Part II: Granulocyte-Colony Stimulating Factor Adjunct Therapy for Biliary Atresia

Study Overview
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Brief Summary
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The Investigators propose to test the hypothesis that GCSF enhances the clinical outcome of biliary atresia in a multi-institutional Phase 2 trial to prospectively evaluate the safety and efficacy of GCSF in each of the 2 groups of newly diagnosed BA patients: KBA (i.e., Kasai-operated) or NoK (i.e., patients who did not undergo Kasai surgery). Subjects who participate in the trial will be followed for 2 years.

Detailed Description
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This is a prospective, randomized, multi-institutional trial in KBA and NoK subjects to be conducted under a Food and Drug Administration approved Investigational New Drug application. The KBA group is composed of just operated Kasai patients with intraoperative liver biopsy-confirmed BA. Their clinical characteristics have been described in the previously completed Phase 1 study under CR00005169 (ie. inclusion and exclusion criteria as described below) The NoK group will be composed of newly diagnosed BA patients, including the following: surgical patients in whom the Kasai was not performed for intraoperative technical reasons or due to advanced liver disease, who also have no option for rescue liver transplantation. Unoperated patients whose family refuses surgery or who are not operative candidates Having met the same inclusion and exclusion criteria as the Kasai KBS group, eligible KBA subjects will be randomized to GCSF vs. no-GCSF at the 10 ug/kg/d dose to be given subcutaneously for 3 consecutive daily doses on the third day following the Kasai procedure. eligible NoK subjects will be randomized to GCSF vs. no-GCSF at the 10 ug/kg/d dose to be given subcutaneously for 3 consecutive daily doses on the third day following diagnostic liver biopsy.

Official Title
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Granulocyte-Colony Stimulating Factor Adjunct Therapy for Biliary Atresia: Part II of a Prospective, Randomized Controlled, Multi-Institutional Trial

Conditions
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Biliary Atresia

Intervention / Treatment
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* Drug: Filgrastim


Participation Criteria
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Eligibility Criteria
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Inclusion criteria preliminary work up for cholestasis suspected or inconclusive diagnosis of BA. Serum Direct bilirubin > 2 mg/dl,GGT> 100 U/L Male or female infants with a gestational age> 36 weeks Admission weight > 2 kg Age > 14 days - 180 days at diagnosis For Kasai operated subjects, Type 3 or 4 anatomy of BA For Kasai operated subjects, cholangiogram (if performed) diagnostic of BA Liver biopsy supporting BA diagnosis Exclusion criteria Patients having access to liver transplantation for immediate liver failure Prior Kasai patients Major cardiac, renal, central nervous system (CNS) malformations Intracranial hemorrhage History of recent total parenteral nutrition (TPN) use within the last 2 weeks Gl tract obstruction For Kasai-operated subjects: Type 1 or 2 biliary atresia anatomy Current systemic infection WBC > 20,000 cells/uL Platelet count < 20,000 cells/uL or >1 million cells/uL Concurrent respiratory, metabolic, neurological, cardiovascular, metabolic, and renal illness Elevated serum creatinine > 1 mg/dL Purpura fulminans or unexplained vascular thrombosis

Ages Eligible for Study
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Minimum Age: 14 Days
Maximum Age: 180 Days

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: GCSF or No-GCSF
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Kasai GCSF<br>The Kasai GCSF group will receive the standard of care PLUS 3 consecutive daily doses of 10 ug/kg of GCSF to be administered subcutaneously by day 3 post Kasai surgery | Drug: Filgrastim<br>* G-CSF is a glycoprotein produced by monocytes, fibroblasts, and endothelial cells. Filgrastim is a human granulocyte colony stimulating factor (G-CSF) produced by recombinant DNA technology with NEUPOGEN® as the Amgen Inc. trademark for filgrastim. G-CSF regulates the production, proliferation and differentiation of neutrophils and hematopoietic stem cell precursors within the bone marrow leading to dose-dependent increase in circulating neutrophils and hematopoietic stem cells in the blood. It is indicated to reduce the incidence of infection in patients with severe neutropenia, for neutrophil recovery in neutropenic patients with bone marrow depletion, to mobilize hematopoietic progenitor stem cell for collection by leukapheresis in hematopoietic stem cell transplantation.<br>* Other names: Neupogen, granulocyte colony stimulating factor;|
| No Intervention: Kasai no GCSF<br>The no GCSF group will not receive GCSF and receives the standard of care | |
| Experimental: No Kasai GCSF<br>The No Kasai GCSF group will receive the standard of care PLUS 3 consecutive daily doses of 10 ug/kg of GCSF to be administered subcutaneously once the diagnosis of BA is established | Drug: Filgrastim<br>* G-CSF is a glycoprotein produced by monocytes, fibroblasts, and endothelial cells. Filgrastim is a human granulocyte colony stimulating factor (G-CSF) produced by recombinant DNA technology with NEUPOGEN® as the Amgen Inc. trademark for filgrastim. G-CSF regulates the production, proliferation and differentiation of neutrophils and hematopoietic stem cell precursors within the bone marrow leading to dose-dependent increase in circulating neutrophils and hematopoietic stem cells in the blood. It is indicated to reduce the incidence of infection in patients with severe neutropenia, for neutrophil recovery in neutropenic patients with bone marrow depletion, to mobilize hematopoietic progenitor stem cell for collection by leukapheresis in hematopoietic stem cell transplantation.<br>* Other names: Neupogen, granulocyte colony stimulating factor;|
| No Intervention: No Kasai No GCSF<br>The No Kasai No GCSF group will receive the standard of care and will not receive GCSF | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| GCSF Response on Bile flow (KBA) | For KBA subjects: Bile flow as measured by the percentage of subjects with total bilirubin< 2 mg/dL at 3 months post-Kasai. | 3 months | 
| GCSF Response on transplant-free survival (NoK) | For NoK subjects: Changes at 6, 12, 18 and 24 months-transplant free survival | 24 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| GCSF response on liver function and outcome (KBA) | KBA subjects: Pediatric end-stage liver disease (PELD) score at 6, 12, 18, and 24 months after GCSF treatment. | 24 months | 
| GCSF response on liver function and outcome (KBA) | KBA subjects: Percentage of patients with transplant-free survival at 6, 12, 18 and 24 months | 24 months | 
| GCSF response on liver function and outcome (KBA) | KBA subjects: Percentage of patients with cholangitis-free transplant-free survival at 6, 12, 18 and 24 months | 24 months | 
| GCSF response on liver function (NoK) | NoK subjects: Changes in Pediatric end-stage liver disease (PELD) score at 6, 12, 18, and 24 months after GCSF treatment. | 24 months |