A Phase I/IIa Trial of Intravenous Immunoglobulin Following Portoenterostomy in Biliary Atresia

ABSTRACT Objectives: Biliary atresia (BA) is a progressive neonatal fibroinflammatory cholangiopathy. We hypothesized that intravenous immunoglobulin (IVIg) would be safe, feasible, acceptable, and efficacious for the treatment of BA. The primary objective of this study was to establish the feasibil...

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Published inJournal of pediatric gastroenterology and nutrition Vol. 68; no. 4; pp. 495 - 501
Main Authors Mack, Cara L., Spino, Cathie, Alonso, Estella M., Bezerra, Jorge A., Moore, Jeffrey, Goodhue, Catherine, Ng, Vicky L., Karpen, Saul J., Venkat, Veena, Loomes, Kathleen M., Wang, Kasper, Sherker, Averell H., Magee, John C., Sokol, Ronald J.
Format Journal Article
LanguageEnglish
Published United States by European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology 01.04.2019
Subjects
adverse events
immunomodulation
liver transplantation
neonatal cholestasis
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Abstract ABSTRACT Objectives: Biliary atresia (BA) is a progressive neonatal fibroinflammatory cholangiopathy. We hypothesized that intravenous immunoglobulin (IVIg) would be safe, feasible, acceptable, and efficacious for the treatment of BA. The primary objective of this study was to establish the feasibility, acceptability, and safety profile of IVIg administration after hepatoportoenterostomy (HPE) in BA. The secondary objective was to determine the treatment efficacy of IVIg based on good bile drainage and survival with the native liver. Methods: A multicenter, prospective, open‐labeled, phase I/IIA trial of IVIg was conducted, with 1 g/kg/dose of IVIg infused at 3–5, 30, and 60 days post‐HPE, and subjects followed for 360 days post‐HPE. Twenty‐nine participants completed the study. Results: Administration of IVIg infusions was feasible and acceptable in 79%. None of the serious adverse events (SAEs) were directly related to IVIg infusions; however, 90% of participants had an SAE. Compared with a historical placebo‐arm group, there was no significant increase in the proportion of IVIg participants with a serum total bilirubin <1.5 mg/dL at 90, 180, or 360 days post‐HPE. Survival with the native liver in the IVIg participants showed no significant benefit over the historical placebo arm, with a difference at 360 days of −11.9% (IVIg: 58.6%, placebo: 70.5%; 90% UCB: 2.1%; P > 0.05). Conclusions: Although IVIg infusions in infants with BA post‐HPE were feasible, acceptable and safe, there was no trend to lower bilirubin levels or improved 360‐day survival with the native liver. Clinical Trial: Safety Study of Intravenous Immunoglobulin Post‐Portoenterostomy in Biliary Atresia; #NCT01854827.
AbstractList OBJECTIVES:Biliary atresia (BA) is a progressive neonatal fibroinflammatory cholangiopathy. We hypothesized that intravenous immunoglobulin (IVIg) would be safe, feasible, acceptable, and efficacious for the treatment of BA. The primary objective of this study was to establish the feasibility, acceptability, and safety profile of IVIg administration after hepatoportoenterostomy (HPE) in BA. The secondary objective was to determine the treatment efficacy of IVIg based on good bile drainage and survival with the native liver. METHODS:A multicenter, prospective, open-labeled, phase I/IIA trial of IVIg was conducted, with 1 g/kg/dose of IVIg infused at 3–5, 30, and 60 days post-HPE, and subjects followed for 360 days post-HPE. Twenty-nine participants completed the study. RESULTS:Administration of IVIg infusions was feasible and acceptable in 79%. None of the serious adverse events (SAEs) were directly related to IVIg infusions; however, 90% of participants had an SAE. Compared with a historical placebo-arm group, there was no significant increase in the proportion of IVIg participants with a serum total bilirubin <1.5 mg/dL at 90, 180, or 360 days post-HPE. Survival with the native liver in the IVIg participants showed no significant benefit over the historical placebo arm, with a difference at 360 days of −11.9% (IVIg58.6%, placebo70.5%; 90% UCB2.1%; P > 0.05). CONCLUSIONS:Although IVIg infusions in infants with BA post-HPE were feasible, acceptable and safe, there was no trend to lower bilirubin levels or improved 360-day survival with the native liver. CLINICAL TRIAL:Safety Study of Intravenous Immunoglobulin Post-Portoenterostomy in Biliary Atresia; #NCT01854827.
OBJECTIVESBiliary atresia (BA) is a progressive neonatal fibroinflammatory cholangiopathy. We hypothesized that intravenous immunoglobulin (IVIg) would be safe, feasible, acceptable, and efficacious for the treatment of BA. The primary objective of this study was to establish the feasibility, acceptability, and safety profile of IVIg administration after hepatoportoenterostomy (HPE) in BA. The secondary objective was to determine the treatment efficacy of IVIg based on good bile drainage and survival with the native liver. METHODSA multicenter, prospective, open-labeled, phase I/IIA trial of IVIg was conducted, with 1 g/kg/dose of IVIg infused at 3-5, 30, and 60 days post-HPE, and subjects followed for 360 days post-HPE. Twenty-nine participants completed the study. RESULTSAdministration of IVIg infusions was feasible and acceptable in 79%. None of the serious adverse events (SAEs) were directly related to IVIg infusions; however, 90% of participants had an SAE. Compared with a historical placebo-arm group, there was no significant increase in the proportion of IVIg participants with a serum total bilirubin <1.5 mg/dL at 90, 180, or 360 days post-HPE. Survival with the native liver in the IVIg participants showed no significant benefit over the historical placebo arm, with a difference at 360 days of -11.9% (IVIg: 58.6%, placebo: 70.5%; 90% UCB: 2.1%; P > 0.05). CONCLUSIONSAlthough IVIg infusions in infants with BA post-HPE were feasible, acceptable and safe, there was no trend to lower bilirubin levels or improved 360-day survival with the native liver. CLINICAL TRIALSafety Study of Intravenous Immunoglobulin Post-Portoenterostomy in Biliary Atresia; #NCT01854827.
Biliary atresia (BA) is a progressive neonatal fibroinflammatory cholangiopathy. We hypothesized that intravenous immunoglobulin (IVIg) would be safe, feasible, acceptable, and efficacious for the treatment of BA. The primary objective of this study was to establish the feasibility, acceptability, and safety profile of IVIg administration after hepatoportoenterostomy (HPE) in BA. The secondary objective was to determine the treatment efficacy of IVIg based on good bile drainage and survival with the native liver. A multicenter, prospective, open-labeled, phase I/IIA trial of IVIg was conducted, with 1 g/kg/dose of IVIg infused at 3-5, 30, and 60 days post-HPE, and subjects followed for 360 days post-HPE. Twenty-nine participants completed the study. Administration of IVIg infusions was feasible and acceptable in 79%. None of the serious adverse events (SAEs) were directly related to IVIg infusions; however, 90% of participants had an SAE. Compared with a historical placebo-arm group, there was no significant increase in the proportion of IVIg participants with a serum total bilirubin <1.5 mg/dL at 90, 180, or 360 days post-HPE. Survival with the native liver in the IVIg participants showed no significant benefit over the historical placebo arm, with a difference at 360 days of -11.9% (IVIg: 58.6%, placebo: 70.5%; 90% UCB: 2.1%; P > 0.05). Although IVIg infusions in infants with BA post-HPE were feasible, acceptable and safe, there was no trend to lower bilirubin levels or improved 360-day survival with the native liver. Safety Study of Intravenous Immunoglobulin Post-Portoenterostomy in Biliary Atresia; #NCT01854827.
ABSTRACT Objectives: Biliary atresia (BA) is a progressive neonatal fibroinflammatory cholangiopathy. We hypothesized that intravenous immunoglobulin (IVIg) would be safe, feasible, acceptable, and efficacious for the treatment of BA. The primary objective of this study was to establish the feasibility, acceptability, and safety profile of IVIg administration after hepatoportoenterostomy (HPE) in BA. The secondary objective was to determine the treatment efficacy of IVIg based on good bile drainage and survival with the native liver. Methods: A multicenter, prospective, open‐labeled, phase I/IIA trial of IVIg was conducted, with 1 g/kg/dose of IVIg infused at 3–5, 30, and 60 days post‐HPE, and subjects followed for 360 days post‐HPE. Twenty‐nine participants completed the study. Results: Administration of IVIg infusions was feasible and acceptable in 79%. None of the serious adverse events (SAEs) were directly related to IVIg infusions; however, 90% of participants had an SAE. Compared with a historical placebo‐arm group, there was no significant increase in the proportion of IVIg participants with a serum total bilirubin <1.5 mg/dL at 90, 180, or 360 days post‐HPE. Survival with the native liver in the IVIg participants showed no significant benefit over the historical placebo arm, with a difference at 360 days of −11.9% (IVIg: 58.6%, placebo: 70.5%; 90% UCB: 2.1%; P > 0.05). Conclusions: Although IVIg infusions in infants with BA post‐HPE were feasible, acceptable and safe, there was no trend to lower bilirubin levels or improved 360‐day survival with the native liver. Clinical Trial: Safety Study of Intravenous Immunoglobulin Post‐Portoenterostomy in Biliary Atresia; #NCT01854827.
Author Loomes, Kathleen M.
Ng, Vicky L.
Alonso, Estella M.
Karpen, Saul J.
Moore, Jeffrey
Magee, John C.
Bezerra, Jorge A.
Venkat, Veena
Wang, Kasper
Spino, Cathie
Goodhue, Catherine
Mack, Cara L.
Sokol, Ronald J.
Sherker, Averell H.
AuthorAffiliation University of Michigan, Ann Arbor, MI
The Hospital for Sick Children, University of Toronto, Toronto, Canada
Childrenʼs Hospital of Pittsburgh, Pittsburgh
National Institute of Diabetes, Digestive and Kidney Diseases, NIH, Bethesda, MA
Ann and Robert H. Lurie Childrenʼs Hospital of Chicago, Chicago, IL
Childrenʼs Hospital of Philadelphia, Philadelphia, PA
Childrenʼs Hospital Colorado, University of Colorado School of Medicine, Aurora, CO
Emory University School of Medicine, Atlanta, GA
Cincinnati Childrenʼs Hospital Medical Center, Cincinnati, OH
Childrenʼs Hospital Los Angeles, Los Angeles, CA
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Clinical Trial Registration: Safety Study of Intravenous Immunoglobulin (IVIG) Post‐Portoenterostomy in Infants with Biliary Atresia (PRIME); #NCT01854827
This work was supported by U01 grants from the National Institute of Diabetes, Digestive and Kidney Diseases (DK 62497 to J.A.B.; DK 62470 to S.J.K.; DK 62481 to K.M.L.; DK 62456 to C.S.; DK 62466 to V.V.; DK 62453 to R.J.S.; DK 84538 to K.W.; DK 62436 to E.M.A.; and DK 642453 to V.L.N). In addition, the project was supported by the National Center for Advancing Translational Sciences, National Institutes of Health, UL1 TR001878 (The Children's Hospital of Philadelphia), Clinical Translational Science AwardsUL1 TR002535 (University of Colorado Denver) and the Cincinnati Center for Translational Science and Training (Cincinnati Children's Hospital). FFF Enterprises (Temecula, California) supplied and shipped the IVIg.
https://clinicaltrials.gov/ct2/show/NCT01854827
www.jpgn.org
.
The authors report no conflicts of interest.
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content type line 23
Drs. Jorge Bezerra and Estella Alonso coordinated and supervised data collection, assisted in data analyses, drafted the initial manuscript and edited the final version.
Drs. Vicky Ng, Saul Karpen, Venna Venkat, Kathleen Loomes, Kasper Wang and Catherine Goodhue coordinated and supervised data collection and edited the final version.
Cathie Spino and Jeffrey Moore carried performed all data analyses, provided biostatistical support and edited the final version.
Drs. Cara Mack, and Ronald Sokol conceptualized and designed the study, coordinated and supervised data collection, assisted in data analyses, drafted the initial manuscript and edited the final version.
Contributors Statement.
Drs. Averell Sherker and John Magee assisted in the data analyses, provided important intellectual input and edited the final version.
All authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work.
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Snippet ABSTRACT Objectives: Biliary atresia (BA) is a progressive neonatal fibroinflammatory cholangiopathy. We hypothesized that intravenous immunoglobulin (IVIg)...
OBJECTIVES:Biliary atresia (BA) is a progressive neonatal fibroinflammatory cholangiopathy. We hypothesized that intravenous immunoglobulin (IVIg) would be...
Biliary atresia (BA) is a progressive neonatal fibroinflammatory cholangiopathy. We hypothesized that intravenous immunoglobulin (IVIg) would be safe,...
OBJECTIVESBiliary atresia (BA) is a progressive neonatal fibroinflammatory cholangiopathy. We hypothesized that intravenous immunoglobulin (IVIg) would be...
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SubjectTerms adverse events
immunomodulation
liver transplantation
neonatal cholestasis
Title A Phase I/IIa Trial of Intravenous Immunoglobulin Following Portoenterostomy in Biliary Atresia
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