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
  Purpose

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.


Condition Intervention Phase
Total Parenteral Nutrition-induced Cholestasis
Drug: Soybean oil based emulsion
Drug: Soybean oil based emulsion+Fish oil based emulsion
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
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

Resource links provided by NLM:


Further study details as provided by University Health Network, Toronto:

Primary Outcome Measures:
  • 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


Secondary Outcome Measures:
  • 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


Other Outcome Measures:
  • 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


Estimated Enrollment: 20
Study Start Date: February 2012
Estimated Study Completion Date: July 2016
Estimated Primary Completion Date: December 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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 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
Active Comparator: Standard treatment (Intralipid)
Intralipid (0.25 g/kg/TPN day) for a period of 6 months
Drug: Soybean oil based emulsion
1. Soybean oil based emulsion: 0.25 g/kg/TPN day
Other Name: Intralipid

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

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   Yes
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.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01565278

Contacts
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

Locations
Canada, Alberta
Foothills Medical Center Recruiting
Calgary, Alberta, Canada, T2N 4Z6
Contact: Maitreyi Raman, MD       Maitreyi.raman@gmail.com   
Principal Investigator: Maitreyi Raman, MD         
University of Alberta Recruiting
Edmonton, Alberta, Canada, T5H 3V9
Contact: Leah Gramlich, MD    780-421-1029    leah.gramlich@ualberta.ca   
Principal Investigator: Leah Gramlich, MD         
Canada, Manitoba
St Boniface Hospital Not yet recruiting
Winnipeg, Manitoba, Canada, R2H 2A6
Contact: Donald Duerksen, MD       dduerkse@sbgh.mb.ca   
Principal Investigator: Donald Duerksen, MD         
Canada, Ontario
University Health Network Recruiting
Toronto, Ontario, Canada, M5G 2N2
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   
Principal Investigator: Johane P Allard, MD,FRCPC         
Sponsors and Collaborators
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
Investigators
Principal Investigator: Johane P Allard, MD,FRCPC University Health Network, Toronto
  More Information

Publications:

Responsible Party: Johane Allard, Professor of Medicine, Gastroenterologist, University Health Network, Toronto
ClinicalTrials.gov Identifier: NCT01565278     History of Changes
Other Study ID Numbers: 11-0298-B, 151342, 155516, 161875, 169378
Study First Received: March 26, 2012
Last Updated: January 9, 2014
Health Authority: Canada: Health Canada

Keywords provided by University Health Network, Toronto:
Parenteral nutrition
fish oil
liver disease
Omegaven
hepatic
liver biopsy
bilirubin

Additional relevant MeSH terms:
Liver Diseases
Cholestasis
Digestive System Diseases
Bile Duct Diseases
Biliary Tract Diseases

ClinicalTrials.gov processed this record on September 30, 2014