Busani 2020.

Study name	Steroids and unfractionated heparin in critically ill patients with pneumonia from COVID‐19 infection
Starting date	25 November 2020
Contact information	Massimo Girardis, PD ICU‐ University Hospital Modena, Modena, Italy, 41124 0594225878 ext 0039 | massimo.girardis@unimore.it
Methods	Multicentre RCT with 3 parallel arms, 1:1:1
Participants	210 participants; ≥ 18 years, female and male Inclusion criteria: Positive SARS‐CoV‐2 diagnostic (on pharyngeal swab of deep airways material) Positive pressure ventilation (either non‐invasive or invasive) from > 24 h Invasive mechanical ventilation from < 96 h PaO2/FiO2 ratio < 150 D‐dimer level > 6 x upper limit of local reference range PCR > 6 fold upper limit of local reference range Exclusion criteria: Age < 18 years On‐going treatment with anticoagulant drugs Platelet count < 100.000/mmc History of heparin‐induced thrombocytopenia Allergy to sodium enoxaparin or other LMWH, unfractionated heparin or methylprednisolone Active bleeding or on‐going clinical condition deemed at high risk of bleeding contraindicating anticoagulant treatment Recent (in the last 1 month prior to randomisation) brain, spinal or ophthalmic surgery Chronic assumption or oral corticosteroids Pregnancy or breastfeeding or positive pregnancy test. In childbearing age women, before inclusion, a pregnancy test will be performed if not available Clinical decision to withhold life‐sustaining treatment or "too sick to benefit" Presence of other severe diseases impairing life expectancy (e.g. patients are not expected to survive 28 days given their pre‐existing medical condition) Lack or withdrawal of informed consent
Interventions	Drug: enoxaparin Enoxaparin will be administered SC at standard prophylactic dose (i.e. 4000 UI once/d, increased to 6000 UI once/d for patients weighting > 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 IV 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 IV at therapeutic doses. The infusion will be started at an infusion rate of 18 IU/kg/h 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
Outcomes	Primary All‐cause mortality at day 28, defined as the comparison of proportions of patients' deaths for any cause at day 28 from randomisation Secondary All‐cause mortality at ICU discharge (time frame: from randomisation to ICU discharge, censored at day 30) All‐cause mortality at hospital discharge (time frame: from randomisation to ICU discharge, censored at day 90) Need of rescue administration of high‐dose steroids or immune‐modulatory drugs (time frame: from randomisation to ICU discharge, censored at day 28) New organ dysfunction during ICU stay (time frame: from randomisation to ICU discharge, censored at day 28) Grade of organ dysfunction during ICU stay (time frame: from randomisation to ICU discharge, censored at day 28) ICU‐free days at day 28 (time frame: from randomisation to day 28) Occurrence of new infections (time frame: from randomisation to day 28) Occurrence of new infections including bacterial infections, fungal infections by Candida, Aspergillus, and viral reactivations including Adenovirus, Herpes virus and Cytomegalovirus Ventilation‐free days at day 28 (time frame: from randomisation to day 28, censored at hospital discharge) Vasopressors free‐days at day 28 (time frame: from randomisation to day 28, censored at hospital discharge) Switch from non‐invasive to invasive mechanical ventilation (time frame: from randomisation to ICU discharge, censored at day 28) Delay from start of non‐invasive ventilation to switch to invasive ventilation (time frame: from randomisation to ICU discharge, censored at day 28) Occurrence of protocol‐related AEs (time frame: from randomisation to day 28). AEs occurred from randomisation to day 28 Occurrence of VTE, stroke or myocardial infarction (time frame: from randomisation to ICU discharge, censored at day 28) Occurrence of major bleeding (safety end point) (time frame: from randomisation to ICU discharge, censored at day 28) Occurrence of clinically relevant non‐major bleeding (safety end point) (time frame: from randomisation to ICU discharge, censored at day 28) Other outcomes Mean arterial pressure (time frame: daily from inclusion until ICU discharge, censored day 28) Heart rate (time frame: daily from inclusion until ICU discharge, censored day 28) Respiratory rate (time frame: daily from inclusion until ICU discharge, censored day 28) Eiuresis (time frame: daily from inclusion until ICU discharge, censored day 28) Systemic body temperature (time frame: daily from inclusion until ICU discharge, censored day 28) Fluid balance (time frame: daily from inclusion until ICU discharge, censored day 28) Haemoglobin concentration (time frame: daily from inclusion to ICU discharge (censored at day 28) Platelets count (time frame: daily from inclusion to ICU discharge (censored at day 28) White blood cells count (time frame: daily from inclusion to ICU discharge (censored at day 28) Troponin (time frame: daily from inclusion to ICU discharge (censored at day 28) Coagulative function (time frame: daily from inclusion to ICU discharge (censored at day 28) D‐dimer (time frame: daily from inclusion to ICU discharge (censored at day 28) Anti‐thrombin (time frame: daily from inclusion to ICU discharge (censored at day 28) Liver function (time frame: daily from inclusion to ICU discharge (censored at day 28) Bilirubin (time frame: daily from inclusion to ICU discharge (censored at day 28) Creatinine (time frame: daily from inclusion to ICU discharge (censored at day 28) Blood cells count (time frame: daily from inclusion to ICU discharge (censored at day 28) C‐reactive protein (CRP) (time frame: daily from inclusion to ICU discharge (censored at day 28) Procalcitonin (PCT) (time frame: daily from inclusion to ICU discharge (censored at day 28) Interleukin 6 (IL‐6) (time frame: daily from inclusion to ICU discharge (censored at day 28) Ventilation mode (time frame: daily from inclusion to ICU discharge (censored at day 28) FiO2 (time frame: daily from inclusion to ICU discharge (censored at day 28) Gas exchanges (time frame: daily from inclusion to ICU discharge (censored at day 28) Lactates (time frame: daily from inclusion to ICU discharge (censored at day 28) pH (time frame: daily from inclusion to ICU discharge (censored at day 28) SpO2 (time frame: daily from inclusion to ICU discharge (censored at day 28) New infections (time frame: from randomisation to day 28) Viral reactivation (time frame: from randomisation to day 28) Need of new renal replacement therapy (time frame: from randomisation to day 28) Adjunctive treatments (time frame: from randomisation to ICU discharge (censored at day 28)
Notes	NCT04528888 | No data provided