Clinical trial NCT01565278: Fish Oil for Patients With Liver Disease Due to Parenteral Nutrition
Official title: Effect of n-3 Polyunsaturated Fatty Acid Lipid Emulsion on Parenteral Nutrition Associated Liver Disease
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE3
Conditions: Total Parenteral Nutrition-induced Cholestasis
Keywords: Parenteral nutrition
fish oil
liver disease
Omegaven
hepatic
liver biopsy
bilirubin
Lead sponsor: University Health Network, Toronto
Sponsor class: OTHER
Collaborators: name: ASPEN Rhoads Research Foundation
name: Fresenius Kabi
name: University of Alberta
name: Foothills Medical Centre
name: St. Boniface Hospital
name: Hamilton Health Sciences Corporation
name: St. Paul's Hospital, Canada
First posted: 2012-03-28
Enrollment: 2
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: Patients who are not able to eat normally for a longer time require parenteral nutrition, i.e. they receive liquids and nutrients directly into their veins. This can have many long-term side effects, including liver problems. This study will examine whether a specific lipid emulsion containing fish oil can improve liver disease in patients on parenteral nutrition. The investigators will compare changes in bilirubin and liver enzymes after 3 months in 10 patients receiving standard lipid emulsion to 10 patients receiving standard lipids + a fish-oil containing emulsion. The investigators will also assess liver histology, the kind of fat, oxidative stress and gene expression in the liver at the beginning and after 6 months of fish-oil. The investigators also want to compare the baseline values from all 20 patients to 20 healthy controls. This will help to explain how fish oil may improve liver disease in patients on parenteral nutrition.

Detailed description: 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

Eligibility criteria: Inclusion Criteria:

* Clinically stable patients on home TPN with PNALD with persistently elevated bilirubin (\>1.5 times \> normal) for at least 3 months despite standard treatment with ursodeoxycholic acid (15-30 mg/kg or at least 500 mg/d orally), changes in TPN (reduction to 25 kcal/kg/TPN day with Intralipid 0.25 g/kg) , and antibiotics (Metronidazole 500 mg bid and Ciprofloxacin 500 mg bid)
* male or female,equal or over 18 years of age
* on stable TPN regimen equal or over 3 days/week
* on a stable drug regimen for equal or over 3 months prior to randomization, which will not changed for the study duration if these drugs are ursodeoxycholic acid given for PNALD or others affecting glucose and lipid metabolism

Exclusion Criteria:

* Not receiving lipid emulsion as part of TPN
* Allergy to fish, egg , soy, and peanuts
* Liver disease of other etiology (e.g. excessive alcohol intake \>20g/d, viral hepatitis, auto-immune or drug-induced, hemochromatosis, alfa 1-antitrypsin deficiency, Wilson's disease)
* Complications of chronic liver disease, such as recurrent variceal bleeding, ascites, encephalopathy or any other reason contraindicating a liver biopsy
* Severe hemorrhagic disorders
* Sepsis - Inflammatory processes
* Taking medications that precipitate steatohepatitis (e.g. corticosteroids, methotrexate, or amiodarone)
* Pregnancy, lactation
* Fluid restriction - Omegaven is more dilute than Intralipid.

Primary outcomes:
measure: Response to treatment at 3 months
timeFrame: 3 months
Secondary outcomes:
measure: Change in total and conjugated bilirubin over time
timeFrame: 0, 3, 6 months on Omegaven
measure: Changes in liver function test (ALP, AST, GGT) over 6 months
timeFrame: 0, 3, 6 months on Omegaven
measure: Changes in liver histology between baseline and 6 months on Omegaven
timeFrame: 0, 6 months on Omegaven
measure: Changes in liver fatty acid composition between baseline and 6 months on Omegaven
timeFrame: 0, 6 months on Omegaven
measure: Changes in liver oxidative stress between baseline and 6 months
timeFrame: 0, 6 months
measure: Changes in hepatic gene expression between baseline and 6 months on Omegaven
timeFrame: 0, 6 months on Omegaven
Other outcomes:
measure: Insulin resistance
timeFrame: 0, 3, 6, 9 months
measure: Blood lipid profile
timeFrame: 0, 3, 6, 9 months
measure: Complete blood count (CBC)
timeFrame: 0, 3, 6, 9 months
measure: international normalized ratio (INR)
timeFrame: 0, 3, 6, 9 months
Locations:
city: Calgary
country: Canada
facility: Foothills Medical Center
state: Alberta
city: Edmonton
country: Canada
facility: University of Alberta
state: Alberta
city: Winnipeg
country: Canada
facility: St Boniface Hospital
state: Manitoba
city: Toronto
country: Canada
facility: University Health Network
state: Ontario
Study officials:
affiliation: University Health Network, Toronto
name: Johane P Allard, MD,FRCPC
role: PRINCIPAL_INVESTIGATOR
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