Graft vs Host Disease Clinical Trial
— BioGvHDOfficial title:
Toward Immune Biomarkers for Tolerance and GvHD in Humans
Verified date | February 2019 |
Source | Assistance Publique - Hôpitaux de Paris |
Contact | n/a |
Is FDA regulated | No |
Health authority | |
Study type | Observational |
Graft-versus-Host Disease (GVHD), is the most frequent and severe complication of allogeneic
hematopoietic stem cell transplantation (HSCT). Much of our knowledge on the pathophysiology
of GVHD has been gained from experimental models but far less from the study of the disease
in humans. Recent developments in basic biology open new avenues to the development of
biomarker sets that could predict GVHD severity and prognosis that could be tested and
validated through well-designed multicenter clinical trials.
The main goal of this project is to further our understanding of the pathogenic mechanisms of
human GVHD on one hand, and of functional immune tolerance on the other. Furthermore, this
study aims at setting up a clinically relevant biomarker set in human GVHD and immune
tolerance in a discovery cohort.
The objectives of this project are:
1. To define phenotypic, functional and molecular correlates of acute GVHD early after
HSCT/at its onset 2. To study thymic reconstitution and the T-cell repertoire after HSCT
during period 2 3. To identify functional and molecular correlates of immune tolerance in
long-term survivors of HSCT 4. Preparing for biomarker validation into a clinical trial We
propose a prospective analysis of a cohort of 680 patients transplanted from an HLA-identical
sibling donor at Saint Louis hospital. Analyses will be performed during 3 critical,
clinically relevant, periods.
1. Period 1: Analysis at the onset of GVHD, or at the time of engraftment 30 days after
HSCT in patients not developing GVHD. An additional blood sample will also be analyzed
90 days after HSCT.
2. Period 2: Thymic function analysis using measurements of T-cell receptor excision
circles (TREC) will be performed at 6 and 12 months post-transplant for all patients.
T-cell receptor analysis on sorted T-cell populations will be performed by NGS.
3. Period 3: In "tolerant" patients (patients more than 2 years after HSCT not requiring
immunosuppressive treatment), or in patients still requiring immunosuppressive therapy
after 2 years. We will also analyze the corresponding immune parameters for each donor.
The longitudinal design of this study will allow us to provide an integrated view of GVHD
pathophysiology and mechanisms of immune tolerance in human.
Prospectively identified phenotypic, molecular or functional biomarkers will then be tested,
in a subsequent study, from biological materials prospectively collected within the French
wide CryoStem cohort. Thus, as the final task of this project, we will perform statistical
analyses taking into account confounding clinical variables influencing the outcome (i.e.
GVHD-related death or tolerance). Preparing for a clinical trial will need moving from
classical Bioinformatics analyses into clinically relevant statistical analyses that include
sequential biological measurement in the discovery set cohort. Main points that will be taken
into accounts for this task are the followings;
1. Transplant-related mortality (TRM) can be estimated in the range of 20%; 2year
post-allogeneic HSCT
2. TRM is mostly (even if totally) due to GVHD and its associated immune deficiency
3. GVHD cumulative incidence can be estimated in the range of 40%
4. 80 patients will be prospectively studied and 30 patients will be analyzed (cross
sectional study) for part 3 only.
5. Since GVHD-related mortality and tolerance are mutually exclusive situation the optimal
calculation for the validation cohort can be expected
6. This calculation will be the basis for the proposal of an interventional clinical trial.
Status | Active, not recruiting |
Enrollment | 60 |
Est. completion date | October 2020 |
Est. primary completion date | February 2019 |
Accepts healthy volunteers | No |
Gender | All |
Age group | N/A and older |
Eligibility |
Inclusion Criteria: - Patients transplanted from an HLA-identical sibling donor Exclusion Criteria: |
Country | Name | City | State |
---|---|---|---|
France | Hopital siant-Louis | Paris |
Lead Sponsor | Collaborator |
---|---|
Assistance Publique - Hôpitaux de Paris | National Research Agency, France |
France,
Type | Measure | Description | Time frame | Safety issue |
---|---|---|---|---|
Primary | acute Graft-versus-Host Disease (GVHD) early after allogeneic hematopoietic stem cell transplantation (HSCT) | 30 days |
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