Back to resultsIntermediate-dose vs Standard Prophylactic Anticoagulation and Statin vs Placebo in ICU Patients With COVID-19 (INSPIRATION)
Primary Purpose
Covid19
Status
Completed
Phase
Phase 3
Locations
Iran, Islamic Republic of
Study Type
Interventional
Intervention
intermediate dose Enoxaparin/ unfractionated heparin
standard prophylactic dose Enoxaparin/ unfractionated heparin
Atorvastatin 20mg
Matched placebo
Sponsored by
About this trial
This is an interventional treatment trial for Covid19 focused on measuring anticoagulation, statin
Eligibility Criteria
Inclusion Criteria for Anticoagulation Hypothesis
- 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
Exclusion Criteria for Anticoagulation Hypothesis
- 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
- Lack or withdrawal of informed consent
Inclusion Criteria for the Statin Randomization
- Patients enrolled for the anticoagulation randomization
- Willingness to participation in the study and providing informed consent
Exclusions Criteria for the Statin Randomization
- Baseline liver function tests> 3 times upper normal limits (ULN) or creatine kinase (CK) >500 U/L
- Active liver disease (LFT>3 ULN plus histologic finding including cirrhosis or inflammation or necrosis)
- Routine use of statins prior to the index hospitalization
- Previous documented statin intolerance
Sites / Locations
- Masih Daneshvari Hospital
Arms of the Study
Arm 1
Arm 2
Arm 3
Arm 4
Arm Type
Experimental
Active Comparator
Experimental
Placebo Comparator
Arm Label
Intermediate dose anticoagulation
Standard Prophylaxis
Atorvastatin 20
Atorvastatin 20 mg Matched placebo
Arm 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.
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.
Atorvastatin 20 mg daily will be the statin therapy of choice in the intervention arm
Matching placebo will be used for the control arm
Outcomes
Primary Outcome Measures
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.
Secondary Outcome Measures
Rate of all-cause mortality
Patient status regarding to being alive or dead at the end of 30-day follow up
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
Ventilator free days
Difference between days of ICU stay and days on invasive mechanical ventilation
Rate of major bleeding
According to the Bleeding Academic Research Consortium (BARC 3 or 5 bleeding)
Rate of clinically-relevant non-major bleeding
Clinically-significant bleeding, not fulfilling criteria for major bleeding)
Rate of severe thrombocytopenia
Platelet count <20.000
Rate of rise in liver enzymes
Increase liver function tests 3 times greater than upper limit of normal
Clinically-diagnosed myopathy
Assessed by clinical and biomarker tests according to the treating physicians.
Objectively-confirmed arterial thrombosis
Imaging confirmed acute arterial thrombosis (by ultrasonography, CT, MRI, or invasive angiography)
Full Information
NCT ID
NCT04486508
First Posted
July 22, 2020
Last Updated
August 14, 2021
Sponsor
Rajaie Cardiovascular Medical and Research Center
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
1. Study Identification
Unique Protocol Identification Number
NCT04486508
Brief Title
Intermediate-dose vs Standard Prophylactic Anticoagulation and Statin vs Placebo in ICU Patients With COVID-19
Acronym
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
Study Type
Interventional
2. Study Status
Record Verification Date
August 2021
Overall Recruitment Status
Completed
Study Start Date
July 30, 2020 (Actual)
Primary Completion Date
April 4, 2021 (Actual)
Study Completion Date
July 5, 2021 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Rajaie Cardiovascular Medical and Research Center
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
4. Oversight
Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes
5. Study Description
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.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Covid19
Keywords
anticoagulation, statin
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 3
Interventional Study Model
Factorial Assignment
Model Description
1:1 multicenter open-label 2x2 factorial design randomized controlled trial with allocation sequence concealment and blinded endpoint adjudication.
Masking
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.
Allocation
Randomized
Enrollment
600 (Actual)
8. Arms, Groups, and Interventions
Arm Title
Intermediate dose anticoagulation
Arm Type
Experimental
Arm 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.
Arm Title
Standard Prophylaxis
Arm Type
Active Comparator
Arm 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.
Arm Title
Atorvastatin 20
Arm Type
Experimental
Arm Description
Atorvastatin 20 mg daily will be the statin therapy of choice in the intervention arm
Arm Title
Atorvastatin 20 mg Matched placebo
Arm Type
Placebo Comparator
Arm Description
Matching placebo will be used for the control arm
Intervention Type
Drug
Intervention Name(s)
intermediate dose Enoxaparin/ unfractionated heparin
Other Intervention Name(s)
Intermediate dose anticoagulation
Intervention Description
Intermediate dose anticoagulation according to creatinine clearance and weight
Intervention Type
Drug
Intervention Name(s)
standard prophylactic dose Enoxaparin/ unfractionated heparin
Other Intervention Name(s)
Standard dose prophylaxis anticoagulation
Intervention Description
Standard prophylaxis anticoagulation according to creatinine clearance and weight
Intervention Type
Drug
Intervention Name(s)
Atorvastatin 20mg
Other Intervention Name(s)
Statin
Intervention Description
Statin
Intervention Type
Drug
Intervention Name(s)
Matched placebo
Other Intervention Name(s)
Statin
Intervention Description
Matched placebo to atorvastatin 20 mg
Primary Outcome Measure Information:
Title
a composite of acute VTE, arterial thrombosis, treatment with ECMO, or all-cause mortality
Description
composite of adjudicated 30-day acute VTE, arterial thrombosis, treatment with extracorporeal membrane oxygenation (ECMO), or all-cause mortality.
Time Frame
30 days from enrollment
Secondary Outcome Measure Information:
Title
Rate of all-cause mortality
Description
Patient status regarding to being alive or dead at the end of 30-day follow up
Time Frame
30 days from enrollment
Title
Rate of objectively-confirmed VTE
Description
Distal or proximal deep vein thrombosis which has been confirmed by ultrasonography or venography/ PE confirmed by at least one CTPA or lung scan
Time Frame
30 days from enrollment
Title
Ventilator free days
Description
Difference between days of ICU stay and days on invasive mechanical ventilation
Time Frame
30 days from enrollment
Title
Rate of major bleeding
Description
According to the Bleeding Academic Research Consortium (BARC 3 or 5 bleeding)
Time Frame
30 days from enrollment
Title
Rate of clinically-relevant non-major bleeding
Description
Clinically-significant bleeding, not fulfilling criteria for major bleeding)
Time Frame
30 days from enrollment
Title
Rate of severe thrombocytopenia
Description
Platelet count <20.000
Time Frame
30 days from enrollment
Title
Rate of rise in liver enzymes
Description
Increase liver function tests 3 times greater than upper limit of normal
Time Frame
30 days from enrollment
Title
Clinically-diagnosed myopathy
Description
Assessed by clinical and biomarker tests according to the treating physicians.
Time Frame
30 days from enrollment
Title
Objectively-confirmed arterial thrombosis
Description
Imaging confirmed acute arterial thrombosis (by ultrasonography, CT, MRI, or invasive angiography)
Time Frame
30 days from enrollment
Other Pre-specified Outcome Measures:
Title
Rate of objectively clinically-diagnosed type I acute myocardial infarction
Description
According to the fourth universal definition of myocardial infraction and confirmed by coronary angiography, intravascular imaging or autopsy
Time Frame
30 days from enrollment
Title
Rate of objectively clinically -diagnosed stroke
Description
Any stroke episode which has been confirmed with appropriate diagnostic imaging (brain CT and/or brain MRI)
Time Frame
30 days from enrollment
Title
Rate of objectively clinically -diagnosed acute peripheral arterial thrombosis
Description
Imaging confirmed acute peripheral arterial thrombosis (by ultrasonography, CT, MRI, or invasive angiography)
Time Frame
30 days from enrollment
Title
Median ICU length of stay
Description
Number of days that a patient has stayed in the ICU
Time Frame
30 days from enrollment
Title
ICU discharge status
Description
Status of patients regarding to mortality (alive/dead) at the time of discharge from ICU
Time Frame
30 days from enrollment
Title
Incident atrial fibrillation
Description
Any AF episode which has been confirmed by at least one ECG or telemetry monitoring, in patients without prior history of AF
Time Frame
30 days from enrollment
Title
Rate of need for renal replacement therapy
Description
Use hemodialysis or veno-venous hemofiltration or peritoneal dialysis for a patient during the hospitalization period, due to acute kidney injury
Time Frame
30 days from enrollment
Title
Post-COVID-19 Functional Status
Description
Based on Post-COVID-19 Functional Status questionnaire, which varies fro score 0 to 4, and higher scores mean worse outcome.
Time Frame
60 and 90 -day
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria for Anticoagulation Hypothesis
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
Exclusion Criteria for Anticoagulation Hypothesis
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
Lack or withdrawal of informed consent
Inclusion Criteria for the Statin Randomization
Patients enrolled for the anticoagulation randomization
Willingness to participation in the study and providing informed consent
Exclusions Criteria for the Statin Randomization
Baseline liver function tests> 3 times upper normal limits (ULN) or creatine kinase (CK) >500 U/L
Active liver disease (LFT>3 ULN plus histologic finding including cirrhosis or inflammation or necrosis)
Routine use of statins prior to the index hospitalization
Previous documented statin intolerance
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Parham Sadeghipour, MD
Organizational Affiliation
Rajaie Cardiovascular Medical and Research Center
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Behnood Bikdeli, MD, MS
Organizational Affiliation
Brigham and Women's Hospital, Harvard Medical School
Official's Role
Principal Investigator
Facility Information:
Facility Name
Masih Daneshvari Hospital
City
Tehran
ZIP/Postal Code
199691110
Country
Iran, Islamic Republic of
12. IPD Sharing Statement
Plan to Share IPD
No
Citations:
PubMed Identifier
32992075
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.
Results Reference
result
PubMed Identifier
35244208
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.
Results Reference
derived
PubMed Identifier
35165110
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.
Results Reference
derived
PubMed Identifier
34996756
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.
Results Reference
derived
PubMed Identifier
33734299
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.
Results Reference
derived
Links:
URL
https://pubmed.ncbi.nlm.nih.gov/32311448/
Description
COVID-19 and Thrombotic or Thromboembolic Disease: Implications for Prevention, Antithrombotic Therapy, and Follow-Up: JACC State-of-the-Art Review
URL
https://pubmed.ncbi.nlm.nih.gov/32473596/
Description
Pharmacological Agents Targeting Thromboinflammation in COVID-19: Review and Implications for Future Research
Learn more about this trial
Intermediate-dose vs Standard Prophylactic Anticoagulation and Statin vs Placebo in ICU Patients With COVID-19
We'll reach out to this number within 24 hrs