim G, Lima FG, Linstrum K, Litton E, Lopez-Sendon J, Lopez-Sendon Moreno JL, Lother SA, Malhotra S, Marcos M, Saud Marinez A, Marshall JC, Marten N, Matthay MA, McAuley DF, McDonald EG, McGlothlin A, McGuinness SP, Middeldorp S, Montgomery SK, Moore SC, Morillo Guerrero R, Mouncey PR, Murthy S, Nair GB, Nair R, Nichol AD, Nunez-Garcia B, Pandey A, Park PK, Parke RL, Parker JC, Parnia S, Paul JD, Pérez González YS, Pompilio M, Prekker ME, Quigley JG, Rost NS, Rowan K, Santos FO, Santos M, Olombrada Santos M, Satterwhite L, Saunders CT, Schutgens REG, Seymour CW, Siegal DM, Silva DG Jr, Shankar-Hari M, Sheehan JP, Singhal AB, Solvason D, Stanworth SJ, Tritschler T, Turner AM, van Bentum-Puijk W, van de Veerdonk FL, van Diepen S, Vazquez-Grande G, Wahid L, Wareham V, Wells BJ, Widmer RJ, Wilson JG, Yuriditsky E, Zampieri FG, Angus DC, McArthur CJ, Webb SA, Farkouh ME, Hochman JS, Zarychanski R. Therapeutic Anticoagulation with Heparin in Noncritically Ill Patients with Covid-19. N Engl J Med. 2021 Aug 26;385(9):790-802. doi: 10.1056/NEJMoa2105911. Epub 2021 Aug 4.

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Responsible Party: Matthew Neal MD, MD, University of Pittsburgh
ClinicalTrials.gov Identifier: NCT04505774    
Obsolete Identifiers: NCT04359277
Other Study ID Numbers: ACTIV-4 ACUTE
1OT2HL156812-01 ( U.S. NIH Grant/Contract )
First Posted: August 10, 2020    Key Record Dates
Last Update Posted: October 29, 2021
Last Verified: October 2021
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
p2y12
endothelial dysfunction
vascular integrity
P-selectin
crizanlizumab
SGLT-2 inhibitor
Additional relevant MeSH terms:
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COVID-19
Respiratory Tract Infections
Infections
Pneumonia, Viral
Pneumonia
Virus Diseases
Coronavirus Infections
Coronaviridae Infections
Nidovirales Infections
RNA Virus Infections
Lung Diseases
Respiratory Tract Diseases
Dapagliflozin
Empagliflozin
Canagliflozin
Ertugliflozin
Sodium-Glucose Transporter 2 Inhibitors
Heparin
Calcium heparin
Enoxaparin
Dalteparin
Tinzaparin
Heparin, Low-Molecular-Weight
Enoxaparin sodium
Clopidogrel
Ticagrelor
Platelet Aggregation Inhibitors
Purinergic P2Y Receptor Antagonists
Purinergic P2 Receptor Antagonists
Purinergic Antagonists