Intermediate-dose vs Standard Prophylactic Anticoagulation and Statin vs Placebo in ICU Patients With COVID-19

Intermediate-dose Versus Standard Prophylactic Anticoagulation In cRitically-ill pATIents With COVID-19: An opeN Label Randomized Controlled Trial---A Randomized Trial of Atorvastatin vs. Placebo In Critically-ill Patients With COVID-19

Sponsors

Lead Sponsor: Rajaie Cardiovascular Medical and Research Center

Collaborator: Brigham and Women's Hospital
Tehran Heart Center
Masih Daneshvari Hospital
Hazrat Rasool Hospital
Modarres Hospital
Firuzgar hospital affiliated to Iran University of Medical Sciences
Imam Khomeini Hospital
Sina Hospital, Iran
Tabriz University of Medical Sciences
Shariati Hospital
Imam Ali Hospital
Labbafinejhad Hospital

Source Rajaie Cardiovascular Medical and Research Center
Brief Summary

In a 2x2 factorial design randomized controlled trial, the investigators aim to elaborate the safety and efficacy of two pharmacological regimens on outcomes of critically-ill patients with COVID-19. The first randomization entails open-label assignment to intermediate versus standard dose prophylactic anticoagulation. The investigators hypothesize that intermediate dose compared with standard prophylactic dose anticoagulation will have a superior efficacy with respect to a composite of venous thromboembolism (VTE), requirement for extracorporeal membrane oxygenation (ECMO), or all-cause mortality. The second randomization will be double-blind assignment of the included patients to atorvastatin 20mg daily versus matching placebo. The hypothesis is that statin therapy, compared with placebo, will reduce the composite of VTE, need for ECMO, or all-cause mortality.

Detailed Description

Coronavirus disease-2019 (COVID-19) -- a viral illness caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) -- has important manifestations outside the pulmonary parenchyma, including microthrombosis and macrothrombosis, with venous thrombosis being the most common form of thrombotic involvement. Existing studies, depending on the type of outcome assessment and type and dose of prophylaxis, have reported thrombotic events in 7-85% of patients with COVID-19. However, the optimal antithrombotic regimen in these patients remains uncertain. Although many clinicians continue to consider standard-dose prophylactic anticoagulation, other believe that more intense anticoagulation may reduce the thrombotic events, and improve outcomes. However, limited high-quality data exist to inform clinical practice and the existing guidelines recommendations are mostly based on expert opinion and consensus. In addition, exuberant inflammatory response is known to play a role in the pathophysiology of acute respiratory distress syndrome (ARDS) and COVID-19. It is possible that the pleiotropic effects of statins, which include anti-inflammatory and antithrombotic effects, prove beneficial in patients with severe COVID-19. This study plans to investigate the safety and efficacy of two pharmacological regimens on outcomes of critically-ill patients with COVID-19 using a 2x2 factorial design. First, patients will be assessed for the eligibility criteria for the anticoagulation hypothesis. Those meeting the criteria, will be assigned to intermediate versus standard dose prophylactic anticoagulation. These patients will subsequently be assessed for eligibility for the second randomization, and if meeting the criteria, will be assigned to atorvastatin 20mg/d or matching placebo.

Overall Status Completed
Start Date 2020-07-30
Completion Date 2021-07-05
Primary Completion Date 2021-04-04
Phase Phase 3
Study Type Interventional
Primary Outcome
Measure Time Frame
a composite of acute VTE, arterial thrombosis, treatment with ECMO, or all-cause mortality 30 days from enrollment
Secondary Outcome
Measure Time Frame
Rate of all-cause mortality 30 days from enrollment
Rate of objectively-confirmed VTE 30 days from enrollment
Ventilator free days 30 days from enrollment
Rate of major bleeding 30 days from enrollment
Rate of clinically-relevant non-major bleeding 30 days from enrollment
Rate of severe thrombocytopenia 30 days from enrollment
Rate of rise in liver enzymes 30 days from enrollment
Clinically-diagnosed myopathy 30 days from enrollment
Objectively-confirmed arterial thrombosis 30 days from enrollment
Enrollment 600
Condition
Intervention

Intervention Type: Drug

Intervention Name: intermediate dose Enoxaparin/ unfractionated heparin

Description: Intermediate dose anticoagulation according to creatinine clearance and weight

Arm Group Label: Intermediate dose anticoagulation

Other Name: Intermediate dose anticoagulation

Intervention Type: Drug

Intervention Name: standard prophylactic dose Enoxaparin/ unfractionated heparin

Description: Standard prophylaxis anticoagulation according to creatinine clearance and weight

Arm Group Label: Standard Prophylaxis

Other Name: Standard dose prophylaxis anticoagulation

Intervention Type: Drug

Intervention Name: Atorvastatin 20mg

Description: Statin

Arm Group Label: Atorvastatin 20

Other Name: Statin

Intervention Type: Drug

Intervention Name: Matched placebo

Description: Matched placebo to atorvastatin 20 mg

Arm Group Label: Atorvastatin 20 mg Matched placebo

Other Name: Statin

Eligibility

Criteria:

Inclusion Criteria for Anticoagulation Hypothesis 1. Adult patients (≥18 years), with polymerase chain reaction (PCR)-confirmed COVID-19 admitted to ICU within 7 days of initial hospitalization , who do not have another firm indication for anticoagulation (such as mechanical valve, high-risk atrial fibrillation (AF), VTE, or left ventricle (LV) thrombus),who are not enrolled in another blinded randomized trial, and are willing to participate in the study and provide informed consent . 2. Estimated survival of at least 24 hours at the discretion of enrolling physician Exclusion Criteria for Anticoagulation Hypothesis 1. Weight <40 Kilogram (kg) 2. Overt bleeding at the day of enrollment 3. Known major bleeding within 30 days (according to the Bleeding Academic Research Consortium (BARC) definition, Appendix A) 4. Platelet count <50,000/Fl 5. Pregnancy (as confirmed by Beta human chorionic gonadotropin (HCG) testing among female patients <50 years) 6. Patients on Extracorporeal Membrane Oxygenation (ECMO) 7. History of heparin induced thrombocytopenia or immune thrombocytopenia 8. Ischemic stroke within the past 2 weeks 9. Craniotomy/major neurosurgery within the past 3 months 10. Major head or spinal trauma in the past 30 days 11. Known brain metastases or vascular malformations (aneurysm) 12. Presence of an epidural, spinal or pericardial catheter 13. Major surgery other than neurosurgery within 14 days prior to enrollment 14. Coexistence of severe obesity (weight >120 kg or BMI>35 kg/m2 along with severe renal insufficiency defined as creatinine clearance (CrCl) <30 mL/sec) 15. Allergic reaction to study medications 16. Lack or withdrawal of informed consent Inclusion Criteria for the Statin Randomization 1. Patients enrolled for the anticoagulation randomization 2. Willingness to participation in the study and providing informed consent Exclusions Criteria for the Statin Randomization 1. Baseline liver function tests> 3 times upper normal limits (ULN) or creatine kinase (CK) >500 U/L 2. Active liver disease (LFT>3 ULN plus histologic finding including cirrhosis or inflammation or necrosis) 3. Routine use of statins prior to the index hospitalization 4. Previous documented statin intolerance

Gender:

All

Minimum Age:

18 Years

Maximum Age:

N/A

Healthy Volunteers:

No

Overall Official
Overall Contact Contact information is only displayed when the study is recruiting subjects.
Location
Facility: Masih Daneshvari Hospital
Location Countries

Iran, Islamic Republic of

Verification Date

2021-08-01

Responsible Party

Type: Principal Investigator

Investigator Affiliation: Rajaie Cardiovascular Medical and Research Center

Investigator Full Name: Parham Sadeghipour

Investigator Title: Associate Professor

Keywords
Has Expanded Access No
Condition Browse
Number Of Arms 4
Arm Group

Label: Intermediate dose anticoagulation

Type: Experimental

Description: Intermediate dose anticoagulation will be the the tested regimen. The anticoagulation regimen will be modified according to weight/ body mass index, and creatinine clearance level (Cl Cr). Enoxaparin will be the primary agent for anticoagulation, with unfractionated heparin reserved only for patients with creatinine clearance of ≤15 mL/min according to Cockcroft-Gault Formula.

Label: Standard Prophylaxis

Type: Active Comparator

Description: Standard prophylaxis dose anticoagulation will be the anticoagulation of choice in the control arm. Enoxaparin will be the primary agent for anticoagulation, with unfractionated heparin reserved only for patients with creatinine clearance of ≤15 mL/min according Cockcroft-Gault Formula.

Label: Atorvastatin 20

Type: Experimental

Description: Atorvastatin 20 mg daily will be the statin therapy of choice in the intervention arm

Label: Atorvastatin 20 mg Matched placebo

Type: Placebo Comparator

Description: Matching placebo will be used for the control arm

Acronym INSPIRATION
Patient Data No
Study Design Info

Allocation: Randomized

Intervention Model: Factorial Assignment

Intervention Model Description: 1:1 multicenter open-label 2x2 factorial design randomized controlled trial with allocation sequence concealment and blinded endpoint adjudication.

Primary Purpose: Treatment

Masking: Single (Outcomes Assessor)

Masking Description: For the first hypothesis, allocation sequence concealment and blinded endpoint adjudication. For the second hypothesis, allocation sequence concealment, double-blind medication administration, and blinded endpoint adjudication.

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