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

Study Overview
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Brief Summary
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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
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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.

Official Title
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A Phase 1/2A Trial of Intravenous Immunoglobulin (IVIG) Therapy Following Portoenterostomy in Infants With Biliary Atresia

Conditions
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Biliary Atresia

Intervention / Treatment
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* Drug: Intravenous immunoglobulin (IVIG)


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 3 Days
Maximum Age: 120 Days

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: IVIG active treatment<br>Intravenous immunoglobulin (IVIG) 10% 1 gm/kg body weight/dose Day 3-5,30, 60 post HPE | Drug: Intravenous immunoglobulin (IVIG)<br>* All participants will receive the same dose of IVIG at the same intervals in an open-label fashion as long as the subject does not have any increased risk for toxicity for any IVIG infusion. IVIG will be initiated on day 3 (up to day 5) after HPE surgery (HPE is day 0) at a dose of 1 gm/kg body weight by slow intravenous infusion over at least 4 hours. The same dose (1 gm/kg) and duration of infusion will be repeated on day 30 and day 60 after HPE.<br>* Other names: Gamunex®;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Feasibility of IVIG Treatment | 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 | 60 days post-HPE | 
| Acceptability of IVIG | 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. | 60 days post-HPE | 
| Serious Adverse Events | Percentage of subjects with any serious adverse events (SAEs) prior to liver transplant | 360 days post-HPE | 
| Level 3-5 Toxicity | Percentage of subjects with any level 3, 4, or 5 toxicity (per NCI CTEP grading system) | 360 days post-HPE | 
| Adverse Events | Percentage of subjects with other expected adverse events | 360 days post-HPE | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Good Bile Drainage at 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 | 90 days post-HPE | 
| Good Bile Drainage at 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 | 180 days post-HPE | 
| Good Bile Drainage at 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 | 360 days post-HPE | 
| Transplant-free Survival | Percentage of subjects who survive with their native liver at 360 days after HPE. | 360 days post-HPE | 
| Circulating Regulatory T-Cells, Inflammatory Cytokines, and Specific Autoantibodies. | 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) | Over 360 days after HPE | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Biliary atresia, Hepatic portoenterostomy, Intravenous immunoglobulin