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

Compassionate Use of an Intravenous Fat Emulsion Comprised of Fish Oil in the Treatment of Parenteral Nutrition Induced Liver Injury in Infants

To provide a mechanism for critically ill infants with parenteral nutrition (PN) associated cholestasis to receive Omegaven for compassionate use situations for which there are no satisfactory alternative treatments.

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: 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. 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 years. 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 years 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

Initiation of Study is defined as the day the Fish Oil Emulsion was initiated. End of Study (EOS) is defined as discontinuation of fish oil emulsion, death, transplant, or discharge from the hospital. In infants who meet the eligibility criteria for Fish Oil Emulsion arm will receive Fish Oil Emulsion after enrollment under the study. Therapy with Fish Oil Emulsion (Omegaven) will be provided at a dose of 1 gm/kg/day (by continuous infusion) and will be infused intravenously through either a central or peripheral catheter in conjunction with parenteral nutrition. If previously on Intralipid, it will be stopped prior to initiation of Fish Oil Emulsion.

In infants who meet the eligibility criteria for Fish Oil Emulsion arm will receive Fish Oil Emulsion after enrollment under the study. Therapy with Fish Oil Emulsion (Omegaven) will be provided at a dose of 1 gm/kg/day (by continuous infusion) and will be infused intravenously through either a central or peripheral catheter in conjunction with parenteral nutrition. If previously on Intralipid, it will be stopped prior to initiation of Fish Oil Emulsion.Fish oil emulsion will be provided as a continuous intravenous emulsion over 24 hours.

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. 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 years. 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 until the infant no longer requires TPN.

Time in days from the initiation of fish oil emulsions (initiation of study) until resolution of cholestasis as defined by serum conjugated bilirubin≤ 2 mg/dL prior to EOS (end of study).

From initiation to end of study (End of Study : Discontinuation of Fish Oil Emulsion, Death, Transplant, or Discharge from the hospital, whichever is achieved first, up to 5 years).

To describe proportion of infants who died secondary to any cause, related or unrelated to Fish Oil Emulsion.

From initiation to end of study (End of Study : Discontinuation of Fish Oil Emulsion, Death, Transplant, or Discharge from the hospital, whichever is achieved first, up to 5 years).

The Z-score indicated the number of standard deviations away from the mean. A weight Z-score of 0 is equal to the mean. A weight Z-score of ≤ -2 indicates an underweight status, while a weight Z-score of ≥ 2 indicates overweight or obese status.

From initiation to end of study (End of Study : Discontinuation of Fish Oil Emulsion, Death, Transplant, or Discharge from the hospital, whichever is achieved first, up to 5 years).

To describe the number of infants who achieved resolution of cholestasis following initiation of fish oil emulsion.

From initiation to end of study (End of Study : Discontinuation of Fish Oil Emulsion, Death, Transplant, or Discharge from the hospital, whichever is achieved first, up to 5 years).

To describe the number of study subjects who experienced a platelet count below <100,000/µL anytime during the duration of the study.

From initiation to end of study (End of Study : Discontinuation of Fish Oil Emulsion, Death, Transplant, or Discharge from the hospital, whichever is achieved first, up to 5 years).

To describe the number of study subjects who experienced an INR ≥1.4 anytime during the duration of the study.

From initiation to end of study (End of Study : Discontinuation of Fish Oil Emulsion, Death, Transplant, or Discharge from the hospital, whichever is achieved first, up to 5 years).

To describe the number of study subjects who experienced a bloodstream infection during the duration of the study. Bloodstream infection as defined by detection by the culture of bacteria or fungus from the blood.

From initiation to end of study (End of Study : Discontinuation of Fish Oil Emulsion, Death, Transplant, or Discharge from the hospital, whichever is achieved first, up to 5 years).

From initiation to end of study (End of Study : Discontinuation of Fish Oil Emulsion, Death, Transplant, or Discharge from the hospital, whichever is achieved first, up to 5 years).

To describe number and percentage of infants who died secondary to any cause, related or unrelated to Fish Oil Emulsion.

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.

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