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

NCT04406389 | Terminated Phase 4 Results DMC FDA Drug

• 1 other identifier: 20-04021936
• Study Type: interventional
• Target: 14
• Locations: 1 country
• Sites: 2

Brief Summary

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.

Conditions

COVID-19

Keywords

COVID-19; Anticoagulation

Outcome Measures

Primary Outcomes (1)

• 30-day Mortality

  Comparison of number of COVID-19 positive patients who have died within 30 days of starting treatment on each treatment arm

  30 days

Secondary Outcomes (3)

• Length of Intensive Care Unit (ICU) Stay in Days

  6 months

• Number of Documented Venous Thromboembolism (VTE), Arterial Thrombosis (Stroke, Myocardial Infarction, Other) and Microthrombosis Events

  6 months

• Number of Major and Clinically Relevant Non-major Bleeding Events

  6 months

Study Arms (2)

Intermediate Dose Prophylaxis

ACTIVE COMPARATOR

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

Drug: Enoxaparin sodium; Drug: Unfractionated heparin; Drug: Fondapariniux

Therapeutic Dose Anticoagulation

EXPERIMENTAL

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

Drug: Enoxaparin sodium; Drug: Unfractionated heparin; Drug: Fondapariniux; Drug: Argatroban

Interventions

Enoxaparin sodium DRUG

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

Also known as: Lovenox

Intermediate Dose Prophylaxis; Therapeutic Dose Anticoagulation

Unfractionated heparin DRUG

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

Also known as: Sodium heparin

Intermediate Dose Prophylaxis; Therapeutic Dose Anticoagulation

Fondapariniux DRUG

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

Also known as: Arixtra

Intermediate Dose Prophylaxis; Therapeutic Dose Anticoagulation

Argatroban DRUG

Therapeutic Dose Anticoagulation Arm: Dosed according to institutional protocol

Therapeutic Dose Anticoagulation

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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).

You may not qualify if:

• 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.

Sponsors & Collaborators

• Weill Medical College of Cornell University: lead

Study Sites (2)

New York Presbyterian Brooklyn Methodist Hospital

Brooklyn, New York, 11215, United States

Location

Weill Cornell Medicine

New York, New York, 10065, United States

Location

Related Publications (16)

• 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.

  PMID: 32073213 BACKGROUND

• 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.

  PMID: 32220112 BACKGROUND

• 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. No abstract available.

  PMID: 32186331 BACKGROUND

• Young E. The anti-inflammatory effects of heparin and related compounds. Thromb Res. 2008;122(6):743-52. doi: 10.1016/j.thromres.2006.10.026. Epub 2007 Aug 28.

  PMID: 17727922 BACKGROUND

• 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.

  PMID: 24336942 BACKGROUND

• 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.

  PMID: 27975101 BACKGROUND

• 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.

  PMID: 27969572 BACKGROUND

• 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. No abstract available.

  PMID: 32239799 BACKGROUND

• 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.

  PMID: 32271988 BACKGROUND

• 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.

  PMID: 32291094 BACKGROUND

• 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. doi: 10.1111/j.1538-7836.2005.01204.x.

  PMID: 15842354 BACKGROUND

• 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, Angles-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.

  PMID: 32367170 BACKGROUND

• Middeldorp S, Coppens M, van Haaps TF, Foppen M, Vlaar AP, Muller 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 Aug;18(8):1995-2002. doi: 10.1111/jth.14888. Epub 2020 Jul 27.

  PMID: 32369666 BACKGROUND

• 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. No abstract available.

  PMID: 32302078 BACKGROUND

• Paranjpe I, Fuster V, Lala A, Russak AJ, 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 Jul 7;76(1):122-124. doi: 10.1016/j.jacc.2020.05.001. Epub 2020 May 6. No abstract available.

  PMID: 32387623 BACKGROUND

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

  PMID: 35244208 DERIVED

MeSH Terms

Conditions

COVID-19

Interventions

enoxaparin sodium; Enoxaparin; Heparin; Fondaparinux; argatroban

Condition Hierarchy (Ancestors)

Pneumonia, Viral; Pneumonia; Respiratory Tract Infections; Infections; Virus Diseases; Coronavirus Infections; Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Lung Diseases; Respiratory Tract Diseases

Intervention Hierarchy (Ancestors)

Heparin, Low-Molecular-Weight; Glycosaminoglycans; Polysaccharides; Carbohydrates; Oligosaccharides

Limitations and Caveats

The statistical analysis plan (and associated statistical power) was based on an expected sample size of 186 participants. As only 14 participants enrolled, this reduced sample size is not sufficient for the statistical analysis plan as written, and, therefore, only descriptive statistics are presented for the study.

Results Point of Contact

• Title: Dr. Maria T. DeSancho
• Organization: Weill Cornell Medicine

mtd2002@med.cornell.edu

646-962-2065

Study Officials

• Maria T DeSancho, MD, MSc

  Weill Medical College of Cornell University

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: May 26, 2020
• First Posted: May 28, 2020
• Study Start: October 13, 2020
• Primary Completion: April 17, 2021
• Study Completion: April 21, 2022
• Last Updated: September 21, 2023
• Results First Posted: September 21, 2023

Record last verified: 2023-08

Data Sharing

• IPD Sharing: Will not share

Locations

US (2)