A Safety and Efficacy Study to Determine if Giving Intravenous Fish Oil Helps Children With Liver Disease

Study Overview
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Brief Summary
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The purpose of the study is to investigate if intravenous fish oil, commercially available as Omegaven, safely and effectively reverses parenteral nutrition associated cholestasis in children.

Detailed Description
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Infants dependent on parenteral nutrition for greater than 1 year who develop parenteral nutrition associated cholestasis will universally face mortality unless they receive a timely liver and/or small bowel transplant. Although transplant survival has improved in recent years, survival is not guaranteed, and transplant care remains costly. Alternative nutritional and pharmacological strategies are imperative to improve the clinical outcomes of infants with intestinal failure and parenteral nutrition associated cholestasis. In both animal and human studies, intravenous fish oil, a lipid emulsion rich in omega-3 fatty acids and Vitamin E, and lacking phytosterols, has been shown to ameliorate parenteral nutrition associated cholestasis and improve morbidity and mortality. The purpose of this pilot study is to investigate if Omegaven, a commercially available intravenous fish oil, at 1 g/kg/d, will safely reverse liver disease in 80 subjects with parenteral nutrition associated cholestasis. Subjects can initially receive a maximum of 6 months (24 weeks) of intravenous fish oil. If the subject re-develops liver disease and still satisfies inclusion/exclusion criteria, the intervention can be restarted. Study subjects will be compared to a historical cohort of children with Short Bowel Syndrome and parenteral nutrition associated cholestasis who have been receiving standard intravenous soybean oil for > 60 days. The fish oil cohort will be followed for a total of 5 years to determine if transplant-free mortality is reduced.

Official Title
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Omegaven and Parenteral Nutrition Associated Cholestasis

Conditions
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Cholestasis

Intervention / Treatment
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* Drug: Omegaven


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Clinical evidence of parenteral nutrition associated cholestasis Direct bilirubin greater or equal to 2 mg/dL on 2 consecutive measurements Expected parenteral nutrition course greater than 30 days Acquired or congenital gastrointestinal disease > 2 weeks of age and < 18 years of age > 60% calories from parenteral nutrition Failed standard therapies to prevent progression of liver disease (Actigal, cyclic parenteral nutrition, avoidance of overfeeding, reduction/removal of copper from parenteral nutrition if elevated my laboratory analysis, advancement of enteral feeds) Exclusion Criteria: Inborn errors of metabolism Extracorporeal Membrane Oxygenation Seafood, egg, or Omegaven allergy Documented case of liver disease other than Parenteral Nutrition Associated Cholestasis Hemorrhagic disorder Anticoagulant therapy Hemodynamically unstable or in shock Comatose state Stroke, pulmonary embolism, recent myocardial infarction Diabetes Fatal chromosomal disorder Enrollment in any other clinical trial involving an investigational agent Patient, parent, or legal guardians unable or unwilling to give consent Patient expected to be weaned from parenteral nutrition in 30 days unable to tolerate necessary monitoring Patient requiring aspirin or toradel or motrin Patient requiring dialysis

Ages Eligible for Study
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Minimum Age: 2 Weeks
Maximum 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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Omegaven<br>0.5 g/kg/d IV x 2 days, then 1 g/kg/d IV for 24 weeks or until parenteral nutrition discontinuation, death or transplant, whichever comes first. Subjects are eligible to restart Omegaven should they re-satisfy inclusion/exclusion criteria. | Drug: Omegaven<br>* 0.5 g/kg/d intravenous every day for 2 days, then 1 g/kg/d intravenous everyday<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to Reversal of Parenteral Nutrition Associated Cholestasis | weeks | 24 weeks, death, transplant, or discontinuation of Parenteral Nutrition (whichever comes first) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Death | expiration | 24 weeks, transplant, or discontinuation of Parenteral Nutrition (whichever comes first) | 
| Number of Participants Who Underwent a Transplant | includes isolated liver or multi-visceral transplant including liver graft | 24 weeks, death, or discontinuation of Parenteral Nutrition (whichever comes first) | 
| Time to Full Enteral Feeds | discontinuation of parenteral nutrition | 24 weeks, death, transplant, or discontinuation of Parenteral Nutrition (whichever comes first) | 
| Growth Z-scores | Weight Z-scores at the end of the study. Formula used: (weight at end of study-average weight of reference population)/standard deviation of weight of reference population. The Z-score indicates the number of standard deviations away from the mean. A weight Z-score of 0 is equal to the mean with negative numbers indicating values lower than the mean and positive values higher. A weight Z-score </= -2 indicates an underweight or malnourished status, while a weight Z-score >/= 2 indicates an overweight or obese status. | 24 weeks, death, transplant, or discontinuation of Parenteral Nutrition (whichever comes first) | 
| Platelet Counts at the End of the Study - Risk of Bleeding | platelet counts at the end of the study | 24 weeks, death, transplant, or discontinuation of Parenteral Nutrition (whichever comes first) | 
| Number of Participants With Essential Fatty Acid Deficiency | triene:tetraene ratio less than 0.2 | 24 weeks, death, transplant, or discontinuation of Parenteral Nutrition (whichever comes first) | 
| Markers of Inflammation | Serum Cytokines - interleukin-8 | 24 weeks, death, or discontinuation of Parenteral Nutrition (whichever comes first) | 
| Markers of Sterol Metabolism | Serum Phytosterols - stigmasterol | 24 weeks, death, or discontinuation of Parenteral Nutrition (whichever comes first) | 
| Markers of Bile Acid Metabolism | Serum Bile acids - total chenodeoxycholic acid | 24 weeks, death, or discontinuation of Parenteral Nutrition (whichever comes first) | 
| Markers of Fatty Acid Metabolism | Erythrocyte fatty acid - Docosahexaenoic Acid | 24 weeks, death, or discontinuation of Parenteral Nutrition (whichever comes first) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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liver, parenteral nutrition, fish oil, omegaven, children