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

Primary Purpose

Biliary Atresia

Status

Completed

Phase

Phase 1

Locations

International

Study Type

Interventional

Intervention

Intravenous immunoglobulin (IVIG)

About this trial

This is an interventional treatment trial for Biliary Atresia focused on measuring Biliary atresia, Hepatic portoenterostomy, Intravenous immunoglobulin

Eligibility Criteria

3 Days - 120 Days (Child)All SexesDoes not accept healthy volunteers

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

Sites / Locations

Children's Hospital Los Angeles
Children's Hospital Colorado
Children's Healthcare of Atlanta
Children's Hospital Medical Center
Children's Hospital of Philadelphia
Children's Hospital at Pittsburgh
Hospital for Sick Children

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

IVIG active treatment

Arm Description

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

Outcomes

Primary Outcome Measures

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

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.

Serious Adverse Events

Percentage of subjects with any serious adverse events (SAEs) prior to liver transplant

Level 3-5 Toxicity

Percentage of subjects with any level 3, 4, or 5 toxicity (per NCI CTEP grading system)

Adverse Events

Percentage of subjects with other expected adverse events

Secondary Outcome Measures

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

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

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

Transplant-free Survival

Percentage of subjects who survive with their native liver at 360 days after 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)

Full Information

NCT ID

NCT01854827

First Posted

September 27, 2012

Last Updated

September 20, 2019

Sponsor

National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

1. Study Identification

Unique Protocol Identification Number

NCT01854827

Brief Title

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

Acronym

PRIME

Official Title

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

Study Type

Interventional

2. Study Status

Record Verification Date

September 2019

Overall Recruitment Status

Completed

Study Start Date

October 2013 (undefined)

Primary Completion Date

July 2016 (Actual)

Study Completion Date

July 2016 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

4. Oversight

Data Monitoring Committee

Yes

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Biliary Atresia

Keywords

Biliary atresia, Hepatic portoenterostomy, Intravenous immunoglobulin

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 1, Phase 2

Interventional Study Model

Single Group Assignment

Masking

None (Open Label)

Allocation

N/A

Enrollment

30 (Actual)

8. Arms, Groups, and Interventions

Arm Title

IVIG active treatment

Arm Type

Experimental

Arm Description

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

Intervention Type

Drug

Intervention Name(s)

Intravenous immunoglobulin (IVIG)

Other Intervention Name(s)

Gamunex-C®, Gamunex®

Intervention Description

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.

Primary Outcome Measure Information:

Title

Feasibility of IVIG Treatment

Description

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

Time Frame

60 days post-HPE

Title

Acceptability of IVIG

Description

Time Frame

60 days post-HPE

Title

Serious Adverse Events

Description

Percentage of subjects with any serious adverse events (SAEs) prior to liver transplant

Time Frame

360 days post-HPE

Title

Level 3-5 Toxicity

Description

Percentage of subjects with any level 3, 4, or 5 toxicity (per NCI CTEP grading system)

Time Frame

360 days post-HPE

Title

Adverse Events

Description

Percentage of subjects with other expected adverse events

Time Frame

360 days post-HPE

Secondary Outcome Measure Information:

Title

Good Bile Drainage at 90 Days Post-HPE

Description

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

Time Frame

90 days post-HPE

Title

Good Bile Drainage at 180 Days Post-HPE

Description

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

Time Frame

180 days post-HPE

Title

Good Bile Drainage at 360 Days Post-HPE

Description

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

Time Frame

360 days post-HPE

Title

Transplant-free Survival

Description

Percentage of subjects who survive with their native liver at 360 days after HPE.

Time Frame

360 days post-HPE

Title

Circulating Regulatory T-Cells, Inflammatory Cytokines, and Specific Autoantibodies.

Description

Time Frame

Over 360 days after HPE

10. Eligibility

Sex

All

Minimum Age & Unit of Time

3 Days

Maximum Age & Unit of Time

120 Days

Accepts Healthy Volunteers

Eligibility Criteria

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

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Ronald Sokol, MD

Organizational Affiliation

Children's Hospital Colorado

Official's Role

Study Chair

First Name & Middle Initial & Last Name & Degree

Ed Doo, MD

Organizational Affiliation

National Institute of Diabetes and Digestive and Kidney Disease (NIDDK)

Official's Role

Study Director

First Name & Middle Initial & Last Name & Degree

Averell Sherker, MD

Organizational Affiliation

National Institute of Diabetes and Digestive and Kidney Disease (NIDDK)

Official's Role

Study Director

Facility Information:

Facility Name

Children's Hospital Los Angeles

City

Los Angeles

State/Province

California

ZIP/Postal Code

90027

Country

United States

Facility Name

Children's Hospital Colorado

City

Aurora

State/Province

Colorado

ZIP/Postal Code

80045

Country

United States

Facility Name

Children's Healthcare of Atlanta

City

Atlanta

State/Province

Georgia

ZIP/Postal Code

30322

Country

United States

Facility Name

Children's Hospital Medical Center

City

Cincinnati

State/Province

Ohio

ZIP/Postal Code

45229

Country

United States

Facility Name

Children's Hospital of Philadelphia

City

Philadelphia

State/Province

Pennsylvania

ZIP/Postal Code

19104

Country

United States

Facility Name

Children's Hospital at Pittsburgh

City

Pittsburgh

State/Province

Pennsylvania

ZIP/Postal Code

15213

Country

United States

Facility Name

Hospital for Sick Children

City

Toronto

State/Province

Ontario

ZIP/Postal Code

M5G 1X8

Country

Canada

12. IPD Sharing Statement

Citations:

PubMed Identifier

30664564

Citation

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.

Results Reference

derived

Links:

URL

https://childrennetwork.org/

Description

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

Learn more about this trial

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

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