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Serum-Free Thymus Transplantation in DiGeorge Anomaly (SerumFree)

Primary Purpose

DiGeorge Anomaly

Status
Terminated
Phase
Phase 1
Locations
Study Type
Interventional
Intervention
Serum Free Thymus Transplantation with Immunosuppression
Serum Free Thymus Transplantation without immunosuppression
Sponsored by
Enzyvant Therapeutics GmBH
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for DiGeorge Anomaly focused on measuring Thymus Transplantation, DiGeorge Anomaly, Athymia, Low T cell numbers, Immunoreconstitution, Immunodeficiency

Eligibility Criteria

undefined - 2 Years (Child)All SexesDoes not accept healthy volunteers

Thymus Recipients Inclusion:

Complete DiGeorge anomaly diagnosis

Must have one of following:

  • congenital heart disease
  • hypocalcemia requiring replacement
  • 22q11 or 10p13 hemizygous
  • CHARGE

Atypical Arm:

  • Must have, or have had, rash. If rash present, skin biopsy must show T cells. If rash resolved, must have >50/cumm T cells; & <50/cumm naive T cells or <5% total
  • PHA response must be <40000 counts per minute(cpm) on immunosuppression; or, <75000cpm off immunosuppression. PHA test must be done 2x
  • CD45RA+CD62L+ CD3+ T cells must be <50/mm3; or, <5% of total CD3. Test must be done 2x

Typical Arm:

  • PHA response <20 fold or <5,000cpm
  • Circulating CD3+CD45RA+CD62L+T cells <50/mm3 or <5% total T cells
  • 2 tests of T cells & PHA response must show similar results

Biological Mother Inclusion:

-Must be recipient's biological mother

Thymus Recipient Exclusion:

  • Heart surgery <4 weeks pre-transplant or within 3 months post-transplant
  • Rejection by surgeon or anesthesiologist as surgical candidates
  • Lack of sufficient muscle tissue to accept transplant
  • Medical condition does not allow to undergo a biopsy
  • HIV
  • CMV(>500 copies/ml blood by PCR on 2 tests)
  • Ventilator dependence
  • GVHD
  • Maternal T cells >20% of total T cells
  • Prior immune reconstitution attempts (e.g., BMT, prior thymus transplant)
  • Hypoparathyroidism meeting criteria for combined thymus/parathyroid transplant & parents desiring it
  • RSV or parainfluenza virus
  • Enterovirus or Adenovirus in stool

Biological Mother Exclusion:

-Unwillingness to sign consent or provide blood/buccal samples

Sites / Locations

    Arms of the Study

    Arm 1

    Arm 2

    Arm Type

    Experimental

    Experimental

    Arm Label

    Atypical Complete DiGeorge

    Typical Complete DiGeorge

    Arm Description

    Thymus Transplantation with Immunosuppression

    Thymus Transplantation without Immunosuppression

    Outcomes

    Primary Outcome Measures

    Survival
    Survival at one year post thymus transplantation.
    Incidence of graft-versus-host-disease (GVHD).
    Development of graft versus host disease in first year after transplantation associated with T cells from the thymus donor.
    Thymopoiesis or graft rejection on biopsy.
    Graft rejection analysis by biopsy at 2 months post-thymus transplantation.

    Secondary Outcome Measures

    Incidence of autoimmune disease.
    Incidence of autoimmune disease by year 2 after transplantation Cytopenias as assessed by complete blood counts and differential. Thyroid disease as assessed by thyroid function tests
    Immune outcomes: T cell development; evaluate T cell numbers, diversity, and function.
    Number of naïve CD4 T cells at one year after transplantation Number of total CD4 T cells at one year after transplantation Proliferative response to PHA at one year after transplantation TCRBV diversity by spectratyping measured by DKL score at one year after transplantation

    Full Information

    First Posted
    February 22, 2009
    Last Updated
    March 21, 2022
    Sponsor
    Enzyvant Therapeutics GmBH
    Collaborators
    National Institutes of Health (NIH), National Institute of Allergy and Infectious Diseases (NIAID), Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
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    1. Study Identification

    Unique Protocol Identification Number
    NCT00849888
    Brief Title
    Serum-Free Thymus Transplantation in DiGeorge Anomaly
    Acronym
    SerumFree
    Official Title
    Phase I Serum-Free Cultured Thymus Transplantation in DiGeorge Anomaly, IND9836
    Study Type
    Interventional

    2. Study Status

    Record Verification Date
    March 2022
    Overall Recruitment Status
    Terminated
    Why Stopped
    The sponsor decided to withdraw the study.
    Study Start Date
    April 2008 (undefined)
    Primary Completion Date
    February 2011 (Actual)
    Study Completion Date
    February 2011 (Actual)

    3. Sponsor/Collaborators

    Responsible Party, by Official Title
    Sponsor
    Name of the Sponsor
    Enzyvant Therapeutics GmBH
    Collaborators
    National Institutes of Health (NIH), National Institute of Allergy and Infectious Diseases (NIAID), Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)

    4. Oversight

    Data Monitoring Committee
    Yes

    5. Study Description

    Brief Summary
    The study purpose is to determine if thymus tissue cultured in a serum-free (SF) solution is a safe and effective treatment for atypical and typical complete DiGeorge anomaly. [Funding Source - FDA OOPD]
    Detailed Description
    Complete DiGeorge anomaly is a congenital disorder characterized by athymia. Without successful treatment, patients remain immunodeficient and usually die by age 2 years. In "typical" complete DiGeorge subjects who have no T cells, thymus transplantation without immunosuppression has resulted in diverse T cell development and good T cell function. In "atypical" complete DiGeorge subjects who have no thymus, a rash, and some T cells that presumably developed extrathymically, thymus transplantation with immunosuppression has resulted in diverse T cell development and good T cell function. Thus far, thymus transplantation studies have used thymus cultured in fetal bovine serum (FBS medium). This protocol's purpose is to determine whether transplanted thymus cultured in serum free medium can safely support thymopoiesis and T cell reconstitution as does FBS medium cultured thymus tissue in DiGeorge anomaly subjects. This protocol includes 2 arms: atypical DiGeorge subjects who will receive immunosuppression and thymus transplantation; and, typical complete DiGeorge subjects who will receive thymus transplantation without immunosuppression. Serum free medium use would reduce concerns of animal product exposure including potential exposure to bovine spongiform encephalopathy(BSE).

    6. Conditions and Keywords

    Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
    DiGeorge Anomaly
    Keywords
    Thymus Transplantation, DiGeorge Anomaly, Athymia, Low T cell numbers, Immunoreconstitution, Immunodeficiency

    7. Study Design

    Primary Purpose
    Treatment
    Study Phase
    Phase 1
    Interventional Study Model
    Parallel Assignment
    Masking
    None (Open Label)
    Allocation
    Non-Randomized
    Enrollment
    2 (Actual)

    8. Arms, Groups, and Interventions

    Arm Title
    Atypical Complete DiGeorge
    Arm Type
    Experimental
    Arm Description
    Thymus Transplantation with Immunosuppression
    Arm Title
    Typical Complete DiGeorge
    Arm Type
    Experimental
    Arm Description
    Thymus Transplantation without Immunosuppression
    Intervention Type
    Biological
    Intervention Name(s)
    Serum Free Thymus Transplantation with Immunosuppression
    Other Intervention Name(s)
    IND 9836, Thymus Tissue Transplant
    Intervention Description
    Cyclosporine pre-transplant (trough 180-220ng/ml) until naive T cells develop. Subjects >4,000/cumm T cells, pre-transplant methylprednisolone or prednisolone 1-2mg/kg/day. All subjects pre-transplant days -5,-4,-3: 3 doses 2mg/kg rabbit anti-thymocyte globulin. Thymus tissue (unrelated donor), donor, & donor's mother screened for safety. Transplant under general anesthesia into quadriceps. First 2 subjects, FBS cultured thymus is transplanted in 1 leg & serum free (SF) in other. After first 2 subjects >10% naïve T cells, 3rd receives only SF thymus. After 3rd subject >10%naive T cells, 4th subject transplanted. Thymus dose 4-18 grams/m2 body surface area. Thymus biopsy 8-12 weeks post-transplant. Skin biopsy at time of transplant & thymus biopsy. Followed by immune evaluations.
    Intervention Type
    Other
    Intervention Name(s)
    Serum Free Thymus Transplantation without immunosuppression
    Other Intervention Name(s)
    IND 9836, Thymus Tissue Transplant
    Intervention Description
    Thymus tissue (unrelated donor), donor, & donor's mother screened for safety. Transplant under general anesthesia into quadriceps. First 2 subjects: FBS cultured thymus transplanted in 1 leg & serum free cultured thymus in other leg. After first 2 subjects have thymopoiesis in serum-free biopsy, >10% naïve T cells, 3rd subject receives only serum free cultured thymus. After 3rd subject >10% naive T cells, 4th subject receives transplant of only serum free cultured thymus. Dose 4-18grams/m2 body surface area. At time of transplant, skin biopsy. Allograft biopsy & skin biopsy done 8 to 12 weeks post-transplant. (Graft biopsy not done if subject medically unstable.) Post-transplant, subjects followed by immune evaluations, using blood samples, for two years.
    Primary Outcome Measure Information:
    Title
    Survival
    Description
    Survival at one year post thymus transplantation.
    Time Frame
    One year post-thymus transplantation.
    Title
    Incidence of graft-versus-host-disease (GVHD).
    Description
    Development of graft versus host disease in first year after transplantation associated with T cells from the thymus donor.
    Time Frame
    One year post-thymus-transplantation.
    Title
    Thymopoiesis or graft rejection on biopsy.
    Description
    Graft rejection analysis by biopsy at 2 months post-thymus transplantation.
    Time Frame
    Two months post-thymus transplantation.
    Secondary Outcome Measure Information:
    Title
    Incidence of autoimmune disease.
    Description
    Incidence of autoimmune disease by year 2 after transplantation Cytopenias as assessed by complete blood counts and differential. Thyroid disease as assessed by thyroid function tests
    Time Frame
    By two years post-thymus transplantation.
    Title
    Immune outcomes: T cell development; evaluate T cell numbers, diversity, and function.
    Description
    Number of naïve CD4 T cells at one year after transplantation Number of total CD4 T cells at one year after transplantation Proliferative response to PHA at one year after transplantation TCRBV diversity by spectratyping measured by DKL score at one year after transplantation
    Time Frame
    One year post-thymus transplantation.

    10. Eligibility

    Sex
    All
    Maximum Age & Unit of Time
    2 Years
    Accepts Healthy Volunteers
    No
    Eligibility Criteria
    Thymus Recipients Inclusion: Complete DiGeorge anomaly diagnosis Must have one of following: congenital heart disease hypocalcemia requiring replacement 22q11 or 10p13 hemizygous CHARGE Atypical Arm: Must have, or have had, rash. If rash present, skin biopsy must show T cells. If rash resolved, must have >50/cumm T cells; & <50/cumm naive T cells or <5% total PHA response must be <40000 counts per minute(cpm) on immunosuppression; or, <75000cpm off immunosuppression. PHA test must be done 2x CD45RA+CD62L+ CD3+ T cells must be <50/mm3; or, <5% of total CD3. Test must be done 2x Typical Arm: PHA response <20 fold or <5,000cpm Circulating CD3+CD45RA+CD62L+T cells <50/mm3 or <5% total T cells 2 tests of T cells & PHA response must show similar results Biological Mother Inclusion: -Must be recipient's biological mother Thymus Recipient Exclusion: Heart surgery <4 weeks pre-transplant or within 3 months post-transplant Rejection by surgeon or anesthesiologist as surgical candidates Lack of sufficient muscle tissue to accept transplant Medical condition does not allow to undergo a biopsy HIV CMV(>500 copies/ml blood by PCR on 2 tests) Ventilator dependence GVHD Maternal T cells >20% of total T cells Prior immune reconstitution attempts (e.g., BMT, prior thymus transplant) Hypoparathyroidism meeting criteria for combined thymus/parathyroid transplant & parents desiring it RSV or parainfluenza virus Enterovirus or Adenovirus in stool Biological Mother Exclusion: -Unwillingness to sign consent or provide blood/buccal samples
    Overall Study Officials:
    First Name & Middle Initial & Last Name & Degree
    M. Louise Markert, M.D., Ph.D
    Organizational Affiliation
    Duke University Medical Center, Pediatrics, Allergy & Immunology
    Official's Role
    Principal Investigator

    12. IPD Sharing Statement

    Citations:
    PubMed Identifier
    17284531
    Citation
    Markert ML, Devlin BH, Alexieff MJ, Li J, McCarthy EA, Gupton SE, Chinn IK, Hale LP, Kepler TB, He M, Sarzotti M, Skinner MA, Rice HE, Hoehner JC. Review of 54 patients with complete DiGeorge anomaly enrolled in protocols for thymus transplantation: outcome of 44 consecutive transplants. Blood. 2007 May 15;109(10):4539-47. doi: 10.1182/blood-2006-10-048652. Epub 2007 Feb 6.
    Results Reference
    background
    PubMed Identifier
    15100156
    Citation
    Markert ML, Alexieff MJ, Li J, Sarzotti M, Ozaki DA, Devlin BH, Sedlak DA, Sempowski GD, Hale LP, Rice HE, Mahaffey SM, Skinner MA. Postnatal thymus transplantation with immunosuppression as treatment for DiGeorge syndrome. Blood. 2004 Oct 15;104(8):2574-81. doi: 10.1182/blood-2003-08-2984. Epub 2004 Apr 20.
    Results Reference
    background
    PubMed Identifier
    12702512
    Citation
    Markert ML, Sarzotti M, Ozaki DA, Sempowski GD, Rhein ME, Hale LP, Le Deist F, Alexieff MJ, Li J, Hauser ER, Haynes BF, Rice HE, Skinner MA, Mahaffey SM, Jaggers J, Stein LD, Mill MR. Thymus transplantation in complete DiGeorge syndrome: immunologic and safety evaluations in 12 patients. Blood. 2003 Aug 1;102(3):1121-30. doi: 10.1182/blood-2002-08-2545. Epub 2003 Apr 17.
    Results Reference
    background
    PubMed Identifier
    18333898
    Citation
    Selim MA, Markert ML, Burchette JL, Herman CM, Turner JW. The cutaneous manifestations of atypical complete DiGeorge syndrome: a histopathologic and immunohistochemical study. J Cutan Pathol. 2008 Apr;35(4):380-5. doi: 10.1111/j.1600-0560.2007.00816.x.
    Results Reference
    background
    PubMed Identifier
    18155964
    Citation
    Chinn IK, Devlin BH, Li YJ, Markert ML. Long-term tolerance to allogeneic thymus transplants in complete DiGeorge anomaly. Clin Immunol. 2008 Mar;126(3):277-81. doi: 10.1016/j.clim.2007.11.009. Epub 2007 Dec 26.
    Results Reference
    background
    PubMed Identifier
    18424759
    Citation
    Markert ML, Li J, Devlin BH, Hoehner JC, Rice HE, Skinner MA, Li YJ, Hale LP. Use of allograft biopsies to assess thymopoiesis after thymus transplantation. J Immunol. 2008 May 1;180(9):6354-64. doi: 10.4049/jimmunol.180.9.6354.
    Results Reference
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    Serum-Free Thymus Transplantation in DiGeorge Anomaly

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