A Prospective, Randomized, Open-label, Interventional Study to Investigate the Efficacy of Sargramostim (Leukine®) in Improving Oxygenation and Short- and Long-term Outcome of COVID-19 (Corona Virus Disease) Patients With Acute Hypoxic Respiratory Failure.
试验速览
- 阶段
- 4 期
- 状态
- 已完成
- 入组人数
- 87
- 试验地点
- 4
- 主要终点
- Improvement in Oxygenation
研究概览
简要总结
Phase IV study to evaluate the effectiveness of additional inhaled sargramostim (GM-CSF) versus standard of care on blood oxygenation in patients with COVID-19 coronavirus infection and acute hypoxic respiratory failure.
详细描述
Leukine® is a yeast-derived recombinant humanized granulocyte-macrophage colony stimulating factor (rhuGM-CSF, sargramostim) and the only FDA approved GM-CSF. GMCSF, a pleiotropic cytokine, is an important leukocyte growth factor known to play a key role in hematopoiesis, effecting the growth and maturation of multiple cell lineages as well as the functional activities of these cells in antigen presentation and cell mediated immunity.
Leukine inhalation or intravenous administration, as an adjuvant therapy, may confer benefit to patients with ARDS (Acute Respiratory Distress Syndrome) due to COVID-19 exposure, who are at significant risk of mortality. While there is no active IND (Investigational New Drug) for Leukine in the proposed patient population, Leukine is being studied in Fase II as an adjuvant therapy in the management of life-threatening infections to boost the hosts innate immune response to fight infection, reduce the risk of secondary infection, and in varied conditions as prevention of infection during critical illness. Inhaled Leukine has also been successfully used as primary therapy to improve oxygenation in patients with disordered gas exchange in the lungs. We propose that based on preclinical and clinical data, Leukine inhalation, as an adjuvant therapy, has an acceptable benefit-risk for use in patients with hypoxic respiratory failure and ARDS due to COVID-19 exposure, who are at significant risk of mortality.
Confirmed COVID19 patients with hypoxic respiratory failure (saturation below 93% on minimal 2 l/min O2) will be randomized to receive sargramostim 125mcg twice daily for 5 days as a nebulized inhalation on top of standard of care, or to receive standard of care treatment. Upon progression of disease requiring initiation of mechanical ventilatory support within the 5 day period, in patients in the active group, inhaled sargramostim will be replaced by intravenous sargramostim 125mcg/m2 body surface area until the 5 day period is reached. From day 6 onwards, progressive patients in the active group will have the option to receive an additional 5 days of IV sargramostim, based on the treating physician's assessment. In the control group progressive disease requiring mechanical ventilatory support, from day 6 onwards, the treating physician will have the option to initiate IV sargramostim 125mcg/m2 body surface area for 5 days. Safety data, including blood leukocyte counts, will be collected in all patients. Efficacy data will also be collected and will include arterial blood gases, oxygenation parameters, need for ventilation, lung compliance, organ function, radiographic changes, ferritin levels, etc. as well as occurrence of secondary bacterial infections.
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 80 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Recent (≤2weeks prior to Randomization) confident diagnosis of COVID-19 confirmed by antigen detection and/or PCR (Polymerase Chain Reaction), and/or seroconversion or any other emerging and validated diagnostic test
- •In some patients, it may be impossible to get a confident laboratory confirmation of COVID-19 diagnosis after 24h of hospital admission because viral load is low and/or problems with diagnostic sensitivity. In those cases, in absence of an alternative diagnosis, and with highly suspect bilateral ground glass opacities on recent (<24h) chest-CT scan (confirmed by a radiologist and pulmonary physician as probable COVID-19), a patient can be enrolled as probable COVID-19 infected. In all cases, this needs confirmation by later seroconversion.
- •Presence of acute hypoxic respiratory failure defined as (either or both)
- •saturation below 93% on minimal 2 l/min O2
- •PaO2/FiO2 below 300
- •Admitted to specialized COVID-19 ward
- •Age 18-80
- •Male or Female
- •Willing to provide informed consent
排除标准
- •Patients with known history of serious allergic reactions, including anaphylaxis, to human granulocyte-macrophage colony stimulating factor such as sargramostim, yeast-derived products, or any component of the product.
- •mechanical ventilation before start of study
- •patients with peripheral white blood cell count above 25.000 per microliter and/or active myeloid malignancy
- •patients on high dose systemic steroids (> 20 mg methylprednisolone or equivalent)
- •patients on lithium carbonate therapy
- •Patients enrolled in another investigational drug study
- •Pregnant or breastfeeding females (all female subjects regardless of childbearing potential status must have negative pregnancy test at screening)
- •Patients with serum ferritin >2000 mcg/ml (which will exclude ongoing HLH)
研究组 & 干预措施
Active sargramostim treatment group
Inhaled sargramostim 125mcg twice daily for 5 days on top of standard of care. Upon progression to ARDS and initiation of mechanical ventilator support within the 5 day period, inhaled sargramostim will be replaced by intravenous sargramostim 125mcg/m2 body surface area once daily until the 5 day period is reached. From day 6 onwards, progressive patients in the active group will have the option to receive an additional 5 days of IV sargramostim, based on the treating physician's assessment
干预措施: Sargramostim (Drug)
Control group
standard of care. Subjects progressing to ARDS and requiring invasive mechanical ventilatory support, from day 6 onwards, will have the option (clinician's decision) to initiate IV sargramostim 125mcg/m2 body surface area once daily for 5 days
干预措施: Sargramostim (Drug)
Control group
standard of care. Subjects progressing to ARDS and requiring invasive mechanical ventilatory support, from day 6 onwards, will have the option (clinician's decision) to initiate IV sargramostim 125mcg/m2 body surface area once daily for 5 days
干预措施: Control (Other)
结局指标
主要结局
Improvement in Oxygenation
时间窗: on Day 6 or hospital discharge, whichever came first
Mean Change from Baseline in PaO2/FiO2 on Day 6 or hospital discharge, whichever came first
次要结局
- Time to Clinical Sign Score < 6 for at Least 24h(During hospital admission (up to 28 days))
- Change in Sequential Organ Failure Assessment (SOFA Score)(at baseline, at day 6)
- Change in Ferritin Level(at baseline, at day 6)
- Change in Lymphocyte Count(at baseline, at day 6)
- Number of Days in Hospital(through study completion, an average of 5 months)
- Death(at 28 days)
- Mean Change in 6-point Ordinal Scale for Clinical Improvement(at Baseline, at Day 6)
- Number of Participants With Nosocomial Infection no./Total no (%)(during hospital admission (up to 28 days))
- Number of Participants Progressed to Mechanical Ventilation and/or ARDS(during hospital admission (up to 28 days))
- Change in Clinical Sign Score(at baseline, at day 6)
- Change in (National Early Warning Score2) NEWS2 Score(at baseline, at day 6)
- Change in D-dimer Level(at baseline, at day 6)
- Change in CRP Level(at baseline, at day 6)
- Change in Eosinophil Count(at baseline, at day 6)
- HRCT (High-Resolution Computed Tomography) Fibrosis Score(at follow-up, 10-20 weeks after day 10 or discharge, whichever comes first)
研究者
Bart N. Lambrecht
Director, VIB-UGent Center for Inflammation Research
University Hospital, Ghent