Clinical trial NCT04486508: Intermediate-dose vs Standard Prophylactic Anticoagulation and Statin vs Placebo in ICU Patients With COVID-19
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Covid19
Keywords: anticoagulation
statin
Lead sponsor: Rajaie Cardiovascular Medical and Research Center
Sponsor class: OTHER
Collaborators: name: Brigham and Women's Hospital
name: Tehran Heart Center
name: Masih Daneshvari Hospital
name: Hazrat Rasool Hospital
name: Modarres Hospital
name: Firuzgar hospital affiliated to Iran University of Medical Sciences
name: Imam Khomeini Hospital
name: Sina Hospital, Iran
name: Tabriz University of Medical Sciences
name: Shariati Hospital
name: Imam Ali Hospital
name: Labbafinejhad Hospital
First posted: 2020-07-24
Enrollment: 600
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: FACTORIAL
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

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.

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

Primary outcomes:
measure: a composite of acute VTE, arterial thrombosis, treatment with ECMO, or all-cause mortality
timeFrame: 30 days from enrollment
Secondary outcomes:
measure: Rate of all-cause mortality
timeFrame: 30 days from enrollment
measure: Rate of objectively-confirmed VTE
timeFrame: 30 days from enrollment
measure: Ventilator free days
timeFrame: 30 days from enrollment
measure: Rate of major bleeding
timeFrame: 30 days from enrollment
measure: Rate of clinically-relevant non-major bleeding
timeFrame: 30 days from enrollment
measure: Rate of severe thrombocytopenia
timeFrame: 30 days from enrollment
measure: Rate of rise in liver enzymes
timeFrame: 30 days from enrollment
measure: Clinically-diagnosed myopathy
timeFrame: 30 days from enrollment
measure: Objectively-confirmed arterial thrombosis
timeFrame: 30 days from enrollment
Other outcomes:
measure: Rate of objectively clinically-diagnosed type I acute myocardial infarction
timeFrame: 30 days from enrollment
measure: Rate of objectively clinically -diagnosed stroke
timeFrame: 30 days from enrollment
measure: Rate of objectively clinically -diagnosed acute peripheral arterial thrombosis
timeFrame: 30 days from enrollment
measure: Median ICU length of stay
timeFrame: 30 days from enrollment
measure: ICU discharge status
timeFrame: 30 days from enrollment
measure: Incident atrial fibrillation
timeFrame: 30 days from enrollment
measure: Rate of need for renal replacement therapy
timeFrame: 30 days from enrollment
measure: Post-COVID-19 Functional Status
timeFrame: 60 and 90 -day
Locations:
city: Tehran
country: Iran, Islamic Republic of
facility: Masih Daneshvari Hospital
Study officials:
affiliation: Rajaie Cardiovascular Medical and Research Center
name: Parham Sadeghipour, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Brigham and Women's Hospital, Harvard Medical School
name: Behnood Bikdeli, MD, MS
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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, Matin S, Amin A, Parhizgar SE, Jimenez D, Gupta A, Madhavan MV, Parikh SA, Monreal M, Hadavand N, Hajighasemi A, Maleki M, Sadeghian S, Mohebbi B, Piazza G, Kirtane AJ, Lip GYH, Krumholz HM, Goldhaber SZ, Sadeghipour P. Intermediate versus standard-dose prophylactic anticoagulation and statin therapy versus placebo in critically-ill patients with COVID-19: Rationale and design of the INSPIRATION/INSPIRATION-S studies. Thromb Res. 2020 Dec;196:382-394. doi: 10.1016/j.thromres.2020.09.027. Epub 2020 Sep 24.
citation: Flumignan RL, Civile VT, Tinoco JDS, Pascoal PI, Areias LL, Matar CF, Tendal B, Trevisani VF, Atallah AN, Nakano LC. Anticoagulants for people hospitalised with COVID-19. Cochrane Database Syst Rev. 2022 Mar 4;3(3):CD013739. doi: 10.1002/14651858.CD013739.pub2.
citation: Erdem S, Ipek F, Bars A, Genc V, Erpek E, Mohammadi S, Altinata A, Akar S. Investigating the effect of macro-scale estimators on worldwide COVID-19 occurrence and mortality through regression analysis using online country-based data sources. BMJ Open. 2022 Feb 14;12(2):e055562. doi: 10.1136/bmjopen-2021-055562.
citation: INSPIRATION-S Investigators. Atorvastatin versus placebo in patients with covid-19 in intensive care: randomized controlled trial. BMJ. 2022 Jan 7;376:e068407. doi: 10.1136/bmj-2021-068407.
citation: INSPIRATION Investigators; Sadeghipour P, Talasaz AH, Rashidi F, Sharif-Kashani B, Beigmohammadi MT, Farrokhpour M, Sezavar SH, Payandemehr P, Dabbagh A, Moghadam KG, Jamalkhani S, Khalili H, Yadollahzadeh M, Riahi T, Rezaeifar P, Tahamtan O, Matin S, Abedini A, Lookzadeh S, Rahmani H, Zoghi E, Mohammadi K, Sadeghipour P, Abri H, Tabrizi S, Mousavian SM, Shahmirzaei S, Bakhshandeh H, Amin A, Rafiee F, Baghizadeh E, Mohebbi B, Parhizgar SE, Aliannejad R, Eslami V, Kashefizadeh A, Kakavand H, Hosseini SH, Shafaghi S, Ghazi SF, Najafi A, Jimenez D, Gupta A, Madhavan MV, Sethi SS, Parikh SA, Monreal M, Hadavand N, Hajighasemi A, Maleki M, Sadeghian S, Piazza G, Kirtane AJ, Van Tassell BW, Dobesh PP, Stone GW, Lip GYH, Krumholz HM, Goldhaber SZ, Bikdeli B. Effect of Intermediate-Dose vs Standard-Dose Prophylactic Anticoagulation on Thrombotic Events, Extracorporeal Membrane Oxygenation Treatment, or Mortality Among Patients With COVID-19 Admitted to the Intensive Care Unit: The INSPIRATION Randomized Clinical Trial. JAMA. 2021 Apr 27;325(16):1620-1630. doi: 10.1001/jama.2021.4152.