Full Dose Heparin Vs. Prophylactic Or Intermediate Dose Heparin in High Risk COVID-19 Patients

NCT04401293 | Completed Phase 3 Results DMC FDA Drug

• 1 other identifier: 20-0340
• Study Type: interventional
• Target: 257
• Locations: 1 country
• Sites: 6

Brief Summary

The aim of this study is to test the hypothesis that prophylaxis of severe COVID-19 patients with treatment dose LMWH leads to better thromboembolic-free outcomes and associated complications during hospitalization than prophylaxis with institutional standard of care with prophylactic to intermediate-doses of UFH or LMWH

Conditions

Sars-CoV2; COVID

Keywords

COVID-19; Anticoagulation; Heparin; Coronavirus; Thrombosis

Outcome Measures

Primary Outcomes (1)

• Composite Outcome of Arterial Thromboembolic Events, Venous Thromboembolic Events and All-cause Mortality at Day 30 ± 2 Days.

  Risk of arterial thromboembolic events (including myocardial infarction, stroke, systemic embolism), venous thromboembolism (including symptomatic deep vein thrombosis (DVT) of the upper or lower extremity, asymptomatic proximal DVT of the lower extremity, non-fatal pulmonary embolism (PE)), and all-cause mortality at Day 30 ± 2 days.

  Day 30 ± 2 days

Secondary Outcomes (6)

• Major Bleeding

  Day 30 ± 2 days

• Composite Outcome of Arterial Thromboembolic Events, Venous Thromboembolic Events and All-cause Mortality at Hospital Day 10 + 4

  Day 10 + 4

• Sepsis-induced Coagulopathy (SIC) Score

  Day 30 ± 2 days.

• Progression to Acute Respiratory Distress Syndrome (ARDS)

  Day 30 ± 2 days.

• Need for Intubation

  Day 30 ± 2 days.

Study Arms (2)

Full Dose LMWH anticoagulation therapy

EXPERIMENTAL

Subjects in this study arm will be treated with therapeutic doses of subcutaneous low-molecular-weight heparin (enoxaparin). Enoxaparin 1mg/kg SQ BID for CrCl ≥ 30ml/min (or Enoxaparin 0.5mg/kg SQ BID for CrCl ≥ 15ml/min and \< 30ml/min) during the course of their hospitalization.

Drug: Enoxaparin

Prophylactic/Intermediate Dose LMWH or UFH therapy

ACTIVE COMPARATOR

Subjects in this study arm will be treated with Local institutional standard-of-care for prophylactic-dose or intermediate-dose UFH or LMWH. Regimens allowed are UFH up to 22,500 IU daily in BID or TID doses (i.e. UFH 5000 IU SQ BID/TID or 7500 IU BID/TID), enoxaparin 30mg and 40mg SQ QD or BID (the use of weight-based enoxaparin i.e. 0.5mg/kg SQ BID for this arm is acceptable but strongly discouraged), dalteparin 2500IU or 5000IU QD.

Drug: Prophylactic/Intermediate Dose Enoxaparin

Interventions

Enoxaparin DRUG

Full Dose LMWH anticoagulation therapy

Full Dose LMWH anticoagulation therapy

Prophylactic/Intermediate Dose Enoxaparin DRUG

Prophylactic/Intermediate Dose LMWH or UFH therapy

Also known as: Unfractionated heparin, dalteparin

Prophylactic/Intermediate Dose LMWH or UFH therapy

Eligibility Criteria

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

You may qualify if:

• Subject (or legally authorized representative) provides written informed consent prior to initiation of any study procedures.
• Understands and agrees to comply with planned study procedures.
• Male or non-pregnant female adult ≥18 years of age at time of enrollment.
• Subject consents to randomization within 72 hours of hospital admission or transfer from another facility within 72 hours of index presentation.
• Subjects with a positive COVID-19 diagnosis by nasal swab or serologic testing.
• Hospitalized with a requirement for supplemental oxygen.
• Have:
• Either a D- Dimer \> 4.0 X ULN, OR
• Sepsis-induced coagulopathy (SIC) score of ≥4

You may not qualify if:

• Indications for therapeutic anticoagulation
• Absolute contraindication to anticoagulation including:
• active bleeding,
• recent (within 1 month) history of bleed,
• dual (but not single) antiplatelet therapy,
• active gastrointestinal and intracranial cancer,
• a history of bronchiectasis or pulmonary cavitation,
• Hepatic failure with a baseline INR \> 1.5,
• CrCl \< 15ml/min,
• a platelet count \< 25,000,
• a history of heparin-induced thrombocytopenia (HIT) within the past 100 days or in the presence of circulating antibodies,
• contraindications to enoxaparin including a hypersensitivity to enoxaparin sodium, hypersensitivity to heparin or pork products, hypersensitivity to benzyl alcohol,
• pregnant female,
• inability to give or designate to give informed consent,
• participation in another blinded trial of investigational drug therapy for COVID-19

Sponsors & Collaborators

• Northwell Health: lead

Study Sites (6)

Beth Israel Newark

Newark, New Jersey, 07112, United States

Location

Southside Hospital

Bay Shore, New York, 11706, United States

Location

Huntington Hospital

Huntington, New York, 11743, United States

Location

Lenox Hill Hospital

New York, New York, 10075, United States

Location

Long Island Jewish Medical Center

Queens, New York, 11040, United States

Location

Staten Island University Hospital

Staten Island, New York, 10309, United States

Location

Related Publications (5)

• Santos BC, Flumignan RL, Civile VT, Atallah AN, Nakano LC. Prophylactic anticoagulants for non-hospitalised people with COVID-19. Cochrane Database Syst Rev. 2023 Aug 16;8(8):CD015102. doi: 10.1002/14651858.CD015102.pub2.

  PMID: 37591523 DERIVED

• 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

• Spyropoulos AC, Goldin M, Giannis D, Diab W, Wang J, Khanijo S, Mignatti A, Gianos E, Cohen M, Sharifova G, Lund JM, Tafur A, Lewis PA, Cohoon KP, Rahman H, Sison CP, Lesser ML, Ochani K, Agrawal N, Hsia J, Anderson VE, Bonaca M, Halperin JL, Weitz JI; HEP-COVID Investigators. Efficacy and Safety of Therapeutic-Dose Heparin vs Standard Prophylactic or Intermediate-Dose Heparins for Thromboprophylaxis in High-risk Hospitalized Patients With COVID-19: The HEP-COVID Randomized Clinical Trial. JAMA Intern Med. 2021 Dec 1;181(12):1612-1620. doi: 10.1001/jamainternmed.2021.6203.

  PMID: 34617959 DERIVED

• Short SAP, Gupta S, Brenner SK, Hayek SS, Srivastava A, Shaefi S, Singh H, Wu B, Bagchi A, Al-Samkari H, Dy R, Wilkinson K, Zakai NA, Leaf DE; STOP-COVID Investigators. d-dimer and Death in Critically Ill Patients With Coronavirus Disease 2019. Crit Care Med. 2021 May 1;49(5):e500-e511. doi: 10.1097/CCM.0000000000004917.

  PMID: 33591017 DERIVED

• Flumignan RL, Tinoco JDS, Pascoal PI, Areias LL, Cossi MS, Fernandes MI, Costa IK, Souza L, Matar CF, Tendal B, Trevisani VF, Atallah AN, Nakano LC. Prophylactic anticoagulants for people hospitalised with COVID-19. Cochrane Database Syst Rev. 2020 Oct 2;10(10):CD013739. doi: 10.1002/14651858.CD013739.

  PMID: 33502773 DERIVED

Related Links

• Cardiovascular Considerations for Patients, Health Care Workers, and Health Systems During the Coronavirus Disease 2019 (COVID-19) Pandemic
• Empirical systemic anticoagulation is associated with decreased venous thromboembolism in critically ill influenza A H1N1 acute respiratory distress syndrome patients
• Abnormal coagulation parameters are associated with poor prognosis in patients with novel coronavirus pneumonia
• Anticoagulant treatment is associated with decreased mortality in severe coronavirus disease 2019 patients with coagulopathy
• Prevalence of venous thromboembolism in patients with severe novel coronavirus pneumonia
• Tissue Plasminogen Activator (tPA) Treatment for COVID-19 Associated Acute Respiratory Distress Syndrome (ARDS): A Case Series
• Pharmacology of Heparin and Related Drugs
• Incidence of thrombotic complications in critically ill ICU patients with COVID-19
• Bivalirudin or Heparin in Patients Undergoing Invasive Management of Acute Coronary Syndromes
• Emergence of Institutional Antithrombotic Protocols for Coronavirus 2019

MeSH Terms

Conditions

COVID-19; Coronavirus Infections; Thrombosis

Interventions

Enoxaparin; Heparin; Dalteparin

Condition Hierarchy (Ancestors)

Pneumonia, Viral; Pneumonia; Respiratory Tract Infections; Infections; Virus Diseases; Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Lung Diseases; Respiratory Tract Diseases; Embolism and Thrombosis; Vascular Diseases; Cardiovascular Diseases

Intervention Hierarchy (Ancestors)

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

Results Point of Contact

• Title: Alex Spyropoulos, MD
• Organization: System Director - Anticoagulation and Clinical Thrombosis Services Northwell Health at Lenox Hill Hospital Affiliation: Northwell Health

aspyropoul@northwell.edu

(212) 434-6776

Study Officials

• Alex C Spyropoulos, MD

  Northwell Health

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR
• Masking Details: Due to the pragmatic nature of this study "open-label multi-center randomized active control trial" with pseudo-blinding mechanisms at the time of randomization the study subject and corresponding Site PIs will be blinded (unaware of specific treatment arm the patient is assigned to i.e. Arm 0 or Arm 1). The study pharmacists as well as data extractors and designated randomization personnel (i.e. research coordinators and/or research nurses performing the randomization process) will be un-blinded (aware of specific treatment arm the patient is assigned to i.e. Arm 0 or Arm 1). At the time of subject randomization study subjects will be stratified to either ICU level of care vs. Non-ICU level of care.
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: System Director - Anticoagulation and Clinical Thrombosis Services Northwell Health at Lenox Hill Hospital

Study Record Dates

• First Submitted: May 20, 2020
• First Posted: May 26, 2020
• Study Start: April 26, 2020
• Primary Completion: May 14, 2021
• Study Completion: May 14, 2021
• Last Updated: November 22, 2021
• Results First Posted: November 22, 2021

Record last verified: 2021-11

Data Sharing

• IPD Sharing: Will not share

Locations

US (6)