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Autologous Stem Cell Transplantation for Crohn's Disease

This study is currently recruiting participants.
Verified October 2017 by Paul Szabolcs, University of Pittsburgh
Sponsor:
ClinicalTrials.gov Identifier:
NCT00692939
First Posted: June 6, 2008
Last Update Posted: October 27, 2017
The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
Information provided by (Responsible Party):
Paul Szabolcs, University of Pittsburgh
  Purpose
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 young adult patients with severe Crohn's disease.

Condition Intervention Phase
Crohn's Disease Biological: autologous CD34-selected peripheral blood stem cells transplant Phase 1 Phase 2

Study Type: Interventional
Study Design: Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Autologous Stem Cell Transplantation With CD34 Selected Peripheral Blood Stem Cells (PBSC) in Pediatric and Young Adult Patients With Severe Crohn's Disease

Resource links provided by NLM:


Further study details as provided by Paul Szabolcs, University of Pittsburgh:

Primary Outcome Measures:
  • To evaluate the safety of administering high-dose immunotherapy followed by infusion of autologous CD34-selected peripheral blood stem cells (PBSC) in pediatric and young adult patients with severe Crohn's disease. [ Time Frame: 100 days ]

Secondary Outcome Measures:
  • To describe the pace of neutrophil and platelet recovery after the administration using ablative therapy and infusion of autologous CD34-selected PBSCs. [ Time Frame: 100 days ]
  • To evaluate the pace of reconstitution of immunity. [ Time Frame: 100 days ]
  • To evaluate long-term complications, such as sterility, endocrinopathy, and growth failure [ Time Frame: 5 years ]
  • To describe the immune function/profile of these patients pre-transplant and attempt to delineate patterns of immune dysfunction in patients with active advanced CD. [ Time Frame: yearly ]
  • To describe the effects of this therapy on the clinical manifestations of CD. [ Time Frame: yearly ]

Estimated Enrollment: 10
Actual Study Start Date: June 26, 2012
Estimated Study Completion Date: December 2020
Estimated Primary Completion Date: December 2019 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: 1
High-dose immunotherapy followed by infusion of autologous CD34-selected peripheral blood stem cells (PBSC)
Biological: autologous CD34-selected peripheral blood stem cells transplant
high-dose immunotherapy followed by infusion of autologous CD34-selected peripheral blood stem cells (PBSC)

Detailed Description:

Crohn's 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 Crohn's Disease, but one series by Farmer et al showed 6% mortality attributable to Crohn's 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 Crohn's 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 Crohn's 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 Crohn's 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.

  Eligibility

Information from the National Library of Medicine

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Ages Eligible for Study:   5 Years to 25 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Patients who have experienced significant morbidity and reduced quality of life secondary to active CD are eligible. In general, CDAI should be >250 or PCDAI should be >30.
  • Patients should be between the ages 5 to 25 years.
  • Patients may be maintained on the optimal combination of medical therapy to stabilize their disease before the administration of high dose cyclophosphamide.
  • Hematopoietic: Platelet count greater than 100,000/mm3. Absolute neutrophil count greater than 1500/mm3 at initial evaluation (unless secondary to 6MP therapy).
  • Renal: Creatinine no greater than 2.0 mg/dL at initial evaluation.
  • Cardiovascular: No history of coronary artery disease: no congestive heart failure, resting LVEF at least 40% or shortening fraction at least 26% at initial evaluation.
  • Pulmonary: FEV1/FVC at least 60% predicted for age; DLCO at least 60% predicted value for age at initial evaluation.
  • Fertile patients must agree to use appropriate contraceptive measures. These patients will also be counseled regarding the potential risks of infertility following cyclophosphamide therapy. They will be advised to discuss sperm banking or egg harvesting from the ovary.
  • Patients must have available full-time caregiver for entire course of treatment with adequate social support.

Exclusion Criteria:

  • Patients <5 years of age or >26 years of age.
  • Patients who have not been treated with adequate dosing of 6-MP, 5-aminosalicylate products and metronidazole.
  • Patients who sustained a decrement of 70 points on the CDAI or 15 points on the PCDAI, and maintain a CDAI < 250 and PCDAI < 30 after at least one 4 month course of prior anti-tumor necrosis factor alpha (infliximab).
  • Patient has localized area of Crohn's disease of intestine which is surgically correctable.
  • Patients with toxic megacolon, intestinal perforation
  • DLCO < 60% of normal value for age
  • Hepatic: Conjugated bilirubin greater than 2.0 mg/dL. Evidence of autoimmune chronic active hepatitis or sclerosing cholangitis
  • Patients with fever > 39o C or active infection within 1 week of stem cell mobilization and/or admission for conditioning regimen
  • Uncontrolled diabetes mellitus or other illness that would preclude study participation
  • Pregnancy or nursing mother
  • Massive splenomegaly
  • Presence of increased anesthetic risk if central line will be inserted or other procedure is expected to be performed under anesthesia.
  • HIV/HTLV seropositive, Hep B surface antigen positive, or HCV RNA positive by PCR
  Contacts and Locations
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): NCT00692939


Contacts
Contact: Paul Szabolcs, M.D. 412-692-6225 Paul.Szabolcs@chp.edu
Contact: Jason Rowan, RN 412-692-6195 jason.rowan@chp.edu

Locations
United States, Pennsylvania
Children's Hospital of Pittsburgh of UPMC Recruiting
Pittsburgh, Pennsylvania, United States, 15224
Contact: Jason Rowan, RN    412-692-6195    jason.rowan@chp.edu   
Principal Investigator: Paul Szabolcs, MD         
Sponsors and Collaborators
Paul Szabolcs
Investigators
Principal Investigator: Paul Szabolcs, MD Children's Hospital of Pittsburgh of UPMC
  More Information

Responsible Party: Paul Szabolcs, Chief, Division of Blood and Marrow Transplantation and Cell Therapy, University of Pittsburgh
ClinicalTrials.gov Identifier: NCT00692939     History of Changes
Other Study ID Numbers: PRO11090340
First Submitted: June 3, 2008
First Posted: June 6, 2008
Last Update Posted: October 27, 2017
Last Verified: October 2017
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Paul Szabolcs, University of Pittsburgh:
Stem cell transplantation
Crohn's Disease

Additional relevant MeSH terms:
Crohn Disease
Inflammatory Bowel Diseases
Gastroenteritis
Gastrointestinal Diseases
Digestive System Diseases
Intestinal Diseases