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

• Sponsor: University of California, Los Angeles (Other)
• Overall Status: Terminated
• CT.gov ID: NCT00969332
• Collaborator: (none)
• Enrollment: 62
• Location: 1
• Arm: 1
• Actual Duration (Months): 114.4
• Patients Per Site Per Month: 0.5

Study Details

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
• 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: Aug 1, 2009
• Actual Primary Completion Date: Jan 12, 2019
• Actual Study Completion Date: Feb 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 [24 weeks, death, transplant, or discontinuation of Parenteral Nutrition (whichever comes first)]

   weeks

Secondary Outcome Measures

1. Death [24 weeks, transplant, or discontinuation of Parenteral Nutrition (whichever comes first)]

   expiration

2. Number of Participants Who Underwent a Transplant [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 [24 weeks, death, transplant, or discontinuation of Parenteral Nutrition (whichever comes first)]

   discontinuation of parenteral nutrition

4. Growth Z-scores [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 [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 [24 weeks, death, transplant, or discontinuation of Parenteral Nutrition (whichever comes first)]

   triene:tetraene ratio less than 0.2

7. Markers of Inflammation [24 weeks, death, or discontinuation of Parenteral Nutrition (whichever comes first)]

   Serum Cytokines - interleukin-8

8. Markers of Sterol Metabolism [24 weeks, death, or discontinuation of Parenteral Nutrition (whichever comes first)]

   Serum Phytosterols - stigmasterol

9. Markers of Bile Acid Metabolism [24 weeks, death, or discontinuation of Parenteral Nutrition (whichever comes first)]

   Serum Bile acids - total chenodeoxycholic acid

10. Markers of Fatty Acid Metabolism [24 weeks, death, or discontinuation of Parenteral Nutrition (whichever comes first)]

    Erythrocyte fatty acid - Docosahexaenoic Acid

Eligibility Criteria

Criteria

• Ages Eligible for Study: 2 Weeks to 18 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

	Site	City	State	Country	Postal Code
1	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)

• Study Protocol and Statistical Analysis Plan - Feb 12, 2018

More Information

Publications

None provided.

• 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: Sep 1, 2009
• Last Update Posted: Feb 26, 2020
• Last Verified: Feb 1, 2020

• Individual Participant Data (IPD) Sharing Statement: No
• 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, Assistant Professor, University of California, Los Angeles: liver; parenteral nutrition; fish oil; omegaven; children
• Additional relevant MeSH terms: Cholestasis

Study Results

Participant Flow

Recruitment Details	Recruitment for this study began in May 2005. Patients were recruited from the inpatient and outpatient setting at the University of California, Los Angeles.
Pre-assignment Detail	There was no wash-out or run-in period.

Arm/Group Title	Omegaven
Arm/Group Description	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.
Period Title: Overall Study
STARTED	62
COMPLETED	51
NOT COMPLETED	11

Baseline Characteristics

Arm/Group Title	Omegaven
Arm/Group Description	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. Omegaven: 0.5 gm/kg/d intravenous every day for 2 days, then 1 gm/kg/d intravenous everyday
Overall Participants	59
Age (Count of Participants)
<=18 years	58 98.3%
Between 18 and 65 years	1 1.7%
>=65 years	0 0%
Age (days) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [days]	707.9 (1366.88)
Sex: Female, Male (Count of Participants)
Female	23 39%
Male	36 61%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	1 1.7%
Asian	4 6.8%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	13 22%
White	41 69.5%
More than one race	0 0%
Unknown or Not Reported	0 0%
Region of Enrollment (Count of Participants)
United States	59 100%

Outcome Measures

1. Primary Outcome

Title	Time to Reversal of Parenteral Nutrition Associated Cholestasis
Description	weeks
Time Frame	24 weeks, death, transplant, or discontinuation of Parenteral Nutrition (whichever comes first)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Omegaven
Arm/Group Description	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. Omegaven: 0.5 gm/kg/d intravenous every day for 2 days, then 1 gm/kg/d intravenous everyday
Measure Participants	59
Mean (Standard Deviation) [weeks]	12.1 (5.2)

2. Secondary Outcome

Title	Death
Description	expiration
Time Frame	24 weeks, transplant, or discontinuation of Parenteral Nutrition (whichever comes first)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Omegaven
Arm/Group Description	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. Omegaven: 0.5 gm/kg/d intravenous every day for 2 days, then 1 gm/kg/d intravenous everyday
Measure Participants	59
Count of Participants [Participants]	4 6.8%

3. Secondary Outcome

Title	Number of Participants Who Underwent a Transplant
Description	includes isolated liver or multi-visceral transplant including liver graft
Time Frame	24 weeks, death, or discontinuation of Parenteral Nutrition (whichever comes first)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Omegaven
Arm/Group Description	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. Omegaven: 0.5 gm/kg/d intravenous every day for 2 days, then 1 gm/kg/d intravenous everyday
Measure Participants	59
Count of Participants [Participants]	4 6.8%

4. Secondary Outcome

Title	Time to Full Enteral Feeds
Description	discontinuation of parenteral nutrition
Time Frame	24 weeks, death, transplant, or discontinuation of Parenteral Nutrition (whichever comes first)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Omegaven
Arm/Group Description	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. Omegaven: 0.5 gm/kg/d intravenous every day for 2 days, then 1 gm/kg/d intravenous everyday
Measure Participants	59
Mean (Standard Deviation) [weeks]	12.49 (5.59)

5. Secondary Outcome

Title	Growth Z-scores
Description	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.
Time Frame	24 weeks, death, transplant, or discontinuation of Parenteral Nutrition (whichever comes first)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Omegaven
Arm/Group Description	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. Omegaven: 0.5 gm/kg/d intravenous every day for 2 days, then 1 gm/kg/d intravenous everyday
Measure Participants	59
Mean (Standard Deviation) [Z-score]	-0.66 (1.07)

6. Secondary Outcome

Title	Platelet Counts at the End of the Study - Risk of Bleeding
Description	platelet counts at the end of the study
Time Frame	24 weeks, death, transplant, or discontinuation of Parenteral Nutrition (whichever comes first)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Omegaven
Arm/Group Description	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. Omegaven: 0.5 gm/kg/d intravenous every day for 2 days, then 1 gm/kg/d intravenous everyday
Measure Participants	59
Mean (Standard Deviation) [x10^3 cells/mL]	220.9 (134.3)

7. Secondary Outcome

Title	Number of Participants With Essential Fatty Acid Deficiency
Description	triene:tetraene ratio less than 0.2
Time Frame	24 weeks, death, transplant, or discontinuation of Parenteral Nutrition (whichever comes first)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Omegaven
Arm/Group Description	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. Omegaven: 0.5 gm/kg/d intravenous every day for 2 days, then 1 gm/kg/d intravenous everyday
Measure Participants	17
Count of Participants [Participants]	0 0%

8. Secondary Outcome

Title	Markers of Inflammation
Description	Serum Cytokines - interleukin-8
Time Frame	24 weeks, death, or discontinuation of Parenteral Nutrition (whichever comes first)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Omegaven
Arm/Group Description	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. Omegaven: 0.5 gm/kg/d intravenous every day for 2 days, then 1 gm/kg/d intravenous everyday
Measure Participants	14
Mean (Standard Deviation) [pg/mL]	16 (2)

9. Secondary Outcome

Title	Markers of Sterol Metabolism
Description	Serum Phytosterols - stigmasterol
Time Frame	24 weeks, death, or discontinuation of Parenteral Nutrition (whichever comes first)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Omegaven
Arm/Group Description	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. Omegaven: 0.5 g/kg/d intravenous every day for 2 days, then 1 g/kg/d intravenous everyday
Measure Participants	14
Mean (Standard Deviation) [mg/dL]	0.1 (0.02)

10. Secondary Outcome

Title	Markers of Bile Acid Metabolism
Description	Serum Bile acids - total chenodeoxycholic acid
Time Frame	24 weeks, death, or discontinuation of Parenteral Nutrition (whichever comes first)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Omegaven
Arm/Group Description	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. Omegaven: 0.5 g/kg/d intravenous every day for 2 days, then 1 g/kg/d intravenous everyday
Measure Participants	14
Mean (Standard Deviation) [umol/L]	4 (2)

11. Secondary Outcome

Title	Markers of Fatty Acid Metabolism
Description	Erythrocyte fatty acid - Docosahexaenoic Acid
Time Frame	24 weeks, death, or discontinuation of Parenteral Nutrition (whichever comes first)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Omegaven
Arm/Group Description	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. Omegaven: 0.5 g/kg/d intravenous every day for 2 days, then 1 g/kg/d intravenous everyday
Measure Participants	14
Mean (Standard Deviation) [Percent of Sum of Fatty Acids]	12.7 (0.7)

Adverse Events

Time Frame	24 weeks
Arm/Group Title	Omegaven
Arm/Group Description	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. Omegaven: 0.5 gm/kg/d intravenous every day for 2 days, then 1 gm/kg/d intravenous everyday
All Cause Mortality
	Omegaven
	Affected / at Risk (%)	# Events
Total	4/59 (6.8%)
Serious Adverse Events
	Omegaven
	Affected / at Risk (%)	# Events
Total	35/59 (59.3%)
Blood and lymphatic system disorders
Thrombocytopenia	8/59 (13.6%)	10
Bleeding	10/59 (16.9%)	16
Cardiac disorders
Hypotension	7/59 (11.9%)	9
Gastrointestinal disorders
Necrotizing Enterocolitis	1/59 (1.7%)	1
Infections and infestations
Sepsis	25/59 (42.4%)	39
Pneumonia	3/59 (5.1%)	4
Urinary Tract Infection	6/59 (10.2%)	6
Nervous system disorders
Seizures	1/59 (1.7%)	1
Renal and urinary disorders
Increased Creatinine	1/59 (1.7%)	31
Respiratory, thoracic and mediastinal disorders
Respiratory Distress	9/59 (15.3%)	12
Other (Not Including Serious) Adverse Events
	Omegaven
	Affected / at Risk (%)	# Events
Total	53/59 (89.8%)
Blood and lymphatic system disorders
Thrombocytopenia	28/59 (47.5%)	148
Thrombocytosis	15/59 (25.4%)	28
Leukopenia	23/59 (39%)	106
Increased International Normalized Ratio	21/59 (35.6%)	106
Clinical Bleeding	9/59 (15.3%)	17
Cardiac disorders
Hypotension	3/59 (5.1%)	3
Endocrine disorders
Hypoglycemia	39/59 (66.1%)	247
Hyperglycemia	24/59 (40.7%)	73
Gastrointestinal disorders
Bowel Rejection	1/59 (1.7%)	1
General disorders
Hyponatremia	11/59 (18.6%)	37
Hypertriglyceridemia	3/59 (5.1%)	7
Metabolic Acidosis	6/59 (10.2%)	7
Acute Life Threatening Event	1/59 (1.7%)	1
Renal and urinary disorders
Increased Creatinine	2/59 (3.4%)	10
Respiratory, thoracic and mediastinal disorders
Respiratory Distress	14/59 (23.7%)	19

Limitations/Caveats

early termination because intervention was FDA approved, single site study, prospective observational study, small sample size, change in clinical practice over time

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.