Clinical Efficacy of Heparin and Tocilizumab in Patients With Severe COVID-19 Infection: a Randomized Clinical Trial
试验速览
- 阶段
- 3 期
- 状态
- 已完成
- 入组人数
- 308
- 试验地点
- 3
- 主要终点
- Proportion of patients with clinical improvement
研究概览
简要总结
The COVID-19 infection primarily manifests itself as a respiratory tract infection, although new evidence indicates that this disease has systemic involvement involving multiple systems including the cardiovascular, respiratory, gastrointestinal, neurological, hematopoietic and immune systems. Recent studies have shown that in its pathophysiology, inflammation and thrombogenesis predominate, especially in the severe forms of COVID-19. Thus, the investigators hypothesized that the use of heparin and tocilizumab could potencially reduce inflammation and thrombogenesis in patients with severe COVID-19 infection, improving patients outcomes and survival.
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
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
- •Age ≥ 18 years;
- •Informed consent form signed by the patient or guardian or by audio with the guardian;
- •Positive result for COVID-19 in PCR (polymerase chain reaction) in nasopharyngeal swab or tracheal secretion up to 10 days before the inclusion and radiological evidence of COVID-19, by chest radiography or chest computed tomography;
- •Need for ≥ 4 L of supplemental oxygen to maintain peripheral oxygen saturation equal to or greater than 93% or need for invasive mechanical ventilation.
排除标准
- •Risk of bleeding:
- •Clinical: active bleeding, major surgery in the last 30 days, gastrointestinal bleeding within 30 days;
- •Laboratory: platelet count <50,000, INR> 2 or APTT> 50s;
- •Known or suspected adverse reaction to UFH, including heparin-induced thrombocytopenia (TIH);
- •Adverse reaction or allergy to tocilizumab;
- •Use of any of the following treatments: UFH to treat a thrombotic event within 12 hours before inclusion; HPBM in therapeutic dose within 12 hours before inclusion; warfarin (if used 7 days before and if INR greater than 2; thrombolytic therapy within 3 days before; and use of glycoprotein IIb / IIIa inhibitors within the previous 7 days;
- •Pregnant or lactating;
- •Absolute indication of anticoagulation due to atrial fibrillation or diagnosed thromboembolic event;
- •Refusal by family members and / or patient;
- •Active tuberculosis;
- •Bacterial infection confirmed by culture;
- •Neutropenia (<1000 neutrophils / mm3);
- •Use of another immunosuppressive therapy that is not a corticosteroid;
- •Septic shock.
研究组 & 干预措施
Group 1 - Therapeutic anticoagulation
- (I) intravenous UFH started at a dose of 18 IU/kg/h, adjusted according to a nomogram to achieve a TTPa of 1.5 to 2.0 times the reference value; OR
- (II) subcutaneous LMWH - enoxaparin 1 mg / kg per dose every 12 hours.
干预措施: Heparin - Therapeutic dosage (Drug)
Group 2 - Prophylactic anticoagulation
- (I) subcutaneous UFH 5,000 IU every 8 hours; OR
- (II) subcutaneous LMWH - enoxaparin 40 mg daily.
干预措施: Heparin - Prophylactic dosage (Drug)
Group 3 - Therapeutic anticoagulation with tocilizumab
- (I) Intravenous UFH initiated at a dose of 18 IU / kg / h, adjusted according to a nomogram to achieve a TTPa of 1.5 to 2.0 times the reference value associated with 8 mg / kg / tocilizumab infusion / intravenous dose in a single dose; OR
- Subcutaneous LMWH - enoxaparin 1 mg / kg per dose every 12 hours associated with an infusion of tocilizumab 8 mg / kg / dose in a single dose.
干预措施: Tocilizumab (Drug)
Group 3 - Therapeutic anticoagulation with tocilizumab
- (I) Intravenous UFH initiated at a dose of 18 IU / kg / h, adjusted according to a nomogram to achieve a TTPa of 1.5 to 2.0 times the reference value associated with 8 mg / kg / tocilizumab infusion / intravenous dose in a single dose; OR
- Subcutaneous LMWH - enoxaparin 1 mg / kg per dose every 12 hours associated with an infusion of tocilizumab 8 mg / kg / dose in a single dose.
干预措施: Heparin - Therapeutic dosage (Drug)
Group 4 - Prophylactic anticoagulation with tocilizumab
- (I) subcutaneous UFH 5,000 IU every 8 hours associated with an infusion of tocilizumab 8 mg / kg / intravenous dose in a single dose; OR
- (II) subcutaneous LMWH - enoxaparin 40 mg daily associated with an infusion of tocilizumab 8 mg / kg / intravenous dose in a single dose.
干预措施: Tocilizumab (Drug)
Group 4 - Prophylactic anticoagulation with tocilizumab
- (I) subcutaneous UFH 5,000 IU every 8 hours associated with an infusion of tocilizumab 8 mg / kg / intravenous dose in a single dose; OR
- (II) subcutaneous LMWH - enoxaparin 40 mg daily associated with an infusion of tocilizumab 8 mg / kg / intravenous dose in a single dose.
干预措施: Heparin - Prophylactic dosage (Drug)
结局指标
主要结局
Proportion of patients with clinical improvement
时间窗: 30 days
Proportion of patients with clinical improvement in 30 days, defined by hospital discharge or a reduction of at least 2 points compared to baseline on the ordinal scale recommended by the World Health Organization: 1. Not hospitalized, with no limitations on activities; 2. Not hospitalized, but limited to activities; 3. Hospitalized, with no need for supplemental oxygen; 4. Hospitalized, needing supplemental oxygen; 5. Hospitalized, requiring high flow oxygen therapy, non-invasive mechanical ventilation or both; 6. Hospitalized, requiring ECMO, invasive mechanical ventilation or both; 7. Death.
次要结局
- Hospital and ICU length of stay;(30 days)
- Duration of invasive mechanical ventilation(30 days)
- Mortality(30, 60 and 90 days)
- Duration of vasopressor use(30 days)
- Renal failure by AKIN criteria(30 days)
- Incidence of cardiovascular complications(30 days)
- Incidence of venous thromboembolism(30 days)
研究者
Ludhmila Abrahão Hajjar MD, PhD
Associate Professor
University of Sao Paulo