Covid19Phase 3HEPMABNCT04600141
Clinical Efficacy of Heparin and Tocilizumab in Patients With Severe COVID-19 Infection
A Phase 3 study testing Tocilizumab, Heparin - Therapeutic dosage and Heparin - Prophylactic dosage in people with Covid19, run by University of Sao Paulo at 3 sites in Brazil.
Trial 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. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Covid19
- What is being tested?
- Tocilizumab, Heparin - Therapeutic dosage and Heparin - Prophylactic dosage
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 308 participants
- Where
- 3 sitesBrazil
- Study dates
- 10 Nov 2020to 31 Dec 2021
- Phase
- Phase 3
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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.
Who cannot join
- 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;
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- 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 locations and contacts
3 sites in 1 country.
Brazil3 sites
Universidade Federal de Sergipe
Aracaju, Sergipe
Fundação São Francisco Xavier
Ipatinga, Minas Gerais
UNIMED Varginha
Varginha, Minas Gerais
About this study
Official title: Clinical Efficacy of Heparin and Tocilizumab in Patients With Severe COVID-19 Infection: a Randomized Clinical Trial
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
- Being tested
- Tocilizumab, Heparin - Therapeutic dosage, Heparin - Prophylactic dosage
- Keywords
- COVID-19, Heparin, Tocilizumab
- Medical subject headings
- COVID-19
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
TocilizumabDrug
Tocilizumab infusion 8mg/kg/dose - Intravenous single dose.
Heparin - Therapeutic dosageDrug
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
Heparin - Prophylactic dosageDrug
Subcutaneous Non-Fractional Heparine 5000U every 8 hours OR Subcutaneous Low Molecular Weight (LMWH) 40mg/day.
| Study group | Role | What they receive |
|---|---|---|
| Group 1 - Therapeutic anticoagulation | Active comparator | * (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. Receives: Drug: Heparin - Therapeutic dosage |
| Group 2 - Prophylactic anticoagulation | Active comparator | * (I) subcutaneous UFH 5,000 IU every 8 hours; OR
* (II) subcutaneous LMWH - enoxaparin 40 mg daily. Receives: Drug: Heparin - Prophylactic dosage |
| Group 3 - Therapeutic anticoagulation with tocilizumab | Experimental | * (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. Receives: Drug: Tocilizumab; Drug: Heparin - Therapeutic dosage |
| Group 4 - Prophylactic anticoagulation with tocilizumab | Experimental | * (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. Receives: Drug: Tocilizumab; Drug: Heparin - Prophylactic dosage |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: 30 days
Secondary outcomes (7)
Hospital and ICU length of stay;
Number of days in hospital and ICU
Measured: 30 days
Duration of invasive mechanical ventilation
Time requiring invasive mechanical ventilation
Measured: 30 days
Duration of vasopressor use
Time of use of vasopressors
Measured: 30 days
Renal failure by AKIN criteria
Renal failure by AKIN criteria in 30 days
Measured: 30 days
Incidence of cardiovascular complications
Myocardial injury; Acute myocardial infarction; Cardiogenic shock; arrhythmias; Myocarditis; Pericarditis; Ventricular dysfunction.
Measured: 30 days
Incidence of venous thromboembolism
Deep vein thrombosis and pulmonary embolism
Measured: 30 days
Mortality
Mortality rate
Measured: 30, 60 and 90 days
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted23 Oct 2020
- Study start10 Nov 2020
- Primary completion20 Oct 2021
- Study completion31 Dec 2021
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Covid19Studies of the same condition, open and under way.
- More trials run by University of Sao PauloThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 3
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Enrolment
- 308 participants (actual)
Sponsor and investigators
- Lead sponsor
- University of Sao Paulo
- Sponsor type
- University, hospital or other
- Collaborators
- Conselho Nacional de Desenvolvimento Científico e Tecnológico
- Responsible party
- Principal investigator, Ludhmila Abrahão Hajjar MD, PhD, University of Sao Paulo
- Investigators
- Ludhmila A Hajjar, MD, PhD, Principal investigator, InCor - University of Sao Paulo Medical School
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT04600141
- Sponsor's protocol ID
- HEPMAB
- Acronym
- HEPMAB
- Status last verified
- Mar 2022
- First submitted
- 22 Oct 2020
- Last updated
- 18 Mar 2022
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- No
Study at a glance
From the registry record, last updated by the sponsor on 18 Mar 2022. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Clinical Efficacy of Heparin and Tocilizumab in Patients With Severe COVID-19 Infection: a Randomized Clinical Trial
- ClinicalTrials.gov ID
- NCT04600141
- Acronym / sponsor ID
- HEPMAB / HEPMAB
- Conditions
- Covid19
- Keywords
- COVID-19, Heparin, Tocilizumab
- Phase
- Phase 3
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 308 participants (actual)
- Lead sponsor
- University of Sao PauloUniversity, hospital or other
- Collaborators
- Conselho Nacional de Desenvolvimento Científico e Tecnológico
- Study start
- 10 Nov 2020 (actual)
- Primary completion
- 20 Oct 2021 (actual)
- Study completion
- 31 Dec 2021 (actual)
- First posted
- 23 Oct 2020 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 4
| Arm | Type | Receives |
|---|---|---|
| Group 1 - Therapeutic anticoagulation | Active comparator | Drug: 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 2 - Prophylactic anticoagulation | Active comparator | Drug: Heparin - Prophylactic dosage* (I) subcutaneous UFH 5,000 IU every 8 hours; OR * (II) subcutaneous LMWH - enoxaparin 40 mg daily. |
| Group 3 - Therapeutic anticoagulation with tocilizumab | Experimental | Drug: Tocilizumab, Drug: 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 4 - Prophylactic anticoagulation with tocilizumab | Experimental | Drug: Tocilizumab, Drug: 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. |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (4 listed)
- 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.
Key exclusion criteria (14 listed)
- Risk of bleeding:
- 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;
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| TocilizumabTocilizumab infusion 8mg/kg/dose - Intravenous single dose. | Drug | Group 3 - Therapeutic anticoagulation with tocilizumab, Group 4 - Prophylactic anticoagulation with tocilizumab |
| Heparin - Therapeutic dosageIntravenous 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 | Drug | Group 1 - Therapeutic anticoagulation, Group 3 - Therapeutic anticoagulation with tocilizumab |
| Heparin - Prophylactic dosageSubcutaneous Non-Fractional Heparine 5000U every 8 hours OR Subcutaneous Low Molecular Weight (LMWH) 40mg/day. | Drug | Group 2 - Prophylactic anticoagulation, Group 4 - Prophylactic anticoagulation with tocilizumab |
Primary outcome
Proportion of patients with clinical improvement
Time frame: 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.
7 secondary outcomes
Hospital and ICU length of stay;
Time frame: 30 days
Duration of invasive mechanical ventilation
Time frame: 30 days
Duration of vasopressor use
Time frame: 30 days
Renal failure by AKIN criteria
Time frame: 30 days
Incidence of cardiovascular complications
Time frame: 30 days
Incidence of venous thromboembolism
Time frame: 30 days
Mortality
Time frame: 30, 60 and 90 days
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 18 Mar 2022.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Ludhmila A Hajjar, MD, PhD principal investigator
InCor - University of Sao Paulo Medical School
3 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 3 study testing Tocilizumab, Heparin - Therapeutic dosage and Heparin - Prophylactic dosage in people with Covid19, run by University of Sao Paulo at 3 sites in Brazil.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 4 inclusion and 14 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 18 Mar 2022. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 3 sites in Brazil. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Proportion of patients with clinical improvement (time frame: 30 days). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 18 Mar 2022.