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

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.

Granulocyte-colony stimulating factor GCSF mobilizes hematopoietic stem cells in Kasai patients with biliary atresia in a phase 1 study and improves short term outcome.

AIMS: In RCT of adults with decompensated cirrhosis, GCSF mobilizes hematopoietic stem cells HSC and improves short-term outcome. An FDA-IND for sequential Kasai-GCSF treatment in biliary atresia BA was approved. This phase 1 study examines GCSF safety in Kasai subjects. Preliminary short-term outcome was evaluated. METHODS: GCSF (Neupogen) at 5 or 10 µg/kg (n = 3/group) was given in 3 daily doses starting on day 3 of Kasai surgery (NCT03395028). Serum CD34+ HSC cell counts, and 1-month of GCSF-related adverse events were monitored. The 6-months Phase 1 clinical outcome was compared against 10 subsequent post Phase 1 Kasai patients who did not receive GCSF. RESULTS: With GCSF, WBC and platelet count transiently increased, LFT and serum creatinine remained stable. Reversible splenic enlargement (by 8.5-20%) occurred in 5/6 subjects. HSC count increased 12-fold and 17.5-fold for the 5 µg/kg and10 ug/kg dose respectively; with respective median total bilirubin levels for GCSF vs no-GCSF groups of 55 vs 91 µM at 1 month, p = 0.05; 15 vs 37 µM at 3 months, p = 0.24); and the 6-months cholangitis frequency of 40% vs 90%, p = 0.077. CONCLUSIONS: GCSF safely mobilizes HSC in Kasai infants and may improve short-term biliary drainage and cholangitis. Phase 2 efficacy outcome of GCSF adjunct therapy for sequential Kasai and GCSF is pending.