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

University of Sao Paulo

Status and phase: Completed; Phase 3

Conditions: Covid19

Treatments: Drug: Heparin - Prophylactic dosage; Drug: Heparin - Therapeutic dosage; Drug: Tocilizumab

Study type: Interventional

Funder types: Other

Identifiers

NCT04600141

HEPMAB

Details and patient eligibility

About

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.

Enrollment: 308 patients

Sex: All

Ages: 18+ years old

Volunteers: No Healthy Volunteers

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.

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: None (Open label)

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308 participants in 4 patient groups

Group 1 - Therapeutic anticoagulation

Active Comparator group

Description:

* (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.

Treatment:

Drug: Heparin - Therapeutic dosage

Group 2 - Prophylactic anticoagulation

Active Comparator group

Description:

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

Treatment:

Drug: Heparin - Prophylactic dosage

Group 3 - Therapeutic anticoagulation with tocilizumab

Experimental group

Description:

* (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.

Treatment:

Drug: Heparin - Therapeutic dosage

Drug: Tocilizumab

Group 4 - Prophylactic anticoagulation with tocilizumab

Experimental group

Description:

* (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.

Treatment:

Drug: Tocilizumab

Drug: Heparin - Prophylactic dosage