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

NCT ID: NCT04600141

Last Updated: 2022-03-18

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE3
• Total Enrollment: 308 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2020-11-10
• Study Completion Date: 2021-12-31

Brief Summary

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.

Conditions

Covid19

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

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.

Group Type: ACTIVE_COMPARATOR

Heparin - Therapeutic dosage

Intervention Type: DRUG

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

Group 2 - Prophylactic anticoagulation

• (I) subcutaneous UFH 5,000 IU every 8 hours; OR
• (II) subcutaneous LMWH - enoxaparin 40 mg daily.

Group Type: ACTIVE_COMPARATOR

Heparin - Prophylactic dosage

Intervention Type: DRUG

Subcutaneous Non-Fractional Heparine 5000U every 8 hours OR Subcutaneous Low Molecular Weight (LMWH) 40mg/day.

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.

Group Type: EXPERIMENTAL

Tocilizumab

Intervention Type: DRUG

Tocilizumab infusion 8mg/kg/dose - Intravenous single dose.

Heparin - Therapeutic dosage

Intervention Type: DRUG

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

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.

Group Type: EXPERIMENTAL

Tocilizumab

Intervention Type: DRUG

Tocilizumab infusion 8mg/kg/dose - Intravenous single dose.

Heparin - Prophylactic dosage

Intervention Type: DRUG

Subcutaneous Non-Fractional Heparine 5000U every 8 hours OR Subcutaneous Low Molecular Weight (LMWH) 40mg/day.

Interventions

Tocilizumab

Tocilizumab infusion 8mg/kg/dose - Intravenous single dose.

Intervention Type: 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

Intervention Type: DRUG

Heparin - Prophylactic dosage

Subcutaneous Non-Fractional Heparine 5000U every 8 hours OR Subcutaneous Low Molecular Weight (LMWH) 40mg/day.

Intervention Type: DRUG

Eligibility Criteria

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.

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Conselho Nacional de Desenvolvimento Científico e Tecnológico

OTHER_GOV

Sponsor Role: collaborator

University of Sao Paulo

OTHER

Sponsor Role: lead

Responsible Party

Ludhmila Abrahão Hajjar MD, PhD

Associate Professor

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Ludhmila A Hajjar, MD, PhD

Role: PRINCIPAL_INVESTIGATOR

InCor - University of Sao Paulo Medical School

Locations

Fundação São Francisco Xavier

Ipatinga, Minas Gerais, Brazil

UNIMED Varginha

Varginha, Minas Gerais, Brazil

Universidade Federal de Sergipe

Aracaju, Sergipe, Brazil

Countries

Brazil

Other Identifiers

HEPMAB

Identifier Type: -

Identifier Source: org_study_id