Parathyroid and Thymus Transplantation in DiGeorge #931

This study is ongoing, but not recruiting participants.
Sponsor:
Collaborators:
Food and Drug Administration (FDA)
Information provided by (Responsible Party):
M. Louise Markert, Duke University Medical Center
ClinicalTrials.gov Identifier:
NCT00566488
First received: November 30, 2007
Last updated: March 31, 2014
Last verified: March 2014
  Purpose

This study has three primary purposes: to assess parathyroid function after parathyroid transplantation in 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.


Condition Intervention Phase
DiGeorge Syndrome
Hypoparathyroidism
Complete DiGeorge Syndrome
Biological: Thymus/Parathyroid Transplantation
Phase 1

Study Type: Interventional
Study Design: Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Parathyroid and Thymus Transplantation in DiGeorge Syndrome, #931

Resource links provided by NLM:


Further study details as provided by Duke University:

Primary Outcome Measures:
  • Efficacy parameter: use of calcium/calcitriol at 1 year post-transplantation. [ Time Frame: 1 year after thymus transplantation ] [ Designated as safety issue: No ]
    Subjects wtih complete DiGeorge anomaly who have received thymus and parathyroid transplants and survived to one year


Secondary Outcome Measures:
  • Efficacy parameters: ionized calcium [ Time Frame: 10-14 months after thymus transplantation ] [ Designated as safety issue: No ]
    Ionized calcium (normal values are 1.2 - 1.37 mmol/L)

  • Efficacy parameters: CD3 count [ Time Frame: 10-14 months after thymus transplantation ] [ Designated as safety issue: No ]
    CD3 count/mm3

  • Efficacy parameters: CD4 count [ Time Frame: 10-14 months after thymus transplantation ] [ Designated as safety issue: No ]
    CD4 count/mm3

  • Efficacy parameters: CD8 count [ Time Frame: 10-14 months after thymus transplantation ] [ Designated as safety issue: No ]
    CD8 count/mm3

  • Efficacy parameters: naive CD4 count [ Time Frame: 10-14 months after thymus transplantation ] [ Designated as safety issue: No ]
    naive CD4 count/mm3

  • Efficacy parameters: naive CD8 count [ Time Frame: 10-14 months after thymus transplantation ] [ Designated as safety issue: No ]
    naive CD8 count/mm3

  • Efficacy parameters: proliferative response to phytohemagglutinin [ Time Frame: approximately 1 year after thymus transplantation (8.9 to 17.8 months after transplantation) ] [ Designated as safety issue: No ]
    proliferative response to phytohemagglutinin in counts per minute

  • Efficacy parameters: proliferative response to tetanus toxoid [ Time Frame: approximately 1 year after thymus transplantation (8.9 to 17.8 months after transplantation) ] [ Designated as safety issue: No ]
    proliferative response to tetanus toxoid in counts per minute

  • Efficacy parameters: spectratyping at 1 year post transplantation [ Time Frame: approximately 1 year after thymus transplantation (12.1 to 18.0 months after transplantation) ] [ Designated as safety issue: No ]
    Variability of CD4 T cell receptor beta repertoire as assessed by the Kullback-Leibler divergence (DKL)


Enrollment: 25
Study Start Date: January 2005
Estimated Study Completion Date: June 2027
Primary Completion Date: August 2007 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Thymus and Parathyroid transplantation
Thymus/Parathyroid Transplantation in Complete DiGeorge Syndrome Infants
Biological: Thymus/Parathyroid Transplantation
Thymus tissue, thymus donor, mother of thymus donor, & parental parathyroid donor screened for transplant safety. Depending on T cell phenotype & function, subjects were given 1 of 2 immunosuppression regimes. All received rabbit anti thymocyte globulin pretransplantation. Others also received cyclosporine pre & post-transplantation. The thymus dose was over 0.2 grams/kg recipient weight. Thymus transplant occurred in operating room; thymic slices were placed in quadriceps. Parathyroid harvest was done under general anesthesia. One parathyroid gland was minced and placed in quadriceps muscle. There was no dose in mg. An open biopsy of thymus allograft was done 2-3 months post-transplant. Biopsy tissue was examined by immunohistochemistry to evaluate for thymopoiesis & graft rejection.
Other Name: IND 9836, Thymus Tissue

Detailed Description:

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, subjects were given one of two 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 thymocyte 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 the 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 thymus allograft biopsy, 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 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 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 who developed T cells, post-transplantation pneumocystis prophylaxis was used for approximately 1 year and IV immunoglobulin for approximately 2 years.

  Eligibility

Ages Eligible for Study:   up to 24 Months
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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 treatment:

    • 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-treatment.
  • 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 Treatment 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-treatment.)

DiGeorge Treatment Exclusion:

  • Heart surgery conducted <4 weeks pre-treatment
  • Heart surgery anticipated w/in 3 months of treatment
  • Rejection by surgeon or anesthesiologist as surgical candidate
  • Lack of sufficient muscle tissue to accept 0.2gms/kg treatment
  • Prior attempts at immune reconstitution, such as bone marrow treatment or previous thymus treatment
  • 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.

  Contacts and Locations
Please refer to this study by its ClinicalTrials.gov identifier: NCT00566488

Locations
United States, North Carolina
Duke University Medical Center
Durham, North Carolina, United States, 27705
Sponsors and Collaborators
M. Louise Markert
Food and Drug Administration (FDA)
Investigators
Principal Investigator: M. Louise Markert, MD, PhD Duke University Medical Center, Pediatrics, Allergy & Immunology
  More Information

Publications:
Markert ML, Devlin BH, McCarthy EA, Chinn IK, Hale LP. Thymus Transplantation in Thymus Gland Pathology: Clinical, Diagnostic, and Therapeutic Features. Eds Lavinin C, Moran CA, Morandi U, Schoenhuber R. Springer-Verlag Italia, Milan, 2008, pp 255-267.

Responsible Party: M. Louise Markert, Professor of Pediatrics, Duke University Medical Center
ClinicalTrials.gov Identifier: NCT00566488     History of Changes
Other Study ID Numbers: Pro00016482 #931, R01AI047040, 5K12HD043494-09, R01AI054843, FDA-FD-R-002606, 2R01AI047040-11A2, R56 Bridge R01AI4704011A1, 3R56AI047040-11A1S1
Study First Received: November 30, 2007
Last Updated: March 31, 2014
Health Authority: United States: Institutional Review Board
United States: Food and Drug Administration

Keywords provided by Duke University:
Thymus Transplantation
Parathyroid Transplantation
DiGeorge Syndrome
Hypoparathyroidism
Athymia

Additional relevant MeSH terms:
Hypoparathyroidism
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
Congenital Abnormalities
Chromosome Disorders
Genetic Diseases, Inborn
Parathyroid Diseases
Endocrine System Diseases

ClinicalTrials.gov processed this record on April 14, 2014