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Study protocol of Phase 2 open-label multicenter randomized controlled trial for granulocyte-colony stimulating factor (GCSF) in post-Kasai Type 3 biliary atresia

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Abstract

Animal studies support RCT findings of improved liver function and short-term benefits using repurposed Granulocyte Colonic Stimulating Factor GCSF in adults with decompensated cirrhosis. We describe the protocol for phase 2 RCT of sequential Kasai-GCSF under an FDA-approved IND to test that GCSF improves early bile flow and post-Kasai biliary atresia BA clinical outcome. Immediate post-Kasai neonates, age 15–180 days, with biopsy-confirmed type 3 BA, without access to early liver transplantation, will be randomized 1:1 to standard of care SOC + GCSF at 10 ug/kg in 3 daily doses within 4 days of Kasai vs SOC + NO-GCSF (ClinicalTrials.gov NCT0437391). They will be recruited from children’s hospitals in Vietnam, Pakistan and one US center. The primary objective is to demonstrate that GCSF decreases the proportion of subjects with a 3-month post-Kasai serum Total Bilirubin ≥ 34 umol/L by 20%, (for a = 0.05, b = 0.80, i.e., calculated sample size of 218 subjects). The secondary objectives are to demonstrate that the frequency of post-Kasai cholangitis at 6-month and 24-month transplant-free survival are improved. The benefits are that GCSF is an affordable BA adjunct therapy, especially in developing countries, to improve biliary complications, enhance quality of liver and survival while diminishing costly liver transplantation.

Clinical trial registration: A phase 1 for GCSF dose and safety determination under ClinicalTrials.gov identifier NCT03395028 was completed in 2019. The current Phase 2 trial was registered under NCT04373941.

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Abbreviations

BA:

Biliary atresia

HSC:

Hematopoietic stem cells

GCSF:

Granulocyte-colony stimulating factor

CD:

Cluster of differentiation

RCT:

Randomized clinical trial

FDA:

Food and drug administration

IND:

Investigational new drug

NCT:

National clinical trial

VN:

Vietnam

TBi:

Total bilirubin

IE:

Inclusion/exclusion

GGT:

Gamma glutamyl transpeptidase

WBC:

White blood cell count

BASM:

Biliary atresia splenic malformation syndrome

CBC:

Complete blood count

LFT:

Liver function test

INR:

International normalized ratio

PELD:

Pediatric end stage liver disease

CD:

Cluster of differentiation

BEC:

Biliary epithelial cell

CMV:

Cytomegalovirus

CTCAE:

Common terminology criteria for adverse events

DR:

Ductular reaction

DSMB:

Data safety monitoring board

PBC:

Primary biliary cirrhosis

PSC:

Primary sclerosing cholangitis

TH17:

T helper 17

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Acknowledgements

Funding is provided by Cures Within Reach and by Prometheus USA organizations.

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Authors and Affiliations

  1. National Children Hospital, Hanoi, Vietnam

    Hoa Pham Anh Nguyen

  2. Department of Medicine, U of Illinois College of Medicine, Peoria, IL, USA

    Jinma Ren

  3. Oregon Health and Science U, Doernbecher Children Hospital, Portland, USA

    Marilyn Butler & Henri Li

  4. The Aga Khan University, Karachi, Pakistan

    Saqib Qazi & Kamran Sadiq

  5. Children Hospital 1, Ho Chi Minh City, Vietnam

    Hieu Trung Dao

  6. Department of Surgery and Pediatrics, U of Illinois College of Medicine, Chicago, IL, USA

    AiXuan Holterman

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  1. Hoa Pham Anh Nguyen
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Nguyen, H.P.A., Ren, J., Butler, M. et al. 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 38, 1019–1030 (2022). https://doi.org/10.1007/s00383-022-05115-0

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