A Safety and Efficacy Study to Determine if Giving Intravenous Fish Oil Helps Children With Liver Disease (FO)

• ClinicalTrials.gov Identifier: NCT00969332
• Recruitment Status: Terminated
• First Posted: September 1, 2009
• Results First Posted: February 12, 2020
• Last Update Posted: February 26, 2020
• Sponsor: University of California, Los Angeles
• Information provided by (Responsible Party): Kara L. Calkins, MD, University of California, Los Angeles

Study Description

Brief Summary:

The purpose of the study is to investigate if intravenous fish oil, commercially available as Omegaven, safely and effectively reverses parenteral nutrition associated cholestasis in children.

Condition or disease	Intervention/treatment	Phase
Cholestasis	Drug: Omegaven	Phase 2

Detailed Description:

Infants dependent on parenteral nutrition for greater than 1 year who develop parenteral nutrition associated cholestasis will universally face mortality unless they receive a timely liver and/or small bowel transplant. Although transplant survival has improved in recent years, survival is not guaranteed, and transplant care remains costly. Alternative nutritional and pharmacological strategies are imperative to improve the clinical outcomes of infants with intestinal failure and parenteral nutrition associated cholestasis. In both animal and human studies, intravenous fish oil, a lipid emulsion rich in omega-3 fatty acids and Vitamin E, and lacking phytosterols, has been shown to ameliorate parenteral nutrition associated cholestasis and improve morbidity and mortality. The purpose of this pilot study is to investigate if Omegaven, a commercially available intravenous fish oil, at 1 g/kg/d, will safely reverse liver disease in 80 subjects with parenteral nutrition associated cholestasis. Subjects can initially receive a maximum of 6 months (24 weeks) of intravenous fish oil. If the subject re-develops liver disease and still satisfies inclusion/exclusion criteria, the intervention can be restarted. Study subjects will be compared to a historical cohort of children with Short Bowel Syndrome and parenteral nutrition associated cholestasis who have been receiving standard intravenous soybean oil for > 60 days. The fish oil cohort will be followed for a total of 5 years to determine if transplant-free mortality is reduced.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 62 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Omegaven and Parenteral Nutrition Associated Cholestasis
• Actual Study Start Date: August 2009
• Actual Primary Completion Date: January 12, 2019
• Actual Study Completion Date: February 12, 2019

Arms and Interventions

Arm	Intervention/treatment
Experimental: Omegaven; 0.5 g/kg/d IV x 2 days, then 1 g/kg/d IV for 24 weeks or until parenteral nutrition discontinuation, death or transplant, whichever comes first. Subjects are eligible to restart Omegaven should they re-satisfy inclusion/exclusion criteria.	Drug: Omegaven; 0.5 g/kg/d intravenous every day for 2 days, then 1 g/kg/d intravenous everyday

Outcome Measures

Primary Outcome Measures :

1. Time to Reversal of Parenteral Nutrition Associated Cholestasis [ Time Frame: 24 weeks, death, transplant, or discontinuation of Parenteral Nutrition (whichever comes first) ]
   weeks

Secondary Outcome Measures :

1. Death [ Time Frame: 24 weeks, transplant, or discontinuation of Parenteral Nutrition (whichever comes first) ]
   expiration
2. Number of Participants Who Underwent a Transplant [ Time Frame: 24 weeks, death, or discontinuation of Parenteral Nutrition (whichever comes first) ]
   includes isolated liver or multi-visceral transplant including liver graft
3. Time to Full Enteral Feeds [ Time Frame: 24 weeks, death, transplant, or discontinuation of Parenteral Nutrition (whichever comes first) ]
   discontinuation of parenteral nutrition
4. Growth Z-scores [ Time Frame: 24 weeks, death, transplant, or discontinuation of Parenteral Nutrition (whichever comes first) ]

   Weight Z-scores at the end of the study. Formula used: (weight at end of study-average weight of reference population)/standard deviation of weight of reference population.

   The Z-score indicates the number of standard deviations away from the mean. A weight Z-score of 0 is equal to the mean with negative numbers indicating values lower than the mean and positive values higher. A weight Z-score </= -2 indicates an underweight or malnourished status, while a weight Z-score >/= 2 indicates an overweight or obese status.

5. Platelet Counts at the End of the Study - Risk of Bleeding [ Time Frame: 24 weeks, death, transplant, or discontinuation of Parenteral Nutrition (whichever comes first) ]
   platelet counts at the end of the study
6. Number of Participants With Essential Fatty Acid Deficiency [ Time Frame: 24 weeks, death, transplant, or discontinuation of Parenteral Nutrition (whichever comes first) ]
   triene:tetraene ratio less than 0.2
7. Markers of Inflammation [ Time Frame: 24 weeks, death, or discontinuation of Parenteral Nutrition (whichever comes first) ]
   Serum Cytokines - interleukin-8
8. Markers of Sterol Metabolism [ Time Frame: 24 weeks, death, or discontinuation of Parenteral Nutrition (whichever comes first) ]
   Serum Phytosterols - stigmasterol
9. Markers of Bile Acid Metabolism [ Time Frame: 24 weeks, death, or discontinuation of Parenteral Nutrition (whichever comes first) ]
   Serum Bile acids - total chenodeoxycholic acid
10. Markers of Fatty Acid Metabolism [ Time Frame: 24 weeks, death, or discontinuation of Parenteral Nutrition (whichever comes first) ]
    Erythrocyte fatty acid - Docosahexaenoic Acid

Eligibility Criteria

• Ages Eligible for Study: up to 18 Years (Child, Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

• Clinical evidence of parenteral nutrition associated cholestasis
• Direct bilirubin greater or equal to 2 mg/dL on 2 consecutive measurements
• Expected parenteral nutrition course greater than 30 days
• Acquired or congenital gastrointestinal disease
• > 2 weeks of age and < 18 years of age
• > 60% calories from parenteral nutrition
• Failed standard therapies to prevent progression of liver disease (Actigal, cyclic parenteral nutrition, avoidance of overfeeding, reduction/removal of copper from parenteral nutrition if elevated my laboratory analysis, advancement of enteral feeds)

Exclusion Criteria:

• Inborn errors of metabolism
• Extracorporeal Membrane Oxygenation
• Seafood, egg, or Omegaven allergy
• Documented case of liver disease other than Parenteral Nutrition Associated Cholestasis
• Hemorrhagic disorder
• Anticoagulant therapy
• Hemodynamically unstable or in shock
• Comatose state
• Stroke, pulmonary embolism, recent myocardial infarction
• Diabetes
• Fatal chromosomal disorder
• Enrollment in any other clinical trial involving an investigational agent
• Patient, parent, or legal guardians unable or unwilling to give consent
• Patient expected to be weaned from parenteral nutrition in 30 days
• unable to tolerate necessary monitoring
• Patient requiring aspirin or toradel or motrin
• Patient requiring dialysis

Contacts and Locations

Locations

United States, California

University of California, Los Angeles

Los Angeles, California, United States, 90095

Sponsors and Collaborators

University of California, Los Angeles

Investigators

• Principal Investigator: Kara L Calkins, MD; University of California, Los Angeles

  Study Documents (Full-Text)

Documents provided by Kara L. Calkins, MD, University of California, Los Angeles:

Study Protocol and Statistical Analysis Plan  [PDF] February 12, 2018

More Information

Publications of Results:

Calkins KL, Dunn JC, Shew SB, Reyen L, Farmer DG, Devaskar SU, Venick RS. Pediatric intestinal failure-associated liver disease is reversed with 6 months of intravenous fish oil. JPEN J Parenter Enteral Nutr. 2014 Aug;38(6):682-92. doi: 10.1177/0148607113495416. Epub 2013 Jul 26.

Calkins KL, DeBarber A, Steiner RD, Flores MJ, Grogan TR, Henning SM, Reyen L, Venick RS. Intravenous Fish Oil and Pediatric Intestinal Failure-Associated Liver Disease: Changes in Plasma Phytosterols, Cytokines, and Bile Acids and Erythrocyte Fatty Acids. JPEN J Parenter Enteral Nutr. 2018 Mar;42(3):633-641. doi: 10.1177/0148607117709196. Epub 2017 Dec 18.

Wang C, Venick RS, Shew SB, Dunn JCY, Reyen L, Gou R, Calkins KL. Long-Term Outcomes in Children With Intestinal Failure-Associated Liver Disease Treated With 6 Months of Intravenous Fish Oil Followed by Resumption of Intravenous Soybean Oil. JPEN J Parenter Enteral Nutr. 2019 Aug;43(6):708-716. doi: 10.1002/jpen.1463. Epub 2018 Nov 8.

Ong ML, Venick RS, Shew SB, Dunn JCY, Reyen L, Grogan T, Calkins KL. Intravenous Fish Oil and Serum Fatty Acid Profiles in Pediatric Patients With Intestinal Failure-Associated Liver Disease. JPEN J Parenter Enteral Nutr. 2019 Aug;43(6):717-725. doi: 10.1002/jpen.1532. Epub 2019 Mar 22.

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Calkins KL, Thamotharan S, Ghosh S, Dai Y, Devaskar SU. MicroRNA 122 Reflects Liver Injury in Children with Intestinal Failure-Associated Liver Disease Treated with Intravenous Fish Oil. J Nutr. 2020 May 1;150(5):1144-1150. doi: 10.1093/jn/nxaa001.

• Responsible Party: Kara L. Calkins, MD, Assistant Professor, University of California, Los Angeles
• ClinicalTrials.gov Identifier: NCT00969332
• Other Study ID Numbers: 09-02-079-02
• First Posted: September 1, 2009
• Results First Posted: February 12, 2020
• Last Update Posted: February 26, 2020
• Last Verified: February 2020

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Kara L. Calkins, MD, University of California, Los Angeles:

liver; parenteral nutrition; fish oil; omegaven; children

Additional relevant MeSH terms:

Cholestasis; Bile Duct Diseases; Biliary Tract Diseases; Digestive System Diseases