LIPIDS-P Trial Phase I/II

Study Overview
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Brief Summary
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Briefly, this pilot clinical trial will evaluate preliminary safety and efficacy of the study drug (Smoflipid) at elevating cholesterol levels (primary outcome) in patients with sepsis and moderate organ dysfunction and will also evaluate measures of organ dysfunction, mortality, and biological activity (secondary outcomes).

Detailed Description
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Sepsis is a life-threatening disease for which there are no effective treatments. It results from metabolic and immunologic derangements that lead to organ dysfunction, shock and sometimes death. Both good (high density lipoprotein, HDL) and bad (low density lipoprotein, LDL) cholesterol should be protective against sepsis by helping to clear bacterial toxins from the blood stream and by providing a fuel for endogenous corticosteroids, part of the body's protective stress-response in shock. However, for partially unknown reasons, cholesterol levels drop to critically low levels in early sepsis, leaving the body unable to protect itself against sepsis via these mechanisms. Currently, lipid emulsions are available that are FDA approved for intravenous nutrition in critically ill patients (including sepsis) and may be capable of elevating serum cholesterol levels. This Phase II randomized pilot clinical trial, proposes to assess the following in a cohort of patients with early sepsis (first 24 hours): 1) safety and tolerability of the proposed lipid injectable emulsion (Smoflipid) and any adverse effects, 2) the drugs ability to optimally elevate cholesterol at 48 hours, and 3) preliminary measures of biological activity and clinical outcomes.

Official Title
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The LIPid Intensive Drug Therapy for Sepsis ¬Pilot (LIPIDS-P) Phase I/II Trial

Conditions
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Sepsis, Severe, Septic Shock

Intervention / Treatment
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* Drug: Smoflipid


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: age > 18, primary diagnosis of sepsis and within 24 hours of sepsis recognition and treated with institutional sepsis algorithm, SOFA score ≥ 4, screening total cholesterol ≤ 100 mg/dL or HDL-C + LDL-C ≤ 70 mg/dL Exclusion Criteria: total bilirubin > 2 mg/dL, serum albumin < 1.5 mg/dL, hypersensitivity to fish, egg, soybean, or peanut protein, or to any of the active ingredients or excipients, severe hyperlipidemia or severe disorders of lipid metabolism with serum triglycerides > 400 mg/dL, alternative/confounding diagnosis causing shock or critical illness (e.g., myocardial infarction or pulmonary embolus, massive hemorrhage, trauma), significant traumatic brain injury (evidence of neurologic injury on CT scan and a GCS <8), refractory shock (likely death within 12 hours), established Do Not Resuscitate status or advanced directives restricting aggressive care or treating physician deems aggressive care unsuitable, anticipated requirement for surgery that would interfere with drug infusion, severe primary blood coagulation disorder, acute pancreatitis accompanied by hyperlipidemia, acute thromboembolic disease, uncontrollable source of sepsis (e.g., irreversible disease state such as unresectable dead bowel), severe immunocompromised state (e.g. subject has neutropenia receiving cytotoxic chemotherapy with absolute neutrophil count < 500/ul or expected to decline to < 500/uL within the next 3 days), pregnancy or lactation already receiving intravenous lipid formulations (e.g., TPN, propofol) will be excluded from the study as lipid infusion will interfere with interpretation of the study results. Child Pugh Class B/C liver disease patients or liver transplant recipient Patients on, or anticipated to be placed on, ECMO within 48 hours of enrollment

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: The study has a Phase I/II design. For the Phase I, which has been completed, 10 patients were enrolled in the study to evaluate for dose limiting toxicity (DLT). For patients enrolled in the Phase I dose-escalation study, there was no control group, with doses starting at 1.0g/kg and increasing incrementally based on weight by 0.2g/kg to a maximum dose of 1.6g/kg. Dose escalation or de-escalation occurred based on whether DLTs were observed at a specific dose, with the threshold for toxicity set at 10%. After evaluating for DLT, the two highest and safest doses will be used to randomize the remaining 48 patients into the Phase II study to either Smoflipid or control (no active treatment) using a Bayesian Optimal Interval Design. Thus, the Phase II arm will include 24 patients per arm randomized to one of the two most efficacious doses of the study drug based on body weight, while the control group will receive no drug.
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Lipid<br>Infusion of drug (Smoflipid) will occur over a 16.5 hour period given once per day for the first two days of study enrollment. | Drug: Smoflipid<br>* Administration of lipid injectable emulsion<br>* Other names: Total parenteral nutrition;|
| No Intervention: Control<br>Control patients will receive no experimental drug (ie, usual care) | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Total Cholesterol | Delta total cholesterol (48 hour - enrollment value) of 0 to +5 mg/dL | 48 hours | 
| Maximum Tolerated Dose | Evaluate for dose limiting toxicities for the Phase I study | First 7 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Lipid Oxidation | HDL inflammatory index (ranges from 0-10) | 48 hours | 
| HDL function | Cholesterol efflux, this is a percentage from 0-100% | 48 hours | 
| Organ Dysfunction | Sequential Organ Failure Assessment (SOFA) Score, this is a numerical score ranging from 0 to 24 | 48 hours, 7 days | 
| Mortality | Mortality | In-hospital, 28 day | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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cholesterol, lipids, total parenteral nutrition