Safety Study of Intravenous Immunoglobulin (IVIG) Post-Portoenterostomy in Infants With Biliary Atresia

Phase 1

Completed

Lead Sponsor: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

Brief Summary: The Children Liver Disease Research and Education Network (ChiLDREN) is conducting a clinical trial to determine the feasibility, acceptability, tolerability and safety profile of IVIG treatment administered to infants after hepatic portoenterostomy (HPE) for biliary atresia, as well as investigate preliminary evidence of activity and explore mechanisms of action.

Detailed Description: In this multicenter prospective phase 1/2A open label trial, the feasibility, tolerability and safety of intravenous immunoglobulin (IVIG) therapy following hepatic portoenterostomy (HPE) will be assessed in 29 infants with biliary atresia (BA), efficacy will be estimated and exploratory mechanistic research studies will be performed. After written consent is obtained from the parent or guardian, the subject will be enrolled and will receive three intravenous doses of IVIG at designated intervals over the first 60 days following HPE and will be followed for 360 days after enrollment. Blood will also be obtained during this study to assess potential mechanisms by which the IVIG may alter or reduce bile duct inflammation and injury and improve bile flow. All infants in this trial will also be treated with standardized doses of other routine standard-of-care treatments for BA during this trial (ursodeoxycholic acid, trimethoprim-sulfamethoxasole, and fat-soluble vitamin supplements). This routine clinical care will not be modified by participation in this study. Subjects in this study will not receive corticosteroid therapy for treatment of biliary atresia, as this is of unproven benefit at the present time.

Recruitment & Eligibility

Inclusion Criteria

Infant under 120 days old with established diagnosis of BA. Subjects in this trial must start treatment within 3-5 days of the Kasai procedure and be part of a prospective study of the natural history of biliary atresia also being conducted by ChiLDREN (http://www.clinicaltrials.gov/ct/show/NCT00061828?order=3).
Standard HPE operation has been performed for BA within the previous 3 days
Post-conception age ≥ 36 weeks at time of enrollment
Weight at enrolment ≥ 2000 gm
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
Infants whose mother is known to be serum HBsAg or hepatitis C virus antibody positive
Previous treatment with intravenous immunoglobulin therapy or corticosteroid therapy
Previous treatment with 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

Arm && Interventions

Group	Intervention	Description
IVIG active treatment	Intravenous immunoglobulin (IVIG)	Intravenous immunoglobulin (IVIG) 10% 1 gm/kg body weight/dose Day 3-5,30, 60 post HPE

Primary Outcome Measures

Name	Time	Method
Level 3-5 Toxicity	360 days post-HPE	Percentage of subjects with any level 3, 4, or 5 toxicity (per NCI CTEP grading system)
Adverse Events	360 days post-HPE	Percentage of subjects with other expected adverse events
Feasibility of IVIG Treatment	60 days post-HPE	Percentage of subjects for whom administration of IVIG is feasible, defined as the successful administration (at least 80% of each dose) of all 3 doses of IVIG
Serious Adverse Events	360 days post-HPE	Percentage of subjects with any serious adverse events (SAEs) prior to liver transplant
Acceptability of IVIG	60 days post-HPE	Percentage of subjects for whom the study is acceptable, defined as the ability of the subject's family or guardian to allow intravenous line placements, blood draws, and other study procedures for the study subjects.

Secondary Outcome Measures

Name	Time	Method
Good Bile Drainage at 180 Days Post-HPE	180 days post-HPE	Percentage of subjects who survive 180 days after HPE with both their native liver and serum total bilirubin \<1.5 mg/dL at 180 days after HPE
Good Bile Drainage at 360 Days Post-HPE	360 days post-HPE	Percentage of subjects who survive 360 days after HPE with both their native liver and serum total bilirubin \<1.5 mg/dL at 360 days after HPE
Transplant-free Survival	360 days post-HPE	Percentage of subjects who survive with their native liver at 360 days after HPE.
Good Bile Drainage at 90 Days Post-HPE	90 days post-HPE	Percentage of subjects who survive 90 days after HPE with both their native liver and serum total bilirubin \<1.5 mg/dL at 90 days after HPE
Circulating Regulatory T-Cells, Inflammatory Cytokines, and Specific Autoantibodies.	Over 360 days after HPE	Percentage and absolute number of Tregs (CD4+CD25+FoxP3+), CD3/4 T cells, CD3/8 T cells, NK cells (CD56), NK T cells (CD3/56), CD19/20 B cells, macrophages (CD14/11b), and neutrophils; plasma levels of anti-enolase antibody; and plasma cytokine levels (Th1/Th2 multiplex and IL17)

Locations (7): Children's Healthcare of Atlanta
🇺🇸
Atlanta, Georgia, United States
Children's Hospital Medical Center
🇺🇸
Cincinnati, Ohio, United States
Children's Hospital at Pittsburgh
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Pittsburgh, Pennsylvania, United States
Hospital for Sick Children
🇨🇦
Toronto, Ontario, Canada
Children's Hospital Colorado
🇺🇸
Aurora, Colorado, United States
Children's Hospital Los Angeles
🇺🇸
Los Angeles, California, United States
Children's Hospital of Philadelphia
🇺🇸
Philadelphia, Pennsylvania, United States