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

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ClinicalTrials.gov Identifier: NCT04486508
Recruitment Status : Active, not recruiting
First Posted : July 24, 2020
Last Update Posted : April 19, 2021
Sponsor:
Collaborators:
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
Information provided by (Responsible Party):
Parham Sadeghipour, Rajaie Cardiovascular Medical and Research Center

Tracking Information
First Submitted Date  ICMJE July 22, 2020
First Posted Date  ICMJE July 24, 2020
Last Update Posted Date April 19, 2021
Actual Study Start Date  ICMJE July 30, 2020
Actual Primary Completion Date April 4, 2021   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: February 4, 2021)
a composite of acute VTE, arterial thrombosis, treatment with ECMO, or all-cause mortality [ Time Frame: 30 days from enrollment ]
composite of adjudicated 30-day acute VTE, arterial thrombosis, treatment with extracorporeal membrane oxygenation (ECMO), or all-cause mortality.
Original Primary Outcome Measures  ICMJE
 (submitted: July 22, 2020)
Composite of incident VTE, undergoing ECMO, and all-cause mortality [ Time Frame: 30 days from enrollment ]
Composite of objectively-confirmed venous thromboembolism, undergoing extracorporeal membrane oxygenation (ECMO), or death from any cause
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: April 6, 2021)
  • Rate of all-cause mortality [ Time Frame: 30 days from enrollment ]
    Patient status regarding to being alive or dead at the end of 30-day follow up
  • Rate of objectively-confirmed VTE [ Time Frame: 30 days from enrollment ]
    Distal or proximal deep vein thrombosis which has been confirmed by ultrasonography or venography/ PE confirmed by at least one CTPA or lung scan
  • Ventilator free days [ Time Frame: 30 days from enrollment ]
    Difference between days of ICU stay and days on invasive mechanical ventilation
  • Rate of major bleeding [ Time Frame: 30 days from enrollment ]
    According to the Bleeding Academic Research Consortium (BARC 3 or 5 bleeding)
  • Rate of clinically-relevant non-major bleeding [ Time Frame: 30 days from enrollment ]
    Clinically-significant bleeding, not fulfilling criteria for major bleeding)
  • Rate of severe thrombocytopenia [ Time Frame: 30 days from enrollment ]
    Platelet count <20.000
  • Rate of rise in liver enzymes [ Time Frame: 30 days from enrollment ]
    Increase liver function tests 3 times greater than upper limit of normal
  • Clinically-diagnosed myopathy [ Time Frame: 30 days from enrollment ]
    Assessed by clinical and biomarker tests according to the treating physicians.
  • Objectively-confirmed arterial thrombosis [ Time Frame: 30 days from enrollment ]
    Imaging confirmed acute arterial thrombosis (by ultrasonography, CT, MRI, or invasive angiography)
Original Secondary Outcome Measures  ICMJE Not Provided
Current Other Pre-specified Outcome Measures
 (submitted: October 16, 2020)
  • Rate of objectively clinically-diagnosed type I acute myocardial infarction [ Time Frame: 30 days from enrollment ]
    According to the fourth universal definition of myocardial infraction and confirmed by coronary angiography, intravascular imaging or autopsy
  • Rate of objectively clinically -diagnosed stroke [ Time Frame: 30 days from enrollment ]
    Any stroke episode which has been confirmed with appropriate diagnostic imaging (brain CT and/or brain MRI)
  • Rate of objectively clinically -diagnosed acute peripheral arterial thrombosis [ Time Frame: 30 days from enrollment ]
    Imaging confirmed acute peripheral arterial thrombosis (by ultrasonography, CT, MRI, or invasive angiography)
  • Median ICU length of stay [ Time Frame: 30 days from enrollment ]
    Number of days that a patient has stayed in the ICU
  • ICU discharge status [ Time Frame: 30 days from enrollment ]
    Status of patients regarding to mortality (alive/dead) at the time of discharge from ICU
  • Incident atrial fibrillation [ Time Frame: 30 days from enrollment ]
    Any AF episode which has been confirmed by at least one ECG or telemetry monitoring, in patients without prior history of AF
  • Rate of need for renal replacement therapy [ Time Frame: 30 days from enrollment ]
    Use hemodialysis or veno-venous hemofiltration or peritoneal dialysis for a patient during the hospitalization period, due to acute kidney injury
  • Post-COVID-19 Functional Status [ Time Frame: 60 and 90 -day ]
    Based on Post-COVID-19 Functional Status questionnaire, which varies fro score 0 to 4, and higher scores mean worse outcome.
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Intermediate-dose vs Standard Prophylactic Anticoagulation and Statin vs Placebo in ICU Patients With COVID-19
Official Title  ICMJE 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
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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE 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.
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.

Primary Purpose: Treatment
Condition  ICMJE Covid19
Intervention  ICMJE
  • Drug: intermediate dose Enoxaparin/ unfractionated heparin
    Intermediate dose anticoagulation according to creatinine clearance and weight
    Other Name: Intermediate dose anticoagulation
  • Drug: standard prophylactic dose Enoxaparin/ unfractionated heparin
    Standard prophylaxis anticoagulation according to creatinine clearance and weight
    Other Name: Standard dose prophylaxis anticoagulation
  • Drug: Atorvastatin 20mg
    Statin
    Other Name: Statin
  • Drug: Matched placebo
    Matched placebo to atorvastatin 20 mg
    Other Name: Statin
Study Arms  ICMJE
  • Experimental: Intermediate dose anticoagulation
    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.
    Intervention: Drug: intermediate dose Enoxaparin/ unfractionated heparin
  • Active Comparator: Standard Prophylaxis
    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.
    Intervention: Drug: standard prophylactic dose Enoxaparin/ unfractionated heparin
  • Experimental: Atorvastatin 20
    Atorvastatin 20 mg daily will be the statin therapy of choice in the intervention arm
    Intervention: Drug: Atorvastatin 20mg
  • Placebo Comparator: Atorvastatin 20 mg Matched placebo
    Matching placebo will be used for the control arm
    Intervention: Drug: Matched placebo
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Active, not recruiting
Actual Enrollment  ICMJE
 (submitted: July 26, 2020)
600
Original Estimated Enrollment  ICMJE
 (submitted: July 22, 2020)
410
Estimated Study Completion Date  ICMJE May 3, 2021
Actual Primary Completion Date April 4, 2021   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Iran, Islamic Republic of
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT04486508
Other Study ID Numbers  ICMJE 99060
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party Parham Sadeghipour, Rajaie Cardiovascular Medical and Research Center
Study Sponsor  ICMJE Rajaie Cardiovascular Medical and Research Center
Collaborators  ICMJE
  • 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
Investigators  ICMJE
Principal Investigator: Parham Sadeghipour, MD Rajaie Cardiovascular Medical and Research Center
Principal Investigator: Behnood Bikdeli, MD, MS Brigham and Women's Hospital, Harvard Medical School
PRS Account Rajaie Cardiovascular Medical and Research Center
Verification Date April 2021

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP