High Versus Low LMWH Dosages in Hospitalized Patients With Severe COVID-19 Pneumonia and Coagulopathy

NCT04408235 | Unknown Phase 3 DMC

• 1 other identifier: EudraCT N°: 2020-001972-13
• Study Type: interventional
• Target: 300
• Locations: 1 country
• Sites: 1

Brief Summary

Randomized, controlled study conducted in hospitalized patients with severe COViD-19 pneumonia and coagulopathy not requiring invasive mechanical ventilation. Aim of this study is to assess whether high doses of Low Molecular Weight Heparin (LMWH) (ie. Enoxaparin 70 IU/kg twice daily) compared to standard prophylactic dose (ie, Enoxaparin 4000 IU once day) are:

1. 1.More effective to prevent clinical worsening, defined as the occurrence of at least one of the following events, whichever comes first, during hospital stay:
2. 2.Death
3. 3.Acute Myocardial Infarction \[AMI\]
4. 4.Objectively confirmed, symptomatic arterial or venous thromboembolism \[TE\]
5. 5.Need for either non-invasive - Continuous Positive Airway Pressure (Cpap) or Non-Invasive Ventilation (NIV) - or invasive mechanical ventilation for patients who are in standard oxygen therapy by delivery interfaces at randomisation
6. 6.Need for invasive mechanical ventilation for patients who are in non-invasive mechanical ventilation at randomisation
7. 7.Similar in terms of major bleeding risk during hospital stay

Conditions

COVID; Pneumonia, Viral; Coagulation Disorder

Keywords

COVID-19; PNEUMONIA; COAGULOPATHY; LOW-MOLECULAR WEIGHT HEPARIN; ENOXAPARIN

Outcome Measures

Primary Outcomes (1)

• Clinical worsening, defined as the occurrence of at least one of the following events, whichever comes first:

  1. Death 2. Acute Myocardial Infarction \[AMI\] 3. Objectively confirmed, symptomatic arterial or venous thromboembolism \[TE\] 4. Need for either non-invasive - Continuous Positive Airway Pressure (Cpap) or Non-Invasive Ventilation (NIV) - or invasive mechanical ventilation for patients, who are in standard oxygen therapy by delivery interfaces at randomisation 5. Need for invasive mechanical ventilation for patients, who are in non-invasive mechanical ventilation at randomisation

  through study completion, up to 30 days

Secondary Outcomes (2)

• Any of the following events occurring within the hospital stay

  through study completion, up to 30 days

• Mortality at 30 days

  30 days

Study Arms (2)

Low-Dose LMWH

ACTIVE COMPARATOR

Enoxaparin 4000 IU daily

Drug: Enoxaparin

High-Dose LMWH

EXPERIMENTAL

Enoxaparin 70 IU/kg twice daily

Drug: Enoxaparin

Interventions

Enoxaparin DRUG

Low-Dose LMWH: enoxaparin 4000 IU daily; High dose LMWH: 70 IU/kg twice daily

Also known as: Inhixa®

High-Dose LMWH; Low-Dose LMWH

Eligibility Criteria

• Age: 18 Years - 80 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Positive SARS-CoV-2 diagnostic (on pharyngeal swab of deep airways material)
• Severe pneumonia defined by the presence of at least one of the following criteria:
• Respiratory Rate ≥25 breaths /min
• Arterial oxygen saturation≤93% at rest on ambient air
• PaO2/FiO2 ≤300 mmHg
• Coagulopathy, defined by the presence of at least one of the following criteria:
• D-dimer \>4 times the upper level of normal reference range
• Sepsis-Induced Coagulopathy (SIC) score \>4
• No need for invasive mechanical ventilation

You may not qualify if:

• Invasive mechanical ventilation
• Thrombocytopenia (platelet count \< 80.000 mm3)
• Coagulopathy: INR \>1.5, aPTT ratio \> 1.4
• Impaired renal function (eGFR calculated by CKD-EPI Creatinine equation \< 30 ml/min)
• Known hypersensitivity to enoxaparin
• History of heparin induced thrombocytopenia
• Presence of an active bleeding or a pathology susceptible of bleeding in presence of anticoagulation (e.g. recent haemorrhagic stroke, peptic ulcer, malignant cancer at high risk of haemorrhage, recent neurosurgery or ophthalmic surgery, vascular aneurysms, arteriovenous malformations)
• Concomitant anticoagulant treatment for other indications (e.g. atrial fibrillation, venous thromboembolism, prosthetic heart valves).
• Concomitant double antiplatelet therapy
• Administration of therapeutic doses of LMWH, fondaparinux, or unfractionated heparin (UFH) for more than 72 hours before randomization; prophylactic doses are allowed
• Pregnancy or breastfeeding or positive pregnancy test
• Presence of other severe diseases impairing life expectancy (e.g. patients are not expected to survive 28 days given their pre-existing medical condition)
• Lack or withdrawal of informed consent

Sponsors & Collaborators

• Azienda Ospedaliero-Universitaria di Modena: lead

Study Sites (1)

Azienda Ospedaliero-Universitaria

Modena, 41124, Italy

Location

Related Publications (9)

• Wu C, Chen X, Cai Y, Xia J, Zhou X, Xu S, Huang H, Zhang L, Zhou X, Du C, Zhang Y, Song J, Wang S, Chao Y, Yang Z, Xu J, Zhou X, Chen D, Xiong W, Xu L, Zhou F, Jiang J, Bai C, Zheng J, Song Y. Risk Factors Associated With Acute Respiratory Distress Syndrome and Death in Patients With Coronavirus Disease 2019 Pneumonia in Wuhan, China. JAMA Intern Med. 2020 Jul 1;180(7):934-943. doi: 10.1001/jamainternmed.2020.0994.

  PMID: 32167524 BACKGROUND

• Leisman DE, Deutschman CS, Legrand M. Facing COVID-19 in the ICU: vascular dysfunction, thrombosis, and dysregulated inflammation. Intensive Care Med. 2020 Jun;46(6):1105-1108. doi: 10.1007/s00134-020-06059-6. Epub 2020 Apr 28. No abstract available.

  PMID: 32347323 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

• 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

• Marietta M, Ageno W, Artoni A, De Candia E, Gresele P, Marchetti M, Marcucci R, Tripodi A. COVID-19 and haemostasis: a position paper from Italian Society on Thrombosis and Haemostasis (SISET). Blood Transfus. 2020 May;18(3):167-169. doi: 10.2450/2020.0083-20. Epub 2020 Apr 8. No abstract available.

  PMID: 32281926 BACKGROUND

• Thachil J, Tang N, Gando S, Falanga A, Cattaneo M, Levi M, Clark C, Iba T. ISTH interim guidance on recognition and management of coagulopathy in COVID-19. J Thromb Haemost. 2020 May;18(5):1023-1026. doi: 10.1111/jth.14810. Epub 2020 Apr 27. No abstract available.

  PMID: 32338827 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

• 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

• 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

MeSH Terms

Conditions

Pneumonia, Viral; Hemostatic Disorders; COVID-19; Pneumonia

Interventions

Enoxaparin

Condition Hierarchy (Ancestors)

Respiratory Tract Infections; Infections; Virus Diseases; Lung Diseases; Respiratory Tract Diseases; Vascular Diseases; Cardiovascular Diseases; Hemorrhagic Disorders; Hematologic Diseases; Hemic and Lymphatic Diseases; Coronavirus Infections; Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections

Intervention Hierarchy (Ancestors)

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

Study Officials

• Marco Marietta, MD

  Azienda Ospedaliero-Universitaria di Modena

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Marco Marietta, MD

CONTACT

0594224640; marco.marietta@unimore.it

Pasquale Mighali

CONTACT

0594225868; mighali.pasquale@aou.mo.it

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: SINGLE
• Who Masked: INVESTIGATOR
• Masking Details: Randomisation will be centrally performed by using a secure, web-based system, which will be developed by the Methodological and Statistical Unit at the Azienda Ospedaliero-Universitaria of Modena. Randomisation stratified by 4 factors: 1) Gender (M/F); 2) Age (\<75/≥75 years); 3) BMI (\<30/≥30); 4) Co-morbidities (0-1/\>2) with random variable block sizes will be generated by STATA software. The web-based system will guarantee the allocation concealment.
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Head, Hemostasis and Thrombosis Unit

Model Details: This is a multicentre, randomised controlled, open label, investigator sponsored, two arms study.

Study Record Dates

• First Submitted: May 26, 2020
• First Posted: May 29, 2020
• Study Start: June 1, 2020
• Primary Completion: June 1, 2021
• Study Completion: June 1, 2021
• Last Updated: May 29, 2020

Record last verified: 2020-05

Data Sharing

• IPD Sharing: Will not share

Locations

IT (1)