Thymus Transplantation Dose in DiGeorge - Full Text View

Sponsors and Collaborators:	Duke University National Institutes of Health (NIH) Food and Drug Administration (FDA)
Information provided by:	Duke University
ClinicalTrials.gov Identifier:	NCT00576836

Purpose

One purpose of this study is to determine whether the amount of thymus tissue transplanted into DiGeorge syndrome infants has any effect on the immune outcome. Another purpose of this study is to determine whether parental parathyroid gland transplantation (in addition to thymus transplantation) can help both the immune and the calcium problems in DiGeorge infants with hypocalcemia.

Condition	Intervention	Phase
DiGeorge Syndrome	Other: Thymus Transplantation Other: Parathyroid Transplantation	Phase II

Genetics Home Reference related topics: 22q11.2 deletion syndrome

MedlinePlus related topics: Calcium

Drug Information available for: Parathyroid Calcium gluconate

U.S. FDA Resources

Study Type:	Interventional
Study Design:	Treatment, Non-Randomized, Open Label, Parallel Assignment, Safety/Efficacy Study
Official Title:	Dose Study of Thymus Transplantation in DiGeorge Syndrome

Further study details as provided by Duke University:

Primary Outcome Measures:

Regression analyses used to correlate dose to immunologic parameters: T cell proliferative response; naïve T cells; and T cell variability. The arms are also compared to determine if parathyroid transplants have adverse effects on immune outcomes. [ Time Frame: 1 year post-transplantation ] [ Designated as safety issue: No ]

Secondary Outcome Measures:

Thymus transplantation efficacy: survival is recorded. Immune reconstitution efficacy: T cell phenotypic and functional parameters are evaluated. This will be evaluated in descriptive fashion. [ Time Frame: Ongoing ] [ Designated as safety issue: No ]
Parental parathyroid transplantation efficacy: number of subjects who are off calcium and calcitriol supplementation. The time that calcium supplementation needs to be resumed is recorded. [ Time Frame: 1 year post-transplantation ] [ Designated as safety issue: No ]
Safety. Particular attention on oligoclonal T cell development; pulmonary complications; infections; and autoimmune diseases. Dose is correlated with number of subjects who get rashes lasting >1 week with development of wheezing or oxygen requirement. [ Time Frame: Ongoing - Post-Transplantation ] [ Designated as safety issue: Yes ]
Correlations between dose and other immune parameters and factors which might affect outcome including HLA matching and thymus donor heart defect. Evaluate whether HLA-DR matching results in increased total CD4 T cell numbers. [ Time Frame: 1 year post-transplantation & ongoing ] [ Designated as safety issue: No ]

Estimated Enrollment:	40
Study Start Date:	February 2006
Estimated Study Completion Date:	June 2027
Estimated Primary Completion Date:	December 2012 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
2: Experimental Thymus Transplantation With Parathyroid Transplantation	Other: Thymus Transplantation Thymus tissue (from unrelated donor), donor, and donor's mother are screened for safety. Thymus transplantation is done in operating room under general anesthesia. Thymus is transplanted into the recipient's quadriceps. Thymus dose must be at least 4 grams/m2 body surface area (0.2 grams/kg body weight) and not >18 grams/m2 body surface area (1.0 grams/kg body weight). At time of transplantation, a skin biopsy is obtained to look for preexisting T cells. 2-3 months post-transplant allograft biopsy is done to evaluate for thymopoiesis & graft rejection. At time of biopsy, a skin biopsy is done to look for T cell clonal populations. (Allograft biopsy is not done if subject not medically stable.) Post-transplant, subjects are followed by routine research immune evaluations, using blood samples. Other: Parathyroid Transplantation Parental parathyroid donors are screened for inclusion eligibility and transplant safety. If both parents meet eligibility criteria, the parathyroid will be harvested from the parent who shares the most HLA alleles with the thymus donor. Parathyroid harvest and transplant is preferably done at the same time as the thymus transplantation. (If parathyroid transplant cannot be done at the same time, then it is done within 3 to 8 weeks of the thymus transplantation.) Parathyroid harvest is done under general anesthesia. One parathyroid gland is minced and placed in quadriceps muscle; there is no dose in mg. No biopsy is done of the parathyroid. Parathyroid donors are monitored as outpatients until recipients' discharge. Recipients' calcium and PTH levels are monitored indefinitely.
1: Experimental Thymus Transplantation Without Parathyroid Transplantation	Other: Thymus Transplantation Thymus tissue (from unrelated donor), donor, and donor's mother are screened for safety. Thymus transplantation is done in operating room under general anesthesia. Thymus is transplanted into the recipient's quadriceps. Thymus dose must be at least 4 grams/m2 body surface area (0.2 grams/kg body weight) and not >18 grams/m2 body surface area (1.0 grams/kg body weight). At time of transplantation, a skin biopsy is obtained to look for preexisting T cells. 2-3 months post-transplant allograft biopsy is done to evaluate for thymopoiesis & graft rejection. At time of biopsy, a skin biopsy is done to look for T cell clonal populations. (Allograft biopsy is not done if subject not medically stable.) Post-transplant, subjects are followed by routine research immune evaluations, using blood samples.

Arms

Assigned Interventions

2: Experimental

Thymus Transplantation With Parathyroid Transplantation

Other: Thymus Transplantation

Thymus tissue (from unrelated donor), donor, and donor's mother are screened for safety. Thymus transplantation is done in operating room under general anesthesia. Thymus is transplanted into the recipient's quadriceps. Thymus dose must be at least 4 grams/m2 body surface area (0.2 grams/kg body weight) and not >18 grams/m2 body surface area (1.0 grams/kg body weight). At time of transplantation, a skin biopsy is obtained to look for preexisting T cells. 2-3 months post-transplant allograft biopsy is done to evaluate for thymopoiesis & graft rejection. At time of biopsy, a skin biopsy is done to look for T cell clonal populations. (Allograft biopsy is not done if subject not medically stable.) Post-transplant, subjects are followed by routine research immune evaluations, using blood samples.

Other: Parathyroid Transplantation

Parental parathyroid donors are screened for inclusion eligibility and transplant safety. If both parents meet eligibility criteria, the parathyroid will be harvested from the parent who shares the most HLA alleles with the thymus donor. Parathyroid harvest and transplant is preferably done at the same time as the thymus transplantation. (If parathyroid transplant cannot be done at the same time, then it is done within 3 to 8 weeks of the thymus transplantation.) Parathyroid harvest is done under general anesthesia. One parathyroid gland is minced and placed in quadriceps muscle; there is no dose in mg. No biopsy is done of the parathyroid. Parathyroid donors are monitored as outpatients until recipients' discharge. Recipients' calcium and PTH levels are monitored indefinitely.

1: Experimental

Thymus Transplantation Without Parathyroid Transplantation

Other: Thymus Transplantation

Thymus tissue (from unrelated donor), donor, and donor's mother are screened for safety. Thymus transplantation is done in operating room under general anesthesia. Thymus is transplanted into the recipient's quadriceps. Thymus dose must be at least 4 grams/m2 body surface area (0.2 grams/kg body weight) and not >18 grams/m2 body surface area (1.0 grams/kg body weight). At time of transplantation, a skin biopsy is obtained to look for preexisting T cells. 2-3 months post-transplant allograft biopsy is done to evaluate for thymopoiesis & graft rejection. At time of biopsy, a skin biopsy is done to look for T cell clonal populations. (Allograft biopsy is not done if subject not medically stable.) Post-transplant, subjects are followed by routine research immune evaluations, using blood samples.

Detailed Description:

DiGeorge syndrome is a congenital disorder in which infants are born with defects of the thymus, heart and parathyroid gland. Complete DiGeorge Syndrome is usually fatal within the first two years of life. This trial will evaluate the role of thymus tissue dose in thymus transplantation in complete (typical) DiGeorge syndrome infants, and will continue safety assessments done in the phase I trial. Studies conducted under this protocol may lead to a Biologic License Application for this procedure for this patient population.

DiGeorge infants who have successful thymus transplants but remain with hypoparathyroidism must go to the clinic for frequent calcium levels and to the hospital for calcium infusions; these infants are at risk for seizures from low calcium. Approximately ½ of infants with profound hypoparathyroidism will develop nephrocalcinosis. This protocol has a parental parathyroid transplant arm for complete DiGeorge infants with athymia and profound hypoparathyroidism.

Eligibility

Genders Eligible for Study:	Both
Accepts Healthy Volunteers:	No

Criteria

Thymus Transplant Inclusion:

Typical DiGeorge Syndrome diagnosis
On 2 separate tests must have > 50 CD3+ T cells/cumm (or > 50 CD3+ T cells/cumm that are CD62L+ CD45RA+), or < 5% naïve phenotype T cells
Must have < 20 fold response to PHA (or < 5,000 cpm) on 2 separate tests
Must have 1 of following: 22q11 or 10p13 hemizygosity; hypocalcemia requiring replacement; congenital heart defect; CHARGE association or CHD7 mutation; or abnormal ears plus mother with diabetes (type I, type II, gestational)

Exclusion Criteria:

Must not be anticipated to need heart surgery 4 weeks prior or 3 months post-transplantation
Present or past lymphadenopathy
Rash associated with T cell infiltration of the dermis and epidermis
Rejection by the surgeon or anesthesiologist as surgical candidate
Lack of sufficient muscle tissue to accept transplant
Prior attempts at immune reconstitution (e.g, BMT or thymus transplantation)
HIV infection

Additional Inclusion Criteria for Parathyroid Transplant Recipient:

2 tests showing: intact parathyroid hormone (PTH) < 5 pg/ml when ionized calcium < 1.1 mmol/L
2 involved parents

Exclusion for Parathyroid Transplant Recipient:

Parents do not meet enrollment criteria.
Parent(s) decline to be parathyroid donor(s).

Parental Parathyroid Donor Inclusion:

> 18 years old
Answers all questionnaire items and meets safety screening criteria
Normal serum calcium
Normal PTH function
HLA typing consistent with parentage
Parent chosen for donation will share HLA-DR allele in thymus donor; if not applicable, then either parent will be selected (if meet all other criteria).
Must not be on anticoagulation or can come off for donation/transplantation

Parental Parathyroid Donor Exclusion:

Donor is only living involved parent or caretaker of the recipient
Hypoparathyroidism - low parathyroid hormone (PTH) in presence of low serum calcium and high serum phosphate
Hyperparathyroidism (or history of) - elevated PTH in presence of high serum calcium and low serum phosphate
History of cancer
Evidence of any of following: HIV-1, HIV-2, HTLV-1, HTLV-2, syphilis, hepatitis B, hepatitis C, West Nile virus, or Trypanosoma Cruzi (Chagas disease)
Elevated AST, ALT, alkaline phosphatase > 3 times upper limit of normal
History including receipt of a xenograft or risk factors for SARS, Mad Cow - Disease or smallpox. Note: if parent has Mad Cow Disease risk factors (but not active disease), parent(s) may give permission for transplantation.
CMV positive urine
Positive CMV IgM antibodies
Positive IgM anti-EBV VCA
On blood thinners and cannot stop for the parathyroid donation
Elevated PT or PTT (> ULN)
Platelets < 100,000
Positive Toxoplasma IgM
The donor will receive a history and physical; may be excluded based on PI's medical judgment
Hemoglobin < 9 g/dl
Infectious lesion on head or neck
Goiter on ultrasound
Abnormal fiberoptic laryngoscopy of vocal cords
Pregnancy
Positive HSV IgG is not an exclusion; however, post transplantation prophylaxis is needed
Positive VZV IgG is not an exclusion; however, post transplantation prophylaxis is needed
Medical concern of otolaryngologist
Concern by medical psychologist or social worker including. Parents are interviewed together and separately regarding following areas: medical history; health habits; substance use; relationships and support; education/work history; mental status/psychological history; readiness for donation.
Questionnaire (safety screening) responses can lead to exclusion.

Biological Mother of DiGeorge Subject Inclusion Criteria:

Competent to provide consent
Willing to provide blood for testing (No other inclusion/exclusion for mother)

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT00576836

Contacts

Contact: M. Louise Markert, MD, PhD	919-684-6263	marke001@mc.duke.edu
Contact: Elizabeth A. McCarthy, RN, MSN	919-684-6828	mccar006@mc.duke.edu

Locations

United States, North Carolina
Duke University Medical Center	Recruiting
Durham, North Carolina, United States, 27710
Contact: M. Louise Markert, MD, PhD 919-684-6263 marke001@mc.duke.edu
Contact: Elizabeth A. McCarthy, RN, MSN 919-684-6828 mccar006@mc.duke.edu
Principal Investigator: M. Louise Markert, MD, PhD

Sponsors and Collaborators

Duke University

National Institutes of Health (NIH)

Food and Drug Administration (FDA)

Investigators

Principal Investigator:

M. Louise Markert, MD, PhD

Duke University Medical Center, Pediatrics, Allergy & Immunology

More Information

Publications of Results:

Markert ML, Devlin BH, Alexieff MJ, Li J, McCarthy EA, Gupton SE, Chinn IK, Hale LP, Kepler TB, He M, Sarzotti M, Skinner MA, Rice HE, Hoehner JC. Review of 54 patients with complete DiGeorge anomaly enrolled in protocols for thymus transplantation: outcome of 44 consecutive transplants. Blood. 2007 May 15;109(10):4539-47. Epub 2007 Feb 6.

Responsible Party:	Duke University Medical Center, Pediatric Allergy & Immunology ( M. Louise Markert, MD, PhD, Director, Laboratory of T Cell Reconstitution; Associate Professor )
Study ID Numbers:	IRB# 4506 DCRU#932, FDA-FD-R-002606, RO1 AI 54843, RO1 AI 47040, (don't fund intervention)
Study First Received:	December 17, 2007
Last Updated:	October 22, 2008
ClinicalTrials.gov Identifier:	NCT00576836
Health Authority:	United States: Food and Drug Administration

Keywords provided by Duke University:

Thymus Transplantation
DiGeorge Syndrome
Athymia
Parathyroid Transplantation
Hypocalcemia

Hypoparathyroidism
Low T cell numbers
Immunoreconstitution
Immunodeficiency

Study placed in the following topic categories:

Calcium, Dietary
Parathyroid Diseases
Hypocalcemia
Endocrine System Diseases
DiGeorge syndrome
Endocrinopathy

Hypoparathyroidism
Velocardiofacial syndrome
Congenital Abnormalities
Immunologic Deficiency Syndromes
DiGeorge Syndrome

Additional relevant MeSH terms:

Pathologic Processes
Disease
Immune System Diseases
Syndrome

ClinicalTrials.gov processed this record on January 16, 2009