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Thymus Transplantation Safety-Efficacy

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ClinicalTrials.gov Identifier: NCT01220531
Expanded Access Status : Available
First Posted : October 14, 2010
Last Update Posted : August 25, 2021
Sponsor:
Collaborators:
National Institutes of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Enzyvant Therapeutics GmbH
Information provided by (Responsible Party):
M. Louise Markert, Duke University

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.


Condition or disease Intervention/treatment
Complete DiGeorge Anomaly DiGeorge Syndrome DiGeorge Anomaly Complete DiGeorge Syndrome Biological: Cultured Thymus Tissue Procedure: Blood Draw Drug: Rabbit anti-thymocyte globulin Drug: Cyclosporine Drug: Tacrolimus Drug: Methylprednisolone or Prednisolone Drug: Mycophenolate mofetil

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.

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Study Type : Expanded Access
Expanded Access Type : Intermediate-size Population, Treatment IND/Protocol
Official Title: Safety and Efficacy of Thymus Transplantation in Complete DiGeorge Anomaly, IND#9836



Intervention Details:
  • 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.
    Other Name: Thymus Tissue Transplant
  • Procedure: Blood Draw
    Other Name: Venipuncture
  • 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.
    Other Name: RATGAM
  • 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.
    Other Name: Csa
  • 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.
    Other Name: FK506
  • 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.
    Other Name: Steroids
  • 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.
    Other Names:
    • MMF
    • CellCept

Information from the National Library of Medicine

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Ages Eligible for Study:   Child, Adult, Older Adult
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01220531


Contacts
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Contact: M. Louise Markert, M.D., Ph.D 919-475-6011 marke001@mc.duke.edu
Contact: Stephanie Gupton, RN, CPNP 919-684-4704 stephanie.gupton@dm.duke.edu

Locations
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United States, North Carolina
Duke University Medical Center Available
Durham, North Carolina, United States, 27710
Contact: M. Louise Markert, M.D., Ph.D    919-475-6011    marke001@mc.duke.edu   
Contact: Stephanie Gupton, RN, CPNP    919-684-4704    stephanie.gupton@dm.duke.edu   
Principal Investigator: M. Louise Markert, M.D., Ph.D         
Sponsors and Collaborators
M. Louise Markert
National Institutes of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Enzyvant Therapeutics GmbH
Investigators
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Principal Investigator: M. Louise Markert, M.D., Ph.D Duke University Medical Center, Pediatrics, Allergy & Immunology
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.
Markert ML and Devlin BH. Thymic reconstitution (in Rich RR, Shearer WT, Fleischer T, Schroeder HW, Weyand CM, Frew A, eds., Clinical Immunology 3rd edn., Elsevier, Edinburgh) p 1253-1262, 2008.
Markert ML. Defects in thymic development (in Sullivan KE, Stiehm ER, eds., Stiehm's Immune Deficiencies, 2nd edition, Academic Press/Elsevier) p 357 - 379, 2020.
Markert ML, McCarthy EA, Gupton SE, Lim AP. Cultured thymic tissue transplantation (in Sullivan KE, Stiehm ER, eds., Stiehm's Immune Deficiencies, 2nd edition, Academic Press/Elsevier) p 1229 - 1239, 2020.

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Responsible Party: M. Louise Markert, Professor of Pediatrics, Duke University
ClinicalTrials.gov Identifier: NCT01220531    
Other Study ID Numbers: Pro00025966
2R01AI047040-11A2 ( U.S. NIH Grant/Contract )
5K12HD043494-09 ( U.S. NIH Grant/Contract )
First Posted: October 14, 2010    Key Record Dates
Last Update Posted: August 25, 2021
Last Verified: August 2021
Keywords provided by M. Louise Markert, Duke University:
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
Additional relevant MeSH terms:
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DiGeorge Syndrome
Craniosynostoses
Marfan Syndrome
Arachnodactyly
Congenital Abnormalities
Syndrome
Disease
Pathologic Processes
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
Synostosis
Dysostoses
Bone Diseases, Developmental
Bone Diseases
Connective Tissue Diseases
Limb Deformities, Congenital