Dataset Information

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 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.

SUBMITTER: Mack CL

PROVIDER: S-EPMC6428610 | biostudies-literature | 2019 Apr

REPOSITORIES: biostudies-literature

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

Mack Cara L CL Spino Cathie C Alonso Estella M EM Bezerra Jorge A JA Moore Jeffrey J Goodhue Catherine C Ng Vicky L VL Karpen Saul J SJ Venkat Veena V Loomes Kathleen M KM Wang Kasper K Sherker Averell H AH Magee John C JC Sokol Ronald J RJ

Journal of pediatric gastroenterology and nutrition 20190401 4

<h4>Objectives</h4>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 drainag ...[more]

PMID: 30664564

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Project description:We investigated noninvasive follow-up markers for histologic liver fibrosis and portal hypertension (PH) in patients with biliary atresia after successful portoenterostomy (PE). Among children with bilirubin <20 µmol/L after PE (n = 39), Metavir fibrosis stage was evaluated at PE and in follow-up protocol liver biopsies (n = 83). PH was defined as endoscopically confirmed esophageal varices or thrombocytopenia associated with splenomegaly. The accuracy of liver biochemistry and stiffness in detecting liver fibrosis and PH was analyzed by the area under the receiving operating characteristic curve (AUROC) and multiple regression models. During a median native liver survival of 8.3 years (interquartile range 2.5-10.8 years), cirrhosis (Metavir F4) had developed in 51% of patients and PH in 54% of patients. Cirrhosis was equally common in all age tertiles of 1.2-2.1 years (n = 10/27), 3.9-5.8 years (n = 12/28), and 9.0-14 years (n = 12/28). In the two oldest age tertiles, histologic liver fibrosis had progressed further in patients with PH than without PH (P < 0.001). PH was accurately predicted by the aspartate aminotransferase-to-platelet ratio index (APRI) (cutoff, 0.70; AUROC, 0.92), bile acids (cutoff, 49 µmol/L; AUROC, 0.91), and liver stiffness (cutoff, 16.9 kPa; AUROC, 0.89; P < 0.001 each) across all age tertiles. Liver stiffness was the most accurate predictor of cirrhosis overall (AUROC, 0.82; P < 0.001), whereas bilirubin was >11 µmol/L in the youngest tertile (AUROC, 0.91; P < 0.001), bile acids was >80 µmol/L in the middle tertile (AUROC, 0.81; P = 0.009), and liver stiffness was >24 kPa in the oldest age tertile (AUROC, 0.96; P = 0.002). Conclusion: After successful PE, development of PH associates with progression of liver fibrosis and can be accurately detected by APRI and stiffness. Liver stiffness most accurately identified cirrhosis in older children, whereas biochemical markers of cholestasis closely reflected histologic cirrhosis in younger children.

Project description:Background and aimsBiliary atresia (BA) is a cholestatic, fibro-obliterative cholangiopathy of unknown etiology. BA is primarily treated by a surgical approach, that is, the Kasai portoenterostomy (KPE), to obtain clearance of jaundice (COJ). The gut microbiota (GM) composition has been associated with the course of several cholestatic liver diseases. It is largely unknown, however, whether GM composition associates with the outcome of KPE. We compared the GM composition of BA patients and controls and assessed if GM composition before KPE was related to COJ after KPE.MethodsWe compared feces of term-born BA patients before KPE and controls (patients undergoing inguinal hernia repair) by 16S rRNA sequencing. Composition and alpha diversity of the GM were compared between BA and controls before KPE and after KPE, between patients with COJ versus without COJ (total serum bilirubin < or ≥20 μmol/L <6 months post-KPE).ResultsAlpha diversity was comparable between BA (n = 12, age 1.6 [1.3-1.8] months) and controls (n = 6, age 2.0 [1.4-2.1] months; P = 0.22). Compared with controls, BA patients had lower abundances of Bifidobacteriaceae (β = -1.98, P < 0.001) and Lachnospiraceae (β = -1.84, P = 0.007), and higher abundances of Streptococcus (β = -1.13, P = 0.003). The alpha diversity before KPE correlated negatively with COJ (R = -0.63, P = 0.03). Lower alpha diversity pre-KPE was associated with COJ [+] (βlogit = -0.64, P = 0.04). We observed greater abundances of genus Acinetobacter (β = 1.27, P = 0.03) and family Clostridiaceae (β = 1.45, P = 0.03) and lower abundances of the family Enterobacteriaceae (genera Klebsiella (β = -1.21, P = 0.01), Salmonella (β = -1.57, P = 0.02)) in COJ [+] versus COJ [-].ConclusionsThe GM of BA patients before Kasai portoenterostomy associates with outcome, clearance of jaundice, suggestive of predictive, and mechanistic roles of the gut microbiota composition in bile homeostasis.

Dataset Information

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

Publications

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

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