Back to resultsClinical Efficacy of Heparin and Tocilizumab in Patients With Severe COVID-19 Infection (HEPMAB)
Primary Purpose
Covid19
Status
Completed
Phase
Phase 3
Locations
Brazil
Study Type
Interventional
Intervention
Tocilizumab
Heparin - Therapeutic dosage
Heparin - Prophylactic dosage
Sponsored by
About this trial
This is an interventional treatment trial for Covid19 focused on measuring COVID-19, Heparin, Tocilizumab
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.
Sites / Locations
- Fundação São Francisco Xavier
- UNIMED Varginha
- Universidade Federal de Sergipe
Arms of the Study
Arm 1
Arm 2
Arm 3
Arm 4
Arm Type
Active Comparator
Active Comparator
Experimental
Experimental
Arm Label
Group 1 - Therapeutic anticoagulation
Group 2 - Prophylactic anticoagulation
Group 3 - Therapeutic anticoagulation with tocilizumab
Group 4 - Prophylactic anticoagulation with tocilizumab
Arm 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.
(I) subcutaneous UFH 5,000 IU every 8 hours; OR (II) subcutaneous LMWH - enoxaparin 40 mg daily.
(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.
(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.
Outcomes
Primary Outcome Measures
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.
Secondary Outcome Measures
Hospital and ICU length of stay;
Number of days in hospital and ICU
Duration of invasive mechanical ventilation
Time requiring invasive mechanical ventilation
Duration of vasopressor use
Time of use of vasopressors
Renal failure by AKIN criteria
Renal failure by AKIN criteria in 30 days
Incidence of cardiovascular complications
Myocardial injury; Acute myocardial infarction; Cardiogenic shock; arrhythmias; Myocarditis; Pericarditis; Ventricular dysfunction.
Incidence of venous thromboembolism
Deep vein thrombosis and pulmonary embolism
Mortality
Mortality rate
Full Information
NCT ID
NCT04600141
First Posted
October 22, 2020
Last Updated
March 17, 2022
Sponsor
University of Sao Paulo
Collaborators
Conselho Nacional de Desenvolvimento Científico e Tecnológico
1. Study Identification
Unique Protocol Identification Number
NCT04600141
Brief Title
Clinical Efficacy of Heparin and Tocilizumab in Patients With Severe COVID-19 Infection
Acronym
HEPMAB
Official Title
Clinical Efficacy of Heparin and Tocilizumab in Patients With Severe COVID-19 Infection: a Randomized Clinical Trial
Study Type
Interventional
2. Study Status
Record Verification Date
March 2022
Overall Recruitment Status
Completed
Study Start Date
November 10, 2020 (Actual)
Primary Completion Date
October 20, 2021 (Actual)
Study Completion Date
December 31, 2021 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
University of Sao Paulo
Collaborators
Conselho Nacional de Desenvolvimento Científico e Tecnológico
4. Oversight
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
Data Monitoring Committee
Yes
5. 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.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Covid19
Keywords
COVID-19, Heparin, Tocilizumab
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 3
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Randomized
Enrollment
308 (Actual)
8. Arms, Groups, and Interventions
Arm Title
Group 1 - Therapeutic anticoagulation
Arm Type
Active Comparator
Arm 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.
Arm Title
Group 2 - Prophylactic anticoagulation
Arm Type
Active Comparator
Arm Description
(I) subcutaneous UFH 5,000 IU every 8 hours; OR
(II) subcutaneous LMWH - enoxaparin 40 mg daily.
Arm Title
Group 3 - Therapeutic anticoagulation with tocilizumab
Arm Type
Experimental
Arm 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.
Arm Title
Group 4 - Prophylactic anticoagulation with tocilizumab
Arm Type
Experimental
Arm 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.
Intervention Type
Drug
Intervention Name(s)
Tocilizumab
Intervention Description
Tocilizumab infusion 8mg/kg/dose - Intravenous single dose.
Intervention Type
Drug
Intervention Name(s)
Heparin - Therapeutic dosage
Intervention Description
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
Intervention Name(s)
Heparin - Prophylactic dosage
Intervention Description
Subcutaneous Non-Fractional Heparine 5000U every 8 hours OR Subcutaneous Low Molecular Weight (LMWH) 40mg/day.
Primary Outcome Measure Information:
Title
Proportion of patients with clinical improvement
Description
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.
Time Frame
30 days
Secondary Outcome Measure Information:
Title
Hospital and ICU length of stay;
Description
Number of days in hospital and ICU
Time Frame
30 days
Title
Duration of invasive mechanical ventilation
Description
Time requiring invasive mechanical ventilation
Time Frame
30 days
Title
Duration of vasopressor use
Description
Time of use of vasopressors
Time Frame
30 days
Title
Renal failure by AKIN criteria
Description
Renal failure by AKIN criteria in 30 days
Time Frame
30 days
Title
Incidence of cardiovascular complications
Description
Myocardial injury; Acute myocardial infarction; Cardiogenic shock; arrhythmias; Myocarditis; Pericarditis; Ventricular dysfunction.
Time Frame
30 days
Title
Incidence of venous thromboembolism
Description
Deep vein thrombosis and pulmonary embolism
Time Frame
30 days
Title
Mortality
Description
Mortality rate
Time Frame
30, 60 and 90 days
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
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.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Ludhmila A Hajjar, MD, PhD
Organizational Affiliation
InCor - University of Sao Paulo Medical School
Official's Role
Principal Investigator
Facility Information:
Facility Name
Fundação São Francisco Xavier
City
Ipatinga
State/Province
Minas Gerais
Country
Brazil
Facility Name
UNIMED Varginha
City
Varginha
State/Province
Minas Gerais
Country
Brazil
Facility Name
Universidade Federal de Sergipe
City
Aracaju
State/Province
Sergipe
Country
Brazil
12. IPD Sharing Statement
Plan to Share IPD
No
Learn more about this trial
Clinical Efficacy of Heparin and Tocilizumab in Patients With Severe COVID-19 Infection
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