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Steroids and Unfractionated Heparin in Critically Ill Patients With Pneumonia From COVID-19 Infection (STAUNCH-19)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04528888
Recruitment Status : Not yet recruiting
First Posted : August 27, 2020
Last Update Posted : August 27, 2020
Sponsor:
Information provided by (Responsible Party):
Massimo Girardis, University of Modena and Reggio Emilia

Brief Summary:
SARS-CoV-2 infection seems to induce in most critical cases an excessive and aberrant hyper-inflammatory host immune response that is associated with a so-called "cytokine storm", moreover pro-thrombotic derangements of haemostatic system is another common finding in most severe forms of COVID19 infections, which may be explained by the activation of coagulative cascade primed by inflammatory stimuli, in line with what is observed in many other forms of sepsis. Targeting inflammatory responses exploiting steroids' anti-inflammatory activity along with thrombosis prevention may be a promising therapeutic option to improve patients' outcome. Despite the biological plausibility, no good evidence is available on the efficacy and safety of heparin on sepsis patients, and many issues have to be addressed, regarding the proper timing, dosages and administration schedules of anticoagulant drugs. The primary objective is to assess the hypothesis that an adjunctive therapy with steroids and unfractionated heparin (UFH) or with steroids and low molecular weight heparin (LMWH) are more effective in reducing any-cause mortality in critically-ill patients with pneumonia from COVID- 19 infection compared to low molecular weight heparin (LMWH) alone. Mortality will be measured at 28 days. The study is designed as a multicenter, national, interventional, randomized, investigator sponsored, three arms study. Patients, who satisfy all inclusion criteria and no exclusion criteria, will be randomly assigned in a ratio 1:1:1 to one of the three treatment groups: LMWH group, LMWH+steroids or UFH+steroid group. A possible result showing the efficacy of the composite treatment in reducing the mortality rate among critically ill patients with pneumonia from COVID-19 infection will lead to a revision of the current clinical approach to this disease.

Condition or disease Intervention/treatment Phase
Covid19 SARS-CoV Infection Pneumonia, Viral Coagulopathy Drug: Enoxaparin Drug: Methylprednisolone Drug: unfractionated heparin Phase 3

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 210 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: The study is designed as a multicenter, national, interventional, randomized, investigator sponsored, three arms study. Patients, who satisfy all inclusion criteria and no exclusion criteria, will be randomly assigned to one of the three treatment groups in a ratio 1:1:1. A block randomisation will be used with variable block sizes (block size 4-6-8), stratified by centre. Central randomisation will be performed using a secure, web-based, randomisation system. The allocation sequence will be generated by the study statistician using computer generated random numbers.
Masking: None (Open Label)
Masking Description: The study in conceived as open-label: the patients and all the health-care personnel will be aware of the assigned group.
Primary Purpose: Treatment
Official Title: Steroids and Unfractionated Heparin in Critically Ill Patients With Pneumonia From COVID-19 Infection. A Multicenter, Interventional, Randomized, Three Arms Study Design
Estimated Study Start Date : September 1, 2020
Estimated Primary Completion Date : June 30, 2021
Estimated Study Completion Date : July 30, 2021


Arm Intervention/treatment
Active Comparator: LMWH group
The treatments will be initiated as soon as possible after randomization (maximum allowed starting time 12h after randomization). Patients in this group will be administered enoxaparin at standard prophylactic dose (i.e., 4000 UI once day, increased to 6000 UI once day for patients weighting more than 90 kg). The treatment with enoxaparin will be initiated as soon as possible after randomization (maximum allowed starting time 12h after randomization). The treatment will be administered subcutaneously, daily up to ICU discharge. After ICU discharge it may be continued or interrupted in the destination ward up to clinical judgement of the attending physician.
Drug: Enoxaparin
Enoxaparin will be administered subcutaneously at standard prophylactic dose (i.e., 4000 UI once day, increased to 6000 UI once day for patients weighting more than 90 kg). The treatment will be administered daily up to ICU discharge. After ICU discharge it may be continued or interrupted in the destination ward up to clinical judgement of the attending physician.
Other Name: Inhixa

Experimental: LMWH + steroids group

The treatments will be initiated as soon as possible after randomization (maximum allowed starting time 12h after randomization).

Patients in this group will receive enoxaparin and methylprednisolone. Enoxaparin will be administered at standard prophylactic dose (i.e., 4000 UI once day, increased to 6000 UI once day for patients weighting more than 90 kg). The treatment will be administered subcutaneously daily up to ICU discharge. After ICU discharge it may be continued or interrupted in the destination ward up to clinical judgement of the attending physician. Methylprednisolone will be administered intravenously with an initial bolus of 0,5 mg/kg followed by administration of 0,5 mg/kg 4 times daily for 7 days, 0,5 mg/kg 3 times daily from day 8 to day 10, 0,5 mg/kg 2 times daily at days 11 and 12 and 0,5 mg/kg once daily at days 13 and 14.

Drug: Enoxaparin
Enoxaparin will be administered subcutaneously at standard prophylactic dose (i.e., 4000 UI once day, increased to 6000 UI once day for patients weighting more than 90 kg). The treatment will be administered daily up to ICU discharge. After ICU discharge it may be continued or interrupted in the destination ward up to clinical judgement of the attending physician.
Other Name: Inhixa

Drug: Methylprednisolone
Methylprednisolone will be administered intravenously with an initial bolus of 0,5 mg/kg followed by administration of 0,5 mg/kg 4 times daily for 7 days, 0,5 mg/kg 3 times daily from day 8 to day 10, 0,5 mg/kg 2 times daily at days 11 and 12 and 0,5 mg/kg once daily at days 13 and 14.
Other Name: solu-medrol

Experimental: UFH + steroid group
The treatments will be initiated as soon as possible after randomization (maximum 12h). Patients will receive unfractionated heparin and methylprednisolone. Unfractionated heparin will be administered intravenously at therapeutic doses. The infusion will be started at an infusion rate of 18 IU/kg/hour and then modified to attain APTT Ratio in the range 1.5-2.0. aPTT will be periodically checked at intervals no longer than 12 hours. The treatment with unfractionated heparin will be administered up to ICU discharge. After ICU discharge anticoagulant therapy may be interrupted or switched to prophylaxis with LMWH in the destination ward up to clinical judgement of the attending physician. Methylprednisolone will be administered intravenously with an initial bolus of 0,5 mg/kg followed by administration of 0,5 mg/kg 4 times daily for 7 days, 0,5 mg/kg 3 times daily from day 8 to day 10, 0,5 mg/kg 2 times daily at days 11 and 12 and 0,5 mg/kg once daily at days 13 and 14.
Drug: Methylprednisolone
Methylprednisolone will be administered intravenously with an initial bolus of 0,5 mg/kg followed by administration of 0,5 mg/kg 4 times daily for 7 days, 0,5 mg/kg 3 times daily from day 8 to day 10, 0,5 mg/kg 2 times daily at days 11 and 12 and 0,5 mg/kg once daily at days 13 and 14.
Other Name: solu-medrol

Drug: unfractionated heparin
Patients in this group will receive unfractionated heparin and methylprednisolone. Unfractionated heparin will be administered intravenously at therapeutic doses. The infusion will be started at an infusion rate of 18 IU/kg/hour and then modified to attain APTT Ratio in the range 1.5-2.0. aPTT will be periodically checked at intervals no longer than 12 hours. The treatment with unfractionated heparin will be administered up to ICU discharge. After ICU discharge anticoagulant therapy may be interrupted or switched to prophylaxis with LMWH in the destination ward up to clinical judgement of the attending physician.
Other Name: Veracer




Primary Outcome Measures :
  1. All-cause mortality at day 28 [ Time Frame: Day 28 from randomization ]
    All-cause mortality at day 28, defined as the comparison of proportions of patients death for any cause at day 28 from randomization.


Secondary Outcome Measures :
  1. All-cause mortality at ICU discharge [ Time Frame: from randomization to ICU discharge, censored at day 30 ]
    All-cause mortality at ICU discharge, defined as the comparison of proportions of patients death for any cause at ICU discharge.

  2. All-cause mortality at hospital discharge [ Time Frame: from randomization to ICU discharge, censored at day 90 ]
    All-cause mortality at Hospital discharge, defined as the comparison of proportions of patients death for any cause at hospital discharge

  3. Need of rescue administration of high-dose steroids or immune-modulatory drugs [ Time Frame: from randomization to ICU discharge, censored at day 28 ]
    Occurrence of rescue administration of high-dose steroids or immune-modulatory drugs

  4. New organ dysfunction during ICU stay [ Time Frame: From randomization to ICU discharge, censored at day 28 ]
    Occurrence of new organ dysfunction during ICU stay. Organ dysfunction is defined as a Sequential Organ Failure Assessment (SOFA) score ≥3 for the corresponding organ occurring after randomization.

  5. Grade of organ dysfunction during ICU stay [ Time Frame: From randomization to ICU discharge, censored at day 28 ]
    Grade of organ dysfunction during ICU stay, grade of dysfunction is measured with Sequential Organ Failure Assessment (SOFA) score daily from randomization to day 28 or ICU discharge.

  6. ICU free days at day 28 [ Time Frame: From randomization to day 28 ]
    Total number of days between ICU discharge and day 28. If death occurs during the ICU stay before day 28 the ICU free days calculation will be 0. The ICU readmission before day 28 after randomization will be considered.

  7. Occurrence of new infections [ Time Frame: from randomization to day 28 ]
    Occurrence of new infections including bacterial infections, fungal infections by Candida, Aspergillus, and viral reactivations including Adenovirus, Herpes Virus e Cytomegalovirus

  8. Ventilation free days at day 28 [ Time Frame: From randomization to day 28, censored at hospital discharge ]
    Total number of days that patient is alive and free of ventilation between randomisation and day 28. Ventilation is considered as positive pressure ventilation, either invasive or non-invasive. Periods of assisted breathing lasting less than 24 hours for surgical procedures will not count against the ventilation free days calculation.

  9. Vasopressors free-days at day 28 [ Time Frame: From randomization to day 28, censored at hospital discharge ]
    Total number of days that patient is alive and free of vasopressors between randomisation and day 28.

  10. Switch from non-invasive to invasive mechanical ventilation [ Time Frame: from randomization to ICU discharge, censored at day 28 ]
    Occurrence of switch from non-invasive to invasive mechanical ventilation

  11. Delay from start of non-invasive ventilation to switch to invasive ventilation [ Time Frame: from randomization to ICU discharge, censored at day 28 ]
    Total number of hours from start of non-invasive to invasive ventilation to switch to invasive ventilation

  12. Occurrence of protocol related adverse events [ Time Frame: From randomization to day 28 ]
    Adverse events occurred from randomization to day 28. Events that are part of the natural history of the primary disease process or expected complications of critical illness will not be reported as adverse events.

  13. Occurrence of venous thromboembolism, stroke or myocardial infarction [ Time Frame: from randomization to ICU discharge, censored at day 28 ]
    Occurrence of objectively confirmed venous thromboembolism, stroke or myocardial infarction

  14. Occurrence of major bleeding (safety end point) [ Time Frame: from randomization to ICU discharge, censored at day 28 ]
    Occurrence of major bleeding defined as transfusion of 2 or more units of packed red blood cells in a day, bleeding that occurs in at least one of the following critical sites [intracranial, intraspinal, intraocular (within the corpus of the eye; thus, a conjunctival bleed is not an intraocular bleed), pericardial, intra-articular, intramuscular with compartment syndrome, or retroperitoneal], bleeding that necessitates surgical intervention and bleeding that is fatal (defined as a bleeding event that was the primary cause of death or contributed directly to death)

  15. Occurrence of clinically relevant non-major bleeding (safety end point) [ Time Frame: from randomization to ICU discharge, censored at day 28 ]
    Occurrence of clinically relevant non-major bleeding defined ad acute clinically overt bleeding that does not meet the criteria for major and consists of any bleeding compromising hemodynamic; spontaneous hematoma larger than 25 cm2, or 100 cm2, intramuscular hematoma documented by ultrasonography, haematuria that was macroscopic and was spontaneous or lasted for more than 24 hours after invasive procedures; haemoptysis, hematemesis or spontaneous rectal bleeding requiring endoscopy or other medical intervention or any other bleeding requiring temporary cessation of a study drug.


Other Outcome Measures:
  1. Mean arterial pressure [ Time Frame: Daily from inclusion until ICU discharge, censored day 28 ]
    Mean arterial pressure will be measured in millimeters of mercury

  2. hearth rate [ Time Frame: Daily from inclusion until ICU discharge, censored day 28 ]
    hearth rate will be measured in beats per minute

  3. respiratory rate [ Time Frame: Daily from inclusion until ICU discharge, censored day 28 ]
    respiratory rate will be measured in breaths per minute

  4. diuresis [ Time Frame: Daily from inclusion until ICU discharge, censored day 28 ]
    diuresis will be measured daily in milliliters of urine output in the previous 24 hours

  5. systemic body temperature [ Time Frame: Daily from inclusion until ICU discharge, censored day 28 ]
    systemic body temperature will be measured in celsius degrees

  6. fluid balance [ Time Frame: Daily from inclusion until ICU discharge, censored day 28 ]
    fluid balance will be measured in milliliters of fluids input and output in the previous 24 hours

  7. Haemoglobin concentration [ Time Frame: Daily from inclusion to ICU discharge (censored at day 28) ]
    Haemoglobin will be measured in mg/dl

  8. platelets count [ Time Frame: Daily from inclusion to ICU discharge (censored at day 28) ]
    platelets count will be measured in U 10^3/mm^3

  9. white blood cells count [ Time Frame: Daily from inclusion to ICU discharge (censored at day 28) ]
    white blood cells count will be measured in U per 10^9/L

  10. troponin [ Time Frame: Daily from inclusion to ICU discharge (censored at day 28) ]
    troponin will be measured in µg/L

  11. coagulative function [ Time Frame: Daily from inclusion to ICU discharge (censored at day 28) ]
    coagulative function will be measured with parameters INR, PT, aPTT

  12. D-dimer [ Time Frame: Daily from inclusion to ICU discharge (censored at day 28) ]
    D-dimer will be measured in µg/ml

  13. anti-thrombin [ Time Frame: Daily from inclusion to ICU discharge (censored at day 28) ]
    anti-thrombin will be measured as a percentage

  14. Liver function [ Time Frame: Daily from inclusion to ICU discharge (censored at day 28) ]
    liver function will be assessed through measurement of AST, ALT in U/L

  15. Bilirubin [ Time Frame: Daily from inclusion to ICU discharge (censored at day 28) ]
    Bilirubin will be measured in mg/dL

  16. Creatinine [ Time Frame: Daily from inclusion to ICU discharge (censored at day 28) ]
    Creatinine will be measured in mg/dL

  17. Blood cells count [ Time Frame: daily from inclusion to ICU discharge (censored at day 28) ]
    Blood cells count will be measured in Units per x 10^9/L of blood

  18. C-reactive protein (CRP) [ Time Frame: daily from inclusion to ICU discharge (censored at day 28) ]
    C-reactive protein (CRP) will be measured in mg/dl

  19. procalcitonin(PCT) [ Time Frame: daily from inclusion to ICU discharge (censored at day 28) ]
    procalcitonin(PCT) wiull be measured in ng/ml

  20. interleukin 6 (IL-6) [ Time Frame: daily from inclusion to ICU discharge (censored at day 28) ]
    interleukin 6 (IL-6) will be measured in pg/ml

  21. Ventilation mode [ Time Frame: Daily from inclusion to ICU discharge (censored at day 28) ]
    Ventilation mode will be cathegorized in spontaneous breathing, invasive or non invasive ventilation

  22. inspired oxygen fraction [ Time Frame: Daily from inclusion to ICU discharge (censored at day 28) ]
    inspired oxygen fraction will be measured in percentage of oxygen in inspired air

  23. Gas exchanges [ Time Frame: Daily from inclusion to ICU discharge (censored at day 28) ]
    Gas exchanges will be assessed by measurement of PaO2, PaCO2 in mmHg by arterial blood gas analysis

  24. lactates [ Time Frame: Daily from inclusion to ICU discharge (censored at day 28) ]
    lactates will be measured in mMol/L

  25. pH [ Time Frame: Daily from inclusion to ICU discharge (censored at day 28) ]
    pH will be measured in pH scale

  26. oxygen saturation in blood [ Time Frame: Daily from inclusion to ICU discharge (censored at day 28) ]
    oxygen saturation in blood will be measured in arterial and venous samples in percentage values

  27. New infections [ Time Frame: From randomization to day 28 ]
    New blood, respiratory and urinary-tract infections will be recorded

  28. Viral reactivation [ Time Frame: From randomization to day 28 ]
    Viral reactivation measured by CMV DNA titres will be recorded.

  29. Need of new renal replacement therapy [ Time Frame: from randomization to day 28 ]
    Need of new renal replacement therapy (intermittent haemodialysis or continuous veno-venous hemofiltration) will be recorded.

  30. Adjunctive treatments [ Time Frame: from randomization to ICU discharge (censored at day 28); ]
    Adjunctive treatment such as pronation cycles, Nitric Oxide or ECMO will be recorded



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Positive SARS-CoV-2 diagnostic (on pharyngeal swab of deep airways material)
  2. Positive pressure ventilation (either non-invasive or invasive) from > 24 hours
  3. Invasive mechanical ventilation from < 96 hours
  4. P/F ratio < 150
  5. D-dimer level > 6 x upper limit of local reference range
  6. PCR > 6 fold upper limit of local reference range

Exclusion Criteria:

  1. Age < 18 years
  2. On-going treatment with anticoagulant drugs
  3. Platelet count <100.000/mmc
  4. History of heparin-induced thrombocytopenia
  5. Allergy to sodium enoxaparine or other LMWH, unfractionated heparin or metylprednisolone;
  6. Active bleeding or on-going clinical condition deemed at high risk of bleeding contraindicating anticoagulant treatment
  7. Recent (in the last 1 month prior to randomization) brain, spinal or ophthalmic surgery
  8. Chronic assumption or oral corticosteroids
  9. Pregnancy or breastfeeding or positive pregnancy test. In childbearing age women, before inclusion, a pregnancy test will be performed if not available;
  10. Clinical decision to withhold life-sustaining treatment or "too sick to benefit";
  11. Presence of other severe diseases impairing life expectancy (e.g. patients are not expected to survive 28 days given their pre-existing medical condition);
  12. Lack or withdrawal of informed consent.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04528888


Contacts
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Contact: Massimo Girardis, PD 0594225878 ext 0039 massimo.girardis@unimore.it
Contact: Stefano Busani 0594224897 ext 0039 stefanobusani7@gmail.com

Sponsors and Collaborators
Massimo Girardis
Investigators
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Principal Investigator: Massimo Girardis, PI University of Modena and Reggio Emilia
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Responsible Party: Massimo Girardis, Professor, University of Modena and Reggio Emilia
ClinicalTrials.gov Identifier: NCT04528888    
Other Study ID Numbers: Staunch-19-1.1-26-04-20
First Posted: August 27, 2020    Key Record Dates
Last Update Posted: August 27, 2020
Last Verified: August 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No
Plan Description: There is no plan to share individual participant data

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
Keywords provided by Massimo Girardis, University of Modena and Reggio Emilia:
Steroids
heparine
critically-ill
ARDS
COVID19
sars-cOv-2
Additional relevant MeSH terms:
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Infection
Communicable Diseases
Coronavirus Infections
Severe Acute Respiratory Syndrome
Pneumonia, Viral
Pneumonia
Critical Illness
Lung Diseases
Respiratory Tract Diseases
Respiratory Tract Infections
Disease Attributes
Pathologic Processes
Coronaviridae Infections
Nidovirales Infections
RNA Virus Infections
Virus Diseases
Methylprednisolone
Methylprednisolone Hemisuccinate
Heparin
Enoxaparin
Calcium heparin
Anti-Inflammatory Agents
Antiemetics
Autonomic Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Gastrointestinal Agents
Glucocorticoids
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists