Clinical trial NCT03395028: GCSF Adjunct Therapy for Biliary Atresia
Official title: Granulocyte-Colony Stimulating Factor Adjunct Therapy for Biliary Atresia
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: EARLY_PHASE1
Conditions: Biliary Atresia
Keywords: Biliary Atresia
Granulocyte Colony Stimulating Factor
GCSF
Lead sponsor: Holterman, Ai-Xuan, M.D.
Sponsor class: INDIV
Collaborators: name: T. Rose Clinical, Inc., United States
name: Children's National Health System
name: Big Leap Research
First posted: 2018-01-09
Enrollment: 6
Sex: ALL
Minimum age (years): 2
Maximum age (years): 180
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Intervention model description: Dose determination for GCSF
Primary purpose: SUPPORTIVE_CARE

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.

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

Primary outcomes:
measure: Dose determination GCSF
timeFrame: 13 months
Secondary outcomes:
Other outcomes:
Locations:
city: Washington
country: United States
facility: Children's National Medical Center
state: District of Columbia
city: Hanoi
country: Vietnam
facility: National Childrens Hospital
Study officials:
affiliation: Children's National Research Institute
name: Evan P Nadler, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Davenport M. Biliary atresia: clinical aspects. Semin Pediatr Surg. 2012 Aug;21(3):175-84. doi: 10.1053/j.sempedsurg.2012.05.010.
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.
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.
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.
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.
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.