GCSF Adjunct Therapy for Biliary Atresia (BA_GCSF)
Primary Purpose
Biliary Atresia
Status
Completed
Phase
Early Phase 1
Locations
International
Study Type
Interventional
Intervention
Granulocyte Colony-Stimulating Factor
Sponsored by
About this trial
This is an interventional supportive care trial for Biliary Atresia focused on measuring Biliary Atresia, Granulocyte Colony Stimulating Factor, GCSF
Eligibility Criteria
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
Sites / Locations
- Children's National Medical Center
- National Childrens Hospital
Outcomes
Primary Outcome Measures
Dose determination GCSF
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.
Secondary Outcome Measures
Full Information
NCT ID
NCT03395028
First Posted
December 22, 2017
Last Updated
February 12, 2020
Sponsor
Holterman, Ai-Xuan, M.D.
Collaborators
T. Rose Clinical, Inc., United States, Children's National Health System, Big Leap Research, Vietnam
1. Study Identification
Unique Protocol Identification Number
NCT03395028
Brief Title
GCSF Adjunct Therapy for Biliary Atresia
Acronym
BA_GCSF
Official Title
Granulocyte-Colony Stimulating Factor Adjunct Therapy for Biliary Atresia
Study Type
Interventional
2. Study Status
Record Verification Date
February 2020
Overall Recruitment Status
Completed
Study Start Date
January 15, 2018 (Actual)
Primary Completion Date
January 31, 2020 (Actual)
Study Completion Date
January 31, 2020 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Holterman, Ai-Xuan, M.D.
Collaborators
T. Rose Clinical, Inc., United States, Children's National Health System, Big Leap Research, Vietnam
4. Oversight
Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes
5. 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.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Biliary Atresia
Keywords
Biliary Atresia, Granulocyte Colony Stimulating Factor, GCSF
7. Study Design
Primary Purpose
Supportive Care
Study Phase
Early Phase 1
Interventional Study Model
Single Group Assignment
Model Description
Dose determination for GCSF
Masking
None (Open Label)
Allocation
N/A
Enrollment
6 (Actual)
8. Arms, Groups, and Interventions
Intervention Type
Drug
Intervention Name(s)
Granulocyte Colony-Stimulating Factor
Other Intervention Name(s)
Filgrastim
Intervention Description
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.
Primary Outcome Measure Information:
Title
Dose determination GCSF
Description
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.
Time Frame
13 months
10. Eligibility
Sex
All
Minimum Age & Unit of Time
2 Weeks
Maximum Age & Unit of Time
180 Days
Accepts Healthy Volunteers
No
Eligibility Criteria
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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Evan P Nadler, MD
Organizational Affiliation
Children's National Research Institute
Official's Role
Principal Investigator
Facility Information:
Facility Name
Children's National Medical Center
City
Washington
State/Province
District of Columbia
ZIP/Postal Code
20010
Country
United States
Facility Name
National Childrens Hospital
City
Hanoi
Country
Vietnam
12. IPD Sharing Statement
Plan to Share IPD
No
Citations:
PubMed Identifier
22800970
Citation
Davenport M. Biliary atresia: clinical aspects. Semin Pediatr Surg. 2012 Aug;21(3):175-84. doi: 10.1053/j.sempedsurg.2012.05.010.
Results Reference
background
PubMed Identifier
18400509
Citation
Panopoulos AD, Watowich SS. Granulocyte colony-stimulating factor: molecular mechanisms of action during steady state and 'emergency' hematopoiesis. Cytokine. 2008 Jun;42(3):277-88. doi: 10.1016/j.cyto.2008.03.002. Epub 2008 Apr 8.
Results Reference
background
PubMed Identifier
15661404
Citation
Yannaki E, Athanasiou E, Xagorari A, Constantinou V, Batsis I, Kaloyannidis P, Proya E, Anagnostopoulos A, Fassas A. G-CSF-primed hematopoietic stem cells or G-CSF per se accelerate recovery and improve survival after liver injury, predominantly by promoting endogenous repair programs. Exp Hematol. 2005 Jan;33(1):108-19. doi: 10.1016/j.exphem.2004.09.005.
Results Reference
background
PubMed Identifier
22395569
Citation
Takami T, Terai S, Sakaida I. Stem cell therapy in chronic liver disease. Curr Opin Gastroenterol. 2012 May;28(3):203-8. doi: 10.1097/MOG.0b013e3283521d6a.
Results Reference
background
PubMed Identifier
27930386
Citation
Prajapati R, Arora A, Sharma P, Bansal N, Singla V, Kumar A. Granulocyte colony-stimulating factor improves survival of patients with decompensated cirrhosis: a randomized-controlled trial. Eur J Gastroenterol Hepatol. 2017 Apr;29(4):448-455. doi: 10.1097/MEG.0000000000000801.
Results Reference
background
PubMed Identifier
35391541
Citation
Nguyen HPA, Ren J, Butler M, Li H, Qazi S, Sadiq K, Dao HT, Holterman A. Study protocol of Phase 2 open-label multicenter randomized controlled trial for granulocyte-colony stimulating factor (GCSF) in post-Kasai Type 3 biliary atresia. Pediatr Surg Int. 2022 Jul;38(7):1019-1030. doi: 10.1007/s00383-022-05115-0. Epub 2022 Apr 7.
Results Reference
derived
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GCSF Adjunct Therapy for Biliary Atresia
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