LIPid Intensive Drug therapy for Sepsis Pilot (LIPIDS-P): Phase I/II clinical trial protocol of lipid emulsion therapy for stabilising cholesterol levels in sepsis and septic shock

Abstract

IntroductionSepsis 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.Methods and analysisThis 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.Ethics and disseminationInvestigators 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.Trial registration numberNCT03405870.

Lipid intensive drug therapy for sepsis pilot: A Bayesian phase I clinical trial

“…Not surprisingly, triglyceride and LDL‐C levels seemed to be more responsive to lipid emulsion therapy at all doses compared with HDL‐C levels, which remained at lower levels overall. All patients had pro‐inflammatory HDL represented by the HII ratio > 1, consistent with our prior work 13,39 . Because of the limited amount of PON‐1 and HII data, it is difficult to make any assessment about the influence of individual drug dosages on HDL antioxidant function.…”

“…All patients had pro-inflammatory HDL represented by the HII ratio > 1, consistent with our prior work. 13,39 Because of the limited amount of PON-1 and HII data, it is difficult to make any assessment about the influence of individual drug dosages on HDL antioxidant function.…”

“…The study protocol has been previously published and registered (NCT03405870) 39 . Briefly, this was a phase I, sequential, dose‐escalation study of lipid emulsion therapy (Smoflipid, Fresenius Kabi, Homburg, Germany) with a Bayesian optimal interval (BOIN) design.…”

“…The specified dose of study drug was administered twice during the first 48 hours after enrollment at 24‐hour intervals so that each patient received 2 doses of the drug at each dose level. Study monitoring was performed in accordance with the study protocol 39 . To meet the requirement for protocol completion, participants must have received both doses of lipid emulsion during the first 48 hours after enrollment and have a 48‐hour lipid panel and research blood drawn.…”

Lipid and Lipoprotein Dysregulation in Sepsis: Clinical and Mechanistic Insights into Chronic Critical Illness

“…Our group has previously shown in a phase I clinical trial, Lipid Intensive Drug therapy for Sepsis Pilot (LIPIDS-P) that omega-3 supplementation through a fish-oil containing lipid emulsion in early sepsis is safe, and promise toward stabilizing early total cholesterol and HDL levels [ 158 ]. A phase II clinical trial (LIPIDS-P) to further evaluate the efficacy is currently underway [ 98 ].…”