Thymus Transplantation Dose in DiGeorge #932

Study Overview
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Brief Summary
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One purpose of this study is to determine whether the amount of cultured thymus tissue implanted into DiGeorge anomaly infants has any effect on the immune outcome. Another purpose of this study is to determine whether parental parathyroid transplantation (in addition to cultured thymus tissue implantation (CTTI) can help both the immune and the calcium problems in DiGeorge infants with hypocalcemia. [Funding Source - FDA Office of Orphan Products Development (OOPD)]

Detailed Description
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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 cultured thymus tissue dose in cultured thymus tissue implantation (CTTI) in complete (typical) DiGeorge anomaly infants, and continues safety assessments. DiGeorge infants who have successful CTTIs 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.

Official Title
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Dose Study of Thymus Transplantation in DiGeorge Anomaly, IND 9836, #932.1

Conditions
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DiGeorge Anomaly, DiGeorge Syndrome, Complete DiGeorge Anomaly, Complete DiGeorge Syndrome

Intervention / Treatment
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* Biological: Cultured Thymus Tissue Implantation (CTTI)
* Other: Cultured Thymus Tissue Implantation with Parathyroid Transplantation


Participation Criteria
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Eligibility Criteria
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Thymus Transplant Inclusion Criteria: A parent or guardian of the DGS subject signed the consent form. Medical screening was completed. For a diagnosis of DGS, the subject had to have one of the following: Congenital heart disease; Hypocalcemia requiring replacement; 22q11.2 hemizygosity or 10p13 hemizygosity; CHARGE association or CHD7 mutation; A subject with abnormal ears whose mother had diabetes (type I, type II, or gestational). To meet the criteria of typical complete DiGeorge Anomaly (cDGA), the subject had to have either: Circulating CD3+ T cell count by flow cytometry < 50/mm3 OR Circulating CD3+ T cells that were also positive for Cluster of Differentiation 45RA (CD45RA)+ CD62L+ and were < 50/mm3 or less than 5% of total T cells. Thymus Transplant Exclusion Criteria: Had heart surgery less than 4 weeks prior to projected implant date; Heart surgery anticipated within 3 months after the proposed time of implantation; 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 a transplant of 4 g/m2 body surface area (BSA) or 0.2 g/kg subject bodyweight; Had human immunodeficiency virus (HIV) infection; Had prior attempts at immune reconstitution, such as bone marrow transplant or previous thymus transplantation; Ventilator support or positive pressure support: Subjects had to be off ventilator or other pressure support such as continuous positive airway pressure (CPAP) or bi-level positive airway pressure (BiPAP) support for 2 weeks prior to enrollment. If the subject was enrolled and was placed back on ventilator or pressure support, the subject had to be able to be weaned off and remain off ventilator or pressure support for 2 weeks. If the subject could not be successfully weaned off ventilator or pressure support, the subject was to be withdrawn from the study. Additional Inclusion Criteria for Parathyroid Transplant Recipient: 2 tests in patient showing: intact parathyroid hormone (PTH) < 5 pg/ml when ionized calcium < 1.1 mmol/L All inclusion criteria for thymus transplant must be met 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. 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)
Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cultured Thymus Tissue Implantation w Parathyroid Transplant<br>Cultured Thymus Tissue Implantation With Parathyroid Tissue Transplantation. Subjects who were enrolled in this arm underwent cultured thymus tissue implantation with parathyroid transplantation, if eligible. No specific dose was assigned. The thymus tissue dose was the number of grams of cultured thymus tissue divided by the weight of the recipient in kg or per square meter of body surface area of the recipient. There was a one time administration of the cultured thymus tissue and parathyroid tissue. | Other: Cultured Thymus Tissue Implantation with Parathyroid Transplantation<br>* Parental parathyroid donors screened for eligibility and safety. If both parents meet eligibility criteria, the parathyroid will be harvested from parent who shares the most Human Leukocyte Antigens (HLA) alleles with thymus donor. Parathyroid harvest & transplant preferably done at same time as CTTI. (If parathyroid transplant cannot be done at same time, then it is done within 3-8 weeks of CTTI.) 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.<br>* Other names: CTTI and Parathyroid Transplant;|
| Experimental: Cultured Thymus Tissue Implantation<br>Cultured Thymus Tissue Implantation. Subjects who were enrolled in this arm underwent cultured thymus tissue implantation (CTTI) only. No specific dose was assigned. The thymus tissue dose was the number of grams of cultured thymus tissue divided by the weight of the recipient in kg or per square meter of body surface area of the recipient. There was a one time administration of the cultured thymus tissue. . | Biological: Cultured Thymus Tissue Implantation (CTTI)<br>* Thymus tissue (from unrelated donor), thymus donor, and thymus donor's birth mother screened for safety. CTTI was done under general anesthesia. Cultured thymus tissue was implanted 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 CTTI, skin biopsy was obtained to look for preexisting T cells. 2-3 months post-CTTI allograft biopsy was 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-CTTI, subjects followed by immune evaluations, using blood samples.<br>* Other names: CTTI;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Survival at 1 Year Post-CTTI | Survival at 1 year post CTTI was assessed using the Kaplan Meier Estimated Survival. This mathematical function estimates the survival for a certain length of time. | 1 year post-CTTI | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Survival at 2 Years Post-CTTI | Survival at 2 years post CTTI was assessed using the Kaplan Meier Estimated Survival. This mathematical function estimates the survival for a certain length of time. | 2 years post-CTTI | 
| Immune Reconstitution Efficacy - CD3 T Cells | The development of total CD3 T cells at one year as measured using flow cytometry | 1 year post-CTTI | 
| Immune Reconstitution Efficacy - CD4 T Cells | The development of total CD4 T cells at one year as measured using flow cytometry | 1 year post-CTTI | 
| Immune Reconstitution Efficacy - CD8 T Cells | The development of total CD8 T cells at one year as measured using flow cytometry | 1 year post-CTTI | 
| Immune Reconstitution Efficacy - Naive CD4 T Cells | The development of naive CD4 T cells at one year as measured using flow cytometry | 1 year post-CTTI | 
| Immune Reconstitution Efficacy - Naive CD8 T Cells | The development of naïve CD8 T cells at one year as measured using flow cytometry. | 1 year post-CTTI | 
| Immune Reconstitution Efficacy - Response to Mitogens | The development of a T cell proliferative response to the mitogen phytohemagglutinin. | 1 year post-CTTI | 
| Thymus Allograft Biopsy | Evidence, on biopsy of the thymus tissue implanted in the recipient muscle, that shows the development of new T cells. | 2 to 3 months post-CTTI | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Thymus Transplantation, DiGeorge Syndrome, DiGeorge Anomaly, Athymia, Parathyroid Transplantation, Hypocalcemia, Hypoparathyroidism, Low T cell numbers, Immunoreconstitution, Immunodeficiency, Complete DiGeorge, Complete DiGeorge Anomaly, Typical DiGeorge, Cultured Thymus Tissue Implantation (CTTI)