A Phase I/IIa Trial of Intravenous Immunoglobulin (IVIG) Therapy Following Portoenterostomy in Infants with Biliary Atresia (PRIME)

General Description

The PRIME study was a multicenter prospective phase I/IIA open label trial, aimed at assessing the feasibility, tolerability, and safety of intravenous immunoglobulin (IVIG) therapy following hepatic portoenterostomy (HPE) in infants with biliary atresia (BA). After enrollment, participants received three intravenous doses of IVIG at designated intervals over the first 60 days following HPE and were followed for 360 days. All infants in this trial were also treated with standardized doses of other routine standard-of-care treatments for BA and this routine clinical care was not modified by participation in this study.

Objectives

The primary objectives the PRIME study were to determine the feasibility, acceptability, tolerability, and safety profile of IVIG treatment administered to infants after hepatic portoenterostomy (HPE) for biliary atresia, and investigate preliminary evidence of activity and explore mechanisms of action.

Outcome Measure

The primary outcome measures were feasibility and acceptability of IVIG treatment, and any serious adverse events.

Criteria

Inclusion criteria:

• Infant under 120 days old with established diagnosis of BA
• Start treatment with 3-5 days of the standard HPE operation performed for BA
• Post-conception age ≥ 36 weeks at time of enrollment
• Weight at enrolment ≥ 2000 grams
• Written informed consent to participate in the study obtained within 3 days of completion of HPE

Exclusion criteria:

• Laparoscopic HPE or "gall bladder Kasai" (cholecysto-portostomy) surgery was performed
• Biliary atresia splenic malformation syndrome (presence of asplenia, polysplenia or double spleen)
• History of a hypercoagulable disorder
• Renal disease defined as serum creatinine > 1.0 mg/dL prior to enrollment or presence of complex renal anomalies found on imaging
• Evidence of congestive heart failure or fluid overload
• Presence of significant systemic hypertension for age (defined as persistent systolic blood pressure ≥ 112 mmHg measured on at least 3 occasions following HPE)
• Infants whose mother is known to have human immunodeficiency virus infection, serum HBsAg, or hepatitis C virus antibody positive
• Previous treatment with intravenous immunoglobulin therapy, corticosteroid therapy, or any other investigational agent
• History of allergic reaction to any human blood product infusion
• Infants with other severe concurrent illnesses, such as neurological, cardiovascular, pulmonary, metabolic, endocrine, and renal disorders, that would interfere with the conduct and results of the study
• Any other clinical condition that is a contraindication to the use of IVIG

Detailed inclusion and exclusion criteria can be found in the study protocol.

Outcome

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 a 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).