Ignite Creation Date:
2024-05-05 @ 7:34 PM
Last Modification Date:
2024-10-26 @ 9:50 AM
Study NCT ID:
NCT00692939
Status:
RECRUITING
Last Update Posted:
2024-02-14
First Post:
2008-06-03
Brief Title:
Autologous Stem Cell Transplantation for Crohns Disease
Sponsor:
Paul Szabolcs
Organization:
University of Pittsburgh
Study Overview
Official Title:
Autologous Stem Cell Transplantation With CD34-Selected Peripheral Blood Stem Cells PBSC in Pediatric and Adult Patients With Severe Crohns Disease
Status:
RECRUITING
Status Verified Date:
2024-02
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief Summary:
The objective of this study is to evaluate the safety and effectiveness of administering high-dose chemotherapy followed by infusion of autologous CD34-selected peripheral blood stem cells PBSC in pediatric and adult patients with severe Crohns disease
Detailed Description:
Crohns disease is considered to be an immune-mediated disease of the intestinal tract typically treated using immune modulating or immune suppressive therapies These treatments include local anti-inflammatory agents such as 5 aminosalicylic acid products broad immune suppression using corticosteroids azathioprine or methotrexate cytokine suppression such as antibody against TNFα IL-12 and antibiotics such as ciprofloxacin and metronidazole that work by decreasing the putative antigen exposure to the intestine There is little in the literature available on mortality data related to Crohns Disease but one series by Farmer et al showed 6 mortality attributable to Crohns disease The mortality rate for selective patients with refractory and severe disease is probably higher
This protocol is based on the premise that the sustained inflammation of the GI tract that is characteristic of Crohns disease is the result of defective mucosal T cell tolerance The mucosal tolerance is normally maintained by CD4 T cells characterized as T helper 3 Th3 and T regulatory 1 TR1 T cell clones producing TGFβ and IL-10 respectively There has been much speculation on a possible infectious etiology of IBD implicating primarily mycobacterial organisms though despite extensive research no pathogenic organisms have definitively been identified In genetic cytokine knockout animal models of IBD the typical nonpathogenic enteric flora is sufficient to induce a chronic inflammatory reaction Autoreactive T cells appear to have broken through the mucosal tolerance with characteristic T helper 1 cytokine profile secreting IL-1 and IFNγ
In theory the most efficient approach to eradicate autoimmune T cell clones is through replacement of the defective immune system with hematopoietic stem cells HSC from a healthy allogeneic donor However the risks of morbidity and mortality associated with allogeneic HSC transplantation currently do not appear to be justified even in treatment of refractory cases of Crohns disease An alternative approach is to use autologous HSC from which potential autoreactive T-cells have been eliminated based on the hypothesis that from the T-cell depleted autologous graft reconstitution of normal immunity will occur without regeneration of autoimmune clones Pilot trials in Crohns and other autoimmune diseases have confirmed the validity of this hypothesis T-cells in the CD34 selected PBSC product are significantly depleted If active disease recurs despite intensive immunoablation it is likely that either CD34 selection did not adequately remove cells responsible for the autoreactive state or that the emerging genetically predisposed immune system was re-exposed to autoantigens
Unlike allogeneic transplants the autologous transplant approach has greatly reduced morbidity and mortality due to the absence of graft rejection and graft versus host disease reactions Currently autologous HSCT demonstrate that transplant-related mortality is around 5 when transplanted for acute leukemia
This protocol is based on the premise that the sustained inflammation of the GI tract that is characteristic of Crohns disease is the result of defective mucosal T cell tolerance The mucosal tolerance is normally maintained by CD4 T cells characterized as T helper 3 Th3 and T regulatory 1 TR1 T cell clones producing TGFβ and IL-10 respectively There has been much speculation on a possible infectious etiology of IBD implicating primarily mycobacterial organisms though despite extensive research no pathogenic organisms have definitively been identified In genetic cytokine knockout animal models of IBD the typical nonpathogenic enteric flora is sufficient to induce a chronic inflammatory reaction Autoreactive T cells appear to have broken through the mucosal tolerance with characteristic T helper 1 cytokine profile secreting IL-1 and IFNγ
In theory the most efficient approach to eradicate autoimmune T cell clones is through replacement of the defective immune system with hematopoietic stem cells HSC from a healthy allogeneic donor However the risks of morbidity and mortality associated with allogeneic HSC transplantation currently do not appear to be justified even in treatment of refractory cases of Crohns disease An alternative approach is to use autologous HSC from which potential autoreactive T-cells have been eliminated based on the hypothesis that from the T-cell depleted autologous graft reconstitution of normal immunity will occur without regeneration of autoimmune clones Pilot trials in Crohns and other autoimmune diseases have confirmed the validity of this hypothesis T-cells in the CD34 selected PBSC product are significantly depleted If active disease recurs despite intensive immunoablation it is likely that either CD34 selection did not adequately remove cells responsible for the autoreactive state or that the emerging genetically predisposed immune system was re-exposed to autoantigens
Unlike allogeneic transplants the autologous transplant approach has greatly reduced morbidity and mortality due to the absence of graft rejection and graft versus host disease reactions Currently autologous HSCT demonstrate that transplant-related mortality is around 5 when transplanted for acute leukemia
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
True
Is a FDA Regulated Device?:
False
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None