Cholestasis
Conditions
Keywords
liver, parenteral nutrition, fish oil, omegaven, children
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.
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.
Interventions
DRUGOmegaven
0.5 g/kg/d intravenous every day for 2 days, then 1 g/kg/d intravenous everyday
Sponsors
University of California, Los Angeles
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
2 Weeks to 18 Years
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Time to Reversal of Parenteral Nutrition Associated Cholestasis | 24 weeks, death, transplant, or discontinuation of Parenteral Nutrition (whichever comes first) | weeks |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 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 |
| Time to Full Enteral Feeds | 24 weeks, death, transplant, or discontinuation of Parenteral Nutrition (whichever comes first) | discontinuation of parenteral nutrition |
| 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. |
| 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 |
| Death | 24 weeks, transplant, or discontinuation of Parenteral Nutrition (whichever comes first) | expiration |
| Markers of Inflammation | 24 weeks, death, or discontinuation of Parenteral Nutrition (whichever comes first) | Serum Cytokines - interleukin-8 |
| Markers of Sterol Metabolism | 24 weeks, death, or discontinuation of Parenteral Nutrition (whichever comes first) | Serum Phytosterols - stigmasterol |
| Markers of Bile Acid Metabolism | 24 weeks, death, or discontinuation of Parenteral Nutrition (whichever comes first) | Serum Bile acids - total chenodeoxycholic acid |
| Markers of Fatty Acid Metabolism | 24 weeks, death, or discontinuation of Parenteral Nutrition (whichever comes first) | Erythrocyte fatty acid - Docosahexaenoic Acid |
| 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 |
Countries
United States
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 details
There was no wash-out or run-in period.
Participants by arm
| Arm | Count |
|---|---|
| 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.
Omegaven: 0.5 gm/kg/d intravenous every day for 2 days, then 1 gm/kg/d intravenous everyday | 59 |
| Total | 59 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Physician Decision | 8 |
| Overall Study | Withdrawal by Subject | 3 |
Baseline characteristics
| Characteristic | Omegaven |
|---|---|
| Age, Categorical <=18 years | 58 Participants |
| Age, Categorical >=65 years | 0 Participants |
| Age, Categorical Between 18 and 65 years | 1 Participants |
| Age, Continuous | 707.9 days STANDARD_DEVIATION 1366.88 |
| Race (NIH/OMB) American Indian or Alaska Native | 1 Participants |
| Race (NIH/OMB) Asian | 4 Participants |
| Race (NIH/OMB) Black or African American | 13 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 41 Participants |
| Region of Enrollment United States | 59 Participants |
| Sex: Female, Male Female | 23 Participants |
| Sex: Female, Male Male | 36 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 4 / 59 |
| other Total, other adverse events | 53 / 59 |
| serious Total, serious adverse events | 35 / 59 |
Outcome results
Primary
Time to Reversal of Parenteral Nutrition Associated Cholestasis
weeks
Time frame: 24 weeks, death, transplant, or discontinuation of Parenteral Nutrition (whichever comes first)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Omegaven | Time to Reversal of Parenteral Nutrition Associated Cholestasis | 12.1 weeks | Standard Deviation 5.2 |
Secondary
Death
expiration
Time frame: 24 weeks, transplant, or discontinuation of Parenteral Nutrition (whichever comes first)
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Omegaven | Death | 4 Participants |
Secondary
Growth Z-scores
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)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Omegaven | Growth Z-scores | -0.66 Z-score | Standard Deviation 1.07 |
Secondary
Markers of Bile Acid Metabolism
Serum Bile acids - total chenodeoxycholic acid
Time frame: 24 weeks, death, or discontinuation of Parenteral Nutrition (whichever comes first)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Omegaven | Markers of Bile Acid Metabolism | 4 umol/L | Standard Deviation 2 |
Secondary
Markers of Fatty Acid Metabolism
Erythrocyte fatty acid - Docosahexaenoic Acid
Time frame: 24 weeks, death, or discontinuation of Parenteral Nutrition (whichever comes first)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Omegaven | Markers of Fatty Acid Metabolism | 12.7 Percent of Sum of Fatty Acids | Standard Deviation 0.7 |
Secondary
Markers of Inflammation
Serum Cytokines - interleukin-8
Time frame: 24 weeks, death, or discontinuation of Parenteral Nutrition (whichever comes first)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Omegaven | Markers of Inflammation | 16 pg/mL | Standard Deviation 2 |
Secondary
Markers of Sterol Metabolism
Serum Phytosterols - stigmasterol
Time frame: 24 weeks, death, or discontinuation of Parenteral Nutrition (whichever comes first)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Omegaven | Markers of Sterol Metabolism | 0.1 mg/dL | Standard Deviation 0.02 |
Secondary
Number of Participants Who Underwent a Transplant
includes isolated liver or multi-visceral transplant including liver graft
Time frame: 24 weeks, death, or discontinuation of Parenteral Nutrition (whichever comes first)
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Omegaven | Number of Participants Who Underwent a Transplant | 4 Participants |
Secondary
Number of Participants With Essential Fatty Acid Deficiency
triene:tetraene ratio less than 0.2
Time frame: 24 weeks, death, transplant, or discontinuation of Parenteral Nutrition (whichever comes first)
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Omegaven | Number of Participants With Essential Fatty Acid Deficiency | 0 Participants |
Secondary
Platelet Counts at the End of the Study - Risk of Bleeding
platelet counts at the end of the study
Time frame: 24 weeks, death, transplant, or discontinuation of Parenteral Nutrition (whichever comes first)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Omegaven | Platelet Counts at the End of the Study - Risk of Bleeding | 220.9 x10^3 cells/mL | Standard Deviation 134.3 |
Secondary
Time to Full Enteral Feeds
discontinuation of parenteral nutrition
Time frame: 24 weeks, death, transplant, or discontinuation of Parenteral Nutrition (whichever comes first)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Omegaven | Time to Full Enteral Feeds | 12.49 weeks | Standard Deviation 5.59 |