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

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

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.

Study Overview

• Status: Completed
• Conditions: Biliary Atresia
• Intervention / Treatment: Drug: Intravenous immunoglobulin (IVIG)

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.

• Study Type: Interventional
• Enrollment (Actual): 30
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• Canada
  • Ontario
    • Toronto, Ontario, Canada, M5G 1X8
      • Hospital for Sick Children
• United States
  • California
    • Los Angeles, California, United States, 90027
      • Children's Hospital Los Angeles
  • Colorado
    • Aurora, Colorado, United States, 80045
      • Children's Hospital Colorado
  • Georgia
    • Atlanta, Georgia, United States, 30322
      • Children's Healthcare of Atlanta
  • Ohio
    • Cincinnati, Ohio, United States, 45229
      • Children's Hospital Medical Center
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • Children's Hospital of Philadelphia
    • Pittsburgh, Pennsylvania, United States, 15213
      • Children's Hospital at Pittsburgh

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 3 days to 3 months (Child)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

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

Drug: Intravenous immunoglobulin (IVIG); 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.; Other Names: Gamunex®; Gamunex-C®

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
• Investigators: Study Chair: Ronald Sokol, MD, Children's Hospital Colorado; Study Director: Ed Doo, MD, National Institute of Diabetes and Digestive and Kidney Disease (NIDDK); Study Director: Averell Sherker, MD, National Institute of Diabetes and Digestive and Kidney Disease (NIDDK)

Publications and helpful links

General Publications

• Mack CL, Spino C, Alonso EM, Bezerra JA, Moore J, Goodhue C, Ng VL, Karpen SJ, Venkat V, Loomes KM, Wang K, Sherker AH, Magee JC, Sokol RJ; The ChiLDReN Network. A Phase I/IIa Trial of Intravenous Immunoglobulin Following Portoenterostomy in Biliary Atresia. J Pediatr Gastroenterol Nutr. 2019 Apr;68(4):495-501. doi: 10.1097/MPG.0000000000002256.

Helpful Links

• Click here for more information about the Children Liver Disease Research and Education Network (ChiLDREN)

Study record dates

Study Major Dates

• Study Start: October 1, 2013
• Primary Completion (Actual): July 1, 2016
• Study Completion (Actual): July 1, 2016

Study Registration Dates

• First Submitted: September 27, 2012
• First Submitted That Met QC Criteria: May 13, 2013
• First Posted (Estimate): May 16, 2013

Study Record Updates

• Last Update Posted (Actual): October 1, 2019
• Last Update Submitted That Met QC Criteria: September 20, 2019
• Last Verified: September 1, 2019

More Information

Terms related to this study

• Keywords: Intravenous immunoglobulin; Biliary atresia; Hepatic portoenterostomy
• Additional Relevant MeSH Terms: Digestive System Diseases; Congenital Abnormalities; Biliary Tract Diseases; Bile Duct Diseases; Digestive System Abnormalities; Biliary Atresia; Physiological Effects of Drugs; Immunologic Factors; Antibodies; Immunoglobulins; Immunoglobulins, Intravenous; gamma-Globulins; Rho(D) Immune Globulin
• Other Study ID Numbers: P007 PRIME; U01DK062456 (U.S. NIH Grant/Contract)