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GCSF Adjunct Therapy for Biliary Atresia (BA_GCSF)

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ClinicalTrials.gov Identifier: NCT03395028
Recruitment Status : Active, not recruiting
First Posted : January 9, 2018
Last Update Posted : August 8, 2019
Sponsor:
Collaborators:
T Rose Clinical, Inc.
Children's National Health System
Information provided by (Responsible Party):
Holterman, Ai-Xuan, M.D.

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.

Condition or disease Intervention/treatment Phase
Biliary Atresia Drug: Granulocyte Colony-Stimulating Factor Early Phase 1

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.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 6 participants
Intervention Model: Single Group Assignment
Intervention Model Description: Dose determination for GCSF
Masking: None (Open Label)
Primary Purpose: Supportive Care
Official Title: Granulocyte-Colony Stimulating Factor Adjunct Therapy for Biliary Atresia
Actual Study Start Date : January 15, 2018
Estimated Primary Completion Date : December 31, 2019
Estimated Study Completion Date : January 31, 2020



Intervention Details:
  • 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 Name: Filgrastim


Primary Outcome Measures :
  1. 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.



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Ages Eligible for Study:   up to 180 Days   (Child)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03395028


Locations
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United States, District of Columbia
Children's National Medical Center
Washington, District of Columbia, United States, 20010
Vietnam
National Childrens Hospital
Hanoi, Vietnam
Sponsors and Collaborators
Holterman, Ai-Xuan, M.D.
T Rose Clinical, Inc.
Children's National Health System
Investigators
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Principal Investigator: Evan P Nadler, MD Children's Research Institute

Publications:
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Responsible Party: Holterman, Ai-Xuan, M.D.
ClinicalTrials.gov Identifier: NCT03395028     History of Changes
Other Study ID Numbers: CR00005169
IND 119679-0007 ( Other Identifier: Food and Drug Administration )
First Posted: January 9, 2018    Key Record Dates
Last Update Posted: August 8, 2019
Last Verified: August 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Holterman, Ai-Xuan, M.D.:
Biliary Atresia
Granulocyte Colony Stimulating Factor
GCSF

Additional relevant MeSH terms:
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Biliary Atresia
Bile Duct Diseases
Biliary Tract Diseases
Digestive System Diseases
Digestive System Abnormalities
Congenital Abnormalities
Lenograstim
Sargramostim
Adjuvants, Immunologic
Immunologic Factors
Physiological Effects of Drugs