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Parathyroid and Thymus Transplantation in DiGeorge
This study is ongoing, but not recruiting participants.
Study NCT00566488   Information provided by Duke University
First Received: November 30, 2007   Last Updated: December 20, 2007   History of Changes

November 30, 2007
December 20, 2007
January 2005
August 2008   (final data collection date for primary outcome measure)
Efficacy parameter: use of calcium/calcitriol at 1 year post-transplantation. [ Time Frame: Recipients followed indefinitely; Parathyroid Donors followed 30-days post-transplant ] [ Designated as safety issue: No ]
Same as current
Complete list of historical versions of study NCT00566488 on ClinicalTrials.gov Archive Site
Efficacy parameters: ionized calcium; CD3, CD4, CD8, CD4 naive, & CD8 naive numbers; proliferative T cell response to mitogens & antigens; & TCR repertoire variability. Endocrine & immunologic results tabulated using standard descriptive statistics. [ Time Frame: Indefinitely ] [ Designated as safety issue: No ]
Efficacy parameters: ionized calcium; CD3,CD4,&CD8 numbers; naive CD4&CD8 numbers; proliferative Tcell response to mitogens & antigens; & TCR repertoire variability. Endocrine & immunologic results will be tabulated using standard descriptive statistics. [ Time Frame: Indefinitely ] [ Designated as safety issue: No ]
 
Parathyroid and Thymus Transplantation in DiGeorge
Parathyroid and Thymus Transplantation in DiGeorge Syndrome, DCRU 931

This study has three primary purposes: to assess parathyroid function after parathyroid transplantation into infants with Complete DiGeorge syndrome; to assess immune function development after transplantation; and, to assess safety and tolerability of the procedures. This is a Phase 1, single site, open, non-randomized clinical protocol. Enrollment is closed and study intervention is complete for all enrolled subjects; but subjects continue for observation and follow-up. Subjects under 2 years old with complete DiGeorge syndrome (atypical or typical) received thymus transplantation. Subjects received pre-transplant immune suppression with rabbit anti human thymocyte globulin. Subjects with hypoparathyroidism and an eligible parental donor received thymus and parental parathyroid transplantation. A primary hypothesis: Thymus/Parathyroid transplant subjects will need less calcium and/or calcitriol supplementation at 1 year post-transplant as compared to historical controls.

Detailed: DiGeorge Syndrome is a complex of three problems, 1) cardiac defects, 2) parathyroid deficiency, and 3) absence of the thymus, resulting in profound T-cell deficiency. There is a spectrum of disease in DiGeorge Syndrome with respect to all three defects. There is no safe and effective treatment for DiGeorge Syndrome and most patients die by the age of two. For patients with a severe T cell defect, the PI has shown that thymus transplantation is safe and efficacious under other clinical protocols. Research subjects with complete typical and atypical DiGeorge syndrome were eligible for this study. Subjects with athymia and profound hypoparathyroidism were eligible for parental parathyroid transplantation in this protocol. DiGeorge syndrome infants, who have successful thymus transplants but have hypoparathyroidism, must go to the clinic for frequent calcium levels and to the hospital for calcium infusions; infants with hypoparathyroidism are at risk for seizures from low calcium. Approximately ½ of infants with profound hypoparathyroidism will develop nephrocalcinosis. Depending on T cell phenotype and function, subject were treated with 2 different immunosuppression regimens. Typical complete DiGeorge subjects (with proliferative T cell function < 50,000 cpm) received Thymoglobulin pre-transplantation. Typical complete DiGeorge subjects (with proliferative cell response to PHA > 50,000 cpm) and atypical DiGeorge subjects (with proliferative T cell response to PHA < 75,000 cpm) received Thymoglobulin (pre-transplantation) and cyclosporine (pre-transplantation and post-transplantation). Thymoglobulin was used in part to prevent graft rejection and also to deplete any T cells in the donor parathyroid. Cyclosporine was used to deplete activated T cells in the recipient. For all subjects, acetaminophen, diphenhydramine, and methylprednisolone were given concurrently with the rabbit anti-human thymocytes globulin. The thymus was cultured in standard medium for 10-21 days to deplete mature thymocytes which could cause GVHD. In the operating room, thymus tissue was placed in quadriceps muscle in one or both legs. The parathyroid donation was preferably done at the same time as the thymus transplantation. Parathyroid tissue was placed in the quadriceps muscle in only one leg, using the same incision as the thymus transplantation. Depending on post-transplant immune status, subjects may have received cyclosporine and steroids.

For 3 months after thymus transplantation, T cells were monitored by flow cytometry approximately every 2-4 weeks. Alternatively, absolute lymphocyte count was used as the maximum possible T cell number. At 2-3 months post-transplant, the subject had a biopsy of the thymus allograft; this was done under general anesthesia in the operating room. The biopsy was approximately 4 pea-sized (3x3mm) portions of muscle tissue where the thymus transplant had been inserted. Using immunohistochemistry, the biopsy determined thymopoiesis and any thymus graft rejection. The parathyroid was not biopsied because it is very small; doing a biopsy could remove all of the parathyroid tissue. A research skin biopsy (at site of skin incision at the time of transplantation) was done to determine whether T cells were present in the recipient's skin pre-transplantation. A skin biopsy was also done at the time of thymus graft biopsy to look for clonal T cell populations. For all subjects, post-transplantation pneumocystis prophylaxis was used for 1 year and IV immunoglobulin for 2 years.

Phase I
Interventional
Treatment, Non-Randomized, Open Label, Uncontrolled, Single Group Assignment, Safety/Efficacy Study
  • DiGeorge Syndrome
  • Hypoparathyroidism
Other: Thymus/Parathyroid Transplantation
Experimental: Thymus/Parathyroid Transplantation in Complete DiGeorge Syndrome Infants
 

*   Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.
 
Active, not recruiting
7
June 2027
August 2008   (final data collection date for primary outcome measure)

Transplant Inclusion:

  • Complete DiGeorge syndrome (typical or atypical) - may have DiGeorge as part of 22q11 hemizygosity, CHARGE association, or diabetic embryopathy or they may have no associated syndromes.
  • Must have 1 of following:

    • Circulating CD3+ T cells < 50/mm3; or
    • Circulating CD3+ T cells that also positive for CD45RA and CD62L must be <50/mm3 or must be < 5% of total T cells.
  • Must be <24 months old
  • Laboratory studies must be done w/in 1 month of tx:

    • Thyroid studies - if abnormal must be on therapy, if recommended by endocrinology:
    • PT and PTT must be <2x upper limits of normal (ULN)
    • Absolute neutrophil count must be >500/mm3
    • Platelet count must be >50,000/mm3
    • AST and ALT must be <5x ULN
    • Creatinine must be <1.5 mg/dl
  • Parents must agree to have infant stay in Durham until thymus biopsy is done 2-3 months post-tx.
  • Typical subjects must not have a rash with T cells on biopsy nor lymphadenopathy.
  • Atypical subjects have rash with T cells on biopsy; may have lymphadenopathy.
  • PHA proliferative responses must be tested 2x • Atypical: PHA response must be <75,000cpm on 2 tests; test can be done while on immunosuppression.

Additional Criteria for Parathyroid Tx Inclusion

  • Hypoparathyroidism
  • At least 1 parent must agree to be parathyroid donor
  • Must require calcium supplementation to maintain ionized calcium >1.0 mmol/L. Alternatively, intact PTH must be <lower limit of normal when ionized calcium is <1.2 mmol/L. (Intact PTH measured 2x pre-tx.)

DiGeorge Tx Exclusion:

  • Heart surgery conducted <4 wks pre-tx
  • Heart surgery anticipated w/in 3 months of tx
  • Rejection by surgeon or anesthesiologist as surgical candidate
  • Lack of sufficient muscle tissue to accept 0.2gms/kg tx
  • Prior attempts at immune reconstitution, such as bone marrow tx or previous thymus tx
  • Doesn't commit to remaining at Duke until thymus allograft biopsy

Parathyroid Donor Inclusion:

  • Serum calcium in normal range
  • Normal parathyroid hormone function
  • HLA typing must be consistent with parentage.
  • Must not be on anticoagulation or can come off
  • Parent chosen for donation will be the 1 sharing most HLA alleles with thymus donor
  • HLA-DR matching preferred over HLA class I matching. If there no HLA matching at all, then either parent will be acceptable if meets other criteria.
  • Negative for EBV; CMV; HIV-1; Syphilis; West Nile virus; Hepatitis B; Hepatitis C; pregnancy; & evidence of head/neck infection
  • Fiberoptic nasolaryngoscopy shows vocal cords functioning normally.
  • Normal thyroid function
  • No history of cancer
  • The infant-recipient has 2 living involved parents.

Parathyroid Donor Exclusion:

  • Infant recipient doesn't have 2 living involved parents
  • Animal tissue/organ recipient
  • EBV
  • CMV
  • HIV-1
  • Syphilis
  • West Nile virus
  • Hepatitis B
  • Hepatitis C
  • Pregnant
  • Evidence of head/neck infection
  • Vocal cords not functioning normally.
  • Thyroid abnormalities
  • Hyperparathyroidism
  • History of cancer
  • Mad cow disease (positive)
  • SARS(and exposure)
  • Smallpox exposure

Biological Mother of DiGeorge Subjects Inclusions:

Mother must be competent to consent or assent to study participation and willing to provide blood sample. No other inclusion/exclusion.

Both
up to 24 Months
No
Contact information is only displayed when the study is recruiting subjects
United States
 
NCT00566488
M. Louise Markert, MD, PhD, Director, Laboratory of T-Cell Reconstitution; Associate Professor, Duke University Medical Center, Pediatric Allergy & Immunology
DCRU 931 IRB 5964, RO1 AI 54843, RO1 AI 47040, FDA-FD-002606, grants don't fund tx, grants for certain research
Duke University
  • Food and Drug Administration (FDA)
  • National Institutes of Health (NIH)
Principal Investigator: M. Louise Markert, MD, PhD Duke University Medical Center, Pediatrics, Allergy & Immunology
Duke University
December 2007

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