- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT02056054
De Novo Autoimmune Hepatitis in Pediatric Liver Transplantation
Study Overview
Status
Conditions
Intervention / Treatment
- Other: Pediatric transplant subject with d-AIH
- Other: Pediatric transplant subject with acute rejection
- Other: Pediatric transplant subject with chronic rejection
- Other: Pediatric control subjects
- Other: Adult non-transplant patients with auto-immune hepatitis
- Other: Adult non-transplant subjects with chronic hepatitis C virus
- 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 Type
Enrollment (Actual)
Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Genders Eligible for Study
Sampling Method
Study Population
Description
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
Study Plan
How is the study designed?
Design Details
Cohorts and Interventions
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.
|
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.
|
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.
|
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).
|
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).
|
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).
|
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).
|
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.
|
What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Liver Allograft Loss
Time Frame: 3 years
|
Assessment to determine the frequency of liver allograft loss.
|
3 years
|
Need for Transplantation
Time Frame: 3 years
|
Assessment to determine the need for re-transplantation.
|
3 years
|
Collaborators and Investigators
Sponsor
Study record dates
Study Major Dates
Study Start (ACTUAL)
Primary Completion (ACTUAL)
Study Completion (ACTUAL)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (ESTIMATE)
Study Record Updates
Last Update Posted (ACTUAL)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Additional Relevant MeSH Terms
Other Study ID Numbers
- 1302011561
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
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