Guirgis Faheem W, Black Lauren Page, Rosenthal Martin Daniel, Henson Morgan, Ferreira Jason, Leeuwenburgh Christiaan, Kalynych Colleen, Moldawer Lyle L, Miller Taylor, Jones Lisa, Crandall Marie, Reddy Srinivasa T, Wu Samuel S, Moore Frederick A
Emergency Medicine, University of Florida College of Medicine - Jacksonville, Jacksonville, Florida, USA
Emergency Medicine, University of Florida College of Medicine - Jacksonville, Jacksonville, Florida, USA.
BMJ Open. 2019 Sep 18;9(9):e029348. doi: 10.1136/bmjopen-2019-029348.
Sepsis is a life-threatening, dysregulated response to infection. Both high-density lipoprotein and low-density lipoprotein cholesterol should protect against sepsis by several mechanisms; however, for partially unknown reasons, cholesterol levels become critically low in patients with early sepsis who experience poor outcomes. An anti-inflammatory lipid injectable emulsion containing fish oil is approved by the Food and Drug Administration as parenteral nutrition for critically ill patients and may prevent this decrease in serum cholesterol levels by providing substrate for cholesterol synthesis and may favourably modulate inflammation. This LIPid Intensive Drug therapy for Sepsis Pilot clinical trial is the first study to attempt to stabilise early cholesterol levels using lipid emulsion as a treatment modality for sepsis.
This is a two-centre, phase I/II clinical trial. Phase I is a non-randomised dose-escalation study using a Bayesian optimal interval design in which up to 16 patients will be enrolled to evaluate the safest and most efficacious dose for stabilising cholesterol levels. Based on phase I results, the two best doses will be used to randomise 48 patients to either lipid injectable emulsion or active control (no treatment). Twenty-four patients will be randomised to one of two doses of the study drug, while 24 control group patients will receive no drug and will be followed during their hospitalisation. The control group will receive all standard treatments mandated by the institutional sepsis alert protocol. The phase II study will employ a permuted blocked randomisation technique, and the primary endpoint will be change in serum total cholesterol level (48 hours - enrolment). Secondary endpoints include change in cholesterol level from enrolment to 7 days, change in Sequential Organ Failure Assessment score over the first 48 hours and 7 days, in-hospital and 28-day mortality, lipid oxidation status, inflammatory biomarkers, and high-density lipoprotein function.
Investigators are trained and follow good clinical practices, and each phase of the study was reviewed and approved by the institutional review boards of each institution. Results of each phase will be disseminated through presentations at national meetings and publication in peer-reviewed journals. If promising, data from the pilot study will be used for a larger, multicentre, phase II clinical trial.
NCT03405870.
脓毒症是一种危及生命的、对感染的失调反应。高密度脂蛋白和低密度脂蛋白胆固醇都应通过多种机制预防脓毒症；然而，部分原因不明的是，早期脓毒症且预后不良的患者胆固醇水平会严重降低。一种含鱼油的抗炎性脂质注射乳剂已获美国食品药品监督管理局批准，可作为重症患者的肠外营养剂，它可能通过为胆固醇合成提供底物来防止血清胆固醇水平下降，并可能有利地调节炎症。这项脓毒症脂质强化药物治疗试点临床试验是首次尝试使用脂质乳剂作为脓毒症治疗方式来稳定早期胆固醇水平的研究。
这是一项两中心的I/II期临床试验。I期是一项采用贝叶斯最优区间设计的非随机剂量递增研究，将招募多达16名患者以评估稳定胆固醇水平的最安全、最有效剂量。根据I期结果，将使用两个最佳剂量将48名患者随机分为脂质注射乳剂组或活性对照组（不治疗）。24名患者将被随机分配到两种剂量的研究药物之一，而24名对照组患者将不接受药物治疗，并在住院期间接受随访。对照组将接受机构脓毒症警报协议规定的所有标准治疗。II期研究将采用置换区组随机化技术，主要终点将是血清总胆固醇水平的变化（48小时 - 入组时）。次要终点包括从入组到7天的胆固醇水平变化、前48小时和7天序贯器官衰竭评估评分的变化、住院和28天死亡率、脂质氧化状态、炎症生物标志物和高密度脂蛋白功能。
研究人员经过培训并遵循良好临床实践，研究的每个阶段均由各机构的机构审查委员会进行审查和批准。每个阶段的结果将通过在全国会议上的报告和在同行评审期刊上发表来传播。如果结果有前景，试点研究的数据将用于更大规模的多中心II期临床试验。
NCT03405870。
