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Thymus Transplantation Safety-Efficacy

Primary Purpose

Complete DiGeorge Anomaly, DiGeorge Syndrome, DiGeorge Anomaly

Status
Approved for marketing
Phase
Locations
United States
Study Type
Expanded Access
Intervention
Cultured Thymus Tissue
Blood Draw
Rabbit anti-thymocyte globulin
Cyclosporine
Tacrolimus
Methylprednisolone or Prednisolone
Mycophenolate mofetil
Sponsored by
Enzyvant Therapeutics GmBH
About
Eligibility
Locations
Outcomes
Full info

About this trial

This is an expanded access trial for Complete DiGeorge Anomaly focused on measuring DiGeorge Anomaly, Thymus Transplantation, DiGeorge Syndrome, Athymia, Low T cell numbers, Immunoreconstitution, Immunodeficiency, Complete DiGeorge, Typical DiGeorge, Atypical DiGeorge, Complete DiGeorge Anomaly, Cultured Thymus Tissue Implantation, Cultured Thymus Tissue, Congenital Athymia

Eligibility Criteria

undefined - undefined (Child, Adult, Older Adult)All SexesDoes not accept healthy volunteers

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.

Sites / Locations

  • John W. Sleasman

Outcomes

Primary Outcome Measures

Secondary Outcome Measures

Full Information

First Posted
September 22, 2010
Last Updated
March 21, 2022
Sponsor
Enzyvant Therapeutics GmBH
Collaborators
National Institutes of Health (NIH), National Institute of Allergy and Infectious Diseases (NIAID), Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
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1. Study Identification

Unique Protocol Identification Number
NCT01220531
Brief Title
Thymus Transplantation Safety-Efficacy
Official Title
Safety and Efficacy of Thymus Transplantation in Complete DiGeorge Anomaly, IND#9836
Study Type
Expanded Access

2. Study Status

Record Verification Date
October 2021
Overall Recruitment Status
Approved for marketing
Study Start Date
undefined (undefined)
Primary Completion Date
undefined (undefined)
Study Completion Date
undefined (undefined)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Enzyvant Therapeutics GmBH
Collaborators
National Institutes of Health (NIH), National Institute of Allergy and Infectious Diseases (NIAID), Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)

4. Oversight

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Complete DiGeorge Anomaly, DiGeorge Syndrome, DiGeorge Anomaly, Complete DiGeorge Syndrome
Keywords
DiGeorge Anomaly, Thymus Transplantation, DiGeorge Syndrome, Athymia, Low T cell numbers, Immunoreconstitution, Immunodeficiency, Complete DiGeorge, Typical DiGeorge, Atypical DiGeorge, Complete DiGeorge Anomaly, Cultured Thymus Tissue Implantation, Cultured Thymus Tissue, Congenital Athymia

7. Study Design

8. Arms, Groups, and Interventions

Intervention Type
Biological
Intervention Name(s)
Cultured Thymus Tissue
Other Intervention Name(s)
Thymus Tissue Transplant
Intervention Description
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.
Intervention Type
Procedure
Intervention Name(s)
Blood Draw
Other Intervention Name(s)
Venipuncture
Intervention Type
Drug
Intervention Name(s)
Rabbit anti-thymocyte globulin
Other Intervention Name(s)
RATGAM
Intervention Description
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.
Intervention Type
Drug
Intervention Name(s)
Cyclosporine
Other Intervention Name(s)
Csa
Intervention Description
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.
Intervention Type
Drug
Intervention Name(s)
Tacrolimus
Other Intervention Name(s)
FK506
Intervention Description
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.
Intervention Type
Drug
Intervention Name(s)
Methylprednisolone or Prednisolone
Other Intervention Name(s)
Steroids
Intervention Description
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.
Intervention Type
Drug
Intervention Name(s)
Mycophenolate mofetil
Other Intervention Name(s)
MMF, CellCept
Intervention Description
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.

10. Eligibility

Sex
All
Accepts Healthy Volunteers
No
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.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
John W. Sleasman, M.D.
Organizational Affiliation
Duke University Medical Center, Pediatrics, Allergy & Immunology
Official's Role
Principal Investigator
Facility Information:
Facility Name
John W. Sleasman
City
Durham
State/Province
North Carolina
ZIP/Postal Code
27710
Country
United States

12. IPD Sharing Statement

Citations:
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17284531
Citation
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Thymus Transplantation Safety-Efficacy

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