Compassionate Use of an Intravenous Fish Oil Emulsion in the Treatment of Liver Injury in Infants

Inpatient Use of Omegaven:

Each family will have the severity of their child's condition explained to them and the
available data regarding the benefit of the novel preparation explained using the preliminary
safety and efficacy data from Boston Children's Hospital and TCH. Families will have the
potential risks and benefits of the product explained. The lack of long-term follow-up
information regarding the effects of Omegaven will be discussed.

Bottles containing 50mL or 100 mL of 10% Omegaven will be purchased from International
Pharmacy of Hamburg, Germany. Omegaven is manufactured by Fresenius Kabi AG, Bad Homburg
v.d.h, Germany. Omegaven is formulated as an emulsion from fish oils. The family (or legal
guardian) will be billed for the Omegaven as part of their hospital bill from Texas
Children's Hospital.

Omegaven will be dispensed per Texas Children's Hospital policy and procedures for fat
emulsions.

All study materials will be stored securely until the time of administration. The bottles
will be stored at room temperature below 30° C (do not freeze). Damaged or suspect drug will
be returned unused to Fresenius- Kabi. Containers should be shaken before use.

All supplies for the study will be accompanied by accountability and shipping documents and
will be maintained by the Investigator or deputy (e.g. research pharmacist). Information
recorded on these accountability and shipping documents will include relevant dates, batch
numbers, quantities received or dispensed, to whom dispensed, returned drug, and drug lost or
damaged. At the end of the study, all used and unused Omegaven will be accounted for. If
expired, the remaining drug supplies will be destroyed.

Details of Omegaven Administration:

Therapy with Omegaven will be provided at a dose of 1 gm/kg/day (by continuous infusion).
Omegaven will be infused intravenously through either a central or peripheral catheter in
conjunction with parenteral nutrition. Parenteral fat emulsion (Intralipid) will be
administered only if necessary to administer adequate calories during Omegaven therapy. The
same standards of care provided to all patients receiving parenteral nutrition solution will
be followed.

Ongoing monitoring during therapy related to safety and efficacy:

Safety will be assessed using the following outcome variables.

First, we will calculate the number (total and daily rate) of bloodstream infections prior to
therapy. We will monitor this rate in each baby receiving Omegaven and compare with the
previous rate. Currently, the rate of infection in infants receiving Omegaven is about half
of the historical control rate at TCH.

Second, we will monitor growth rate using weight, length and head circumference growth.
Growth will be compared both to the pre-treatment period and the expected rate of growth. We
have established and have guidelines for optimal growth targets and management will be
targeted on achieving these rates. We will monitor these carefully. For babies in the NICU or
Level 2 nurseries, Dr. Abrams will supervise the nutritional management directly. Infants in
the PICU or PCU will be followed by Dr. Carter with the critical care staff. This approach
has been in place for the current group of 16 infants and growth has been excellent although
final calculations are pending.

Third, we will monitor infants who are not receiving any enteral feeding at all for more than
4 weeks for any evidence of essential fatty acid (EFA) deficiency. Measurements will be
repeated at the end of every 4 weeks that the subject remains without any enteral nutrition
intake. Although the exact value suggestive of a deficiency is controversial, usually a level
greater than 0.4 is considered evidence of EFA deficiency. This measurement may be made using
0.2 mL of serum in the lab of Dr. William Heird. Samples will be drawn monthly for infants
who are NPO and run as a batch in Dr. Heird's lab in the CNRC every 6 months. Because data
are not available for clinical use, we will include in the consent the possibility of EFA
deficiency. We note again that no infant ever treated with Omegaven has ever shown clinical
evidence of EFA deficiency, that very transient mild deficiency may occur in about 5% of
infants and that there is no clinical intervention we would use in this case or that has ever
been given without clinically apparent EFA deficiency.

Fourth, we will record and monitor the following lab and clinical results for the DSMB:
electrolytes, calcium, phosphorus, magnesium, alkaline phosphatase, glucose, triglycerides,
BUN, creatinine, conjugated and unconjugated bilirubin, albumin, prealbumin, CRP, WBC, RBC,
platelets, PT, PTT, any evidence of bleeding, and positive blood cultures. These labs will be
drawn as clinically relevant, not as a specific result of the study.

Finally, with regard to developmental follow-up we will indicate to families that all infants
with cholestasis may be at risk for developmental delays and recommend that they be followed.
There is no mechanism in place to assure this follow-up occurs for any infants in the TCH
nurseries however.

Dose Modification

Hypertriglyceridemia:

If hypertriglyceridemia develops, defined as serum triglyceride levels > 300 mg/dL, the
following will be considered prior to reducing the dose:

1. If the level was obtained while the patient was receiving a continuous 24- hour infusion
of Omegaven, the total dose should be infused over 20 hours, and a repeat serum
triglyceride level obtained prior to resuming the infusion 4 hours later.

2. Other sources of hypertriglyceridemia should be considered and addressed (drugs, renal
disease)

If necessary if the triglycerides continue to remain high despite the aforementioned
interventions, a dosage reduction of 25% will be considered.

Duration of Therapy

Patients will remain on Omegaven until weaned from PN.

In the event that a patient who has been listed for a liver or liver/intestinal transplant
has an organ become available, the participation in this protocol will not preclude them from
receiving the transplant. Omegaven will not be administered post transplant.

Treatment will be given for as long as the child needs any TPN AND has a conjugated bilirubin
greater than 2 mg/dL for a maximum of 5 months. If the infant no longer is requiring any TPN,
then the Omegaven will be stopped regardless of bilirubin. If the bilirubin is less than 2
mg/dL but the child still requires TPN, then the Omegaven will be continued up to a total of
5 months or whenever the infant no longer requires TPN. The reason for stopping Omegaven when
the infant no longer requires TPN is that this would be the only reason many infants would
still need IV access and therefore the risk of maintaining IV access only for the medication
is likely to exceed the benefit of Omegaven at that point.

Legal and Ethics Requirements:

This study has been approved by the BCM IRB under a FDA Investigational New Drug Application
using IND #102,843.

The Investigators will be responsible for obtaining an Informed Consent signed by each
patient or his/her legally authorized representative prior to his/her participation in the
study in accordance with the Code of Federal Regulations, Title 21, Part 50.20. Informed
Consent will be obtained from a patient or his/her legally authorized representative after a
full explanation of the purpose of the study, the risks and discomforts involved, potential
benefits, etc. have been provided by the Investigator or designee, both verbally and in
writing. The person who signed the consent will be given a copy of the signed consent form.
The lack of long-term follow-up information regarding the effects of Omegaven will be
discussed.

Home Use of Omegaven:

In order for a subject to receive the Omegaven® at home through the home health care agency,
subjects will first be required to be admitted to Texas Children's Hospital for 72 hours in
initiate the administration of the Omegaven®. This will allow time for observation of any
unexpected side effects and for parents to be provided education on home TPN and Omegaven®.

If a subject has already received Omegaven® either at TCH or at another hospital, they will
not be required to be admitted for the 72 hour inpatient admission prior to starting
Omegaven® at home. Parent training will occur during the previous hospital admission and will
continue through the TCH Pediatric Intestinal Rehabilitation Clinic.

This population will include infants up to 5 years of age. The Omegaven® dose for home use
will be the same as that used while in the hospital: 1 gm/kg/day. As with the inpatient part
of the protocol, this is a maximum dose and may be decreased at the discretion of the TCH
Pediatric Intestinal Rehabilitation Clinic Team.

Outpatient Monitoring:

After the initial evaluation by the TCH Pediatric Intestinal Rehabilitation Clinic
physicians, subjects will return to the clinic for routine follow-up. Subjects will be asked
to return to the clinic every 2 weeks for the first 2 months of treatment. Thereafter,
subjects will return to the clinic on a monthly basis, or as directed by the clinic team.
Orders for home use of Omegaven® will be signed by the physician at the clinic visits,
ensuring that subjects are compliant with study parameters while receiving the treatment
drug.

Routine monitoring done at clinic appointments and at home will be recorded for study
purposes and data collection. No blood work will be done for study purposes only. Lab
monitoring will typically be done every week to two weeks at home and at each clinic visit.

FDA Contact:

Division of Gastroenterology and Inborn Errors Products Division of Drug Information (DDI)
(855) 543-3784 or (301) 796-3400; druginfo@fda.hhs.gov

Inclusion Criteria:

- Be greater than 14 days old and less than 5 years old

- Conjugated bilirubin greater than 2 mg/dL.

- Be expected to require intravenous nutrition for at least an additional 28 days

Exclusion Criteria:

- Have a congenitally lethal condition (e.g. Trisomy 13).

- Have clinically severe bleeding not able to be managed with routine measures.

- Have evidence of a viral hepatitis or primary liver disease as the primary etiology of
their cholestasis.

- Have other health problems such that survival is extremely unlikely even if the
infant's cholestasis improves.

Home Use of Omegaven®:

In order for a subject to receive the Omegaven® at home through a home health care agency,
subjects will first be required to be admitted to Texas Children's Hospital for 72 hours in
initiate the administration of the Omegaven®. This will allow time for observation of any
unexpected side effects and for parents to be provided education on home TPN and Omegaven®.

If a subject has already received Omegaven® either at TCH or at another hospital, they will
not be required to be admitted for the 72 hour inpatient admission prior to starting
Omegaven® at home. Parent training will occur during the previous hospital admission and
will continue through the TCH Pediatric Intestinal Rehabilitation Clinic.

Outpatient Monitoring:

After the initial evaluation by the TCH Pediatric Intestinal Rehabilitation Clinic
physicians, subjects will return to the clinic for routine follow-up. Subjects will be
asked to return to the clinic every 2 weeks for the first 2 months of treatment.
Thereafter, subjects will return to the clinic on a monthly basis, or as directed by the
clinic team.