Thymus Transplantation Safety-Efficacy

Study Overview
=================
Brief Summary
-----------------
Complete DiGeorge anomaly (cDGA) is a disorder in which there is no thymus function. With no thymus function, bone marrow stem cells do not develop into educated T cells, which fight infection. Without successful treatment, patients with cDGA must remain in reverse isolation to prevent infection and subsequent death. Cultured thymus tissue with and without immunosuppression (drugs given before and after implantation) has resulted in the development of good T cell function in subjects with complete DiGeorge anomaly. This expanded access study continues cultured thymus tissue safety and efficacy research for the treatment of complete DiGeorge anomaly. Eligible participants receive cultured thymus tissue. Immune function testing is continued for one year post-implantation.

Detailed Description
-----------------
Complete DiGeorge anomaly (cDGA) is a congenital disorder characterized by athymia. Without successful treatment, patients with cDGA must remain in reverse isolation to prevent infection and subsequent death. In patients with cDGA, implantation of cultured thymus tissue with and without immunosuppression has resulted in diverse T cell development and good T cell function. The purpose of this expanded access study is to continue cultured thymus tissue safety and efficacy research for the treatment of athymia in patients with cDGA. Until administration of cultured thymus tissue is FDA approved as standard care for cDGA, research study participation is the only means by which a patient may have access to this potentially life-saving procedure. This protocol includes 4 groups: one for subjects who do not require immunosuppression; and 3 immunosuppression groups for subjects with different T cell function levels to be suppressed adequately. Eligible subjects receive cultured thymus tissue and may undergo an allograft biopsy. Protocol specified studies continue until approximately one year post-implantation. Study participation lasts two years.

Official Title
-----------------
Safety and Efficacy of Thymus Transplantation in Complete DiGeorge Anomaly, IND#9836

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

Intervention / Treatment
-----------------
* Biological: Cultured Thymus Tissue
* Procedure: Blood Draw
* Drug: Rabbit anti-thymocyte globulin
* Drug: Cyclosporine
* Drug: Tacrolimus
* Drug: Methylprednisolone or Prednisolone
* Drug: Mycophenolate mofetil


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion criteria for implantation of cultured thymus tissue: Must have 1 of following: 22q11.2ds or 10p13 hemizygosity; hypocalcemia requiring replacement; congenital heart disease; or CHARGE syndrome or CHD7 mutation Complete DiGeorge: <50 CD3+ T cells/cumm or <50 CD3+ T cells/cumm that are CD62L+ CD45RA+, or <5% of CD3+ cells are CD62L+ CD45RA+ Atypical DiGeorge subjects must have, or have had, a rash. Group 1 •Typical cDGA whose T cells have a phytohemagglutinin (PHA) response of < 5,000 counts per minute (cpm) and < 20 fold PHA response. Group 2 •Typical cDGA whose T cells have a PHA response of >5,000 cpm and <50,000 cpm and >20 fold PHA response. Group 3 Typical cDGA whose T cells have a PHA response of >50,000 cpm. Typical cDGA with maternal engraftment Atypical cDGA whose T cells have a PHA response of <40,000 cpm when on immunosuppression or <75,000 cpm to PHA when not on immunosuppression. Atypical cDGA with group 3 PHA response & maternal engraftment Group 4 Atypical cDGA with PHA responses of >75,000 cpm while on no immunosuppression or a PHA responses of >40,000 cpm while on immunosuppression. Atypical cDGA with maternal engraftment and group 4 PHA response Exclusion criteria for implantation of cultured thymus tissue: Heart surgery conducted less than 4 weeks prior to projected implantation date. Heart surgery anticipated within 3 months after the proposed time of implantation Rejection by surgeon or anesthesiologist as surgical candidate Lack of sufficient muscle tissue to accept a transplant HIV infection Prior attempts at immune reconstitution, such as bone marrow transplant or previous thymus transplant CMV infection: For Groups 2, 3, and 4 CMV infection documented by >500 copies/ml in the blood by PCR on two consecutive assays. Ventilator Dependence or Positive Pressure Support: Ventilator support or positive pressure support, such as Continuous Positive Airway Pressure (CPAP) or Bi-level Positive Airway Pressure (BiPAP) support for a condition that is deemed to be severe or irreversible or which renders the subject too clinically unstable to undergo the procedures.
Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Arms and Interventions

| Intervention/Treatment |
| --- |
|Biological: Cultured Thymus Tissue|Potential recipients of cultured thymus tissue are screened for eligibility. The thymus tissue (from an unrelated donor), the donor, and the donor's mother are screened for safety. Cultured thymus tissue is implanted under general anesthesia in the operating room. Cultured thymus tissue is placed into the subject's quadriceps. Two to three months post-implantation, if medically stable, subjects may undergo an allograft biopsy. Subjects undergo laboratory testing for approximately one-year post-implantation. At approximately year 2 post-implantation, subjects are contacted for data collection.|
|Procedure: Blood Draw|nan|
|Drug: Rabbit anti-thymocyte globulin|Three IV doses of 2 mg/kg RATGAM are given prior to implantation of cultured thymus tissue for immune suppression groups 2, 3, and 4. Each dose is given over 12 hours. RATGAM is usually given on days -5, -4, and -3 prior to implantation of cultured thymus tissue.|
|Drug: Cyclosporine|Csa may be given every 8 or every 12 hours orally or IV before and after implantation of cultured thymus tissue for immune suppression groups 3 and 4. The Csa dose is dependent on T cell numbers and the target CSA trough levels. Csa is weaned as per protocol.|
|Drug: Tacrolimus|If unable to tolerate cyclosporine, then FK506 is given. FK506 may be given every 8 or every 12 hours orally or IV before and after implantation of cultured thymus tissue. FK506 dose is dependent on T cell numbers and the target FK506 trough levels. FK506 is weaned as per protocol.|
|Drug: Methylprednisolone or Prednisolone|Steroids IV or orally may be given before and/or after implantation of cultured thymus tissue. Steroid administration and dosage depends on T cell numbers. Steroids are weaned as per protocol.|
|Drug: Mycophenolate mofetil|Mycophenolate mofetil (MMF) may be given if the T cell count remains elevated 5 days after implantation of cultured thymus tissue. If MMF is given, the dose is 15 mg/kg/dose every 8 hours IV or orally. MMF may be stopped at 35 days or continued for up to six months after implantation of cultured thymus tissue.|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Thymus Transplantation, DiGeorge Anomaly, Immunoreconstitution, Immunodeficiency, Complete DiGeorge, Typical DiGeorge, Atypical DiGeorge, Complete DiGeorge Anomaly, Cultured Thymus Tissue Implantation, Cultured Thymus Tissue, Congenital Athymia, DiGeorge Syndrome, Athymia, Low T cell numbers