Serum-Free Thymus Transplantation in DiGeorge Anomaly (SerumFree)

This study has been terminated.
(The sponsor decided to withdraw the study.)
Sponsor:
Collaborators:
Information provided by (Responsible Party):
M. Louise Markert, Duke University Medical Center
ClinicalTrials.gov Identifier:
NCT00849888
First received: February 22, 2009
Last updated: February 12, 2013
Last verified: February 2013

February 22, 2009
February 12, 2013
April 2008
February 2011   (final data collection date for primary outcome measure)
  • Survival [ Time Frame: One year post-thymus transplantation. ] [ Designated as safety issue: Yes ]
    Survival at one year post thymus transplantation.
  • Incidence of graft-versus-host-disease (GVHD). [ Time Frame: One year post-thymus-transplantation. ] [ Designated as safety issue: Yes ]
    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. [ Time Frame: Two months post-thymus transplantation. ] [ Designated as safety issue: Yes ]
    Graft rejection analysis by biopsy at 2 months post-thymus transplantation.
  • Survival [ Time Frame: One year post-thymus transplantation. ] [ Designated as safety issue: Yes ]
  • Incidence of graft-versus-host-disease (GVHD). [ Time Frame: One year post-thymus-transplantation. ] [ Designated as safety issue: Yes ]
  • Thymopoiesis or graft rejection on biopsy. [ Time Frame: Two months post-thymus transplantation. ] [ Designated as safety issue: Yes ]
Complete list of historical versions of study NCT00849888 on ClinicalTrials.gov Archive Site
  • Incidence of autoimmune disease. [ Time Frame: By two years post-thymus transplantation. ] [ Designated as safety issue: Yes ]
    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. [ Time Frame: One year post-thymus transplantation. ] [ Designated as safety issue: No ]
    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
  • Incidence of autoimmune disease. [ Time Frame: By two years post-thymus transplantation. ] [ Designated as safety issue: Yes ]
  • Immune outcomes: T cell development; evaluate T cell numbers, diversity, and function. [ Time Frame: One year post-thymus transplantation. ] [ Designated as safety issue: No ]
Not Provided
Not Provided
 
Serum-Free Thymus Transplantation in DiGeorge Anomaly
Phase I Serum-Free Cultured Thymus Transplantation in DiGeorge Anomaly, IND9836

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]

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).

Interventional
Phase 1
Allocation: Non-Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
DiGeorge Anomaly
  • Biological: Serum Free Thymus Transplantation with Immunosuppression
    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.
    Other Names:
    • IND 9836
    • Thymus Tissue Transplant
  • Other: Serum Free Thymus Transplantation without immunosuppression
    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.
    Other Names:
    • IND 9836
    • Thymus Tissue Transplant
  • Experimental: Atypical Complete DiGeorge
    Thymus Transplantation with Immunosuppression
    Intervention: Biological: Serum Free Thymus Transplantation with Immunosuppression
  • Experimental: Typical Complete DiGeorge
    Thymus Transplantation without Immunosuppression
    Intervention: Other: Serum Free Thymus Transplantation without immunosuppression

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Terminated
2
February 2011
February 2011   (final data collection date for primary outcome measure)

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

Both
up to 2 Years
No
Contact information is only displayed when the study is recruiting subjects
Not Provided
 
NCT00849888
Pro00006109, 1R01-FD003528-01, 2R01AI047040-11A2, 5K12HD043494-09, R01AI047040, R01AI054843, R56 Bridge R01AI4704011A1
Yes
M. Louise Markert, Duke University Medical Center
M. Louise Markert
  • 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)
Principal Investigator: M. Louise Markert, M.D., Ph.D Duke University Medical Center, Pediatrics, Allergy & Immunology
Duke University
February 2013

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