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

NCT04373941 | Unknown Phase 2 DMC FDA Drug

• 1 other identifier: HoltermanA
• Study Type: interventional
• Target: 400
• Locations: 3 countries
• Sites: 4

Brief 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.

Conditions

Biliary Atresia

Outcome Measures

Primary Outcomes (2)

• 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

• GCSF Response on transplant-free survival (NoK)

  For NoK subjects: Changes at 6, 12, 18 and 24 months-transplant free survival

  24 months

Secondary Outcomes (4)

• GCSF response on liver function and outcome (KBA)

  24 months

• GCSF response on liver function and outcome (KBA)

  24 months

• GCSF response on liver function and outcome (KBA)

  24 months

• GCSF response on liver function (NoK)

  24 months

Study Arms (4)

Kasai GCSF

EXPERIMENTAL

The Kasai GCSF group will receive the standard of care PLUS 3 consecutive daily doses of 10 ug/kg of GCSF to be administered subcutaneously by day 3 post Kasai surgery

Drug: Filgrastim

Kasai no GCSF

NO INTERVENTION

The no GCSF group will not receive GCSF and receives the standard of care

No Kasai GCSF

EXPERIMENTAL

The No Kasai GCSF group will receive the standard of care PLUS 3 consecutive daily doses of 10 ug/kg of GCSF to be administered subcutaneously once the diagnosis of BA is established

Drug: Filgrastim

No Kasai No GCSF

NO INTERVENTION

The No Kasai No GCSF group will receive the standard of care and will not receive GCSF

Interventions

Filgrastim DRUG

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.

Also known as: Neupogen, granulocyte colony stimulating factor

Kasai GCSF; No Kasai GCSF

Eligibility Criteria

• Age: 14 Days - 180 Days
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17)

You may qualify if:

• preliminary work up for cholestasis suspected or inconclusive diagnosis of BA.
• Serum Direct bilirubin \> 2 mg/dl,GGT\> 100 U/L
• Male or female infants with a gestational age\> 36 weeks
• Admission weight \> 2 kg
• Age \> 14 days - 180 days at diagnosis
• For Kasai operated subjects, Type 3 or 4 anatomy of BA
• For Kasai operated subjects, cholangiogram (if performed) diagnostic of BA
• Liver biopsy supporting BA diagnosis

You may not qualify if:

• Patients having access to liver transplantation for immediate liver failure
• Prior Kasai patients
• Major cardiac, renal, central nervous system (CNS) malformations
• Intracranial hemorrhage
• History of recent total parenteral nutrition (TPN) use within the last 2 weeks
• Gl tract obstruction
• For Kasai-operated subjects: Type 1 or 2 biliary atresia anatomy
• Current systemic infection
• WBC \> 20,000 cells/uL
• Platelet count \< 20,000 cells/uL or \>1 million cells/uL
• Concurrent respiratory, metabolic, neurological, cardiovascular, metabolic, and renal illness
• Elevated serum creatinine \> 1 mg/dL
• Purpura fulminans or unexplained vascular thrombosis

Sponsors & Collaborators

• Holterman, Ai-Xuan, M.D.: lead
• T Rose Clinical, Inc.: collaborator
• Big Leap Research: collaborator
• Prometheus USA: collaborator

Study Sites (4)

Oregon Health & Science University (OHSU)

Portland, Oregon, 97239, United States

NOT YET RECRUITING

Aga Khan University

Karachi, Pakistan

NOT YET RECRUITING

Nation Children's Hospital

Hanoi, Dong Da District, Vietnam

RECRUITING

Children Hospital 1

Ho Chi Minh City, Vietnam

ENROLLING BY INVITATION

Related Publications (9)

• 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.

  PMID: 29604222 BACKGROUND

• 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.

  PMID: 24027727 BACKGROUND

• 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.

  PMID: 26725209 BACKGROUND

• 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.

  PMID: 25749502 BACKGROUND

• 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.

  PMID: 31335841 BACKGROUND

• 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.

  PMID: 29278428 BACKGROUND

• 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.

  PMID: 18537187 BACKGROUND

• 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.

  PMID: 21460243 BACKGROUND

• 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.

  PMID: 35391541 DERIVED

MeSH Terms

Conditions

Biliary Atresia

Interventions

Filgrastim; Granulocyte Colony-Stimulating Factor

Condition Hierarchy (Ancestors)

Bile Duct Diseases; Biliary Tract Diseases; Digestive System Diseases; Digestive System Abnormalities; Congenital Abnormalities; Congenital, Hereditary, and Neonatal Diseases and Abnormalities

Intervention Hierarchy (Ancestors)

Colony-Stimulating Factors; Glycoproteins; Glycoconjugates; Carbohydrates; Hematopoietic Cell Growth Factors; Cytokines; Intercellular Signaling Peptides and Proteins; Peptides; Amino Acids, Peptides, and Proteins; Proteins; Biological Factors

Central Study Contacts

AiXuan Holterman, MD

CONTACT

8473340230; Aithanh@uic.edu

Sherri J Boykin

CONTACT

9195596061; Sboykin@trclinical.com

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDIV
• Responsible Party: SPONSOR

Model Details: GCSF or No-GCSF

Study Record Dates

• First Submitted: August 13, 2019
• First Posted: May 5, 2020
• Study Start: September 1, 2023
• Primary Completion: August 31, 2024
• Study Completion: October 31, 2025
• Last Updated: September 8, 2023

Record last verified: 2023-09

Data Sharing

• IPD Sharing: Will not share

Locations

VN (2); US (1); PA (1)