Value of Early Treatment With Polyvalent Immunoglobulin in the Management of Acute Respiratory Distress Syndrome Associated With SARS-CoV-2 Infections
试验速览
- 阶段
- 3 期
- 状态
- 已完成
- 发起方
- 入组人数
- 146
- 试验地点
- 42
- 主要终点
- Ventilator-free days
研究概览
简要总结
As of 30/03/2020, 715600 people have been infected with COVID-19 worldwide and 35500 people died, essentially due to respiratory distress syndrome (ARDS) complicated in 25% of the with acute renal failure. No specific pharmacological treatment is available yet. The lung lesions are related to both the viral infection and to an intense inflammatory reaction. Because of it's action, as an immunomodulatory agent that can attenuate the inflammatory reaction and also strengthen the antiviral response, it is proposed to evaluate the effectiveness and safety of intravenous immunoglobulin administration (IGIV) in patients developing ARDS post-SARS-CoV2. IGIV modulates immunity, and this effect results in a decrease of pro-inflammatory activity, key factor in the ARDS related to the COVID-19. It should be noted that IGIV is part of the treatments in various diseases such as autoimmune and inflammatory diffuse interstitial lung diseases. In addition, they have been beneficial in the post-influenza ARDS but also have been in 3 cases of post-SARS-CoV2 ARDS. IGIV is a treatment option because it is well tolerated, especially concerning the kidney. These elements encourage a placebo-controlled trial testing the benefit of IGIV in ARDS post-SARS-CoV2.
详细描述
As of 30/03/2020, 715600 people have been infected with COVID-19 worldwide and 35 500 people have died, mainly from acute respiratory distress syndrome (ARDS) complicated in 25% of cases with acute renal failure. No specific pharmacological treatment is available yet. Pulmonary lesions in these patients are related to both viral infection and an inflammatory reaction. Patients admitted to intensive care have an important inflammatory response and increased plasma concentrations of IL2, IL7, IL10, GCSF, IP10, MCP1, MIP1A, and TNFα.
In the blood, the number of peripheral CD4 and CD8 T cells appears to be significantly reduced, while their status is hyperactivated. This is evidenced by immunoreactive cytometrics for HLA-DR (CD4 3-47%) and CD38 (CD8 39-4%) or by an increase in the proportion of highly pro-inflammatory Th 17 CCR6+ lymphocytes. In addition, CD8 T cells would exhibit a highly cytotoxic profile characterized by high concentrations of cytotoxic granules, perforin+, granulysin+ or double positive, suggesting associated complement activation. Because of their immunomodulatory action, which can attenuate the inflammatory response; and also strengthen the anti-viral defence, it is proposed to evaluate the efficacy and safety of intravenous immunoglobulin (IGIV) administration in patients developing post-SARS-CoV2 ARDS.
IGIV modifies cell function of dendritic cells, cytokine and chemokine networks and T-lymphocytes, resulting in the proliferation of regulatory T cells to regulate the activity of T lymphocytes CD4 or CD8. The action of IGIV induces an activation more particularly of lymphocytes T regulators that could modulate the effects of the lymphocyte populations described in the study by Xu et al during COVID-19. In addition, IGIV modulate humoral acquired immunity, through their effect on the idiotypic network and antibody production. They also act on innate immunity, through antigen neutralization and modulation of phagocytic cells. These effects result in a decrease in the production of pro-inflammatory cytokines and complement activation, key factors in post-SARS-CoV2 ARDS.
IGIV is part of the treatment for a variety of autoimmune and inflammatory diseases. The standard IGIV as well as polyclonal IGIV significantly reduced mortality in patients with septic shock and in Kawasaki disease, which is post-viral vasculitis of the child. In addition, they would not only be beneficial in post-influenza ARDS, but also would also in 3 cases of post-SARS-CoV2 ARDS. IVIG is a treatment option because it is well tolerated, especially regarding renal function.
These factors are encouraging to quickly conduct a multicentre randomized placebo-controlled trial testing the benefit of IGIV in post-SARS-CoV2 ARDS.
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
- Double (Participant, Care Provider)
盲法说明
The double blinding will be provided by the hospital pharmacy of each establishment with the help of opaque sleeves to mask the product packaging and should be returned to the pharmacy when empty.
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
- •Any patient in intensive care:
- •Receiving invasive mechanical ventilation for less than 72 hours
- •ARDS meeting the Berlin criteria
- •PCR-proven SARS-CoV-2 infection
- •Patient, family or deferred consent (emergency clause)
- •Affiliation to a social security scheme (or exemption from affiliation)
排除标准
- •Allergy to polyvalent immunoglobulins
- •Pregnant woman or minor patient
- •Known IgA deficiency
- •Patient with renal failure on admission defined by a 3 times baseline creatinine or creatinine >354 micromol/L or a diuresis of less than 0.3 mL/Kg for 24 hours or anuria for 12 hours
- •Participation in another interventional trial
研究组 & 干预措施
Intervention - IGIV
Participants in the intervention group will receive a 2g/Kg infusion of human immunoglobulin which should be started before the 96th hours after the start of mechanical ventilation in 4 injections of 0.5 g/Kg over 4 consecutive days.
干预措施: Human immunoglobulin (Drug)
Placebo
Participants of the placebo group will receive an equivalent volume of sodium chloride 0.9% for the same duration.
干预措施: Placebo (Drug)
结局指标
主要结局
Ventilator-free days
时间窗: 28 days
Sum of the days the patient did not receive VM, but if death occurs before D28, the score is zero
次要结局
- Mortality(28 and 90 days)
- Sequential Organ Failure Assessment Score(Days 1, 3, 7, 14, 21 and 28)
- P/F ratio(Days 1, 3, 7, 14, 21 and 28)
- Lung compliance(Days 1, 3, 7, 14, 21 and 28)
- Radiological score(Days 1, 3, 7, 14, 21 and 28)
- Biological efficacy endpoints - Procalcitonin(Days 1, 3, 7, 14, 21 and 28)
- Immunological profile(Up to 28 days)
- Number of patients using other treatments for COVID-19 related ARDS(Up to 28 days)
- Occurrence of deep vein thrombosis or pulmonary embolism(28 days)
- Total duration of mechanical ventilation, ventilatory weaning and curarisation(28 days)
- Kidney Disease: Improving Global Outcomes (KDIGO) score and need for dialysis(28 days)
- Occurrence of adverse event related to immunoglobulins(28 days)
- Occurrence of critical illness neuromyopathy(Up to 28 days)
- Occurrence of ventilator-acquired pneumonia(Up to 28 days)
- Biological efficacy endpoints - C-reactive protein(Days 1, 3, 7, 14, 21 and 28)