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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 11, 2022
Information provided by (Responsible Party):
Paul Szabolcs, University of Pittsburgh

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.

Condition or disease Intervention/treatment Phase
Crohn's Disease 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 Phase 1 Phase 2

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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 20 participants
Allocation: N/A
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 Adult Patients With Severe Crohn's Disease
Actual Study Start Date : June 26, 2012
Estimated Primary Completion Date : December 2025
Estimated Study Completion Date : December 2026

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Crohn's Disease

Arm Intervention/treatment
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)

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
Other Name: Cytoxan

Drug: G-CSF
Other Name: Neupogen, Granix, Zarxio, Filgrastim

Drug: Mesna

Primary Outcome Measures :
  1. Number of participants with regimen-related toxicities. [ Time Frame: From baseline to 24 months post bone marrow transplant ]
  2. Number of participants with life-threatening infections. [ Time Frame: From baseline to 24 months post bone marrow transplant ]
  3. Change and duration in the Harvey Bradshaw Index (HBI). [ Time Frame: Change from Baseline to 24 months post Bone Marrow Transplant ]
  4. Change and duration in the Crohn's Disease Activity Index (CDAI). [ Time Frame: Change from Baseline to 24 months post Bone Marrow Transplant ]
  5. Change and duration in the Pediatric Crohn's Disease Activity Index (PCDAI). [ Time Frame: Change from Baseline to 24 months post Bone Marrow Transplant ]

Secondary Outcome Measures :
  1. 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. ]
  2. 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. ]
  3. Number of days it takes for T cell Recovery [ Time Frame: 24 months post Bone Marrow Transplant ]
  4. Number of participants who have long term cardiac complications [ Time Frame: 24 months post Bone Marrow Transplant ]
  5. Number of participants who have long term endocrine complications [ Time Frame: 24 months post Bone Marrow Transplant ]
  6. 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 ]
  7. Biomarker identification for relapse [ Time Frame: From baseline to 24 months post bone marrow transplant ]

Information from the National Library of Medicine

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Ages Eligible for Study:   10 Years to 60 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

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.

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

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Contact: Shawna H McIntyre, RN 412-692-5552 ext 4126925552 mcintyresm@upmc.edu

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United States, Pennsylvania
UPMC Prebyterian- Adult Gastroenterology Recruiting
Pittsburgh, Pennsylvania, United States, 15213
Contact: David Binion, MD    412-383-6968    binion@pitt.edu   
Contact: Beata Pasek, RN    412-648-6995    BBP10@pitt.edu   
Children's Hospital of Pittsburgh of UPMC-Bone Marrow Team Recruiting
Pittsburgh, Pennsylvania, United States, 15224
Contact: Shawna H McIntyre, RN    412-692-5552    mcintyresm@upmc.edu   
Principal Investigator: Paul Szabolcs, MD         
Sponsors and Collaborators
Paul Szabolcs
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Principal Investigator: Paul Szabolcs, MD University of Pittsburgh
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Responsible Party: Paul Szabolcs, Chief, Division of Blood and Marrow Transplantation and Cell Therapy, University of Pittsburgh
ClinicalTrials.gov Identifier: NCT00692939    
Other Study ID Numbers: PRO11090340
First Posted: June 6, 2008    Key Record Dates
Last Update Posted: February 11, 2022
Last Verified: February 2022
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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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:
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Crohn Disease
Inflammatory Bowel Diseases
Gastrointestinal Diseases
Digestive System Diseases
Intestinal Diseases
Antilymphocyte Serum
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antirheumatic Agents
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Myeloablative Agonists
Antineoplastic Agents, Immunological