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Biochemical Correction of Severe EB by Allo HSCT and "Off-the-shelf" MSCs

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. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT01033552
Recruitment Status : Completed
First Posted : December 16, 2009
Last Update Posted : February 8, 2023
Sponsor:
Information provided by (Responsible Party):
Masonic Cancer Center, University of Minnesota

Tracking Information
First Submitted Date  ICMJE December 14, 2009
First Posted Date  ICMJE December 16, 2009
Last Update Posted Date February 8, 2023
Actual Study Start Date  ICMJE January 2010
Actual Primary Completion Date August 12, 2021   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: June 14, 2017)
Event-free survival rate [ Time Frame: 1 year and 2 Years Post-transplant ]
Event-free survival rate, with an event defined as death or failure to have a demonstrable increase in collagen, laminin, intergrin, keratin or plakin deposition.
Original Primary Outcome Measures  ICMJE
 (submitted: December 14, 2009)
Event-free survival [ Time Frame: 1 year and 2 Years Post-transplant ]
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: February 25, 2022)
  • Transplant-related mortality (TRM) [ Time Frame: 180 Days Post Transplant ]
    Incidence of transplant-related mortality (TRM)
  • Pattern of biochemical improvement [ Time Frame: Through 1 Year Post-Transplant ]
    Describe pattern of biochemical improvement as measured by an increase in protein expression (collagen, laminin, integrin, keratin, or plakin) and related structural and physical changes
  • Measure patients Quality of Life using a questionnaire [ Time Frame: Pretreatment, Day 100, 6 months, 1 and 2 years ]
    Health quality of life questionnaire or iscorEB as compared to pretreatment results
  • Durability of HSC and third party MSC engraftment in the skin [ Time Frame: 100 Days ]
    Incidence of HSC and third party MSC engraftment in the skin
  • Probability of Survival [ Time Frame: 1 Year ]
    Number of surviving patients one year after engraftment
  • Number of participants experiencing Acute GVHD [ Time Frame: 100 Days ]
    Incidence of acute GCHD
Original Secondary Outcome Measures  ICMJE
 (submitted: December 14, 2009)
  • Incidence of transplant-related mortality (TRM) [ Time Frame: 180 Days Post Transplant ]
  • Pattern of biochemical improvement measured by increase in protein expression (collagen, laminin, integrin or plakin) [ Time Frame: Through 1 Year Post-Transplant ]
  • Quality of Life [ Time Frame: Pretreatment, Day 365 and Day 730 ]
  • Overall Survival [ Time Frame: 6 Months, 1 Year and 2 Years Post-Transplant ]
  • Pattern and durability of hematopoietic stem cell transplant [ Time Frame: 6 Months, 1 Year and 2 Years Post-transplant ]
  • Mesenchymal stem cell (MSC) transplant engraftment [ Time Frame: Day 28, 60 and 100, 6 months, 1 year and 2 Years Post Transplant ]
  • Incidence of Acute and Chronic Graft Versus Host Disease [ Time Frame: Day 100, 6 Months, 1 Year and 2 Years Post-Transplant ]
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Biochemical Correction of Severe EB by Allo HSCT and "Off-the-shelf" MSCs
Official Title  ICMJE MT2009-09: Biochemical Correction of Severe Epidermolysis Bullosa by Allogeneic Stem Cell Transplantation and "Off-the-shelf" Mesenchymal Stem Cells
Brief Summary This is an open-label, single institution, phase II study in patients with epidermolysis bullosa (EB). The underlying hypothesis is that the infusion of bone marrow or umbilical cord blood from a healthy unaffected donor will correct the collagen, laminin, integrin, or plakin deficiency and reduce the skin fragility characteristic of severe forms of EB. A secondary hypothesis is that mesenchymal stem cells from a healthy donor will enhance the safety and efficacy of the allogeneic hematopoietic stem cell transplant as well as serve as a source of renewable cells for the treatment of focal areas of residual blistering.
Detailed Description

The primary objective of this study is to estimate the event-free survival rate by 1 year post-transplant with an event defined as a death or failure to have a demonstrable increase in collagen, laminin, integrin, keratin or plakin deposition by 1 year post-transplant or other biochemical, structural or physical measure of improvement.

The secondary objectives of this study are to i) determine the incidence of transplant-related mortality (TRM) at 180 days; ii) describe the pattern of biochemical improvement as measured by an increase in protein expression (collagen, laminin, integrin, keratin or plakin) and related structural and physical changes; iii) describe health quality of life at day 365 and 730 as compared to pretreatment results; iv) describe the pattern and durability of HSC and third party MSC engraftment in the skin; v) determine the probability of survival at 1 year.

Patients with severe epidermolysis bullosa will be screened to meet the eligibility requirements, related or unrelated donor marrow or UCB will be infused, and subjects will be followed for a minimum of 5 years after stem cell transplant. A target accrual of 75 subjects over 5 years will be recruited to the study.

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 Epidermolysis Bullosa
Intervention  ICMJE
  • Drug: Cyclophosphamide
    Cyclophosphamide 50 mg/kg/day IV over 2 hours x 1 day, total dose 50 mg/kg will be administered on Day -6.
    Other Name: Cytoxan
  • Drug: Fludarabine
    40 mg/m^2/day intravenously on Days -6, -5, -4, -3 and -2.
    Other Name: Fludara
  • Drug: Anti-thymocyte globulin
    30 mg/kg on Days -4, -3 and -2.
    Other Name: ATG
  • Drug: Cyclosporine A
    Days -3 to 100+ to maintain a level of >200 ng/ml; initial dose 2.5 mg/kg over 2 hours every 8-12 hours for children.
    Other Name: CSA
  • Drug: Mycophenolate mofetil
    15 mg/kg intravenous twice per day on days -3 through 30.
    Other Name: CellCept(R)
  • Procedure: Mesenchymal stem cell transplantation
    infused via intravenous drip on Day 0
    Other Name: MSCT
  • Radiation: Total body irradiation
    300 cGY on Day -1 administered in a single fraction at a dose rate of 10-19 cGy/minute prescribed to the midplane of the patient at the level of the umbilicus.
  • Procedure: Bone marrow or umbilical cord blood (UCG) stem cell transplantation
    Bone marrow or UCB products will be infused as soon as the product arrives and within 30 minutes. The product is infused via IV drip.
    Other Name: UCBSCT
Study Arms  ICMJE Experimental: Transplant in Epidermolysis Bullosa
Interventions:
  • Drug: Cyclophosphamide
  • Drug: Fludarabine
  • Drug: Anti-thymocyte globulin
  • Drug: Cyclosporine A
  • Drug: Mycophenolate mofetil
  • Procedure: Mesenchymal stem cell transplantation
  • Radiation: Total body irradiation
  • Procedure: Bone marrow or umbilical cord blood (UCG) stem cell transplantation
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 Completed
Actual Enrollment  ICMJE
 (submitted: February 25, 2022)
32
Original Estimated Enrollment  ICMJE
 (submitted: December 14, 2009)
75
Actual Study Completion Date  ICMJE August 12, 2021
Actual Primary Completion Date August 12, 2021   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Diagnosis of severe form of epidermolysis bullosa (EB) characterized by collagen, laminin, integrin, keratin or plakin deficiency. Assessment criteria for severe EB:

    • Documented collagen, laminin, integrin, keratin or plakin deficiency (by immunofluorescence staining with protein specific antibodies or Western blotting and by mutation analysis)
  • Adequate Organ Function Criteria

    • Renal: glomerular filtration rate within normal range for age
    • Hepatic: bilirubin, aspartate aminotransferase/alanine aminotransferase (AST/ALT), Alkaline phosphatase (ALP) < 5 x upper limit of normal
    • Pulmonary: adequate pulmonary function in the opinion of the enrolling investigator
    • Cardiac: left ventricular ejection fraction ≥ 45%, normal electrocardiogram (EKG) or approved by Cardiology for transplant.
  • Available Healthy HSC Donor (order of preference)

    • Related Donor (marrow or UCB)

      • HLA-A, B, C, DRB1 genotypic identical (sibling) donor
      • HLA-A, B, C, DRB1 phenotypic identical donor
      • 7/8 HLA matched donor at HLA-A, B, C, DRB1
    • Unrelated Donor

      • Marrow

        • HLA-A, B, C, DRB1 phenotypic identical donor
        • 7/8 HLA matched donor at HLA-A, B, C, DRB1
      • UCB

        • HLA-A, B (antigen level) and DRB1 (allele level) matched donor
        • 5/6 HLA matched donor at HLA-A, B, DRB1
        • 4/6 HLA matched donor at HLA-A, B, DRB1
  • Voluntary written consent

Absence of Exclusion Criteria:

  • Active systemic infection at time of transplantation (including active infection with Aspergillus or other mold within 30 days).
  • History of human immunodeficiency virus (HIV) infection
  • Evidence of squamous cell carcinoma
  • Donor has EB
  • Pregnancy females of child-bearing age must have a documented negative pregnancy test and agree to use contraception as a condition for enrollment.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE up to 25 Years   (Child, Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT01033552
Other Study ID Numbers  ICMJE MT2009-09
0911M74035 ( Other Identifier: IRB, University of Minnesota )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
IPD Sharing Statement  ICMJE Not Provided
Current Responsible Party Masonic Cancer Center, University of Minnesota
Original Responsible Party John E. Wagner, M.D., Masonic Cancer Center, University of Minnesota
Current Study Sponsor  ICMJE Masonic Cancer Center, University of Minnesota
Original Study Sponsor  ICMJE Same as current
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Jakub Tolar, MD, PhD Masonic Cancer Center, University of Minnesota
PRS Account Masonic Cancer Center, University of Minnesota
Verification Date February 2023

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