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

Covid19 Clinical Trial

— INSPIRATION  

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT04486508
• Other study ID #: 99060
• Status: Completed
• Phase: Phase 3
• Start date: July 30, 2020
• Est. completion date: July 5, 2021

Study information

• Verified date: August 2021
• Source: Rajaie Cardiovascular Medical and Research Center
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 600
• Est. completion date: July 5, 2021
• Est. primary completion date: April 4, 2021
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Covid19

Intervention

Drug:
• intermediate dose Enoxaparin/ unfractionated heparin
Intermediate dose anticoagulation according to creatinine clearance and weight
• standard prophylactic dose Enoxaparin/ unfractionated heparin
Standard prophylaxis anticoagulation according to creatinine clearance and weight
• Atorvastatin 20mg
Statin
• Matched placebo
Matched placebo to atorvastatin 20 mg

Locations

Country	Name	City	State
Iran, Islamic Republic of	Masih Daneshvari Hospital	Tehran

Sponsors (13)

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

Country where clinical trial is conducted

Iran, Islamic Republic of, 

References & Publications (1)

Bikdeli B, Talasaz AH, Rashidi F, Sharif-Kashani B, Farrokhpour M, Bakhshandeh H, Sezavar H, Dabbagh A, Beigmohammadi MT, Payandemehr P, Yadollahzadeh M, Riahi T, Khalili H, Jamalkhani S, Rezaeifar P, Abedini A, Lookzadeh S, Shahmirzaei S, Tahamtan O, Mat — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Rate of objectively clinically-diagnosed type I acute myocardial infarction	According to the fourth universal definition of myocardial infraction and confirmed by coronary angiography, intravascular imaging or autopsy	30 days from enrollment
Other	Rate of objectively clinically -diagnosed stroke	Any stroke episode which has been confirmed with appropriate diagnostic imaging (brain CT and/or brain MRI)	30 days from enrollment
Other	Rate of objectively clinically -diagnosed acute peripheral arterial thrombosis	Imaging confirmed acute peripheral arterial thrombosis (by ultrasonography, CT, MRI, or invasive angiography)	30 days from enrollment
Other	Median ICU length of stay	Number of days that a patient has stayed in the ICU	30 days from enrollment
Other	ICU discharge status	Status of patients regarding to mortality (alive/dead) at the time of discharge from ICU	30 days from enrollment
Other	Incident atrial fibrillation	Any AF episode which has been confirmed by at least one ECG or telemetry monitoring, in patients without prior history of AF	30 days from enrollment
Other	Rate of need for renal replacement therapy	Use hemodialysis or veno-venous hemofiltration or peritoneal dialysis for a patient during the hospitalization period, due to acute kidney injury	30 days from enrollment
Other	Post-COVID-19 Functional Status	Based on Post-COVID-19 Functional Status questionnaire, which varies fro score 0 to 4, and higher scores mean worse outcome.	60 and 90 -day
Primary	a composite of acute VTE, arterial thrombosis, treatment with ECMO, or all-cause mortality	composite of adjudicated 30-day acute VTE, arterial thrombosis, treatment with extracorporeal membrane oxygenation (ECMO), or all-cause mortality.	30 days from enrollment
Secondary	Rate of all-cause mortality	Patient status regarding to being alive or dead at the end of 30-day follow up	30 days from enrollment
Secondary	Rate of objectively-confirmed VTE	Distal or proximal deep vein thrombosis which has been confirmed by ultrasonography or venography/ PE confirmed by at least one CTPA or lung scan	30 days from enrollment
Secondary	Ventilator free days	Difference between days of ICU stay and days on invasive mechanical ventilation	30 days from enrollment
Secondary	Rate of major bleeding	According to the Bleeding Academic Research Consortium (BARC 3 or 5 bleeding)	30 days from enrollment
Secondary	Rate of clinically-relevant non-major bleeding	Clinically-significant bleeding, not fulfilling criteria for major bleeding)	30 days from enrollment
Secondary	Rate of severe thrombocytopenia	Platelet count <20.000	30 days from enrollment
Secondary	Rate of rise in liver enzymes	Increase liver function tests 3 times greater than upper limit of normal	30 days from enrollment
Secondary	Clinically-diagnosed myopathy	Assessed by clinical and biomarker tests according to the treating physicians.	30 days from enrollment
Secondary	Objectively-confirmed arterial thrombosis	Imaging confirmed acute arterial thrombosis (by ultrasonography, CT, MRI, or invasive angiography)	30 days from enrollment

External Links

•   COVID-19 and Thrombotic or Thromboembolic Disease: Implications for Prevention, Antithrombotic Therapy, and Follow-Up: JACC State-of-the-Art Review
•   Pharmacological Agents Targeting Thromboinflammation in COVID-19: Review and Implications for Future Research