Part II: Granulocyte-Colony Stimulating Factor Adjunct Therapy for Biliary Atresia

Biliary Atresia Clinical Trial

— BA_GCSF2b  

Official title:

Granulocyte-Colony Stimulating Factor Adjunct Therapy for Biliary Atresia: Part II of a Prospective, Randomized Controlled, Multi-Institutional Trial

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04373941
• Other study ID #: HoltermanA
• Status: Recruiting
• Phase: Phase 2
• Start date: September 1, 2023
• Est. completion date: October 31, 2025

Study information

• Verified date: September 2023
• Source: Holterman, Ai-Xuan, M.D.
• Contact: AiXuan Holterman, MD
• Phone: 8473340230
• Email: Aithanh[@]uic.edu
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The Investigators propose to test the hypothesis that GCSF enhances the clinical outcome of biliary atresia in a multi-institutional Phase 2 trial to prospectively evaluate the safety and efficacy of GCSF in each of the 2 groups of newly diagnosed BA patients: KBA (i.e., Kasai-operated) or NoK (i.e., patients who did not undergo Kasai surgery). Subjects who participate in the trial will be followed for 2 years.

Description:

This is a prospective, randomized, multi-institutional trial in KBA and NoK subjects to be conducted under a Food and Drug Administration approved Investigational New Drug application.

The KBA group is composed of just operated Kasai patients with intraoperative liver biopsy-confirmed BA. Their clinical characteristics have been described in the previously completed Phase 1 study under CR00005169 (ie. inclusion and exclusion criteria as described below)

The NoK group will be composed of newly diagnosed BA patients, including the following:

• surgical patients in whom the Kasai was not performed for intraoperative technical reasons or due to advanced liver disease, who also have no option for rescue liver transplantation.

• Unoperated patients whose family refuses surgery or who are not operative candidates

Having met the same inclusion and exclusion criteria as the Kasai KBS group,

• eligible KBA subjects will be randomized to GCSF vs. no-GCSF at the 10 ug/kg/d dose to be given subcutaneously for 3 consecutive daily doses on the third day following the Kasai procedure.

• eligible NoK subjects will be randomized to GCSF vs. no-GCSF at the 10 ug/kg/d dose to be given subcutaneously for 3 consecutive daily doses on the third day following diagnostic liver biopsy.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 400
• Est. completion date: October 31, 2025
• Est. primary completion date: August 31, 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 14 Days to 180 Days

Eligibility

Inclusion criteria

1. preliminary work up for cholestasis suspected or inconclusive diagnosis of BA.

2. Serum Direct bilirubin > 2 mg/dl,GGT> 100 U/L

3. Male or female infants with a gestational age> 36 weeks

4. Admission weight > 2 kg

5. Age > 14 days - 180 days at diagnosis

6. For Kasai operated subjects, Type 3 or 4 anatomy of BA

7. For Kasai operated subjects, cholangiogram (if performed) diagnostic of BA

8. Liver biopsy supporting BA diagnosis

Exclusion criteria

1. Patients having access to liver transplantation for immediate liver failure

2. Prior Kasai patients

3. Major cardiac, renal, central nervous system (CNS) malformations

4. Intracranial hemorrhage

5. History of recent total parenteral nutrition (TPN) use within the last 2 weeks

6. Gl tract obstruction

For Kasai-operated subjects: Type 1 or 2 biliary atresia anatomy

7. Current systemic infection

8. WBC > 20,000 cells/uL

9. Platelet count < 20,000 cells/uL or >1 million cells/uL

10. Concurrent respiratory, metabolic, neurological, cardiovascular, metabolic, and renal illness

11. Elevated serum creatinine > 1 mg/dL

12. Purpura fulminans or unexplained vascular thrombosis

Related Conditions & MeSH terms

• Biliary Atresia

Intervention

Drug:
• Filgrastim
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
Pakistan	Aga Khan University	Karachi
United States	Oregon Health & Science University (OHSU)	Portland	Oregon
Vietnam	Nation Children's Hospital	Hanoi	Dong Da District
Vietnam	Children Hospital 1	Ho Chi Minh City

Sponsors (4)

Lead Sponsor	Collaborator
Holterman, Ai-Xuan, M.D.	Big Leap Research, Prometheus USA, T Rose Clinical, Inc.

Countries where clinical trial is conducted

United States,  Vietnam,  Pakistan, 

References & Publications (8)

Bezerra JA, Wells RG, Mack CL, Karpen SJ, Hoofnagle JH, Doo E, Sokol RJ. Biliary Atresia: Clinical and Research Challenges for the Twenty-First Century. Hepatology. 2018 Sep;68(3):1163-1173. doi: 10.1002/hep.29905. — View Citation

Chaudhuri J, Mitra S, Mukhopadhyay D, Chakraborty S, Chatterjee S. Granulocyte Colony-stimulating Factor for Preterms with Sepsis and Neutropenia: A Randomized Controlled Trial. J Clin Neonatol. 2012 Oct;1(4):202-6. doi: 10.4103/2249-4847.105993. — View Citation

Fanna M, Masson G, Capito C, Girard M, Guerin F, Hermeziu B, Lachaux A, Roquelaure B, Gottrand F, Broue P, Dabadie A, Lamireau T, Jacquemin E, Chardot C. Management of Biliary Atresia in France 1986 to 2015: Long-term Results. J Pediatr Gastroenterol Nutr. 2019 Oct;69(4):416-424. doi: 10.1097/MPG.0000000000002446. — View Citation

Kedarisetty CK, Anand L, Bhardwaj A, Bhadoria AS, Kumar G, Vyas AK, David P, Trehanpati N, Rastogi A, Bihari C, Maiwall R, Garg HK, Vashishtha C, Kumar M, Bhatia V, Sarin SK. Combination of granulocyte colony-stimulating factor and erythropoietin improves outcomes of patients with decompensated cirrhosis. Gastroenterology. 2015 Jun;148(7):1362-70.e7. doi: 10.1053/j.gastro.2015.02.054. Epub 2015 Mar 4. — View Citation

Korbling M, Freireich EJ. Twenty-five years of peripheral blood stem cell transplantation. Blood. 2011 Jun 16;117(24):6411-6. doi: 10.1182/blood-2010-12-322214. Epub 2011 Apr 1. — View Citation

Shneider BL, Magee JC, Karpen SJ, Rand EB, Narkewicz MR, Bass LM, Schwarz K, Whitington PF, Bezerra JA, Kerkar N, Haber B, Rosenthal P, Turmelle YP, Molleston JP, Murray KF, Ng VL, Wang KS, Romero R, Squires RH, Arnon R, Sherker AH, Moore J, Ye W, Sokol RJ; Childhood Liver Disease Research Network (ChiLDReN). Total Serum Bilirubin within 3 Months of Hepatoportoenterostomy Predicts Short-Term Outcomes in Biliary Atresia. J Pediatr. 2016 Mar;170:211-7.e1-2. doi: 10.1016/j.jpeds.2015.11.058. Epub 2015 Dec 24. — View Citation

Spahr L, Lambert JF, Rubbia-Brandt L, Chalandon Y, Frossard JL, Giostra E, Hadengue A. Granulocyte-colony stimulating factor induces proliferation of hepatic progenitors in alcoholic steatohepatitis: a randomized trial. Hepatology. 2008 Jul;48(1):221-9. doi: 10.1002/hep.22317. — View Citation

Verma N, Kaur A, Sharma R, Bhalla A, Sharma N, De A, Singh V. Outcomes after multiple courses of granulocyte colony-stimulating factor and growth hormone in decompensated cirrhosis: A randomized trial. Hepatology. 2018 Oct;68(4):1559-1573. doi: 10.1002/hep.29763. Epub 2018 Jul 25. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	GCSF Response on Bile flow (KBA)	For KBA subjects: Bile flow as measured by the percentage of subjects with total bilirubin< 2 mg/dL at 3 months post-Kasai.	3 months
Primary	GCSF Response on transplant-free survival (NoK)	For NoK subjects: Changes at 6, 12, 18 and 24 months-transplant free survival	24 months
Secondary	GCSF response on liver function and outcome (KBA)	KBA subjects: Pediatric end-stage liver disease (PELD) score at 6, 12, 18, and 24 months after GCSF treatment.	24 months
Secondary	GCSF response on liver function and outcome (KBA)	KBA subjects: Percentage of patients with transplant-free survival at 6, 12, 18 and 24 months	24 months
Secondary	GCSF response on liver function and outcome (KBA)	KBA subjects: Percentage of patients with cholangitis-free transplant-free survival at 6, 12, 18 and 24 months	24 months
Secondary	GCSF response on liver function (NoK)	NoK subjects: Changes in Pediatric end-stage liver disease (PELD) score at 6, 12, 18, and 24 months after GCSF treatment.	24 months