E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Coagulopathy of COVID-19 appears to afflict approximately 20% of patients with severe COVID-19 and is associated with need for critical care and death. COVID-19 coagulopathy is characterized by elevated D-dimer, an indicator of fibrin formation and clot lysis, and a mildly prolonged prothrombin time (PT), suggestive of coagulation consumption |
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E.1.1.1 | Medical condition in easily understood language |
Excessive blood clotting as a result of a severe inflammatory response appears to afflict approximately 20% of patients with severe COVID-19 and is associated with need for critical care and death. |
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E.1.1.2 | Therapeutic area | Diseases [C] - Virus Diseases [C02] |
MedDRA Classification |
E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
Primary Objective: To determine the effect of therapeutic anticoagulation, with LMWH (enoxaparin sodium), compared to standard care in hospitalized patients admitted for COVID-19 with an elevated D-dimer on the composite outcome of intensive care unit (ICU) admission, non-invasive positive pressure ventilation, invasive mechanical ventilation or death at 28 days.
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E.2.2 | Secondary objectives of the trial |
Determine effect of therapeutic anticoagulation (enoxaparin sodium) compared to standard care in hospitalized patients up to day 28, on: 1. All-cause death 2. Composite of ICU admission or all-cause death 3. Composite of mechanical ventilation or all-cause death 4. Major bleeding as defined by the ISTH-SSC recommendation 5. Red blood cell transfusion (>1 unit) 6. Transfusion of platelets, frozen plasma, prothrombin complex concentrate, cryoprecipitate and/or fibrinogen concentrate 7. Renal replacement therapy defined as CRRT or IHD 8. Hospital-free days alive 9. ICU-free days alive 10. Ventilator-free days alive 11. Organ support-free days alive 12. Venous thromboembolism 13. Arterial thromboembolism 14. Heparin induced thrombocytopenia 15. Trajectories of COVID-19 disease-related biomarkers Tertiary Objective
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
4.1. The inclusion criteria are: 1) Laboratory confirmed COVID-19 (diagnosis of SARS-CoV-2 via reverse transcriptase polymerase chain reaction as per the World Health Organization protocol or by nucleic acid based isothermal amplification); positive test prior to hospital admission OR within first 5 days (ie 120 hours) after hospital admission 2) Admitted to hospital for COVID-19; 3) One D-dimer value above ULN (within 5 days (ie 120 hours) of hospital admission) AND EITHER: a. D-Dimer ≥2 times ULN OR b. D-Dimer above ULN and Oxygen saturation ≤ 93% on room air; 4) > 18 years of age; 5) Informed consent from the patient (or legally authorized substitute decision maker).
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E.4 | Principal exclusion criteria |
1) pregnancy; 2) hemoglobin <80 g/L in the last 72 hours; 3) platelet count <50 x 109/L in the last 72 hours; 4) known fibrinogen <1.5 g/L (if testing deemed clinically indicated by the treating physician prior to the initiation of anticoagulation); 5) known INR >1.8 (if testing deemed clinically indicated by the treating physician prior to the initiation of anticoagulation); 6) patient already on intermediate dosing of LMWH that cannot be changed (determination of what constitutes an intermediate dose is to be at the discretion of the treating clinician taking the local institutional thromboprophylaxis protocol for high risk patients into consideration); 7) patient already on therapeutic anticoagulation at the time of screening (low or high dose nomogram UFH, LMWH, warfarin, direct oral anticoagulant (any dose of dabigatran, apixaban, rivaroxaban, edoxaban); 8) patient on dual antiplatelet therapy, when one of the agents cannot be stopped safely; 9) known bleeding within the last 30 days requiring emergency room presentation or hospitalization; 10) known history of a bleeding disorder of an inherited or active acquired bleeding disorder; 11) known history of heparin-induced thrombocytopenia; 12) known allergy to UFH or LMWH; 13) admitted to the intensive care unit at the time of screening 14) treated with non-invasive positive pressure ventilation or invasive mechanical ventilation at the time of screening (of note: high flow oxygen delivery via nasal cannula is acceptable and is not an exclusion criterion); 15) Imminent death according to the judgement of the most responsible physician; 16) enrollment in another clinical trial of antithrombotic therapy involving pre-intensive care unit hospitalized patients.
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary composite outcome of ICU admission, non-invasive positive pressure ventilation, invasive mechanical ventilation or death at 28 days. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
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E.5.2 | Secondary end point(s) |
Secondary outcomes (secondary endpoints), evaluated up to day 28, include: 1) All-cause death; 2) Composite of ICU admission or all-cause death; 3) Composite of mechanical ventilation intubation or all-cause death; 4) Major bleeding as defined by the ISTH Scientific and Standardization Committee (ISTH-SSC) recommendation (21); 5) Red blood cell transfusion (>1 unit); 6) Transfusion of platelets, frozen plasma, prothrombin complex concentrate, cryoprecipiate and/or fibrinogen concentrate; 7) Renal replacement therapy defined as continuous renal replacement therapy {CRRT} or intermittent hemodialysis {IHD}; 8) Hospital-free days alive; 9) ICU-free days alive; 10) Ventilator-free days alive; 11) Organ support-free days alive (see Appendix 4 for definition); 12) Venous thromboembolism (defined as symptomatic or incidental, suspected or confirmed via diagnostic imaging and/or electrocardiogram where appropriate recognizing that access to diagnostic imaging may be limited in the midst of the COVID-19 pandemic, however confirmatory testing at a later date once exposure risk/personal protective utilization is not an issue is encouraged); 13) Arterial thromboembolism (defined as suspected or confirmed via diagnostic imaging and/or electrocardiogram where appropriate recognizing that access to diagnostic imaging may be limited in the midst of the COVID-19 pandemic, however confirmatory testing at a later date once exposure risk/personal protective utilization is not an issue is encouraged); 14) Heparin induced thrombocytopenia; 15) Trajectories of COVID-19 disease-related biomarkers.
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Up to day 28 (including days 1, 3, 7, 14, 28) |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | Yes |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | Yes |
E.8.2.3.1 | Comparator description |
standard care in hospitalized patients admitted for COVID-19 with an elevated D-dimer. |
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E.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
E.8.4 | The trial involves multiple sites in the Member State concerned | No |
E.8.5 | The trial involves multiple Member States | No |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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Completion of the global trial with St Michael's Hospital. |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 2 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | 0 |