Thymus Transplantation Dose in DiGeorge #932

Phase 2

Completed

Conditions: DiGeorge Anomaly
Complete DiGeorge Anomaly
DiGeorge Syndrome
Complete DiGeorge Syndrome

Interventions: Other: Cultured Thymus Tissue Implantation with Parathyroid Transplantation
Biological: Cultured Thymus Tissue Implantation (CTTI)

Registration Number: NCT00576836

Lead Sponsor: Sumitomo Pharma Switzerland GmbH

Brief Summary: 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: 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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 7

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)

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Cultured Thymus Tissue Implantation w Parathyroid Transplant	Cultured Thymus Tissue Implantation with Parathyroid Transplantation	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.
Cultured Thymus Tissue Implantation	Cultured Thymus Tissue Implantation (CTTI)	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. .

Primary Outcome Measures

Name	Time	Method
Survival at 1 Year Post-CTTI	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.

Secondary Outcome Measures

Name	Time	Method
Immune Reconstitution Efficacy - CD4 T Cells	1 year post-CTTI	The development of total CD4 T cells at one year as measured using flow cytometry
Immune Reconstitution Efficacy - Naive CD4 T Cells	1 year post-CTTI	The development of naive CD4 T cells at one year as measured using flow cytometry
Immune Reconstitution Efficacy - Naive CD8 T Cells	1 year post-CTTI	The development of naïve CD8 T cells at one year as measured using flow cytometry.
Immune Reconstitution Efficacy - Response to Mitogens	1 year post-CTTI	The development of a T cell proliferative response to the mitogen phytohemagglutinin.
Thymus Allograft Biopsy	2 to 3 months post-CTTI	Evidence, on biopsy of the thymus tissue implanted in the recipient muscle, that shows the development of new T cells.
Immune Reconstitution Efficacy - CD3 T Cells	1 year post-CTTI	The development of total CD3 T cells at one year as measured using flow cytometry
Immune Reconstitution Efficacy - CD8 T Cells	1 year post-CTTI	The development of total CD8 T cells at one year as measured using flow cytometry
Survival at 2 Years Post-CTTI	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.