GCSF Adjunct Therapy for Biliary Atresia
Condition: Biliary Atresia
MeSH terms: Biliary Atresia
Study type: Interventional
Phase: Early Phase 1

Summary: 
      The Investigators propose to test the hypothesis that GCSF therapy enhances the clinical
      outcome of Kasai operated Biliary Atresia (BA) patients. In this study, Investigators will
      conduct a dose determination for GCSF use in post Kasai subjects to support a future phase 2
      efficacy study. The first 3 post Kasai BA subjects with liver biopsy-confirmed BA will be
      given 5 ug/kg/d of GCSF in 3 daily subcutaneous doses starting on post Kasai day 3. A second
      group of 3 subjects will be assigned to the 10 ug/Kg/d dose after the 5ug/kg/d dose has been
      proven to be safe. The levels of circulating hematopoietic stem cells and a 1-month safety
      profile will be analyzed.
    

Detailed description: 
      In BA, neonatal fibrous obliteration of the biliary tract obstructs biliary drainage and
      promotes biliary fibrosis. BA is the leading cause of pediatric chronic end-stage liver
      disease and pediatric liver transplantation. Relief of cholestasis by the Kasai
      portoenterostomy is only partly successful with continued progression of fibrosis to hepatic
      insufficiency and, for long term survival, with eventual need for liver transplantation in
      the majority of the patients. In animal models of liver injury, GCSF enhances hematopoietic
      stem cell HSC mobilization and engraftment in the liver with associated improved liver repair
      response and attenuated hepatic necrosis and fibrosis. Randomized controlled trials of GCSF
      intervention for chronic liver failure in adult patients with acute hepatic decompensation
      showed improved short-term survival and hepatic indices such the model for end-stage liver
      disease (MELD) scores.

      The Investigators propose that post Kasai GCSF therapy attenuates biliary fibrosis and
      progression to cirrhosis. The objectives are meant to demonstrate that Kasai-GCSF sequential
      therapy improves biliary drainage, and delays the progression of hepatic insufficiency.
      Toward this goal, Investigators will first evaluate in post Kasai subjects the maximum
      tolerated dose of GCSF in mobilizing circulating CD34+ hematopoietic stem cells, with the
      limiting dose based on GCSF-related severe adverse effects. A one-month safety of GCSF will
      be tested with the 2 standard doses of 5 ug/kg/d and 10 ug/kg/d.
    

Intervention name(s): Granulocyte Colony-Stimulating Factor
Intervention type(s): Drug
Intervention description(s): 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.
Other intervention name(s): Filgrastim
Intervention MeSH terms: Lenograstim
Intervention model: Single Group Assignment
Intervention model description: Dose determination for GCSF
Masking: None (Open Label)
Primary purpose: Supportive Care
Keywords: Biliary Atresia; Granulocyte Colony Stimulating Factor; GCSF