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Serum-Free Thymus Transplantation in DiGeorge Anomaly (SerumFree)

This study has been terminated.
(The sponsor decided to withdraw the study.)
Sponsor:
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)
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
History of Changes
  Purpose

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]


Condition Intervention Phase
DiGeorge Anomaly
 Biological: Serum Free Thymus Transplantation with Immunosuppression
Other: Serum Free Thymus Transplantation without immunosuppression
 Phase 1

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Phase I Serum-Free Cultured Thymus Transplantation in DiGeorge Anomaly, IND9836

Resource links provided by NLM:

U.S. FDA Resources

Further study details as provided by Duke University:

Primary Outcome Measures:
  • 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.


Secondary Outcome Measures:
  • 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


Enrollment: 2
Study Start Date: April 2008
Study Completion Date: February 2011
Primary Completion Date: February 2011 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Atypical Complete DiGeorge
Thymus Transplantation with Immunosuppression
 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
Experimental: Typical Complete DiGeorge
Thymus Transplantation without Immunosuppression
 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

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).

  Eligibility

Ages Eligible for Study:   up to 2 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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

  Contacts and Locations
Please refer to this study by its ClinicalTrials.gov identifier: NCT00849888

Sponsors and Collaborators
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)
Investigators
Principal Investigator: M. Louise Markert, M.D., Ph.D Duke University Medical Center, Pediatrics, Allergy & Immunology
  More Information

Publications:

Responsible Party: M. Louise Markert, Professor of Pediatrics, Duke University Medical Center
ClinicalTrials.gov Identifier: NCT00849888     History of Changes
Other Study ID Numbers: Pro00006109, 1R01-FD003528-01, 2R01AI047040-11A2, 5K12HD043494-09, R01AI047040, R01AI054843, R56 Bridge R01AI4704011A1
Study First Received: February 22, 2009
Last Updated: February 12, 2013
Health Authority: United States: Food and Drug Administration

Keywords provided by Duke University:
Thymus Transplantation
DiGeorge Anomaly
Athymia
 Low T cell numbers
Immunoreconstitution
Immunodeficiency

Additional relevant MeSH terms:
Congenital Abnormalities
DiGeorge Syndrome
22q11 Deletion Syndrome
Craniofacial Abnormalities
Musculoskeletal Abnormalities
Musculoskeletal Diseases
Heart Defects, Congenital
Cardiovascular Abnormalities
Cardiovascular Diseases
 Heart Diseases
Lymphatic Abnormalities
Lymphatic Diseases
Abnormalities, Multiple
Chromosome Disorders
Genetic Diseases, Inborn
Hypoparathyroidism
Parathyroid Diseases
Endocrine System Diseases

ClinicalTrials.gov processed this record on May 16, 2013