Fish Oil for Patients With Liver Disease Due to Parenteral Nutrition

This study is currently recruiting participants. (see Contacts and Locations)
Verified December 2013 by University Health Network, Toronto
Sponsor:
Collaborators:
ASPEN Rhoads Research Foundation
Fresenius Kabi
University of Alberta
Foothills Medical Centre
St. Boniface General Hospital Research Centre
Hamilton Health Sciences Corporation
St. Paul's Hospital, Canada
Information provided by (Responsible Party):
Johane Allard, University Health Network, Toronto
ClinicalTrials.gov Identifier:
NCT01565278
First received: March 26, 2012
Last updated: January 9, 2014
Last verified: December 2013

March 26, 2012
January 9, 2014
February 2012
December 2015   (final data collection date for primary outcome measure)
Response to treatment at 3 months [ Time Frame: 3 months ] [ Designated as safety issue: No ]
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 plasma total bilirubin between baseline and 3 months [ Time Frame: 3 months ] [ Designated as safety issue: No ]
Complete list of historical versions of study NCT01565278 on ClinicalTrials.gov Archive Site
  • Change in total and conjugated bilirubin over time [ Time Frame: 0, 3, 6 months on Omegaven ] [ Designated as safety issue: Yes ]
  • Changes in liver function test (ALP, AST, GGT) over 6 months [ Time Frame: 0, 3, 6 months on Omegaven ] [ Designated as safety issue: Yes ]
  • Changes in liver histology between baseline and 6 months on Omegaven [ Time Frame: 0, 6 months on Omegaven ] [ Designated as safety issue: Yes ]
  • Changes in liver fatty acid composition between baseline and 6 months on Omegaven [ Time Frame: 0, 6 months on Omegaven ] [ Designated as safety issue: No ]
    Fatty acid composition by gas chromatography
  • Changes in liver oxidative stress between baseline and 6 months [ Time Frame: 0, 6 months ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
    Hepatic gene expression (mRNA) by microarray
Change in total bilirubin, ALP, AST, ALT, GGT, liver histology, liver FA composition, liver oxidative stress and liver gene expression over 6 months -. [ Time Frame: 6 months ] [ Designated as safety issue: No ]
Second liver biopsy only done in patients receiving the experimental drug (fish oil supplementation)
  • Insulin resistance [ Time Frame: 0, 3, 6, 9 months ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: Yes ]
    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 ] [ Designated as safety issue: Yes ]
    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 ] [ Designated as safety issue: Yes ]
    0, 3, 6 months in Omegaven group 0, 3, 6, 9 months in Intralipid-group switching to Omegaven
Not Provided
 
Fish Oil for Patients With Liver Disease Due to Parenteral Nutrition
Effect of n-3 Polyunsaturated Fatty Acid Lipid Emulsion on Parenteral Nutrition Associated Liver Disease

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.

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

Interventional
Phase 3
Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Total Parenteral Nutrition-induced Cholestasis
  • Drug: Soybean oil based emulsion
    1. Soybean oil based emulsion: 0.25 g/kg/TPN day
    Other Name: Intralipid
  • Drug: Soybean oil based emulsion+Fish oil based emulsion
    Intralipid+Omegaven: 0.25 g/kg/TPN Intralipid day+0.4 g/kg/TPN Omegaven day for 6 months
    Other Name: Intralipid, Omegaven
  • 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.
    Intervention: Drug: Soybean oil based emulsion+Fish oil based emulsion
  • Active Comparator: Standard treatment (Intralipid)
    Intralipid (0.25 g/kg/TPN day) for a period of 6 months
    Intervention: Drug: Soybean oil based emulsion

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruiting
20
July 2016
December 2015   (final data collection date for primary outcome measure)

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.
Both
18 Years and older
Yes
Contact: Johane P Allard, MD,FRCPC 416-340-5159 johane.allard@uhn.on.ca
Contact: Bianca M Arendt, PhD 416-340-4104 barendt@uhnresearch.ca
Canada
 
NCT01565278
11-0298-B, 151342, 155516, 161875, 169378
No
Johane Allard, University Health Network, Toronto
Johane Allard
  • ASPEN Rhoads Research Foundation
  • Fresenius Kabi
  • University of Alberta
  • Foothills Medical Centre
  • St. Boniface General Hospital Research Centre
  • Hamilton Health Sciences Corporation
  • St. Paul's Hospital, Canada
Principal Investigator: Johane P Allard, MD,FRCPC University Health Network, Toronto
University Health Network, Toronto
December 2013

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP