About: Randomised controlled trial comparing efficacy and safety of high versus low Low-Molecular Weight Heparin dosages in hospitalized patients with severe COVID-19 pneumonia and coagulopathy not requiring invasive mechanical ventilation (COVID-19 HD): a structured summary of a study protocol

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About: Randomised controlled trial comparing efficacy and safety of high versus low Low-Molecular Weight Heparin dosages in hospitalized patients with severe COVID-19 pneumonia and coagulopathy not requiring invasive mechanical ventilation (COVID-19 HD): a structured summary of a study protocol Goto Sponge NotDistinct Permalink

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type	Academic Article research paper schema:ScholarlyArticle
isDefinedBy	Covid-on-the-Web dataset
has title	Randomised controlled trial comparing efficacy and safety of high versus low Low-Molecular Weight Heparin dosages in hospitalized patients with severe COVID-19 pneumonia and coagulopathy not requiring invasive mechanical ventilation (COVID-19 HD): a structured summary of a study protocol
Creator	Coluccio, Valeria D'amico, Roberto Marietta, Marco Mighali, Pasquale Vandelli, Paola Vicini, Roberto
Source	Medline; PMC; WHO
abstract	OBJECTIVES: a. 1. Death. 2. Acute Myocardial Infarction [AMI]. 3. Objectively confirmed, symptomatic arterial or venous thromboembolism [TE]. 4. a. Continuous Positive Airway Pressure (Cpap) or Non-Invasive Ventilation (NIV) or b. IMV in patients who at randomisation were receiving standard oxygen therapy. 5. IMV in patients who at randomisation were receiving non-invasive mechanical ventilation. b. Similar in terms of major bleeding risk. TRIAL DESIGN: Multicentre, randomised controlled, superiority, open label, parallel group, two arms (1:1 ratio), in-hospital study. PARTICIPANTS: Inpatients will be recruited from 7 Italian Academic and non-Academic Internal Medicine Units, 2 Infectious Disease Units and 1 Respiratory Disease Unit. INCLUSION CRITERIA (ALL REQUIRED): 1. Age > 18 and < 80 years. 2. Positive SARS-CoV-2 diagnostic (on pharyngeal swab of deep airways material). 3. a. Respiratory Rate ≥25 breaths /min. b. Arterial oxygen saturation≤93% at rest on ambient air. c. PaO2/FiO2 ≤300 mmHg. 4. a. D-dimer >4 times the upper level of normal reference range. b. Sepsis-Induced Coagulopathy (SIC) score >4. 5. No need of IMV. EXCLUSION CRITERIA: 1. Age <18 and >80 years. 2. IMV. 3. Thrombocytopenia (platelet count < 80.000 mm3). 4. Coagulopathy: INR >1.5, aPTT ratio > 1.4. 5. Impaired renal function (eGFR calculated by CKD-EPI Creatinine equation < 30 ml/min). 6. Known hypersensitivity to enoxaparin. 7. History of heparin induced thrombocytopenia. 8. Presence of an active bleeding or a pathology susceptible of bleeding in presence of anticoagulation (e.g. recent haemorrhagic stroke, peptic ulcer, malignant cancer at high risk of haemorrhage, recent neurosurgery or ophthalmic surgery, vascular aneurysms, arteriovenous malformations). 9. Concomitant anticoagulant treatment for other indications (e.g. atrial fibrillation, venous thromboembolism, prosthetic heart valves). 10. Concomitant double antiplatelet therapy. 11. Administration of therapeutic doses of LMWH, fondaparinux, or unfractionated heparin (UFH) for more than 72 hours before randomization; prophylactic doses are allowed. 12. Pregnancy or breastfeeding or positive pregnancy test. 13. Presence of other severe diseases impairing life expectancy (e.g. patients are not expected to survive 28 days given their pre-existing medical condition). 14. Lack or withdrawal of informed consent. INTERVENTION AND COMPARATOR: Control Group (Low-Dose LMWH): patients in this group will be administered Enoxaparin (Inhixa®) at standard prophylactic dose (i.e., 4000 UI subcutaneously once day). Intervention Group (High-Dose LMWH): patients in this group will be administered Enoxaparin (Inhixa®) at dose of 70 IU/kg every 12 hours, as reported in the following table. This dose is commonly used in Italy when a bridging strategy is required for the management of surgery or invasive procedures in patients taking anti-vitamin K oral anticoagulants The treatment with Enoxaparin will be initiated soon after randomization (maximum allowed starting time 12h after randomization). The treatment will be administered every 12 hours in the intervention group and every 24 hours in the control group. Treatments will be administered in the two arms until hospital discharge or the primary outcomes detailed below occur. MAIN OUTCOMES: Primary Efficacy Endpoint: 1. Death. 2. Acute Myocardial Infarction [AMI]. 3. Objectively confirmed, symptomatic arterial or venous thromboembolism [TE]. 4. a. Continuous Positive Airway Pressure (Cpap) or Non-Invasive Ventilation (NIV) or b. IMV in patients who at randomisation were in standard oxygen therapy by delivery interfaces. 5. Need for IMV, in patients who at randomisation were in Cpap or NIV. Time to the occurrence of each of these events will be recorded. Clinical worsening will be analysed as a binary outcome as well as a time-to-event one. Secondary Efficacy Endpoints: : 1. Death. 2. Acute Myocardial Infarction [AMI]. 3. Objectively confirmed, symptomatic arterial or venous thromboembolism [TE]. 4. a. Continuous Positive Airway Pressure (Cpap) or Non-Invasive Ventilation (NIV) or b. IMV in patients who at randomisation were in standard oxygen therapy by delivery interfaces. 5. Need for IMV in patients who at randomisation were in Cpap or NIV. 6. o D-dimer level; o Plasma fibrinogen levels; o Mean Platelet Volume; o Lymphocyte/Neutrophil ratio; o IL-6 plasma levels. MORTALITY AT 30 DAYS: Information about patients’ status will be sought in those who are discharged before 30 days on Day 30 from randomisation. Time to the occurrence of each of these events will be recorded. Each of these events will be analysed as a binary outcome and as a time-to-event one. Primary safety endpoint: Decrease in haemoglobin of 2 g/dl or more; Transfusion of 2 or more units of packed red blood cells; 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 is fatal (defined as a bleeding event that was the primary cause of death or contributed directly to death); Bleeding that necessitates surgical intervention. Time to the occurrence of each of these events will be recorded. Each of these events will be analysed as a binary outcome and as a time-to-event one. Secondary safety endpoint: 1. Any bleeding compromising hemodynamic. 2. Spontaneous hematoma larger than 25 cm2, or 100 cm2 if there was a traumatic cause. 3. Intramuscular hematoma documented by ultrasonography. 4. Epistaxis or gingival bleeding requiring tamponade or other medical intervention. 5. Bleeding from venipuncture for >5 minutes. 6. Haematuria that was macroscopic and was spontaneous or lasted for more than 24 hours after invasive procedures. 7. Haemoptysis, hematemesis or spontaneous rectal bleeding requiring endoscopy or other medical intervention. 8. Any other bleeding requiring temporary cessation of a study drug. Time to the occurrence of each of these events will be recorded. Each of these events will be analysed as a binary outcome and as a time-to-event one. RANDOMISATION: Randomisation (with a 1:1 randomisation ratio) will be centrally performed by using a secure, web-based system, which will be developed by the Methodological and Statistical Unit at the Azienda Ospedaliero-Universitaria of Modena. Randomisation stratified by 4 factors: 1) Gender (M/F); 2) Age (<75/≥75 years); 3) BMI (<30/≥30); 4) Comorbidities (0-1/>2) with random variable block sizes will be generated by STATA software. The web-based system will guarantee the allocation concealment. Blinding (masking) The study is conceived as open-label: patients and all health-care personnel involved in the study will be aware of the assigned group. NUMBERS TO BE RANDOMISED (SAMPLE SIZE): The target sample size is based on the hypothesis that LMWH administered at high doses versus low doses will significantly reduce the risk of clinical worsening. The overall sample size in this study is expected to be 300 with 150 in the Low-Dose LMWH control group and 150 in the High-Dose LMWH intervention group, recruited over 10-11 months. Assuming an alpha of 5% (two tailed) and a percentage of patients who experience clinical worsening in the control group being between 25% and 30%, the study will have 80% power to detect at least 50% relative reduction in the risk of death between low and high doses of heparin. TRIAL STATUS: Protocol version 1.2 of 11/05/2020. Recruitment start (expected): 08/06/2020 Recruitment finish (expected): 30/04/2021 Trial registration EudraCT 2020-001972-13, registered on April 17th, 2020 Full protocol The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol.
has issue date	2020-06-26(xsd:dateTime)
bibo:doi	10.1186/s13063-020-04475-z
bibo:pmid	32586394
has license	cc-by
sha1sum (hex)	c5d47dafd64ab68984c89f3db6b0bf57e13842ac
schema:url	https://doi.org/10.1186/s13063-020-04475-z
resource representing a document's title	Randomised controlled trial comparing efficacy and safety of high versus low Low-Molecular Weight Heparin dosages in hospitalized patients with severe COVID-19 pneumonia and coagulopathy not requiring invasive mechanical ventilation (COVID-19 HD): a structured summary of a study protocol
has PubMed Central identifier	PMC7316577
has PubMed identifier	32586394
schema:publication	Trials
resource representing a document's body	covid:c5d47dafd64ab68984c89f3db6b0bf57e13842ac#body_text
is schema:about of	named entity 'Enoxaparin' named entity 'defined' named entity 'prophylactic' named entity 'Enoxaparin' named entity 'high' named entity 'Invasive Mechanical Ventilation' named entity 'prophylactic' named entity 'tamponade' named entity 'anticoagulant' named entity 'neurosurgery' named entity 'oxygen' named entity 'haemorrhage' named entity 'pharyngeal' named entity 'retroperitoneal' named entity 'conjunctival' named entity 'D-dimer' named entity 'sample size' named entity 'BMI' named entity 'hematoma' named entity 'LMWH' named entity 'Coagulopathy' named entity 'COVID' named entity 'LMWH' named entity 'INR' named entity 'prophylactic' named entity 'sample size' named entity 'hematoma' named entity 'Clinically Relevant' named entity 'Inpatients' named entity 'haemorrhagic stroke' named entity 'starting time' named entity 'random variable' named entity 'peptic ulcer' named entity '1.2' named entity 'open label' named entity 'Pregnancy' named entity 'prosthetic heart valves' named entity 'Sepsis' named entity 'Impaired renal function' named entity 'eGFR' named entity 'ambient air' named entity 'health-care' named entity 'pre-existing medical condition' named entity 'Low-molecular weight heparin' named entity 'aPTT' named entity 'heparin' named entity 'severe diseases' named entity 'hypersensitivity' named entity 'PaO2/FiO2' named entity 'platelet count' named entity 'Pneumonia' named entity 'venipuncture' named entity 'normal reference range' named entity 'Respiratory Rate' named entity 'malignant cancer' named entity 'ophthalmic surgery' named entity 'Continuous Positive Airway Pressure' named entity 'Coagulopathy' named entity 'Italy' named entity 'aneurysms' named entity 'venous thromboembolism' named entity 'haemoglobin' named entity 'informed consent' named entity 'control group' named entity 'atrial fibrillation' named entity 'Coagulopathy' named entity 'SIC' named entity 'surgical intervention' named entity 'ultrasonography' named entity 'gingival' named entity 'NIV' named entity 'pericardial' named entity 'hemodynamic' named entity 'Epistaxis' named entity 'sample size' named entity 'LMWH'

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