Omegaven Treatment of Parenteral Nutrition (PN) Induced Liver Injury

Study Overview
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Brief Summary
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This study examines the hypothesis that administering intravenous fish oil, in lieu of intravenous soybean oil, can ameliorate the progression of PN-associated cholestatic liver disease in pediatric patients with elevated direct bilirubin requiring PN for more than 30 days.

Detailed Description
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In the United States, patients dependent upon parenteral nutrition (PN) receive parenteral fat emulsions composed of soybean oils. Lipids are necessary in PN dependent patients due to their high caloric value and essential fatty acid content. They have been implicated in predisposing patients to PN associated liver disease. Phytosterols such as those contained in soybean oils are thought to have a deleterious effect on biliary secretion. Children requiring prolonged PN are at risk for developing PN associated liver disease. We hypothesize that although omega-6 fatty acid emulsions prevent fatty acid deficiency, they are not cleared in a manner similar to enteral chylomicrons and therefore accumulate in the liver and resulting in steatotic liver injury. We further hypothesize that a fat emulsion comprised of omega-3 fatty acids (i.e., fish oil) such as Omegaven™ would be beneficial in the management of steatotic liver injury by its inhibition of de novo lipogenesis, the reduction of arachidonic acid-derived inflammatory mediators, prevention of essential fatty acid deficiency through the presence of small amounts of arachidonic acid, and improved clearance of lipids from the serum. Animal studies have shown that IV fat emulsions (IFE) such as fish oil that are high in eicosapentaenic and docashexaaenoic acid reduce impairment of bile flow which is seen in cholestasis caused by conventional fat emulsions. Intravenous omega three fatty acids may be well tolerated and might reduce the inflammatory effect in the liver of prolonged PN exposure and could potentially reverse any hepatic dysfunction due to PN/IFE use. By administering Omegaven™ in place of conventional phytosterol/soybean fat emulsions we may reverse or prevent the progression of PN associated cholestasis and thus allow the patient to be maintained on adequate PN until they are able to ingest adequate nutrition enterally.

Official Title
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Research Study of an Intravenous Fat Emulsion Comprised of Fish Oils (Omegaven) in the Treatment of Parenteral Nutrition (PN) Induced Liver Injury

Conditions
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Liver Injury

Intervention / Treatment
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* Drug: Omegaven™
* Other: Historical Controls


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients will be parenteral nutrition dependent and are expected to require PN for at least another 30 days Patients must have parenteral nutrition associated liver disease (PNALD) as defined by having at least 2 consecutive direct bilirubins >2 mg/dl. Exclusion Criteria: Pregnancy Other causes of liver disease Enrollment in any other clinical trial involving an investigational agent (unless approved by the designated physicians on the multidisciplinary team) Direct bilirubin < 2 mg/dl Allergy to any fish product, egg protein, and/or previous allergy to Omegaven Active coagulopathy characterized by on-going bleeding or acute need for clotting factor replacement such as FFP or cryoprecipitate to maintain homeostasis Impaired lipid metabolism as defined by serum Tg level >400 at time of initiation of Omegaven Unstable diabetes mellitus Recent stroke/embolism, not including catheter related thrombosis, which is a common complication of central venous catheter. Collapse and shock Undefined coma status Untreated infection at time of initiation of Omegaven Hemodynamic instability > 21 years of age

Ages Eligible for Study
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Maximum Age: 21 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: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: Historical controls<br>A subset of patients previously seen, who have had at least 2 consecutive direct bilirubin levels > 2 mg/dL, who depended on parenteral nutrition for at least 90 days after surgical therapy for congenital or acquired intestinal diseases | Other: Historical Controls<br>* Standard of Care<br>|
| Experimental: Omegaven™<br> | Drug: Omegaven™<br>* 1 g/kg/d of Omegaven until discontinuation of PN<br>* Other names: Highly refined fish oil for intravenous administration (10% Omegaven™);|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Rate of reduction of direct bilirubin |  | normalization of direct bilirubin: an expected average of approximately 5 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Pediatric patients with Parenteral Nutrition (PN) induced Liver Injury