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Autologous Stem Cell Transplantation for Crohn's Disease

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ClinicalTrials.gov Identifier: NCT00692939
Recruitment Status : Recruiting
First Posted : June 6, 2008
Last Update Posted : February 5, 2021
Sponsor:
Information provided by (Responsible Party):
Paul Szabolcs, University of Pittsburgh

Tracking Information
First Submitted Date  ICMJE June 3, 2008
First Posted Date  ICMJE June 6, 2008
Last Update Posted Date February 5, 2021
Actual Study Start Date  ICMJE June 26, 2012
Estimated Primary Completion Date December 2025   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: January 29, 2018)
  • Number of participants with regimen-related toxicities. [ Time Frame: From baseline to 24 months post bone marrow transplant ]
  • Number of participants with life-threatening infections. [ Time Frame: From baseline to 24 months post bone marrow transplant ]
  • Change and duration in the Harvey Bradshaw Index (HBI). [ Time Frame: Change from Baseline to 24 months post Bone Marrow Transplant ]
  • Change and duration in the Crohn's Disease Activity Index (CDAI). [ Time Frame: Change from Baseline to 24 months post Bone Marrow Transplant ]
  • Change and duration in the Pediatric Crohn's Disease Activity Index (PCDAI). [ Time Frame: Change from Baseline to 24 months post Bone Marrow Transplant ]
Original Primary Outcome Measures  ICMJE
 (submitted: June 5, 2008)
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 ]
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: August 23, 2018)
  • Number of days it takes for Absolute Neutrophil Count (ANC) to reach greater than 500. [ Time Frame: 3 consecutive days once ANC is greater than 500. ]
  • Number of days it takes for Platelet count to reach greater than 20,000/mm3 [ Time Frame: From baseline to 24 months post Bone Marrow Transplant. ]
  • Number of days it takes for T cell Recovery [ Time Frame: 24 months post Bone Marrow Transplant ]
  • Number of participants who have long term cardiac complications [ Time Frame: 24 months post Bone Marrow Transplant ]
  • Number of participants who have long term endocrine complications [ Time Frame: 24 months post Bone Marrow Transplant ]
  • Number of participants with active advanced Crohn's disease who have immune dysregulation evolution and correction. [ Time Frame: From Baseline to 24 months post bone marrow transplant ]
  • Biomarker identification for relapse [ Time Frame: From baseline to 24 months post bone marrow transplant ]
Original Secondary Outcome Measures  ICMJE
 (submitted: June 5, 2008)
  • 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 ]
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Autologous Stem Cell Transplantation for Crohn's Disease
Official Title  ICMJE Autologous Stem Cell Transplantation With CD34-Selected Peripheral Blood Stem Cells (PBSC) in Pediatric and Adult Patients With Severe Crohn's Disease
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 Crohn's disease.
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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Phase 2
Study Design  ICMJE Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Crohn's Disease
Intervention  ICMJE
  • Biological: autologous CD34-selected peripheral blood stem cells transplant
    high-dose immunotherapy followed by infusion of autologous CD34-selected peripheral blood stem cells (PBSC)
  • Drug: Alemtuzumab
    Transplant conditioning
    Other Name: Campath-1H
  • Drug: ATG
    Transplant conditioning
    Other Name: Anti-thymocyte globulin, rabbit; Thymoglobulin
  • Drug: Melphalan
    Transplant conditioning
    Other Name: L-phenylalanine mustard, phenylalanine mustard, L-PAM, or L-sarcolysin
  • Drug: Thiotepa
    Transplant conditioning
  • Drug: Rituximab
    Transplant conditioning
    Other Name: Rituxan
  • Drug: Cyclophosphamide
    Mobilization
    Other Name: Cytoxan
  • Drug: G-CSF
    Mobilization
    Other Name: Neupogen, Granix, Zarxio, Filgrastim
  • Drug: Mesna
    Mobilization
Study Arms  ICMJE Experimental: 1
High-dose immunotherapy followed by infusion of autologous CD34-selected peripheral blood stem cells (PBSC)
Interventions:
  • Biological: autologous CD34-selected peripheral blood stem cells transplant
  • Drug: Alemtuzumab
  • Drug: ATG
  • Drug: Melphalan
  • Drug: Thiotepa
  • Drug: Rituximab
  • Drug: Cyclophosphamide
  • Drug: G-CSF
  • Drug: Mesna
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: July 18, 2018)
20
Original Estimated Enrollment  ICMJE
 (submitted: June 5, 2008)
10
Estimated Study Completion Date  ICMJE December 2026
Estimated Primary Completion Date December 2025   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

5.1 Inclusion Criteria

  1. Subject and/or guardian must be able to understand and provide informed consent.
  2. Male or female, 10 through 60 years old, inclusive at time of informed consent.
  3. Examples of subjects for whom stem cell transplant therapy would be appropriate include, but are not limited to:

    • Patients who have had prior surgery and subsequent severe recurrent disease in spite of aggressive maintenance therapy, necessitating consideration of further extensive surgical resections.
    • Patients who have diffuse small bowel and colonic disease and who are refractory to aggressive medical treatment, and not eligible for treatment using a surgical approach without the risk of precipitating short bowel syndrome and dependence of parenteral nutrition or who have other conditions that preclude surgery
    • Patients with a persistently high Harvey Bradshaw Index (HBI) (>6), CDAI (>250) or Pediatric CD Activity Index (PCDAI>45) (44) score or those in the lower, moderate range (HBI ≤ 6), (CDAI < 250), (PCDAI 30-45), but who are dependent on daily doses of corticosteroids, that are unable to be withdrawn, and aggressive medical treatment to maintain moderate disease status.
    • Patients who have resistant complications of CD unresponsive to medical management including multiple enteric fistulas, enterovesicular or enterovaginal fistulas, severe perianal disease, debilitating arthritis, severe skin lesions (pyoderma), and severe bony complications of the disease and therapy (aseptic necrosis, pathologic fractures).
    • Patients who developed severe complications to while receiving medical management such as pancreatitis following 6-Mercaptopurine, colitis following 5-ASA or those with severe hypersensitivity to TNFalpha inhibitors (infliximab, adalimumab, certolizumab pegol), anti-integrin agents (natalizumab, vedolizumab) or anti-IL12/23 agents (ustekinumab).
    • Patients with stomas are eligible.
  4. No surgical therapeutic option secondary to risk of short bowel syndrome or patient refusal.
  5. Harvey Bradshaw Index (HBI) or CD activity score >5, CDAI >250 or PCDAI >30.
  6. Platelet count greater than 100,000/mm3.
  7. Absolute neutrophil count greater than 1500/mm3 (unless secondary to 6MP therapy).
  8. Creatinine ≤ 2.0 mg/dL.
  9. No history of coronary artery disease; resting LVEF ≥ 40% or shortening fraction ≥ 26%.
  10. FEV1/FVC ≥ 60% predicted for age; DLCO ≥ 60% predicted value for age.
  11. Negative pregnancy test for females ≥ 10 years old or who have reached menarche, unless surgically sterilized.
  12. All females or childbearing potential and sexually active males must agree to use a FDA approved method of birth control for up to 24 months after PBSC transplant or for as long as they are taking any medication that may harm a pregnancy, an unborn child or may cause a birth defect.

5.2 Exclusion Criteria

  1. Patients who have not been treated with adequate dosing of 6-MP, 5-ASA products and metronidazole.
  2. Patients who achieved a sustained, corticosteroid free response to anti-TNF alpha therapy, anti-integrin therapy or anti-IL12/23 therapy after a 4 month course of treatment.
  3. Toxic megacolon, intestinal perforation
  4. Conjugated bilirubin > 2.0 mg/dL.
  5. Pregnancy or nursing mother
  6. HIV/HTLV seropositive, HBsAg, or HCV RNA positive by PCR
  7. Active infection, as determined by the appropriate confirmatory testing e.g. blood cultures, PCR testing, etc., within two weeks of mobilization and high dose chemotherapy.
  8. Past or current medical problems or findings from physical examination or laboratory testing that are not listed above, which, in the opinion of the investigator, may pose additional risks from participation in the study, may interfere with the participant's ability to comply with study requirements or that may impact the quality or interpretation of the data obtained from the study.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 10 Years to 60 Years   (Child, Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Shawna H McIntyre, RN 412-692-5552 ext 4126925552 mcintyresm@upmc.edu
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT00692939
Other Study ID Numbers  ICMJE PRO11090340
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party Paul Szabolcs, University of Pittsburgh
Study Sponsor  ICMJE Paul Szabolcs
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Paul Szabolcs, MD University of Pittsburgh
PRS Account University of Pittsburgh
Verification Date February 2021

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP