Anticoagulation in Critically Ill Patients With COVID-19 (The IMPACT Trial)

Overview

The purpose of this study is to determine if therapeutic dose anticoagulation (experimental group) improves 30-day mortality in participants with COVID-19 compared to those patients receiving the intermediate dose prophylaxis (control group). Following screening, subjects will be randomized 1:1 to intermediate dose prophylaxis or therapeutic dose anticoagulation treatment arms.Treatment will continue for 28 days, followed by a 6 month follow-up period.

Full Title of Study: “InterMediate ProphylACtic Versus Therapeutic Dose Anticoagulation in Critically Ill Patients With COVID-19: A Prospective Randomized Study (The IMPACT Trial)”

Study Type

  • Study Type: Interventional
  • Study Design
    • Allocation: Randomized
    • Intervention Model: Parallel Assignment
    • Primary Purpose: Treatment
    • Masking: None (Open Label)
  • Study Primary Completion Date: December 2020

Interventions

  • Drug: Enoxaparin sodium
    • Intermediate Dose Prophylaxis Arm: 0.5 mg/kg subcutaneously every 12 hours if creatinine clearance greater than or equal to 30 ml/min –OR– 0.5 mg/kg subcutaneously every 24 hours if creatinine clearance less than 30 ml/min Therapeutic Dose Anticoagulation Arm: 1 mg/kg subcutaneously every 12 hours
  • Drug: Unfractionated heparin
    • Intermediate Dose Prophylaxis Arm: 7,500 units subcutaneously every 8 hours Therapeutic Dose Anticoagulation Arm: Dosed to target anti-Xa level 0.3 – 0.7 IU/mL or activated partial thromboplastin time (aPTT), according to institutional protocol
  • Drug: Fondapariniux
    • Intermediate Dose Prophylaxis Arm: 2.5 mg daily subcutaneously Therapeutic Dose Anticoagulation Arm: Dose by weight: If greater than or equal to 100 kg: 10 mg daily If less than 100 kg but greater than or equal to 50 kg: 7.5 mg daily If less than 50 kg: 5 mg daily
  • Drug: Argatroban
    • Therapeutic Dose Anticoagulation Arm: Dosed according to institutional protocol

Arms, Groups and Cohorts

  • Active Comparator: Intermediate Dose Prophylaxis
    • Subjects will receive one of the following interventions, at their physician’s discretion: Enoxaparin 0.5 mg/kg subcutaneously every 12 hours if creatinine clearance greater than or equal to 30 ml/min Enoxaparin 0.5 mg/kg subcutaneously every 24 hours if creatinine clearance less than 30 mL/min If patient develops acute kidney injury: unfractionated heparin 7,500 units subcutaneously every 8 hours. Fondaparinux (if history of heparin-inducted thrombocytopenia [HIT]) 2.5 mg daily subcutaneously
  • Experimental: Therapeutic Dose Anticoagulation
    • Subjects will receive one of the following interventions, at their physician’s discretion: Unfractionated heparin (UFH) to target anti-Xa level 0.3 -0.7 IU/mL or activated partial thromboplastin time (aPTT) (according to institutional protocol). Enoxaparin 1 mg/kg subcutaneously every 12 hours Argatroban (if heparin-induced thrombocytopenia [HIT]), dosed according to institutional protocol. Fondaparinux (if HIT and creatinine clearance greater than or equal to 50 ml/min) dosed by weight: ≥100 kg: 10 mg daily <100 kg but ≥50 kg: 7.5 mg daily <50 kg: 5 mg daily

Clinical Trial Outcome Measures

Primary Measures

  • 30-day mortality
    • Time Frame: 30 days
    • Comparison of number of COVID-19 positive patients who have died within 30 days of starting treatment on each treatment arm

Secondary Measures

  • Length of Intensive Care Unit (ICU) Stay in Days
    • Time Frame: 6 months
    • Comparison of length of ICU stay in days between each treatment arm.
  • Number of documented venous thromboembolism (VTE), arterial thrombosis (stroke, myocardial infarction, other) and microthrombosis events
    • Time Frame: 6 months
    • Comparison of number of documented VTE, arterial thrombosis and microthrombosis events on each treatment arm
  • Number of major and clinically relevant non-major bleeding events
    • Time Frame: 6 months
    • Comparison of major and clinically-relevant non-major bleeding events on each treatment arm, as defined by the International Society of Thrombosis and Haemostasis (ISTH) criteria.

Participating in This Clinical Trial

Inclusion Criteria

  • Age >18 years old
  • COVID-19 positive on (RT-PCR) nasopharyngeal swab, or suspected COVID-19 infection with detectable SARS-CoV-2 IgG or IgM.
  • Intensive care unit (ICU) patient or non-ICU patient on invasive mechanical ventilation, BiPAP, 100% non-rebreather mask, or high flow oxygen or supplemental oxygen of at least 4 liters per minute nasal cannula.
  • D dimer level greater than 700 ng/mL (3 times the upper limit of normal).

Exclusion Criteria

  • Objectively documented deep vein thrombosis or pulmonary embolism
  • Patients in whom there is very high suspicion for pulmonary embolism and are on full-dose anticoagulation as per the treating physician
  • Platelets <30,000 not due to disseminated intravascular coagulation (DIC), based on the International Society of Thrombosis and Haemostasis (ISTH) criteria and American Society of Hematology (ASH) Frequently Asked Questions
  • Active bleeding that poses a contraindication to therapeutic anticoagulation in the opinion of the investigator.
  • History of bleeding diathesis (e.g., hemophilia, severe von Willebrand disease, severe thrombocytopathy)
  • History of intracranial hemorrhage in the last 90 days
  • History of ischemic stroke in the past 2 weeks
  • Major neurosurgical procedure in the past 30 days
  • Cardiothoracic surgery in the past 30 days
  • Intra-abdominal surgery in the past 30 days
  • Intracranial malignancy
  • Patients who require therapeutic anticoagulation for other reasons like atrial fibrillation, deep venous thrombosis, pulmonary embolism, or antiphospholipid syndrome.

Gender Eligibility: All

Minimum Age: 18 Years

Maximum Age: N/A

Are Healthy Volunteers Accepted: No

Investigator Details

  • Lead Sponsor
    • Weill Medical College of Cornell University
  • Provider of Information About this Clinical Study
    • Sponsor
  • Overall Official(s)
    • Maria T DeSancho, MD, MSc, Principal Investigator, Weill Medical College of Cornell University
  • Overall Contact(s)
    • Maria T DeSancho, MD, MSc, 646-962-2065, mtd2002@med.cornell.edu

References

Tang N, Li D, Wang X, Sun Z. Abnormal coagulation parameters are associated with poor prognosis in patients with novel coronavirus pneumonia. J Thromb Haemost. 2020 Apr;18(4):844-847. doi: 10.1111/jth.14768. Epub 2020 Mar 13.

Tang N, Bai H, Chen X, Gong J, Li D, Sun Z. Anticoagulant treatment is associated with decreased mortality in severe coronavirus disease 2019 patients with coagulopathy. J Thromb Haemost. 2020 May;18(5):1094-1099. doi: 10.1111/jth.14817. Epub 2020 Apr 27.

Xiong TY, Redwood S, Prendergast B, Chen M. Coronaviruses and the cardiovascular system: acute and long-term implications. Eur Heart J. 2020 May 14;41(19):1798-1800. doi: 10.1093/eurheartj/ehaa231.

Young E. The anti-inflammatory effects of heparin and related compounds. Thromb Res. 2008;122(6):743-52. Epub 2007 Aug 28. Review.

Esmon CT. Targeting factor Xa and thrombin: impact on coagulation and beyond. Thromb Haemost. 2014 Apr 1;111(4):625-33. doi: 10.1160/TH13-09-0730. Epub 2013 Dec 12. Review.

Poterucha TJ, Libby P, Goldhaber SZ. More than an anticoagulant: Do heparins have direct anti-inflammatory effects? Thromb Haemost. 2017 Feb 28;117(3):437-444. doi: 10.1160/TH16-08-0620. Epub 2016 Dec 15. Review.

Hanify JM, Dupree LH, Johnson DW, Ferreira JA. Failure of chemical thromboprophylaxis in critically ill medical and surgical patients with sepsis. J Crit Care. 2017 Feb;37:206-210. doi: 10.1016/j.jcrc.2016.10.002. Epub 2016 Oct 11.

Thachil J. The versatile heparin in COVID-19. J Thromb Haemost. 2020 May;18(5):1020-1022. doi: 10.1111/jth.14821. Epub 2020 Apr 27.

Cui S, Chen S, Li X, Liu S, Wang F. Prevalence of venous thromboembolism in patients with severe novel coronavirus pneumonia. J Thromb Haemost. 2020 Jun;18(6):1421-1424. doi: 10.1111/jth.14830. Epub 2020 May 6.

Klok FA, Kruip MJHA, van der Meer NJM, Arbous MS, Gommers DAMPJ, Kant KM, Kaptein FHJ, van Paassen J, Stals MAM, Huisman MV, Endeman H. Incidence of thrombotic complications in critically ill ICU patients with COVID-19. Thromb Res. 2020 Jul;191:145-147. doi: 10.1016/j.thromres.2020.04.013. Epub 2020 Apr 10.

Schulman S, Kearon C; Subcommittee on Control of Anticoagulation of the Scientific and Standardization Committee of the International Society on Thrombosis and Haemostasis. Definition of major bleeding in clinical investigations of antihemostatic medicinal products in non-surgical patients. J Thromb Haemost. 2005 Apr;3(4):692-4.

Helms J, Tacquard C, Severac F, Leonard-Lorant I, Ohana M, Delabranche X, Merdji H, Clere-Jehl R, Schenck M, Fagot Gandet F, Fafi-Kremer S, Castelain V, Schneider F, Grunebaum L, Anglés-Cano E, Sattler L, Mertes PM, Meziani F; CRICS TRIGGERSEP Group (Clinical Research in Intensive Care and Sepsis Trial Group for Global Evaluation and Research in Sepsis). High risk of thrombosis in patients with severe SARS-CoV-2 infection: a multicenter prospective cohort study. Intensive Care Med. 2020 Jun;46(6):1089-1098. doi: 10.1007/s00134-020-06062-x. Epub 2020 May 4.

Middeldorp S, Coppens M, van Haaps TF, Foppen M, Vlaar AP, Müller MCA, Bouman CCS, Beenen LFM, Kootte RS, Heijmans J, Smits LP, Bonta PI, van Es N. Incidence of venous thromboembolism in hospitalized patients with COVID-19. J Thromb Haemost. 2020 May 5. doi: 10.1111/jth.14888. [Epub ahead of print]

Goyal P, Choi JJ, Pinheiro LC, Schenck EJ, Chen R, Jabri A, Satlin MJ, Campion TR Jr, Nahid M, Ringel JB, Hoffman KL, Alshak MN, Li HA, Wehmeyer GT, Rajan M, Reshetnyak E, Hupert N, Horn EM, Martinez FJ, Gulick RM, Safford MM. Clinical Characteristics of Covid-19 in New York City. N Engl J Med. 2020 Jun 11;382(24):2372-2374. doi: 10.1056/NEJMc2010419. Epub 2020 Apr 17.

Paranjpe I, Fuster V, Lala A, Russak A, Glicksberg BS, Levin MA, Charney AW, Narula J, Fayad ZA, Bagiella E, Zhao S, Nadkarni GN. Association of Treatment Dose Anticoagulation with In-Hospital Survival Among Hospitalized Patients with COVID-19. J Am Coll Cardiol. 2020 May 5. pii: S0735-1097(20)35218-9. doi: 10.1016/j.jacc.2020.05.001. [Epub ahead of print]

Clinical trials entries are delivered from the US National Institutes of Health and are not reviewed separately by this site. Please see the identifier information above for retrieving further details from the government database.

At TrialBulletin.com, we keep tabs on over 200,000 clinical trials in the US and abroad, using medical data supplied directly by the US National Institutes of Health. Please see the About and Contact page for details.