GCSF Adjunct Therapy for Biliary Atresia

Biliary Atresia Clinical Trial

— BA_GCSF  

Official title:

Granulocyte-Colony Stimulating Factor Adjunct Therapy for Biliary Atresia

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03395028
• Other study ID #: CR00005169
• Secondary ID: IND 119679-0007
• Status: Completed
• Phase: Early Phase 1
• Start date: January 15, 2018
• Est. completion date: January 31, 2020

Study information

• Verified date: February 2020
• Source: Holterman, Ai-Xuan, M.D.
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 6
• Est. completion date: January 31, 2020
• Est. primary completion date: January 31, 2020
• Accepts healthy volunteers: No
• Gender: All
• Age group: N/A to 180 Days

Eligibility

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

Related Conditions & MeSH terms

• Biliary Atresia

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.

Locations

Country	Name	City	State
United States	Children's National Medical Center	Washington	District of Columbia
Vietnam	National Childrens Hospital	Hanoi

Sponsors (4)

Lead Sponsor	Collaborator
Holterman, Ai-Xuan, M.D.	Big Leap Research, Vietnam, Children's National Health System, T. Rose Clinical, Inc., United States

Countries where clinical trial is conducted

United States,  Vietnam, 

References & Publications (5)

Davenport M. Biliary atresia: clinical aspects. Semin Pediatr Surg. 2012 Aug;21(3):175-84. doi: 10.1053/j.sempedsurg.2012.05.010. Review. — View 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. Review. — View 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. — View 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. Review. — View 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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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.	13 months