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

Phase 3

Completed

• Conditions: Covid19
• Interventions: Drug: Heparin - Prophylactic dosage; Drug: Heparin - Therapeutic dosage; Drug: Tocilizumab

• Registration Number: NCT04600141
• Lead Sponsor: University of Sao Paulo

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.

Detailed Description

Not available

Study Timeline

• Study First Submitted: 2020-10-22
• Study First Submitted QC: 2020-10-22
• Study First Posted: 2020-10-23
• Study Start: 2020-11-10
• Primary Completion: 2021-10-20
• Study Completion: 2021-12-31
• Status Verified: 2022-03
• Last Update Submitted: 2022-03-17
• Last Update Posted: 2022-03-18

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 308

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 & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Group 2 - Prophylactic anticoagulation	Heparin - Prophylactic dosage	* (I) subcutaneous UFH 5,000 IU every 8 hours; OR * (II) subcutaneous LMWH - enoxaparin 40 mg daily.
Group 4 - Prophylactic anticoagulation with tocilizumab	Heparin - Prophylactic dosage	* (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 1 - Therapeutic anticoagulation	Heparin - Therapeutic dosage	* (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 3 - Therapeutic anticoagulation with tocilizumab	Heparin - Therapeutic dosage	* (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 3 - Therapeutic anticoagulation with tocilizumab	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 4 - Prophylactic anticoagulation with tocilizumab	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.

Primary Outcome Measures

Name	Time	Method
Proportion of patients with clinical improvement	30 days	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: 1. Not hospitalized, with no limitations on activities; 2. Not hospitalized, but limited to activities; 3. Hospitalized, with no need for supplemental oxygen; 4. Hospitalized, needing supplemental oxygen; 5. Hospitalized, requiring high flow oxygen therapy, non-invasive mechanical ventilation or both; 6. Hospitalized, requiring ECMO, invasive mechanical ventilation or both; 7. Death.

Secondary Outcome Measures

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

Trial Locations

Locations (3)

Fundação São Francisco Xavier; 🇧🇷 Ipatinga, Minas Gerais, Brazil

UNIMED Varginha; 🇧🇷 Varginha, Minas Gerais, Brazil

Universidade Federal de Sergipe; 🇧🇷 Aracaju, Sergipe, Brazil