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

NCT04486508 | Completed Phase 3 DMC

• 1 other identifier: 99060
• Study Type: interventional
• Target: 600
• Locations: 1 country
• Sites: 1

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.

Conditions

Covid19

Keywords

anticoagulation; statin

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (9)

• 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

Other Outcomes (8)

• Rate of objectively clinically-diagnosed type I acute myocardial infarction

  30 days from enrollment

• Rate of objectively clinically -diagnosed stroke

  30 days from enrollment

• Rate of objectively clinically -diagnosed acute peripheral arterial thrombosis

  30 days from enrollment

Study Arms (4)

Intermediate dose anticoagulation

EXPERIMENTAL

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.

Drug: intermediate dose Enoxaparin/ unfractionated heparin

Standard Prophylaxis

ACTIVE COMPARATOR

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.

Drug: standard prophylactic dose Enoxaparin/ unfractionated heparin

Atorvastatin 20

EXPERIMENTAL

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

Drug: Atorvastatin 20mg

Atorvastatin 20 mg Matched placebo

PLACEBO COMPARATOR

Matching placebo will be used for the control arm

Drug: Matched placebo

Interventions

intermediate dose Enoxaparin/ unfractionated heparin DRUG

Intermediate dose anticoagulation according to creatinine clearance and weight

Also known as: Intermediate dose anticoagulation

Intermediate dose anticoagulation

standard prophylactic dose Enoxaparin/ unfractionated heparin DRUG

Standard prophylaxis anticoagulation according to creatinine clearance and weight

Also known as: Standard dose prophylaxis anticoagulation

Standard Prophylaxis

Atorvastatin 20mg DRUG

Statin

Also known as: Statin

Atorvastatin 20

Matched placebo DRUG

Matched placebo to atorvastatin 20 mg

Also known as: Statin

Atorvastatin 20 mg Matched placebo

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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 .
• Estimated survival of at least 24 hours at the discretion of enrolling physician

You may not qualify if:

• Weight \<40 Kilogram (kg)
• Overt bleeding at the day of enrollment
• Known major bleeding within 30 days (according to the Bleeding Academic Research Consortium (BARC) definition, Appendix A)
• Platelet count \<50,000/Fl
• Pregnancy (as confirmed by Beta human chorionic gonadotropin (HCG) testing among female patients \<50 years)
• Patients on Extracorporeal Membrane Oxygenation (ECMO)
• History of heparin induced thrombocytopenia or immune thrombocytopenia
• Ischemic stroke within the past 2 weeks
• Craniotomy/major neurosurgery within the past 3 months
• Major head or spinal trauma in the past 30 days
• Known brain metastases or vascular malformations (aneurysm)
• Presence of an epidural, spinal or pericardial catheter
• Major surgery other than neurosurgery within 14 days prior to enrollment
• 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)
• Allergic reaction to study medications

Sponsors & Collaborators

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

Study Sites (1)

Masih Daneshvari Hospital

Tehran, 199691110, Iran

Location

Related Publications (6)

• 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.

  PMID: 32992075 RESULT

• Talasaz AH, Sadeghipour P, Bakhshandeh H, Sharif-Kashani B, Rashidi F, Beigmohammadi MT, Moghadam KG, Rezaian S, Dabbagh A, Sezavar SH, Farrokhpour M, Abedini A, Aliannejad R, Riahi T, Yadollahzadeh M, Lookzadeh S, Rezaeifar P, Matin S, Tahamtan O, Mohammadi K, Zoghi E, Rahmani H, Hosseini SH, Mousavian SM, Abri H, Sadeghipour P, Baghizadeh E, Rafiee F, Jamalkhani S, Amin A, Mohebbi B, Parhizgar SE, Soleimanzadeh M, Aghakouchakzadeh M, Eslami V, Payandemehr P, Khalili H, Talakoob H, Tojari T, Shafaghi S, Tabrizi S, Kakavand H, Kashefizadeh A, Najafi A, Jimenez D, Gupta A, Madhavan MV, Sethi SS, Parikh SA, Monreal M, Hadavand N, Hajighasemi A, Ansarin K, Maleki M, Sadeghian S, Barco S, Siegerink B, Spatz ES, Piazza G, Kirtane AJ, Tassell BWV, Lip GYH, Klok FA, Goldhaber SZ, Stone GW, Krumholz HM, Bikdeli B. Atorvastatin versus Placebo in ICU Patients with COVID-19: Ninety-day Results of the INSPIRATION-S Trial. Thromb Haemost. 2023 Jul;123(7):723-733. doi: 10.1055/a-2059-4844. Epub 2023 Mar 21.

  PMID: 36944357 DERIVED

• 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.

  PMID: 35244208 DERIVED

• 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.

  PMID: 35165110 DERIVED

• 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.

  PMID: 34996756 DERIVED

• 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.

  PMID: 33734299 DERIVED

Related 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

MeSH Terms

Conditions

COVID-19

Interventions

Heparin; Atorvastatin; Hydroxymethylglutaryl-CoA Reductase Inhibitors

Condition Hierarchy (Ancestors)

Pneumonia, Viral; Pneumonia; Respiratory Tract Infections; Infections; Virus Diseases; Coronavirus Infections; Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Lung Diseases; Respiratory Tract Diseases

Intervention Hierarchy (Ancestors)

Glycosaminoglycans; Polysaccharides; Carbohydrates; Pyrroles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Heptanoic Acids; Fatty Acids; Lipids; Anticholesteremic Agents; Hypolipidemic Agents; Antimetabolites; Molecular Mechanisms of Pharmacological Action; Pharmacologic Actions; Chemical Actions and Uses; Enzyme Inhibitors; Lipid Regulating Agents; Therapeutic Uses

Study Officials

• Parham Sadeghipour, MD

  Rajaie Cardiovascular Medical and Research Center

  PRINCIPAL INVESTIGATOR

• Behnood Bikdeli, MD, MS

  Brigham and Women's Hospital, Harvard Medical School

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: SINGLE
• Who Masked: OUTCOMES ASSESSOR
• Masking Details: 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.
• Purpose: TREATMENT
• Intervention Model: FACTORIAL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Associate Professor

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

Study Record Dates

• First Submitted: July 22, 2020
• First Posted: July 24, 2020
• Study Start: July 30, 2020
• Primary Completion: April 4, 2021
• Study Completion: July 5, 2021
• Last Updated: August 17, 2021

Record last verified: 2021-08

Data Sharing

• IPD Sharing: Will not share

Locations

IR (1)