Fish Oil for Patients With Liver Disease Due to Parenteral Nutrition
|Total Parenteral Nutrition-induced Cholestasis||Drug: Soybean oil (Standard treatment) Drug: Soybean oil + Fish oil||Phase 3|
|Study Design:||Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
|Official Title:||Effect of n-3 Polyunsaturated Fatty Acid Lipid Emulsion on Parenteral Nutrition Associated Liver Disease|
- Response to treatment at 3 months [ Time Frame: 3 months ]Response is defined as improvement of at least one PNALD parameter by 20% or more; PNALD parameters are: ALP, GGT, ALT, total bilirubin Yes/No
- Change in total and conjugated bilirubin over time [ Time Frame: 0, 3, 6 months on Omegaven ]
- Changes in liver function test (ALP, AST, GGT) over 6 months [ Time Frame: 0, 3, 6 months on Omegaven ]
- Changes in liver histology between baseline and 6 months on Omegaven [ Time Frame: 0, 6 months on Omegaven ]
- Changes in liver fatty acid composition between baseline and 6 months on Omegaven [ Time Frame: 0, 6 months on Omegaven ]Fatty acid composition by gas chromatography
- Changes in liver oxidative stress between baseline and 6 months [ Time Frame: 0, 6 months ]Lipid peroxides in liver tissue (test-kit)
- Changes in hepatic gene expression between baseline and 6 months on Omegaven [ Time Frame: 0, 6 months on Omegaven ]Hepatic gene expression (mRNA) by microarray
- Insulin resistance [ Time Frame: 0, 3, 6, 9 months ]HOMA-insulin resistance 0, 3, 6 months in Omegaven group 0, 3, 6, 9 months in Intralipid-group switching to Omegaven after 3 months
- Blood lipid profile [ Time Frame: 0, 3, 6, 9 months ]Triglycerides, total cholesterol, LDL, HDL 0, 3, 6 months in Omegaven group 0, 3, 6, 9 months in Intralipid-group switching to Omegaven after 3 months
- Complete blood count (CBC) [ Time Frame: 0, 3, 6, 9 months ]0, 3, 6 months in Omegaven group 0, 3, 6, 9 months in Intralipid-group switching to Omegaven after 3 months
- international normalized ratio (INR) [ Time Frame: 0, 3, 6, 9 months ]0, 3, 6 months in Omegaven group 0, 3, 6, 9 months in Intralipid-group switching to Omegaven
|Study Start Date:||February 2012|
|Study Completion Date:||August 2015|
|Primary Completion Date:||August 2015 (Final data collection date for primary outcome measure)|
Experimental: Soybean oil + Fish oil
Intralipid (0.25 g/kg/TPN day) + Omegaven (0.4 g/kg/TPN day) for a period of 6 months.
Drug: Soybean oil + Fish oil
Intralipid+Omegaven: 0.25 g/kg/TPN Intralipid day+0.4 g/kg/TPN Omegaven day for 6 months
Other Name: Intralipid, Omegaven
Active Comparator: Soybean oil (Standard treatment)
Standard treatment: Intralipid (0.25 g/kg/TPN day) for a period of 6 months
Drug: Soybean oil (Standard treatment)
1. Standard treatment: Soybean oil based emulsion: 0.25 g/kg/TPN day
Other Name: Intralipid
Chronic exposure to total parenteral nutrition (TPN) can cause parenteral nutrition associated liver disease (PNALD), a progressive condition that may severely affect the liver and lead to end-stage liver disease. Fish oil has been shown to exert beneficial effects as it favorably alters metabolism and inflammation. It has been used parenterally (Omegaven) in young children with short bowel syndrome and PNALD with encouraging results. In adults it has mostly been used in peri-surgical settings as well as in critically ill patients, again proving its effectiveness.
The goal of this proposal is to show that Omegaven use in home-TPN patients with PNALD and elevated bilirubin despite conventional treatment, is beneficial in improving cholestasis and reducing intrahepatic inflammation. Primary objective is to compare the response to treatment between the Omegaven and the Intralipid group. Secondary objectives are to study the effect of Omegaven supplementation on single liver function tests, liver histology, liver fatty acid composition, liver oxidative stress and gene expression. In addition, the investigators want to compare the baseline values of all 20 patients to 20 healthy controls subjects.
After establishing that the patients' liver disease does not improve with conventional medical treatments for 3 months, as evidenced by repeated blood work at that time, they will all have a liver biopsy done as per diagnostic standards. They will then be randomized to either continue receiving Intralipid (0.25 g/kg/TPN day) or a mixture of Intralipid (0.25 g/kg/TPN day) and Omegaven (0.4 g/kg/TPN day) for a period of 3 months. After that, patients in the Omegaven arm will continue their treatment for 3 more months. Those in the Intralipid arm will be switched over to also receive Omegaven for the following 6 months.
Blood work will be repeated every 3 months after the initiation of the intervention. A repeat liver biopsy will be done in both groups after 6 months.
Main outcome is response to treatment (improvement in liver function tests) after 3 months (comparing Intralipid to Omegaven). In addition, change in liver function tests during the 6 months on Omegaven will be assessed. Lipid peroxidation and oxidative stress, fatty acid composition, and gene expression in the liver will be compared before and after 6 months on Omegaven.
In a second part of the study baseline values from all 20 patients will be compared to 20 healthy controls. Controls will be recruited from the healthy living liver donor transplant program at the University Health Network (UHN). Liver samples will be obtained at the time of hepatectomy for transplantation. The same measurements as for the patient livers will be performed in healthy liver tissue.
Significance: The investigators aim to reveal the beneficial effects of fish oil supplementation in the setting of PNALD. Should this pilot study show improvement in the liver disease with Omegaven, a larger, randomized trial should follow. Comparison with healthy controls will provide further insight into the pathogenesis of PNALD, which to date is not completely understood
Please refer to this study by its ClinicalTrials.gov identifier: NCT01565278
|Foothills Medical Center|
|Calgary, Alberta, Canada, T2N 4Z6|
|University of Alberta|
|Edmonton, Alberta, Canada, T5H 3V9|
|St Boniface Hospital|
|Winnipeg, Manitoba, Canada, R2H 2A6|
|University Health Network|
|Toronto, Ontario, Canada, M5G 2N2|
|Principal Investigator:||Johane P Allard, MD,FRCPC||University Health Network, Toronto|