Steroids and Unfractionated Heparin in Critically Ill Patients With Pneumonia From COVID-19 Infection. A Multicenter, Interventional, Randomized, Three Arms Study Design
试验速览
- 阶段
- 3 期
- 发起方
- 入组人数
- 210
- 试验地点
- 1
- 主要终点
- All-cause mortality at day 28
研究概览
简要总结
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.
详细描述
Rationale It is very likely that the most severe manifestations of COVID-19 may be linked to an excessive and aberrant hyper-inflammatory host immune response along with pro-thrombotic derangements of haemostatic system, two processes mutually reinforcing.
Steroids exert potent anti-inflammatory activity by inhibition of leucocytes extravasation, function of macrophages and antigen-presenting cells, production of TNF alpha, interleukin-1 and nitric oxide. A Chinese report on 201 patients with COVID-19 pneumonia pointed out a survival benefit of more than 15% among patients with ARDS who received Methylprednisolone compared to those who did not .
The use of Low Molecular Weight Heparin (LMWH) or Unfractionated Heparin (UFH) at prophylactic doses has been demonstrated to be associated with a reduced 28-day in more severe patients with Sepsis Induced Coagulopathy (SIC) score ≥4 (40.0% vs 64.2%, P=0.029), or D-dimer > 6 fold of upper limit of normal (32.8% vs 52.4%, P=0.017) . This finding agrees with the already described immune-modulatory properties and protective action of glycocalyx from shedding displayed by heparin. 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.
Targeting inflammatory responses along with thrombosis prevention may be a promising therapeutic option to improve outcomes in patients with COVID-19.
Study objective The primary objective is to assess the hypothesis that an adjunctive therapy with steroids and unfractionated heparin or with steroids and 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. 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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
盲法说明
The study in conceived as open-label: the patients and all the health-care personnel will be aware of the assigned group.
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Positive SARS-CoV-2 diagnostic (on pharyngeal swab of deep airways material)
- •Positive pressure ventilation (either non-invasive or invasive) from > 24 hours
- •Invasive mechanical ventilation from < 96 hours
- •P/F ratio < 150
- •D-dimer level > 6 x upper limit of local reference range
- •PCR > 6 fold upper limit of local reference range
排除标准
- •Age < 18 years
- •On-going treatment with anticoagulant drugs
- •Platelet count <100.000/mmc
- •History of heparin-induced thrombocytopenia
- •Allergy to sodium enoxaparine or other LMWH, unfractionated heparin or metylprednisolone;
- •Active bleeding or on-going clinical condition deemed at high risk of bleeding contraindicating anticoagulant treatment
- •Recent (in the last 1 month prior to randomization) 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.
研究组 & 干预措施
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.
干预措施: Enoxaparin (Drug)
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.
干预措施: Enoxaparin (Drug)
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.
干预措施: Methylprednisolone (Drug)
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.
干预措施: Methylprednisolone (Drug)
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.
干预措施: unfractionated heparin (Drug)
结局指标
主要结局
All-cause mortality at day 28
时间窗: 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.
次要结局
- Switch from non-invasive to invasive mechanical ventilation(from randomization to ICU discharge, censored at day 28)
- Ventilation free days at day 28(From randomization to day 28, censored at hospital discharge)
- Vasopressors free-days at day 28(From randomization to day 28, censored at hospital discharge)
- All-cause mortality at ICU discharge(from randomization to ICU discharge, censored at day 30)
- All-cause mortality at hospital discharge(from randomization to ICU discharge, censored at day 90)
- Need of rescue administration of high-dose steroids or immune-modulatory drugs(from randomization to ICU discharge, censored at day 28)
- New organ dysfunction during ICU stay(From randomization to ICU discharge, censored at day 28)
- Grade of organ dysfunction during ICU stay(From randomization to ICU discharge, censored at day 28)
- ICU free days at day 28(From randomization to day 28)
- Occurrence of new infections(from randomization to day 28)
- Delay from start of non-invasive ventilation to switch to invasive ventilation(from randomization to ICU discharge, censored at day 28)
- Occurrence of protocol related adverse events(From randomization to day 28)
- Occurrence of venous thromboembolism, stroke or myocardial infarction(from randomization to ICU discharge, censored at day 28)
- Occurrence of major bleeding (safety end point)(from randomization to ICU discharge, censored at day 28)
- Occurrence of clinically relevant non-major bleeding (safety end point)(from randomization to ICU discharge, censored at day 28)
研究者
Massimo Girardis
Professor
University of Modena and Reggio Emilia