Omegaven for Compassionate Use in the Treatment of Parenteral Nutrition-Associated Liver Disease

1. The overall purpose of the treatment is to offer alternative treatment to children who
developed parenteral nutrition-associated liver disease (PNALD) and have not responded
positively to currently available medical therapies. PNALD develops in newborns
dependent on parenteral nutrition (PN) and are unable to tolerate adequate enteral
feedings to support fluid and nutritional fluids; although PN is necessary and life
sustaining, it can result in severe liver disease.

The investigators want to see if a form of intravenous fat mixture, Omegaven, helps in
the treatment of children with PNALD. Experimental data has shown that the intravenous
fat mixture (Intralipid) that is currently being used as a part of newborn PN, may be
contributing to the liver disease. Omegaven is different fat mixture manufactured and
used in Europe in adults. It is different in that it is made from highly refined fish
oil, while Intralipid is made from soybeans. Case control studies only, and not
randomized clinical trials, show that Omegaven may reverse or treat PNALD. Since
Omegaven is not currently approved for use in the United States, treatment IND was
obtained from Food and Drug Administration (FDA).

2. Feeding intolerance is a common pathway of a broad array of medical and surgical disease
states encountered in the neonatal population. Consequently, a high percentage of
patients in neonatal intensive care units (NICU) need to rely on PN if they are to
survive and grow. Through decades of research the development of PN has been a great
success in that its use has maintained countless patients in sufficient nutritional
status to recover from medical or surgical conditions. However, one complication of PN
that remains poorly understood and that still causes considerable morbidity and
mortality is PNALD.

There are a wide variety of case scenarios for PNALD. There are scenarios in which
newborns suffer irrecoverable bowel loss from some process (e.g., necrotizing
enterocolitis totalis, mid gut volvulus) and consequently require long term PN as they
await bowel transplant; as a result they almost always also require liver transplant
secondary to PNALD. This further delays their surgery as they wait for two organs
instead of one (Chungfat, Dixler et al. 2007). More commonly, cases involve patients who
have prolonged bowel dysfunction that requires long term use of PN but who slowly
recover and gradually transition to enteral feeds. For these infants the race between
bowel recovery and PNALD progression often decides whether the patient lives or dies.

3. Although the etiology of PNALD is poorly understood and likely to be multi-factorial
(Steinbach, Clark et al. 2008), recent animal research and human case studies suggest
that altering the dose and the composition of the lipid component of PN might alter the
course of PNALD (Alwayn, Gura et al. 2005; Gura, Parsons et al. 2005; Gura, Duggan et
al. 2006; Gura, Lee et al. 2008). The lipid products used for PN in the United States
are derived from soy oil; the brand used at Cardinal Glennon Children's Hospital is
Intralipid®. Soy-based PN lipids are rich in omega-6 FA and also contain small amounts
of omega-3 FA in the form of linolenic acid precursor. The potential toxicity of omega-6
fatty acids as it relates to PNALD has been recently revealed (Diamond, Sterescu et al.
2008; de Meijer, Gura et al 2009). This FA composition is sufficient to prevent
essential FA deficiency (EFAD), historically measured as the ratio of specific omega-6
FA in the blood (Gura, Lee et al 2009).

In a published article (Gura, Duggan et al. 2006) reporting 2 cases in depth and in a
subsequent paper (Gura, Lee et al. 2008) reporting 18 patients with established PNALD who
required continued PN, investigators replaced the standard soy based lipid component of PN
with a fish oil derived parenteral lipid (Omegaven™) that contains a high percentage (30 to
60%) of omega-3 FA. This therapy, which is still experimental in the United States, was
associated with a gradual but ultimately profound correction of PNALD as indicated by
laboratory markers such as conjugated bilirubin and circulating liver enzymes; the median
time to reduce serum direct bilirubin from >2mg/dl to <2mg/dl was 9.4 weeks. No significant
adverse effects of Omegaven™ in the doses utilized were identified.

The current study is to identify infants with PNALD of moderate severity or worse, defined as
two consecutive measurements of direct bilirubin of 3 mg/dL after being on PN for > 3 weeks
and who are anticipated to require PN for another 3 weeks, which puts them at risk of further
progression of PNALD. For inclusion, other causes of liver disease must be ruled out. Upon
meeting entry criteria, infant families will be offered, through an Institutional Review
Board (IRB) approved consent process, the same treatment protocol for their infants that was
successfully applied in the above cited clinical cases and detailed below. Monitoring for
side effects, complications and disease progression or regression will be instituted. Therapy
will be stopped when direct bilirubin is < 1 mg/dL for 2 weekly measurements or when the
patient is tolerating enough enteral nutrition so that PN is no longer needed. Clinical and
laboratory monitoring will be continued for 2 weeks post Omegaven™ infusion and as indicated
by events thereafter. Additional endpoint criteria are: patients receiving transplants;
AST/ALT, GGTP, C-reactive protein and albumin, mortality, infection rates and types, and
frequency of red blood cell transfusions; if infant worsens with treatment or does not
tolerate treatment with Omegaven, specifically for the adverse event of severe uncontrolled
bleeding as listed in the risk section.

Inclusion Criteria:

1. Age < 1 years; inpatient use only

2. PN dependency (unable to meet nutritional needs solely by enteral nutrition);

3. Present PNALD, as evidenced by two consecutive direct bilirubin > 3.0 mg/dL (at
interval of one week);

4. Failed standard therapies to prevent the progression of liver disease:

Avoiding overfeeding, reduction/removal of copper and manganese from PN, advancement
of enteral feeding and the use of Ursodiol, if possible.

5. At the time the diagnosis PNALD is made, the patient is expected to continue PN at
least an additional 3 weeks

Exclusion Criteria:

1. Any other cause of chronic liver disease (i.e., hepatitis B or C, cystic fibrosis,
biliary atresia, or alpha 1 anti-trypsin deficiency etc.)

2. enrollment in any other clinical trial involving an investigational agent (unless
approved by the designated physicians on the multidisciplinary team);

3. Lack of informed consent;

4. Intent to transfer to another healthcare facility

5. allergy to any seafood product, egg protein, and/or previous allergy to Omegaven

6. active coagulopathy characterized by ongoing bleeding or by a requirement for clotting
factor replacement (e.g. fresh frozen plasma or cryoprecipitate) to maintain
homeostasis

7. impaired lipid metabolism or severe hyperlipidemia with or without pancreatitis

8. unstable DM or hyperglycemia

9. stroke/embolism

10. collapse and shock

11. undefined coma status

12. recent MI

13. cholestasis due to any reason other than PNALD

14. active new infection at time of initiation of Omegaven

15. hemodynamic instability

16. unable to tolerate necessary laboratory monitoring

17. severe renal insufficiency