VIB-UGent Inflammatie-researchcentrum, Oost-Vlaanderen, Ghent, Belgium.
Trials. 2020 Jun 5;21(1):491. doi: 10.1186/s13063-020-04451-7.
The hypothesis of the proposed intervention is that Granulocyte-macrophage colony-stimulating factor (GM-CSF) has profound effects on antiviral immunity, and can provide the stimulus to restore immune homeostasis in the lung with acute lung injury post COVID-19, and can promote lung repair mechanisms, that lead to a 25% improvement in lung oxygenation parameters. Sargramostim is a man-made form of the naturally-occurring protein GM-CSF.
A phase 4 academic, prospective, 2 arm (1:1 ratio), randomized, open-label, controlled trial.
Patients aged 18-80 years admitted to specialized COVID-19 wards in 5 Belgian hospitals with recent (< 2 weeks prior to randomization) confirmed COVID-19 infection and acute respiratory failure defined as a PaO2/FiO2 below 350 mmHg or SpO2 below 93% on minimal 2 L/min supplemental oxygen. Patients were excluded from the trial in case of (1) known serious allergic reactions to yeast-derived products, (2) lithium carbonate therapy, (3) mechanical ventilation prior to randomization, (4) peripheral white blood cell count above 25.000/μL and/or active myeloid malignancy, (5) high dose systemic steroid therapy (> 20 mg methylprednisolone or equivalent), (6) enrolment in another investigational study, (7) pregnant or breastfeeding or (8) ferritin levels > 2000 μg/mL.
Inhaled sargramostim 125 μg twice daily for 5 days in addition to standard care. Upon progression of disease requiring mechanical ventilation or to acute respiratory distress syndrome (ARDS) and initiation of mechanical ventilator support within the 5 day period, inhaled sargramostim will be replaced by intravenous sargramostim 125 μg/m 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. Intervention will be compared to standard of care. Subjects progressing to ARDS and requiring invasive mechanical ventilatory support, from day 6 onwards in the standard of care group will have the option (clinician's decision) to initiate IV sargramostim 125m μg/m body surface area once daily for 5 days.
The primary endpoint of this intervention is measuring oxygenation after 5 days of inhaled (and intravenous) treatment through assessment of a change in pretreatment and post-treatment ratio of PaO2/FiO2 and through measurement of the P(A-a)O2 gradient (PAO2= Partial alveolar pressure of oxygen, PaO2=Partial arterial pressure of oxygen; FiO2= Fraction of inspired oxygen).
Patients will be randomized in a 1:1 ratio. Randomization will be done using REDCap (electronic IWRS system).
BLINDING (MASKING): In this open-label trial neither participants, caregivers, nor those assessing the outcomes will be blinded to group assignment.
NUMBERS TO BE RANDOMISED (SAMPLE SIZE): A total of 80 patients with confirmed COVID-19 and acute hypoxic respiratory failure will be enrolled, 40 in the active and 40 in the control group.
SARPAC protocol Version 2.0 (April 15 2020). Participant recruitment is ongoing in 5 Belgian Hospitals (i.e. University Hospital Ghent, AZ Sint-Jan Bruges, AZ Delta Roeselare, University Hospital Brussels and ZNA Middelheim Antwerp). Participant recruitment started on March 26 2020. Given the current decline of the COVID-19 pandemic in Belgium, it is difficult to anticipate the rate of participant recruitment.
The trial was registered on Clinical Trials.gov on March 30, 2020 (ClinicalTrials.gov Identifier: NCT04326920) - retrospectively registered; https://clinicaltrials.gov/ct2/show/NCT04326920?term=sarpac&recrs=ab&draw=2&rank=1 and on EudraCT on March 24th, 2020 (Identifier: 2020-001254-22).
The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol.
提出的干预措施的假设是粒细胞-巨噬细胞集落刺激因子（GM-CSF）对抗病毒免疫有深远的影响，并能为 COVID-19 后急性肺损伤的肺部提供恢复免疫平衡的刺激，促进肺修复机制，从而使氧合参数改善 25%。沙格司亭是一种天然存在的 GM-CSF 的人工形式。
一项 4 期学术性、前瞻性、2 组（1:1 比例）、随机、开放标签、对照试验。
5 家比利时医院专门的 COVID-19 病房中年龄在 18-80 岁之间的患者，最近（随机分组前 2 周内）确诊为 COVID-19 感染和急性呼吸衰竭，定义为 PaO2/FiO2 低于 350mmHg 或 SpO2 低于 93%在最低 2 L/min 的补充氧气下。如果患者有以下情况，则将其排除在试验之外：（1）已知对酵母源性产品严重过敏，（2）碳酸锂治疗，（3）随机分组前进行机械通气，（4）外周白细胞计数高于 25,000/μL 和/或活跃的髓系恶性肿瘤，（5）高剂量全身类固醇治疗（> 20mg 甲基强的松龙或等效物），（6）参加其他研究，（7）怀孕或哺乳，或（8）铁蛋白水平> 2000μg/mL。
标准治疗基础上加用每日两次、每次 125μg 沙格司亭吸入治疗 5 天。在疾病进展需要机械通气或发展为急性呼吸窘迫综合征（ARDS）并在 5 天内开始机械通气支持的情况下，吸入沙格司亭将被每日一次、每次 125μg/m2 体表面积的静脉内沙格司亭替代，直到 5 天结束。从第 6 天开始，活跃组中进展的患者将根据治疗医生的评估选择接受额外的 5 天静脉内沙格司亭治疗。干预将与标准护理进行比较。在标准护理组中，从第 6 天开始进展为 ARDS 并需要侵入性机械通气支持的患者将有选择（临床医生的决定）开始每日一次、每次 125mμg/m2 体表面积的静脉内沙格司亭治疗 5 天。
该干预措施的主要终点是通过评估治疗前和治疗后 PaO2/FiO2 比值的变化以及测量肺泡-动脉氧分压差（PAO2=部分肺泡氧分压，PaO2=动脉氧分压；FiO2=吸入氧分数）来测量 5 天吸入（和静脉内）治疗后的氧合情况。
患者将以 1:1 的比例随机分组。随机化将使用 REDCap（电子 IWRS 系统）进行。
盲法（掩蔽）：在这项开放标签试验中，既不会对参与者、护理人员或评估结果的人员进行分组。
随机数量（样本量）：总共将招募 80 名确诊为 COVID-19 且有急性低氧性呼吸衰竭的患者，40 名在活性组，40 名在对照组。
SARPAC 方案版本 2.0（2020 年 4 月 15 日）。参与者正在 5 家比利时医院（根特大学医院、AZ Sint-Jan Bruges、AZ Delta Roeselare、布鲁塞尔大学医院和安特卫普 ZNA Middelheim）招募。参与者招募于 2020 年 3 月 26 日开始。考虑到目前比利时 COVID-19 疫情的下降，预计参与者的招募速度会比较困难。
该试验于 2020 年 3 月 30 日在 ClinicalTrials.gov 上注册（ClinicalTrials.gov 标识符：NCT04326920）- 回溯性注册；https://clinicaltrials.gov/ct2/show/NCT04326920?term=sarpac&recrs=ab&draw=2&rank=1 和 EudraCT 于 2020 年 3 月 24 日（标识符：2020-001254-22）。
完整的方案作为附加文件附在试验网站上（附加文件 1）。为了加快传播这一材料的速度，熟悉的格式已被删除；这封信是对完整方案关键要素的总结。
