GCSF Adjunct Therapy for Biliary Atresia

ID: NCT03395028
Status: Enrolling by invitation
Phase: Early Phase 1
Start Date: January 15, 2018
First Submitted: December 22, 2017
Last Updated: February 20, 2018
Results: N/A
Sponsors & Collaborators: Holterman, Ai-Xuan, M.D., T Rose Clinical, Inc., Children's National Health System, Prometheus USA, Ltd. Co.
Location: United States
Conditions: Biliary Atresia
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Study Description

Brief 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.
Condition or disease Intervention/treatment Phase

Biliary Atresia

Drug: Granulocyte Colony-Stimulating Factor
Other Names
Filgrastim
Early Phase 1

Tracking Information

First Submitted DateDecember 22, 2017
Last Update Posted DateFebruary 20, 2018
Actual Start DateJanuary 15, 2018
Anticipated Completion DateJanuary 31, 2019
Actual Primary Completion DateDecember 31, 2018
Results First Submitted DateN/A
Received Results Disposit DateN/A

Current Primary Outcome Measures

  • 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.

Original Primary Outcome Measures

Not Available

Current Secondary Outcome Measures

Not Available

Original Secondary Outcome Measures

Not Available

Study Design

Brief TitleGCSF Adjunct Therapy for Biliary Atresia
Official TitleGranulocyte-Colony Stimulating Factor Adjunct Therapy for Biliary Atresia
Brief 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.

Study TypeInterventional
Study PhaseEarly Phase 1
Estimated Enrollment
6
Allocation
Not Available
Interventional Model
Single Group Assignment
Masking
None (Open Label)
Primary Purpose
Supportive Care
Conditions
Biliary Atresia
Target Follow-Up Duration N/A
Biospecimen:
N/A
Sampling MethodN/A
Study PopulationN/A
Intervention
Drug: Granulocyte Colony-Stimulating Factor

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
Study Groups/Cohorts
Not Available
Study Arms
Not Available
Arm Intervention/Treatment

Recruitment Information

Recruitment Status:Enrolling by invitation
Enrollment6
Completion DateJanuary 31, 2019
Eligibility Criteria: Inclusion Criteria:
1. Completed the preliminary work up for cholestasis with suspected or inconclusive diagnosis of BA
2. Gestational Age > 36wks
3. Weight > 2 Kg
4. Age >-2 weeks-<180 days at diagnosis
5. Serum Direct Bilirubin > 2 mg/dL GGT > 100 U/L
6. Kasai operated patients for Type 3 or 4 anatomy of BA
7. Cholangiogram/porta hepatis findings diagnostic of BA
8. Liver biopsy supporting BA diagnosis

Exclusion Criteria:
1. Having access to liver transplantation for immediate Kasai failure
2. Prior Kasai patients
3. Major cardiac, renal, CNS malformations with poor prognosis
4. Intracranial hemorrhage
5. History of recent TPN use within the last 2 weeks of surgery
6. GI tract obstruction
7. Laparoscopic Kasai repair
GenderAll
Age N/A to 180 Days
Accepts Healthy VolunteersNo
Contacts
Not Available
Listed Location Countries
United States

Administrative Information

NCT Number:NCT03395028
Other Study ID Numbers
CR00005169
IND 119679-0007
Has Data Monitoring CommitteeYes
U.S. FDA-regulated Product Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Device Product Not Approved or Cleared by U.S. FDA: No
IPD Sharing Statement
Not Available
Responsible Party,
Study Sponsor
Holterman, Ai-Xuan, M.D.
Collaborators
T Rose Clinical, Inc.
Children's National Health System
Prometheus USA, Ltd. Co.
Investigators
Principal Investigator
Evan P Nadler, MD
Children's Research Institute