Thymus Transplantation Dose in DiGeorge #932 - Full Text View

Sponsor:	Duke University
Collaborators:	National Institutes of Health (NIH) Food and Drug Administration (FDA) National Institute of Allergy and Infectious Diseases (NIAID) Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
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 anomaly 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 Anomaly DiGeorge Syndrome Complete DiGeorge Anomaly Complete DiGeorge Syndrome	Other: Thymus Transplantation Other: Parathyroid Transplantation	Phase II

Study Type:	Interventional
Study Design:	Allocation: Non-Randomized Endpoint Classification: Safety/Efficacy Study Intervention Model: Parallel Assignment Masking: Open Label Primary Purpose: Treatment
Official Title:	Dose Study of Thymus Transplantation in DiGeorge Anomaly, IND 9836, #932.1

Resource links provided by NLM:

Genetics Home Reference related topics: 17q21.31 microdeletion syndrome 22q11.2 deletion syndrome Baller-Gerold syndrome Crouzon syndrome tetrasomy 18p

MedlinePlus related topics: Calcium

Drug Information available for: Parathyroid

U.S. FDA Resources

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. [ 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 is 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 ]

Enrollment:	28
Study Start Date:	February 2006
Estimated Study Completion Date:	June 2027
Primary Completion Date:	August 2010 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
Experimental: 2 Thymus Transplantation With Parathyroid Transplantation	Other: Thymus Transplantation Thymus tissue (from unrelated donor), donor, and donor's mother screened for safety. Thymus transplantation done under general anesthesia. Thymus transplanted into quadriceps. Thymus dose at least 4grams/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 transplant, skin biopsy obtained to look for preexisting T cells. 2-3 months post-transplant allograft biopsy done to evaluate for thymopoiesis & graft rejection. At time of biopsy, skin biopsy done to look for T cell clonal populations. (Allograft biopsy not done if subject medically unstable.) Post-transplant, subjects followed by immune evaluations, using blood samples. Other Names: Thymus Tissue IND 9836 Other: Parathyroid Transplantation Parental parathyroid donors screened for eligibility and transplant safety. If both parents meet eligibility criteria, the parathyroid will be harvested from parent who shares the most HLA alleles with thymus donor. Parathyroid harvest & transplant preferably done at same time as thymus transplant. (If parathyroid transplant cannot be done at same time, then it is done within 3-8 weeks of thymus transplant.) Parathyroid harvest done under general anesthesia. One parathyroid gland is minced & placed in quadriceps muscle; there is no dose in mg. No biopsy done of the parathyroid. Parathyroid donors are monitored as outpatients until recipients' discharge. Recipients' calcium and PTH levels are monitored indefinitely.
Experimental: 1 Thymus Transplantation Without Parathyroid Transplantation	Other: Thymus Transplantation Thymus tissue (from unrelated donor), donor, and donor's mother screened for safety. Thymus transplantation done under general anesthesia. Thymus transplanted into quadriceps. Thymus dose at least 4grams/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 transplant, skin biopsy obtained to look for preexisting T cells. 2-3 months post-transplant allograft biopsy done to evaluate for thymopoiesis & graft rejection. At time of biopsy, skin biopsy done to look for T cell clonal populations. (Allograft biopsy not done if subject medically unstable.) Post-transplant, subjects followed by immune evaluations, using blood samples. Other Names: Thymus Tissue IND 9836

Arms

Assigned Interventions

Experimental: 2

Thymus Transplantation With Parathyroid Transplantation

Other: Thymus Transplantation

Thymus tissue (from unrelated donor), donor, and donor's mother screened for safety. Thymus transplantation done under general anesthesia. Thymus transplanted into quadriceps. Thymus dose at least 4grams/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 transplant, skin biopsy obtained to look for preexisting T cells. 2-3 months post-transplant allograft biopsy done to evaluate for thymopoiesis & graft rejection. At time of biopsy, skin biopsy done to look for T cell clonal populations. (Allograft biopsy not done if subject medically unstable.) Post-transplant, subjects followed by immune evaluations, using blood samples.

Other Names:

Thymus Tissue
IND 9836

Other: Parathyroid Transplantation

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

Experimental: 1

Thymus Transplantation Without Parathyroid Transplantation

Other: Thymus Transplantation

Thymus tissue (from unrelated donor), donor, and donor's mother screened for safety. Thymus transplantation done under general anesthesia. Thymus transplanted into quadriceps. Thymus dose at least 4grams/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 transplant, skin biopsy obtained to look for preexisting T cells. 2-3 months post-transplant allograft biopsy done to evaluate for thymopoiesis & graft rejection. At time of biopsy, skin biopsy done to look for T cell clonal populations. (Allograft biopsy not done if subject medically unstable.) Post-transplant, subjects followed by immune evaluations, using blood samples.

Other Names:

Thymus Tissue
IND 9836

Detailed Description:

DiGeorge anomaly is a congenital disorder in which infants are born with defects of the thymus, heart and parathyroid gland. Complete DiGeorge Anomaly is usually fatal within the first two years of life. This trial evaluates the role of thymus tissue dose in thymus transplantation in complete (typical) DiGeorge anomaly infants, and continues safety assessments.

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 had 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 Complete DiGeorge Anomaly 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
Ventilator Dependence

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

Locations

United States, North Carolina
Duke University Medical Center
Durham, North Carolina, United States, 27710

Sponsors and Collaborators

Duke University

National Institutes of Health (NIH)

Food and Drug Administration (FDA)

National Institute of Allergy and Infectious Diseases (NIAID)

Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)

Investigators

Principal Investigator:

M. Louise Markert, MD, PhD

Duke University Medical Center, Pediatrics, Allergy & Immunology

More Information

Publications:

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.

Markert ML, Devlin BH, McCarthy EA. Thymus transplantation. Clin Immunol. 2010 May;135(2):236-46. Epub 2010 Mar 16. Review.

Markert ML, Devlin BH, Chinn IK, McCarthy EA, Li YJ. Factors affecting success of thymus transplantation for complete DiGeorge anomaly. Am J Transplant. 2008 Aug;8(8):1729-36. Epub 2008 Jun 28.

Markert ML, Li J, Devlin BH, Hoehner JC, Rice HE, Skinner MA, Li YJ, Hale LP. Use of allograft biopsies to assess thymopoiesis after thymus transplantation. J Immunol. 2008 May 1;180(9):6354-64.

Hudson LL, Louise Markert M, Devlin BH, Haynes BF, Sempowski GD. Human T cell reconstitution in DiGeorge syndrome and HIV-1 infection. Semin Immunol. 2007 Oct;19(5):297-309. Epub 2007 Nov 26. Review.

Markert ML, Devlin BH, Chinn IK, McCarthy EA. Thymus transplantation in complete DiGeorge anomaly. Immunol Res. 2009;44(1-3):61-70.

Chinn IK, Devlin BH, Li YJ, Markert ML. Long-term tolerance to allogeneic thymus transplants in complete DiGeorge anomaly. Clin Immunol. 2008 Mar;126(3):277-81. Epub 2007 Dec 26.

Markert ML, Sarzotti M, Ozaki DA, Sempowski GD, Rhein ME, Hale LP, Le Deist F, Alexieff MJ, Li J, Hauser ER, Haynes BF, Rice HE, Skinner MA, Mahaffey SM, Jaggers J, Stein LD, Mill MR. Thymus transplantation in complete DiGeorge syndrome: immunologic and safety evaluations in 12 patients. Blood. 2003 Aug 1;102(3):1121-30. Epub 2003 Apr 17.

Responsible Party:	M. Louise Markert, MD, PhD, Associate Professor, Duke University Medical Center, Pediatric Allergy & Immunology
ClinicalTrials.gov Identifier:	NCT00576836 History of Changes
Other Study ID Numbers:	Pro00016144 #932, FDA-FD-R-002606, 2R01AI047040-11A2, R56 Bridge R01AI4704011A1, 5K12HD043494-09, R01AI054843, R01AI047040, 3R56AI047040-11A1S1
Study First Received:	December 17, 2007
Last Updated:	July 28, 2011
Health Authority:	United States: Food and Drug Administration; United States: Institutional Review Board

Keywords provided by Duke University:

Thymus Transplantation
DiGeorge Syndrome
DiGeorge Anomaly
Athymia
Parathyroid Transplantation
Hypocalcemia
Hypoparathyroidism

Low T cell numbers
Immunoreconstitution
Immunodeficiency
Complete DiGeorge
Complete DiGeorge Anomaly
Typical DiGeorge

Additional relevant MeSH terms:

Congenital Abnormalities
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
Chromosome Disorders
Genetic Diseases, Inborn
Hypoparathyroidism
Parathyroid Diseases
Endocrine System Diseases

ClinicalTrials.gov processed this record on February 13, 2012