Parenteral Nutrition Associated Liver Disease: Early Markers and Therapy Wih Enteral Omega-3 Supplementation

This study is currently recruiting participants. (see Contacts and Locations)
Verified June 2011 by University of Tennessee
Sponsor:
Information provided by:
University of Tennessee
ClinicalTrials.gov Identifier:
NCT01157780
First received: March 30, 2010
Last updated: June 16, 2011
Last verified: June 2011
  Purpose

Cholestatic liver disease is a common complication associated with long term parenteral nutrition (PN). PN associated liver disease (PNALD) is much more common in premature infants and the incidence increases with duration of PN. The use of intravenous omega-3 long chain polyunsaturated fatty acids (ω3PUFA) or fish oil has recently shown promise in the treatment of PNALD. We hypothesize that there are early markers for PNALD that precede the increase in total and direct bilirubin. We further hypothesize that patients with PNALD who receive enteral ω3PUFA supplementation will have an improvement in PNALD or reversal of PNALD. These hypotheses will be tested by a two part study that includes an initial observation period when markers for PNALD are evaluated, followed by a randomized, controlled trial of enteral ω3PUFA supplementation for treatment of PNALD. Infants expected to be on PN for 4 weeks or longer will be eligible for enrollment in this study. The observational part of the study will entail periodic assessment of potential markers for PNALD. Markers will be evaluated for inflammatory cytokines (IL-1, IL-6, TNF-alpha), oxidative stress (8-isoprostane, 8-hydroxydeoxyguanosine, glutathione peroxidase), liver fibrosis (TIMP-1), endogenous steroid production (glucagon and ACTH), total serum bile acids, essential fatty acid profiles, and calprotectin, a novel marker of gut inflammation. Patients will be observed for 6 months duration. Patients enrolled in the study who develop PNALD will be randomized to either the current standard of care (control group) or enteral ω3PUFA supplementation (treatment group). Once able to take oral medications, treatment group patients will receive enteral ω3PUFA 1 g/kg/day for 12 weeks. At the end of the 12 weeks, the protocol will be open label in which any patients who continue to have PNALD in either group will receive enteral ω3PUFA. All patients enrolled in the study (whether or not they develop PNALD or receive ω3PUFA supplementation) will be followed for a total of 6 months. The results of this study will increase our knowledge of the pathogenesis of PNALD, as well as potentially confirm the effectiveness of a novel therapy for this costly and debilitating disease.


Condition Intervention
Parenteral Nutrition Associated Liver Disease
Drug: Lovaza (fish oil)

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Parenteral Nutrition Associated Liver Disease: Early Markers and Therapy Wih Enteral Omega-3 Supplementation

Resource links provided by NLM:


Further study details as provided by University of Tennessee:

Primary Outcome Measures:
  • Determine if enteral ω3PUFA supplementation is effective for the treatment and/or reversal of PNALD. [ Time Frame: 3 years for study completion, 12 weeks per patients ] [ Designated as safety issue: Yes ]
    In order to answer our this objective, we will conduct a randomized controlled trial of enteral ω3PUFA supplementation in patients that develop PNALD. We will evaluate direct bilirubin, AST, ALT, and clinical presentation as outcomes as success of enteral ω3PUFA supplementation. We will evaluate baseline and serial fatty acid analysis to show that enteral fish oil is absorbed and effecting ω3PUFA concentrations. We will evaluate resolution of PNALD in patients receiving ω3PUFA compared to patients not supplimented with ω3PUFA. Time to resolution of disease will also be evaluated.


Secondary Outcome Measures:
  • Evaluate serum markers that may be early indicators of PNALD in infants receiving long term PN. [ Time Frame: 3 years for total study, 6 months per patient ] [ Designated as safety issue: No ]
    In order to answer this objective, we will conduct assessment for IL-1, IL-6, TNF-alpha, 8-isoprostane, 8-hydroxydeoxyguanosine, glutathione peroxidase, TIMP-1, glucagon, ACTH, total serum bile acids, and calprotectin in all patients at baseline and sequentially for the six month study period until the patient develops PNALD or PN is discontinued. We aim to evaluate early abnormalities in these markers as predictors of PNALD.


Estimated Enrollment: 100
Study Start Date: October 2008
Estimated Study Completion Date: December 2014
Estimated Primary Completion Date: June 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: fish oil
When a subject develops PNALD (three consecutive direct bilirubin concentrations > 2 mg/dL), and is able to tolerate at least trophic feeds (1 mL Q12h), the subject will be randomized to either the control group (our current hospital practice including advancement of enteral feeding, ursodiol, and cyclic PN, but not ω3PUFA) or the active treatment group (current hospital practice plus the addition of enteral ω3PUFA supplementation of 1 g/kg/day with a maximum dose of 4 g/day for a 12 week period). All patients will be started at 1 g/kg/day with a maximum dose of 4 g/day.
Drug: Lovaza (fish oil)
Patients will receive fish supplementation of 1 g/kg/day with a maximum dose of 4 g/day for a 12 week period.
Other Name: Lovaza
No Intervention: standard of care
When a subject develops PNALD (three consecutive direct bilirubin concentrations > 2 mg/dL), and is able to tolerate at least trophic feeds (1 mL Q12h), the subject will be randomized to either the control group (our current hospital practice including advancement of enteral feeding, ursodiol, and cyclic PN, but not ω3PUFA) or the active treatment group (current hospital practice plus the addition of enteral ω3PUFA supplementation of 1 g/kg/day with a maximum dose of 4 g/day for a 12 week period). All patients will be started at 1 g/kg/day with a maximum dose of 4 g/day.

  Show Detailed Description

  Eligibility

Ages Eligible for Study:   up to 1 Year
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Neonates / infants < 1 year of age (there is no minimum age for enrollment and subjects may be male or female)
  • Enrolled prior to the development of PNALD
  • Anticipated duration of PN of 4 weeks or greater including patients with:

    • Short bowel syndrome resulting from surgical management of NEC, congenital bowel defects (omphalocele and gastroschisis), intestinal atresias, midgut volvulus, and other intestinal processes
    • Functional short bowel syndrome
  • Subjects must be deemed clinically stable with a life expectancy of at least 6 months before enrollment

Exclusion Criteria:

  • Bleeding risk (platelets count < 50 thousand units/μL)
  • Receiving aspirin or other anticoagulation agent
  • Patient's who are deemed clinically unstable:

    • Severe multi-system disease
    • Genetic disorders
    • DNR
  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: NCT01157780

Contacts
Contact: Emma M Tillman, PharmD (901)287-5349 etillman@uthsc.edu

Locations
United States, Tennessee
Le Bonheur Children's Medical Center Recruiting
Memphis, Tennessee, United States, 38103
Contact: Emma M Tillman, PharmD    901-287-5349    etillman@uthsc.edu   
Principal Investigator: Emma M Tillman, PharmD         
Sub-Investigator: Catherine M Crill, PharmD         
Sub-Investigator: Dennis D Black, MD         
Sub-Investigator: Richard A Helms, PharmD         
Sponsors and Collaborators
University of Tennessee
Investigators
Principal Investigator: Emma Tillman, PharmD University of Tennessee
  More Information

No publications provided

Responsible Party: Emma Tillman, Pharm.D., University of Tennessee Health Science Center
ClinicalTrials.gov Identifier: NCT01157780     History of Changes
Other Study ID Numbers: 128695
Study First Received: March 30, 2010
Last Updated: June 16, 2011
Health Authority: United States: Institutional Review Board

Keywords provided by University of Tennessee:
Fish oil

Additional relevant MeSH terms:
Liver Diseases
Digestive System Diseases

ClinicalTrials.gov processed this record on July 29, 2014