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De Novo Autoimmune Hepatitis in Pediatric Liver Transplantation

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ClinicalTrials.gov Identifier: NCT02056054
Recruitment Status : Recruiting
First Posted : February 5, 2014
Last Update Posted : May 31, 2019
Sponsor:
Information provided by (Responsible Party):
Yale University

Study Description
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Brief Summary:
The purpose of this study is to provide insights into the cause, development and effects of de novo autoimmune hepatitis so that prevention and treatment strategies can be developed in order to reduce post-liver transplant morbidity, the frequency of liver allograft loss and the need for re-transplantation.

Condition or disease Intervention/treatment
De Novo Autoimmune Hepatitis Other: Pediatric transplant subject with d-AIH Other: Pediatric transplant subject with acute rejection Other: Pediatric transplant subject with chronic rejection Other: Adult non-transplant patients with auto-immune hepatitis Other: Adult non-transplant subjects with chronic hepatitis C virus Other: Pediatric control subjects Other: Adult transplanted subjects with de novo autoimmune hepatitis

Detailed Description:

This is a multi-site study with Yale University as the coordinating site. Our research plan is as follows:

Aim 1: To conduct a refined phenotypical and functional analysis of regulatory T cells in study and control patient groups.

Rationale: We would like to extend our preliminary data observations in a larger patient group and use this extended data set to conduct a refined phenotypical and functional analysis of regulatory T cells in order to explore if the regulatory T cell phenotype and function in d-AIH differs: (A) from that in controls defined as (i) non-transplanted patients with autoimmune hepatitis (AIH), (ii) LT recipients with acute rejection, (iii) LT recipients with chronic rejection, (iv) non-transplanted patients with chronic hepatitis C; (B) according to the disease etiology leading to transplantation; (C) according to immunosuppressive regimen prior to diagnosis of d-AIH being made and (D) over time during the disease course. This could potentially give us some insight into the causes for immune tolerance breakdown in d-AIH.

Aim 2: To investigate how over expression of IL-17A and HDAC9 genes relates to the regulatory T cell defect observed in liver transplant recipients with d-AIH.

Rationale: Histone/protein deacetylases regulate chromatin remodeling, gene expression and the functions of many transcription factors. Acetylation of histones leads to an open chromatin structure permissive for the initiation of gene transcription and expression. Histone deacetylase inhibition by Trichostatin-A (TSA) has been demonstrated to prevent the production of IL-17A and sustain Foxp3 expression in human T-regs. Importantly, if differentiation of T-regs into a Th17-like phenotype can be inhibited by TSA in d-AIH, this might be of interest for the development of new therapeutic modalities.

We would like to first of all confirm our preliminary data observations in a larger patient population and address any concerns about RNA integrity in formalin fixed paraffin embedded tissue by using fresh liver biopsy tissue to assess the expression of genes involved in T-cell anergy and immune tolerance in LT recipients.

Study Design
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Study Type : Observational
Estimated Enrollment : 180 participants
Observational Model: Cohort
Time Perspective: Prospective
Official Title: De Novo Autoimmune Hepatitis in Pediatric Liver Transplantation
Study Start Date : March 2013
Estimated Primary Completion Date : May 2020
Estimated Study Completion Date : May 2021

Resource links provided by the National Library of Medicine


Groups and Cohorts
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Group/Cohort Intervention/treatment
Subjects with d-AIH
Pediatric transplant patients with de novo autoimmune hepatitis (d-AIH) will be enrolled at an outside center.
 Other: Pediatric transplant subject with d-AIH
30 ml of blood will be collected during periods of disease quiescence and activity in recipients with d-AIH who are enrolled. The exact number of blood draws will depend on the patient's pattern of disease activity. No more than one blood draw will take place during an 8-week period. The maximum amount of blood draws over the 2 year study period will be 8.
Subjects with Acute Rejection
Pediatric transplant patients with acute rejection will be enrolled at an outside center.
 Other: Pediatric transplant subject with acute rejection
Recipients with acute rejection will have blood drawn at time of diagnosis before treatment for rejection is instituted.
Subjects with Chronic Rejection
Pediatric transplant patients with chronic rejection will be enrolled at an outside center.
 Other: Pediatric transplant subject with chronic rejection
Recipients with chronic rejection will have blood drawn either at diagnosis before treatment is instituted or for those with ongoing chronic rejection at the time of enrollment.
Control Subjects
Healthy pediatric patients will be enrolled at the coordinating center (Yale).
 Other: Pediatric control subjects
2 tablespoons of blood (30 ml) will be collected at each blood draw over a 2-year period. . The maximum amount of blood draws will be 3 however there will be no more than 1 blood draw within an 8-week period.
Subjects with Auto-immune Hepatitis
Adult non-transplant patients with auto-immune hepatitis will be enrolled at the coordinating center (Yale).
 Other: Adult non-transplant patients with auto-immune hepatitis

75 ml of blood will be collected during periods of disease quiescence and activity in non transplanted subjects with AIH who are enrolled. Research blood draws will be drawn along with clinical blood draws.

The exact number of blood draws for each subject will depend on his or her pattern of disease activity. No more than one blood draw will take place during an 8-week period. The maximum amount of blood draws over the 2 year study period will be 8.

Liver tissue (2 mm) will be obtained at the time a clinically indicated liver biopsy is performed.

In the event that any enrolled subject undergoes liver transplantation, a portion of the explanted liver will be obtained and stored in special media.
Subjects with Chronic Hepatitis C Virus
Adult non-transplant patients with chronic hepatitis C will be enrolled at the coordinating center (Yale).
 Other: Adult non-transplant subjects with chronic hepatitis C virus

For enrolled patients with chronic hepatitis C, 75 ml of blood will be collected before the start of treatment. This will be a onetime blood draw prior to treatment. Liver tissue (2 mm) will be obtained at the time a clinically indicated liver biopsy is performed.

In the event that any enrolled patient undergoes liver transplantation, a portion of the explanted liver will be obtained and stored in special media.
Adult Subjects with d-AIH
Adult transplanted patients with de novo autoimmune hepatitis will be enrolled at the coordinating center (Yale).
 Other: Adult transplanted subjects with de novo autoimmune hepatitis
75 ml of blood will be collected during periods of disease quiescence and activity in recipients with d-AIH who are enrolled. The exact number of blood draws for each subject will depend on his or her pattern of disease activity. However, no more than one blood draw will take place during an 8-week period. The maximum amount of blood draws over the 2-year study period will be 8.


Outcome Measures
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Primary Outcome Measures :
  1. Liver Allograft Loss [ Time Frame: 3 years ]
    Assessment to determine the frequency of liver allograft loss.

  2. Need for Transplantation [ Time Frame: 3 years ]
    Assessment to determine the need for re-transplantation.


Eligibility Criteria
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Information from the National Library of Medicine

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Ages Eligible for Study:   3 Months and older   (Child, Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Sampling Method:   Non-Probability Sample
Study Population
Cohorts will be obtained from clinical settings and include pediatric and adult subjects. See eligibility criteria for detailed descriptions of the population.
Criteria

Inclusion Criteria:

Pediatric Transplant Patients

  • Is >3-months and <21 years of age and a recipient of a single organ liver transplant
  • Has allograft dysfunction (an ALT and/or GGTP > 2 times the upper limit of normal) due to acute rejection without a prior diagnosis of d-AIH
  • Has allograft dysfunction (an ALT and/or GGT > 2 times the upper limit of normal) due to chronic rejection without a prior diagnosis of d-AIH
  • Has a diagnosis of d-AIH

Healthy Pediatric Control Subjects (Enrolled at Yale)

  • Is ≥ 1-year and < 18-years of age
  • Not on any immune modulators
  • Not on steroid therapy
  • Has no underlying chronic inflammatory condition

Adult Control Subjects (Enrolled at Yale) Non-transplanted Adult patients with autoimmune hepatitis and chronic hepatitis C will also be enrolled.

  • Non-transplanted adults "18 Years or > " with Autoimmune Hepatitis
  • Non-transplanted adults "18 Years or > " with chronic hepatitis C who are treatment naive.

Exclusion Criteria:

Pediatric Transplant Patients - Multi-visceral organ transplant recipient

Healthy Pediatric Control Subjects (Enrolled at Yale)

  • <1-year and > 18-years of age
  • Has chronic inflammatory condition
  • On immune modulators or steroids
  • On chronic medication(s)

Adult transplanted patients with d-AIH (enrolled at Yale)

- Transplanted Adults ≥21-years of age with a diagnosis of d-AIH

Contacts and Locations
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02056054


Contacts
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Contact: Udeme Ekong, MD, MPH 203-785-4649 udeme.ekong@yale.edu

Locations
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United States, Connecticut
Yale University School of Medicine Recruiting
New Haven, Connecticut, United States, 06520
Contact: Udeme Ekong, MD, MPH    203-785-4649    udeme.ekong@yale.edu   
Contact: Danielle Paquette, CCRP    203-785-7526    danielle.paquette@yale.edu   
Principal Investigator: Udeme Ekong, MD, MPH         
Sponsors and Collaborators
Yale University
Investigators
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Principal Investigator: Udeme Ekong, MD, MPH Yale University
More Information
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Responsible Party: Yale University
ClinicalTrials.gov Identifier: NCT02056054    
Other Study ID Numbers: 1302011561
First Posted: February 5, 2014    Key Record Dates
Last Update Posted: May 31, 2019
Last Verified: May 2019
Keywords provided by Yale University:
Autoimmune hepatitis
Liver transplantation
Hepatitis C
Additional relevant MeSH terms:
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Hepatitis A
Hepatitis
Hepatitis, Autoimmune
Liver Diseases
Digestive System Diseases
Hepatitis, Viral, Human
Virus Diseases
 Enterovirus Infections
Picornaviridae Infections
RNA Virus Infections
Hepatitis, Chronic
Autoimmune Diseases
Immune System Diseases