Parathyroid and Thymus Transplantation in DiGeorge #931

Study Details

Study Description

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.

Study Design

Study Type:

Interventional

Actual Enrollment :

25 participants

Allocation:

N/A

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 :

Jan 1, 2005

Actual Primary Completion Date :

Aug 1, 2007

Actual Study Completion Date :

Dec 1, 2019

Arms and Interventions

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 Names: IND 9836, Thymus Tissue

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 Names:

IND 9836, Thymus Tissue

Outcome Measures

Primary Outcome Measures

Efficacy parameter: use of calcium/calcitriol at 1 year post-transplantation. [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

Efficacy parameters: ionized calcium [10-14 months after thymus transplantation]
Ionized calcium (normal values are 1.2 - 1.37 mmol/L)
Efficacy parameters: CD3 count [10-14 months after thymus transplantation]
CD3 count/mm3
Efficacy parameters: CD4 count [10-14 months after thymus transplantation]
CD4 count/mm3
Efficacy parameters: CD8 count [10-14 months after thymus transplantation]
CD8 count/mm3
Efficacy parameters: naive CD4 count [10-14 months after thymus transplantation]
naive CD4 count/mm3
Efficacy parameters: naive CD8 count [10-14 months after thymus transplantation]
naive CD8 count/mm3
Efficacy parameters: proliferative response to phytohemagglutinin [approximately 1 year after thymus transplantation (8.9 to 17.8 months after transplantation)]
proliferative response to phytohemagglutinin in counts per minute
Efficacy parameters: proliferative response to tetanus toxoid [approximately 1 year after thymus transplantation (8.9 to 17.8 months after transplantation)]
proliferative response to tetanus toxoid in counts per minute
Efficacy parameters: spectra typing at 1 year post transplantation [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)

Eligibility Criteria

Criteria

Ages Eligible for Study:

N/A to 24 Months

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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

Locations

	Site	City	State	Country	Postal Code
1	Duke University Medical Center	Durham	North Carolina	United States	27705

Sponsors and Collaborators

Enzyvant Therapeutics GmBH
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)