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

Sponsor

University of Sao Paulo (Other)

Overall Status

Completed

CT.gov ID

NCT04600141

Collaborator

Conselho Nacional de Desenvolvimento Científico e Tecnológico (Other)

308

Enrollment

Locations

Arms

13.7

Actual Duration (Months)

102.7

Patients Per Site

7.5

Patients Per Site Per Month

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Covid19	Drug: Tocilizumab Drug: Heparin - Therapeutic dosage Drug: Heparin - Prophylactic dosage	Phase 3

Study Design

Study Type:

Interventional

Actual Enrollment :

308 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

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

Actual Study Start Date :

Nov 10, 2020

Actual Primary Completion Date :

Oct 20, 2021

Actual Study Completion Date :

Dec 31, 2021

Arms and Interventions

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: Tocilizumab Tocilizumab infusion 8mg/kg/dose - Intravenous 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
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: Tocilizumab Tocilizumab infusion 8mg/kg/dose - Intravenous single dose. Drug: Heparin - Prophylactic dosage Subcutaneous Non-Fractional Heparine 5000U every 8 hours OR Subcutaneous Low Molecular Weight (LMWH) 40mg/day.

Outcome Measures

Primary Outcome Measures

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: 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.

Secondary Outcome Measures

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
Duration of vasopressor use [30 days]
Time of use of vasopressors
Renal failure by AKIN criteria [30 days]
Renal failure by AKIN criteria in 30 days
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
Mortality [30, 60 and 90 days]
Mortality rate

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts 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.

Contacts and Locations

Locations

	Site	City	State	Country
1	Fundação São Francisco Xavier	Ipatinga	Minas Gerais	Brazil
2	UNIMED Varginha	Varginha	Minas Gerais	Brazil
3	Universidade Federal de Sergipe	Aracaju	Sergipe	Brazil