GCSF Adjunct Therapy for Biliary Atresia

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.

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Key information

Conditions

Biliary Atresia Bile Duct Diseases Biliary Tract Diseases Congenital Abnormalities Congenital, Hereditary, and Neonatal Diseases and Abnormalities Digestive System Abnormalities Digestive System Diseases

Age range

2 week–180 day

Sex eligibility

All sexes

Study type

Interventional

Phase

Early Phase 1

Primary location

Children's National Medical Center, Washington D.C., District of Columbia, United States

About this study

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.

Who can participate

Healthy volunteers accepted: No

Only the study team can determine whether someone qualifies for participation.

Inclusion criteria

Completed the preliminary work up for cholestasis with suspected or inconclusive diagnosis of BA
Gestational Age > 36wks
Weight > 2 Kg
Age >-2 weeks-<180 days at diagnosis
Serum Direct Bilirubin > 2 mg/dL GGT > 100 U/L
Kasai operated patients for Type 3 or 4 anatomy of BA
Cholangiogram/porta hepatis findings diagnostic of BA
Liver biopsy supporting BA diagnosis

Exclusion criteria

Having access to liver transplantation for immediate Kasai failure
Prior Kasai patients
Major cardiac, renal, CNS malformations with poor prognosis
Intracranial hemorrhage
History of recent TPN use within the last 2 weeks of surgery
GI tract obstruction
Laparoscopic Kasai repair

Treatment and study plan

Granulocyte Colony-Stimulating Factor

Drug

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 names: Filgrastim

Primary outcomes

Dose determination GCSF

Time frame: 13 months

To determine the maximum tolerated dose of GCSF based on GCSF dose limiting toxicity and the extent of peripheral blood stem cell mobilization as measured by increases in CD34+cells with upper levels limited by white blood cells (WBCs) less than 50,000 per microliter (mcL) of blood.

Sponsors and collaborators

Lead sponsor

Holterman, Ai-Xuan, M.D.

Indiv

Collaborators

Big Leap Research
Children's National Research Institute
T. Rose Clinical, Inc., United States

Registry information

Official study title

Granulocyte-Colony Stimulating Factor Adjunct Therapy for Biliary Atresia

Acronym: BA_GCSF

Important dates

Study start: 2018
Primary completion: 2020
Study completion: 2020
First posted: Jan 9, 2018
Registry last updated: Feb 17, 2020

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

Published trials that share one or more normalized conditions with this study.

Completed