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Parathyroid and Thymus Transplantation in DiGeorge #931

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT00566488
Recruitment Status : Active, not recruiting
First Posted : December 3, 2007
Last Update Posted : May 7, 2019
Food and Drug Administration (FDA)
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)
Enzyvant Therapeutics GmbH
Information provided by (Responsible Party):
M. Louise Markert, Duke University

Brief Summary:
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 or disease Intervention/treatment Phase
DiGeorge Syndrome Hypoparathyroidism Complete DiGeorge Syndrome Biological: Thymus/Parathyroid Transplantation Phase 1

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. 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 may have 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.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 25 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Parathyroid and Thymus Transplantation in DiGeorge Syndrome, #931
Study Start Date : January 2005
Actual Primary Completion Date : August 2007
Estimated Study Completion Date : June 2027

Arm Intervention/treatment
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

Primary Outcome Measures :
  1. Efficacy parameter: use of calcium/calcitriol at 1 year post-transplantation. [ Time Frame: 1 year after thymus transplantation ]
    Subjects wtih complete DiGeorge anomaly who have received thymus and parathyroid transplants and survived to one year

Secondary Outcome Measures :
  1. Efficacy parameters: ionized calcium [ Time Frame: 10-14 months after thymus transplantation ]
    Ionized calcium (normal values are 1.2 - 1.37 mmol/L)

  2. Efficacy parameters: CD3 count [ Time Frame: 10-14 months after thymus transplantation ]
    CD3 count/mm3

  3. Efficacy parameters: CD4 count [ Time Frame: 10-14 months after thymus transplantation ]
    CD4 count/mm3

  4. Efficacy parameters: CD8 count [ Time Frame: 10-14 months after thymus transplantation ]
    CD8 count/mm3

  5. Efficacy parameters: naive CD4 count [ Time Frame: 10-14 months after thymus transplantation ]
    naive CD4 count/mm3

  6. Efficacy parameters: naive CD8 count [ Time Frame: 10-14 months after thymus transplantation ]
    naive CD8 count/mm3

  7. Efficacy parameters: proliferative response to phytohemagglutinin [ Time Frame: approximately 1 year after thymus transplantation (8.9 to 17.8 months after transplantation) ]
    proliferative response to phytohemagglutinin in counts per minute

  8. Efficacy parameters: proliferative response to tetanus toxoid [ Time Frame: approximately 1 year after thymus transplantation (8.9 to 17.8 months after transplantation) ]
    proliferative response to tetanus toxoid in counts per minute

  9. Efficacy parameters: spectra typing at 1 year post transplantation [ Time Frame: approximately 1 year after thymus transplantation (12.1 to 18.0 months after transplantation) ]
    Variability of CD4 T cell receptor beta repertoire as assessed by the Kullback-Leibler divergence (DKL)

Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.

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Ages Eligible for Study:   up to 24 Months   (Child)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT00566488

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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)
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)
Enzyvant Therapeutics GmbH
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Principal Investigator: M. Louise Markert, MD, PhD Duke University Medical Center, Pediatrics, Allergy & Immunology

Publications of Results:
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.
Markert ML and Devlin BH. Thymic reconstitution (in Rich RR, Shearer WT, Fleischer T, Schroeder HW, Weyand CM, Frew A, eds., Clinical Immunology 3rd edn., Elsevier, Edinburgh) p 1253-1262, 2008.

Other Publications:

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Responsible Party: M. Louise Markert, Professor of Pediatrics, Duke University Identifier: NCT00566488    
Other Study ID Numbers: Pro00016482
R01AI047040 ( U.S. NIH Grant/Contract )
5K12HD043494-09 ( U.S. NIH Grant/Contract )
R01AI054843 ( U.S. NIH Grant/Contract )
FDA-FD-R-002606 ( Other Grant/Funding Number: FDA )
2R01AI047040-11A2 ( U.S. NIH Grant/Contract )
R56 Bridge R01AI4704011A1 ( Other Grant/Funding Number: [NIH American Recovery and Reinvestment Act (ARRA) of 2009] )
3R56AI047040-11A1S1 ( U.S. NIH Grant/Contract )
First Posted: December 3, 2007    Key Record Dates
Last Update Posted: May 7, 2019
Last Verified: May 2019

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by M. Louise Markert, Duke University:
Thymus Transplantation
Parathyroid Transplantation
DiGeorge Syndrome
Additional relevant MeSH terms:
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Calcium-Regulating Hormones and Agents
DiGeorge Syndrome
Marfan Syndrome
Pathologic Processes
Parathyroid Diseases
Endocrine System Diseases
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
Bone Diseases, Developmental
Bone Diseases
Connective Tissue Diseases