Gastrointestinal Disease, Parenteral Nutrition Associated Liver Disease, Short Bowel Syndrome
Conditions
Keywords
PNALD, Omegaven, Parenteral Nutrition Associated Liver Disease, Cholestasis, Short Bowel Syndrome
Brief summary
The purpose of this study is to determine whether Omegaven is effective in the treatment of parenteral nutrition associated liver disease (PNALD).
Detailed description
The purpose of this study is to determine whether the omega-3 fatty acid emulsion (Omegaven), when used in lieu of the conventional soy-based fat emulsion (Intralipid), is effective in the treatment of parenteral nutrition associated liver disease (PNALD).
Interventions
DRUGOmegaven®
10% Omegaven® 1g/kg/day, IV (in the vein) until the patient no longer requires parenteral nutrition or until participation in the study is terminated
Sponsors
Mark Puder
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
No minimum to 17 Years
Healthy volunteers
No
Inclusion criteria
1. Patients will be PN dependent (unable to meet nutritional needs solely by enteral nutrition) and are expected to require PN for at least another 30 days 2. Patients considered eligible for study participation must have parenteral nutrition associated liver disease (PNALD) as defined as a direct bilirubin of \> 2 mg/dl or currently on Omegaven through another protocol. Other causes of liver disease should be excluded. A liver biopsy is not necessary for treatment. 3. Direct bilirubin \> 2.0 mg/dl or already on Omegaven through another protocol 4. Signed patient informed consent. 5. The patient must have utilized standard therapies to prevent the progression of his/her liver disease including surgical treatment, cyclic PN, avoiding overfeeding, reduction/removal of copper and manganese from PN, advancement of enteral feeding, and the use of ursodiol (i..e., Actigall®).
Exclusion criteria
1. Pregnancy 2. Other causes of chronic liver disease (Hepatitis C, biliary atresia, and alpha 1 anti-trypsin deficiency). 3. Enrollment in any other clinical trial involving an investigational agent (unless approved by the designated physicians on the multidisciplinary team) 4. The parent or guardian or child unwilling to provide consent or assent In rare instances, patients diagnosed with PNALD may later be found to have liver disease due to other causes in addition to the use of PN (i.e., inborn errors of metabolism, viral infections ). Such causes may not be known at the time of enrollment and will not preclude them from continuing in the study. For the sake of statistical analysis, however, these patients will be excluded although all data will be collected and reviewed.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Reversal of Cholestasis, Defined as a Direct Bilirubin to <= 2.0 mg/dL. | Duration of treatment | Time to reversal of established parenteral nutrition associated liver disease, defined as a decrease in direct bilirubin to \<= 2.0 mg/dL. |
Countries
United States
Participant flow
Recruitment details
Between August 2006 and November 2007, 42 patients with IFALD were prospectively enrolled to receive compassionate use open label treatment with 10% FOLE (Omegaven®) as part of their PN. For comparison, retrospective data were retrieved for 49 historical control patients who had received 20% SOLE (Intralipid® 20%) as part of their PN between 1999 and 2006. Patients in both treatment arms were required to have a direct bilirubin level \>=2mg/dL upon initiation of their respective lipid emulsion.
Participants by arm
| Arm | Count |
|---|---|
| Omegaven 1g/kg/day for duration of study participation for all participants
Omegaven®: 10% Omegaven® 1g/kg/day, IV (in the vein) until the patient no longer requires parenteral nutrition or until participation in the study is terminated | 42 |
| Intralipid (Historical Control) Patients who received Intralipid between 1999-2006 and whose direct bilirubin was ever \>=2.0 mg/dL. | 49 |
| Total | 91 |
Baseline characteristics
| Characteristic | Intralipid (Historical Control) | Omegaven | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 49 Participants | 42 Participants | 91 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 0 Participants | 0 Participants | 0 Participants |
| Direct bilirubin | 3.3 mg/dL | 5.5 mg/dL | 3.9 mg/dL |
| Duration of PN before enrollment (d), median (IQR) | 40 Days | 63 Days | 54 Days |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 8 Participants | 9 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 34 Participants | 33 Participants | 67 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 14 Participants | 1 Participants | 15 Participants |
| Sex: Female, Male Female | 18 Participants | 14 Participants | 32 Participants |
| Sex: Female, Male Male | 31 Participants | 28 Participants | 59 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 3 / 42 | 12 / 49 |
| other Total, other adverse events | 7 / 42 | 17 / 49 |
| serious Total, serious adverse events | 0 / 42 | 0 / 49 |
Outcome results
Primary
Reversal of Cholestasis, Defined as a Direct Bilirubin to <= 2.0 mg/dL.
Time to reversal of established parenteral nutrition associated liver disease, defined as a decrease in direct bilirubin to \<= 2.0 mg/dL.
Time frame: Duration of treatment
Population: The primary efficacy end-point was time to reversal of cholestasis (direct bilirubin \<= 2.0 mg/dL).
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Omegaven | Reversal of Cholestasis, Defined as a Direct Bilirubin to <= 2.0 mg/dL. | 11.7 Weeks |
| Intralipid (Historical Control) | Reversal of Cholestasis, Defined as a Direct Bilirubin to <= 2.0 mg/dL. | 6.4 Weeks |
Comparison: The primary efficacy end-point was time to reversal of cholestasis (direct bilirubin \[DB\]\<=2 mg/dL). Crude (unadjusted) hazard ratios were estimated using proportional hazard regression. Subjects who died, were transplanted, or still on PN at the end of follow-up were censored (Ref: PMID 19661785).p-value: =0.00195% CI: [2, 37.3]Regression, Cox
Comparison: The primary efficacy end-point was time to reversal of cholestasis (direct bilirubin \[DB\]\<=2 mg/dL). Adjusted hazard ratios were estimated using proportional hazard regression adjusted for baseline covariates (including duration of parenteral nutrition (PN) and baseline DB). Subjects who died, were transplanted, or still on PN at the end of follow-up were censored (Ref: PMID 19661785).p-value: 0.00195% CI: [3.7, 83]Regression, Cox
Comparison: Comparison of proportion with reversal of cholestasis (direct bilirubin \<=2.0 mg/dL).p-value: <0.0001Fisher Exact