Clinical Efficacy of Heparin and Tocilizumab in Patients With Severe COVID-19 Infection (HEPMAB)

Clinical Efficacy of Heparin and Tocilizumab in Patients With Severe COVID-19 Infection: a Randomized Clinical Trial

The COVID-19 infection primarily manifests itself as a respiratory tract infection, although new evidence indicates that this disease has systemic involvement involving multiple systems including the cardiovascular, respiratory, gastrointestinal, neurological, hematopoietic and immune systems. Recent studies have shown that in its pathophysiology, inflammation and thrombogenesis predominate, especially in the severe forms of COVID-19. Thus, the investigators hypothesized that the use of heparin and tocilizumab could potencially reduce inflammation and thrombogenesis in patients with severe COVID-19 infection, improving patients outcomes and survival.

Study Overview

• Status: Completed
• Conditions: Covid19
• Intervention / Treatment: Drug: Heparin - Therapeutic dosage; Drug: Heparin - Prophylactic dosage; Drug: Tocilizumab

• Study Type: Interventional
• Enrollment (Actual): 308
• Phase: Phase 3

Contacts and Locations

Study Locations

• Brazil
  • Minas Gerais
    • Ipatinga, Minas Gerais, Brazil
      • Fundação São Francisco Xavier
    • Varginha, Minas Gerais, Brazil
      • UNIMED Varginha
  • Sergipe
    • Aracaju, Sergipe, Brazil
      • Universidade Federal de Sergipe

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Age ≥ 18 years;
• Informed consent form signed by the patient or guardian or by audio with the guardian;
• Positive result for COVID-19 in PCR (polymerase chain reaction) in nasopharyngeal swab or tracheal secretion up to 10 days before the inclusion and radiological evidence of COVID-19, by chest radiography or chest computed tomography;
• Need for ≥ 4 L of supplemental oxygen to maintain peripheral oxygen saturation equal to or greater than 93% or need for invasive mechanical ventilation.

Exclusion Criteria:

• Risk of bleeding:

  • Clinical: active bleeding, major surgery in the last 30 days, gastrointestinal bleeding within 30 days;
  • Laboratory: platelet count <50,000, INR> 2 or APTT> 50s;
• Known or suspected adverse reaction to UFH, including heparin-induced thrombocytopenia (TIH);
• Adverse reaction or allergy to tocilizumab;
• Use of any of the following treatments: UFH to treat a thrombotic event within 12 hours before inclusion; HPBM in therapeutic dose within 12 hours before inclusion; warfarin (if used 7 days before and if INR greater than 2; thrombolytic therapy within 3 days before; and use of glycoprotein IIb / IIIa inhibitors within the previous 7 days;
• Pregnant or lactating;
• Absolute indication of anticoagulation due to atrial fibrillation or diagnosed thromboembolic event;
• Refusal by family members and / or patient;
• Active tuberculosis;
• Bacterial infection confirmed by culture;
• Neutropenia (<1000 neutrophils / mm3);
• Use of another immunosuppressive therapy that is not a corticosteroid;
• Septic shock.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Group 1 - Therapeutic anticoagulation; (I) intravenous UFH started at a dose of 18 IU/kg/h, adjusted according to a nomogram to achieve a TTPa of 1.5 to 2.0 times the reference value; OR; (II) subcutaneous LMWH - enoxaparin 1 mg / kg per dose every 12 hours.	Drug: Heparin - Therapeutic dosage; Intravenous Non-Fractional Heparine (HNF) starting at 18UI/kg/h adjusted according to a nomogram to achieve an Activated Partial Thromboplastin Time (ATTP) from 1.5 To 2.0 times the reference Value; or Low Molecular Weight Heparin (LMWH) subcutaneous dosage of 1mg/kg per dose every 12 hours
Active Comparator: Group 2 - Prophylactic anticoagulation; (I) subcutaneous UFH 5,000 IU every 8 hours; OR; (II) subcutaneous LMWH - enoxaparin 40 mg daily.	Drug: Heparin - Prophylactic dosage; Subcutaneous Non-Fractional Heparine 5000U every 8 hours OR Subcutaneous Low Molecular Weight (LMWH) 40mg/day.
Experimental: Group 3 - Therapeutic anticoagulation with tocilizumab; (I) Intravenous UFH initiated at a dose of 18 IU / kg / h, adjusted according to a nomogram to achieve a TTPa of 1.5 to 2.0 times the reference value associated with 8 mg / kg / tocilizumab infusion / intravenous dose in a single dose; OR; Subcutaneous LMWH - enoxaparin 1 mg / kg per dose every 12 hours associated with an infusion of tocilizumab 8 mg / kg / dose in a single dose.	Drug: Heparin - Therapeutic dosage; Intravenous Non-Fractional Heparine (HNF) starting at 18UI/kg/h adjusted according to a nomogram to achieve an Activated Partial Thromboplastin Time (ATTP) from 1.5 To 2.0 times the reference Value; or Low Molecular Weight Heparin (LMWH) subcutaneous dosage of 1mg/kg per dose every 12 hours; Drug: Tocilizumab; Tocilizumab infusion 8mg/kg/dose - Intravenous single dose.
Experimental: Group 4 - Prophylactic anticoagulation with tocilizumab; (I) subcutaneous UFH 5,000 IU every 8 hours associated with an infusion of tocilizumab 8 mg / kg / intravenous dose in a single dose; OR; (II) subcutaneous LMWH - enoxaparin 40 mg daily associated with an infusion of tocilizumab 8 mg / kg / intravenous dose in a single dose.	Drug: Heparin - Prophylactic dosage; Subcutaneous Non-Fractional Heparine 5000U every 8 hours OR Subcutaneous Low Molecular Weight (LMWH) 40mg/day.; Drug: Tocilizumab; Tocilizumab infusion 8mg/kg/dose - Intravenous single dose.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Proportion of patients with clinical improvement	Proportion of patients with clinical improvement in 30 days, defined by hospital discharge or a reduction of at least 2 points compared to baseline on the ordinal scale recommended by the World Health Organization: Not hospitalized, with no limitations on activities;; Not hospitalized, but limited to activities;; Hospitalized, with no need for supplemental oxygen;; Hospitalized, needing supplemental oxygen;; Hospitalized, requiring high flow oxygen therapy, non-invasive mechanical ventilation or both;; Hospitalized, requiring ECMO, invasive mechanical ventilation or both;; Death.	30 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Hospital and ICU length of stay;	Number of days in hospital and ICU	30 days
Duration of invasive mechanical ventilation	Time requiring invasive mechanical ventilation	30 days
Duration of vasopressor use	Time of use of vasopressors	30 days
Renal failure by AKIN criteria	Renal failure by AKIN criteria in 30 days	30 days
Incidence of cardiovascular complications	Myocardial injury; Acute myocardial infarction; Cardiogenic shock; arrhythmias; Myocarditis; Pericarditis; Ventricular dysfunction.	30 days
Incidence of venous thromboembolism	Deep vein thrombosis and pulmonary embolism	30 days
Mortality	Mortality rate	30, 60 and 90 days

Collaborators and Investigators

• Sponsor: University of Sao Paulo
• Collaborators: Conselho Nacional de Desenvolvimento Científico e Tecnológico
• Investigators: Principal Investigator: Ludhmila A Hajjar, MD, PhD, InCor - University of Sao Paulo Medical School

Study record dates

Study Major Dates

• Study Start (Actual): November 10, 2020
• Primary Completion (Actual): October 20, 2021
• Study Completion (Actual): December 31, 2021

Study Registration Dates

• First Submitted: October 22, 2020
• First Submitted That Met QC Criteria: October 22, 2020
• First Posted (Actual): October 23, 2020

Study Record Updates

• Last Update Posted (Actual): March 18, 2022
• Last Update Submitted That Met QC Criteria: March 17, 2022
• Last Verified: March 1, 2022

More Information

Terms related to this study

• Keywords: COVID-19; Tocilizumab; Heparin
• Additional Relevant MeSH Terms: Coronavirus Infections; Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Virus Diseases; Infections; Respiratory Tract Infections; Respiratory Tract Diseases; Pneumonia, Viral; Pneumonia; Lung Diseases; COVID-19; Molecular Mechanisms of Pharmacological Action; Fibrinolytic Agents; Fibrin Modulating Agents; Anticoagulants; Heparin; Calcium heparin
• Other Study ID Numbers: HEPMAB

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No