Accelerating COVID-19 Therapeutic Interventions and Vaccines 4 ACUTE (ACTIV-4A)
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| ClinicalTrials.gov Identifier: NCT04505774 |
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Recruitment Status :
Recruiting
First Posted : August 10, 2020
Last Update Posted : January 31, 2022
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| Condition or disease | Intervention/treatment | Phase |
|---|---|---|
| Covid19 | Drug: theraputic heparin Drug: prophylactic heparin Drug: P2Y12 Drug: Crizanlizumab Injection Drug: SGLT2 inhibitor | Phase 4 |
Show detailed description
| Study Type : | Interventional (Clinical Trial) |
| Estimated Enrollment : | 3000 participants |
| Allocation: | Randomized |
| Intervention Model: | Sequential Assignment |
| Intervention Model Description: | This is an adaptive design |
| Masking: | None (Open Label) |
| Masking Description: | There will be independent masked adjudicators. |
| Primary Purpose: | Treatment |
| Official Title: | A Multicenter, Adaptive, Randomized Controlled Platform Trial of the Safety and Efficacy of Antithrombotic and Additional Strategies in Hospitalized Adults With COVID-19 |
| Actual Study Start Date : | September 4, 2020 |
| Estimated Primary Completion Date : | September 2022 |
| Estimated Study Completion Date : | December 2022 |
| Arm | Intervention/treatment |
|---|---|
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Therapeutic Dose Anticoagulation
increased dose of heparin above standard of care. 1.0 - This arm was stopped in severe patients in December 2020 and results are published in PMID: 34351722 (NEJM, August, 2021) (see reference section for citation) 1.1 - this arm was stopped for moderate patients in June 2021 |
Drug: theraputic heparin
increased dose of heparin above standard of care.
Other Names:
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Prophylactic Dose Anticoagulation
Heparin standard of care 1.0 - this arm was stopped for all patients in January, 2021 and results are published in PMID: 34351721 (NEJM, August, 2021) (see reference section for citation) 1.1 - this arm was reinstated for severe patients. |
Drug: prophylactic heparin
standard of care dose of heparin
Other Names:
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Therapeutic Dose Anticoagulation + P2Y12 inhibitor
increased dose of heparin above standard of care with an added P2Y12 inhibitor This Arm enrolled moderate illness patients only. Enrollment of moderate illness patients in the trial was ended per DSMB on June 19, 2021. |
Drug: theraputic heparin
increased dose of heparin above standard of care.
Other Names:
Drug: P2Y12 added P2Y12 inhibitor
Other Names:
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Prophylactic Dose Anticoagulation + P2Y12 inhibitor
Heparin standard of care with an added P2Y12 inhibitor This Arm enrolled severe illness patients only. |
Drug: prophylactic heparin
standard of care dose of heparin
Other Names:
Drug: P2Y12 added P2Y12 inhibitor
Other Names:
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Standard of Care + Crizanlizumab
Standard of care plus crizanlizumab infusion This arm will enroll moderate and severe illness patients |
Drug: Crizanlizumab Injection
crizanlizumab injection |
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Standard of Care + SGLT2 inhibitor
Standard of care plus SGLT2 inhibitor This arm will enroll moderate and severe illness patients |
Drug: SGLT2 inhibitor
sglt2 inhibitor
Other Names:
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- 21 Day Organ Support (respiratory or vasopressor) Free Days [ Time Frame: 21 days from study enrollment ]which is defined as the number of days that a patient is alive and free of organ support through the first 21 days after trial entry. Organ Support is defined as receipt of non-invasive mechanical ventilation, high flow nasal canula oxygen, mechanical ventilation, or vasopressor therapy, with death at any time during the index hospitalization assigned -1 days.
- Secondary Endpoint all cause mortality [ Time Frame: 28 days from study enrollment ]Categorization of the primary endpoint into a three-level ordinal outcome (Death, invasive mechanical ventilation without death, neither invasive mechanical ventilation nor death)
- Other Platform Secondary Endpoints of Morbidity and Hospitalization [ Time Frame: 28 days from study enrollment ]Categorization of the primary endpoint into a three-level ordinal outcome (Death, organ support (any respiratory or cardiovascular) without death, neither organ support nor death) (for moderate illness severity at enrollment)
- Days free of death [ Time Frame: 28 days from enrollment ]Days free of death and respiratory and cardiovascular organ support and renal replacement therapy (RRT) during Index Hospitalization through Day 28.
- Death Composite [ Time Frame: 28 days from enrollment ]Composite endpoint of death, pulmonary embolism, systemic arterial thromboembolism, myocardial infarction, or ischemic stroke at hospital discharge or 28 days, whichever occurs first.
- Acute kidney injury [ Time Frame: 90 days from enrollment ]Individual endpoints comprising the primary and secondary endpoint components; death during hospitalization, WHO clinical scale and 90 day mortality
- Primary Safety Endpoint of Major Bleeding [ Time Frame: 28 days from study enrollment ]Major bleeding (as defined by the ISTH)
- Secondary Safety Endpoint of HIT [ Time Frame: 28 days from study enrollment ]Confirmed heparin induced thrombocytopenia (HIT)
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.
| Ages Eligible for Study: | 18 Years and older (Adult, Older Adult) |
| Sexes Eligible for Study: | All |
| Accepts Healthy Volunteers: | No |
Inclusion Criteria:
- ≥ 18 years of age
- Hospitalized for COVID-19
- Enrolled within 72 hours of hospital admittance or 72 hours of positive COVID test
- Expected to require hospitalization for > 72 hours
Exclusion Criteria:
- Imminent death
- Requirement for chronic mechanical ventilation via tracheostomy prior to hospitalization
- Pregnancy
Inclusion Criteria for Arm E
Inclusion criteria contained in the master protocol in addition to the following:
Moderate illness severity - defined as non-ICU level of care at the time of randomization (not receiving high flow nasal oxygen (HFNO), non-invasive ventilation (NIV), invasive ventilation (IV), vasopressors or inotropes, or extracorporeal membrane oxygenation (ECMO) OR Severe illness severity - defined as ICU level of care at the time of randomization (receiving HFNO, NIV, IV, vasopressors or inotropes, or ECMO)
For moderate illness severity, participants are required to meet one or more of the following risk criteria:
- Age ≥ 65 years or
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≥2 of the following -
- O2 supplementation > 2 liters per minute
- BMI ≥ 35
- GFR ≤ 60
- History of Type 2 diabetes
- History of heart failure (regardless of ejection fraction)
- D dimer ≥ 2x the site's upper limit of normal (ULN)
- Troponin ≥ 2x the site's ULN
- BNP≥100 pg/mL or NT-proBNP≥300 pg/mL
- CRP ≥50 mg/L
Exclusion Criteria for Arm E
- Exclusion criteria contained in the master protocol, and
- Any condition that, in the opinion of the investigator, precludes the use of crizanlizumab such as uncontrolled bleeding or severe anemia (hemoglobin<4 g/dL)
- Open label treatment with crizanlizumab within the past three months
Inclusion Criteria for Arm F
Inclusion criteria contained in the master protocol in addition to the following:
Moderate illness severity - defined as non-ICU level of care at the time of randomization (not receiving high flow nasal oxygen (HFNO), non-invasive ventilation (NIV), invasive ventilation (IV), vasopressors or inotropes, or extracorporeal membrane oxygenation (ECMO)) OR Severe illness severity - defined as ICU level of care at the time of randomization (receiving HFNO, NIV, IV, vasopressors or inotropes, or ECMO)
For moderate illness severity, participants are required to meet one or more of the following risk criteria:
- Age ≥ 65 years or
-
≥2 of the following-
- O2 supplementation > 2 liters per minute
- BMI ≥ 35
- GFR ≤ 60
- History of Type 2 diabetes
- History of heart failure (regardless of ejection fraction)
- D dimer ≥ 2x the site's upper limit of normal (ULN)
- Troponin ≥ 2x the site's ULN
- BNP≥100 pg/mL or NT-proBNP≥300 pg/mL
- CRP ≥50 mg/L
Exclusion Criteria for Arm F
In addition to the exclusion criteria noted in the master protocol, arm-specific exclusion criteria are as follows:
- Known hypersensitivity to any SGLT2 inhibitors
- Type 1 diabetes
- History of diabetic ketoacidosis
- eGFR <20 and/or requirement for renal replacement therapy
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Open label treatment with any SGLT2 inhibitor
- Based on a recommendation from the ACTIV4 DSMB on December 19, 2020, enrollment of patients requiring ICU level of care into the therapeutic anti-coagulation arm was stopped due to meeting a futility threshold and a potential for harm for this sub-group could not be excluded. Enrollment continues for moderately ill hospitalized COVID-19 patients.
- Based on a recommendation from the ACTIV4 DSMB on June 18, 2021, enrollment of patients not requiring ICU level of care and randomized to P2Y12 or standard care was stopped due to meeting a futility threshold. Enrollment continues for severely ill (ICU level of care) hospitalized COVID-19 patients.
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04505774
| Contact: Judith Hochman, MD | 212-263-6927 | Judith.Hochman@nyulangone.org | |
| Contact: Matthew Neal, MD | 412-692-2850 | nealm2@upmc.edu |
Show 102 study locations
| Study Chair: | Judith Hochman, MD | New York University - Grossman School of Medicine | |
| Principal Investigator: | Scott Solomon, MD | Brigham and Women's Hospital | |
| Principal Investigator: | Mikhail Kosiborod, MD | Saint Lukes | |
| Principal Investigator: | Jeffrey Berger, MD | New York University - Grossman School of Medicine | |
| Study Chair: | MATTHEW D NEAL, MD | University of Pittsburgh |
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
| Responsible Party: | Matthew Neal MD, MD, University of Pittsburgh |
| ClinicalTrials.gov Identifier: | NCT04505774 |
| Obsolete Identifiers: | NCT04359277 |
| Other Study ID Numbers: |
ACTIV-4 ACUTE 1OT2HL156812-01 ( U.S. NIH Grant/Contract ) |
| First Posted: | August 10, 2020 Key Record Dates |
| Last Update Posted: | January 31, 2022 |
| Last Verified: | January 2022 |
| Individual Participant Data (IPD) Sharing Statement: | |
| Plan to Share IPD: | Yes |
| Plan Description: | Data will be shared as per NIH guidelines. |
| Supporting Materials: |
Study Protocol Statistical Analysis Plan (SAP) Informed Consent Form (ICF) Clinical Study Report (CSR) Analytic Code |
| Studies a U.S. FDA-regulated Drug Product: | Yes |
| Studies a U.S. FDA-regulated Device Product: | No |
| Product Manufactured in and Exported from the U.S.: | No |
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anti-coagulation antithrombosis anticoagulation ACTIV inpatient heparin |
p2y12 endothelial dysfunction vascular integrity P-selectin crizanlizumab SGLT-2 inhibitor |
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COVID-19 Respiratory Tract Infections Infections Pneumonia, Viral Pneumonia Virus Diseases Coronavirus Infections Coronaviridae Infections Nidovirales Infections RNA Virus Infections Lung Diseases Respiratory Tract Diseases Dapagliflozin Empagliflozin Canagliflozin |
Ertugliflozin Sodium-Glucose Transporter 2 Inhibitors Heparin Calcium heparin Enoxaparin Dalteparin Tinzaparin Heparin, Low-Molecular-Weight Enoxaparin sodium Clopidogrel Ticagrelor Platelet Aggregation Inhibitors Purinergic P2Y Receptor Antagonists Purinergic P2 Receptor Antagonists Purinergic Antagonists |