Thymus Transplantation Dose in DiGeorge #932

This study is ongoing, but not recruiting participants.
Sponsor:
Collaborators:
Information provided by (Responsible Party):
M. Louise Markert, Duke University Medical Center
ClinicalTrials.gov Identifier:
NCT00576836
First received: December 17, 2007
Last updated: March 31, 2014
Last verified: March 2014
  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. [Funding Source - FDA OOPD]


Condition Intervention Phase
DiGeorge Anomaly
DiGeorge Syndrome
Complete DiGeorge Anomaly
Complete DiGeorge Syndrome
Biological: Thymus Tissue for Transplantation
Other: Parathyroid Tissue for Transplantation
Phase 2

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:


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 Tissue for Transplantation With Parathyroid Tissue for Transplantation
Biological: Thymus Tissue for 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 Name: Thymus Tissue for Transplantation
Other: Parathyroid Tissue for 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 Tissue for Transplantation Without Parathyroid Tissue for Transplantation
Biological: Thymus Tissue for 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 Name: Thymus Tissue for Transplantation

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
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, see Learn About Clinical Studies.

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
M. Louise Markert
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: 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: March 31, 2014
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 July 26, 2014