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Thymus Transplantation With Immunosuppression (884)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT00579709
Recruitment Status : Active, not recruiting
First Posted : December 24, 2007
Last Update Posted : July 12, 2018
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)
Enzyvant Therapeutics GmbH
Information provided by (Responsible Party):
M. Louise Markert, Duke University

Brief Summary:
The research purpose is to determine if thymus transplantation with immunosuppression is a safe and effective treatment for complete DiGeorge anomaly. The research includes studies to evaluate whether thymus transplantation results in complete DiGeorge anomaly subjects developing a normal immune system.

Condition or disease Intervention/treatment Phase
DiGeorge Syndrome DiGeorge Anomaly Complete DiGeorge Anomaly Complete DiGeorge Syndrome Biological: Thymus Tissue for Transplantation Phase 1

Detailed Description:

DiGeorge anomaly is a complex of cardiac defects, parathyroid deficiency, and thymus absence, resulting in profound T-cell deficiency. There is a spectrum of disease in DiGeorge anomaly with respect to all three defects. For complete DiGeorge anomaly subjects with severe T cell defect, the PI had shown that thymus transplantation is safe and efficacious without pretransplantation immunosuppression and with pretransplantation Thymoglobulin and cyclosporine.

Some DiGeorge patients have very poor T cell function and are at risk of death from infection or other immune problems; however, these patients have enough T cell function to reject grafts. This protocol was designed for these patients. Atypical phenotype and some typical phenotype DiGeorge subjects were included in this protocol.

Atypical complete DiGeorge anomaly patients have rash, lymphadenopathy, and oligoclonal T cell proliferations. The T cells have no markers of thymic function (they do not co-express CD45RA and CD62L; they do not contain T cell receptor rearrangement excision circles, TRECs).

Typical complete DiGeorge anomaly patients in this protocol are those whose PHA response >20 fold. Although these patients have very low T cell function, it may be enough to reject a transplant, so Thymoglobulin was used.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 15 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Thymus Transplantation With Immunosuppression, #884
Study Start Date : July 2002
Actual Primary Completion Date : December 2006
Estimated Study Completion Date : June 2027

Arm Intervention/treatment
Experimental: 1
Thymus Tissue for Transplantation
Biological: Thymus Tissue for Transplantation

3 Thymoglobulin doses given prior to thymus tx. Atypical subjects given Cyclosporine (Csa) pre-tx. Desired Csa concentration 180-300ng/ml. If post-tx T cell count remained <4000/cumm Csa weaned over 8 weeks. If T cell >4,000/cumm, Csa held at 180-300ng/ml.

Thymus tissue, donor, & mother of donor were screened for transplant safety. In operating room, thymic slices were transplanted into quadriceps muscle in 1 or both legs.

Subjects had routine blood research immune evaluations. 2-3 months post-tx, open biopsy of allograft. Immune blood studies continued on surviving subjects until January 2010. Biological Mother: Mother provided blood sample used for DNA extraction, to identify/look for maternal T cell presence in recipient pre-tx, and/or for immune testing post-tx.

Other Names:
  • IND 9836
  • Thymus Tissue Transplant

Primary Outcome Measures :
  1. Safety & tolerability of Thymoglobulin and cyclosporine followed by thymus transplantation: Survival at 1 year post-transplantation. [ Time Frame: 1 year post-transplantation ]

Secondary Outcome Measures :
  1. Use of additional post transplant immunosuppression after that listed in the protocol. [ Time Frame: The post thymus transplantation period ]
    Use of additional post transplant immunosuppression after that listed in the protocol.

  2. Allograft biopsy used to evaluate graft rejection [ Time Frame: 2 to 4 months post-transplant ]
    Evidence of thymus allograft rejection by immunohistochemistry of biopsy

  3. CD3 count [ Time Frame: 10 - 14 months post-transplantation ]
    CD3 count in cells/mm3

  4. Thymopoiesis [ Time Frame: 2-4 months after thymus transplantation ]
    Evidence of thymopoiesis in thymus allograft by immunohistochemistry of a biopsy

  5. CD4 count [ Time Frame: 10-14 months after thymus transplantation ]
    CD4 count in cells/mm3

  6. CD8 count [ Time Frame: 10-14 months after thymus transplantation ]
    CD8 count in cells/mm3

  7. naive CD4 count [ Time Frame: 10-14 months after thymus transplantation ]
    naive CD4 count in cells/mm3

  8. naive CD8 count [ Time Frame: 10-14 months after thymus transplantation ]
    naive CD8 count in cells/mm3

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

Transplant Inclusion

  • No age limit
  • Thyroid studies must be done and if abnormal, must be on therapy

DiGeorge diagnosis - must have 1 symptom from the following list:

  • Heart defect
  • Hypocalcemia requiring replacement
  • 22q11 hemizygosity
  • 10p13 hemizygosity
  • CHARGE association
  • Abnormal ears plus mother with diabetes (type I, type II, or gestational)

Atypical Diagnosis:

  • Must have, or have had, a rash. If rash present, biopsy of rash must show T cells in skin. If rash & adenopathy resolved, must still have oligoclonal T cells.
  • Within 1 month of tx must have PHA response >20 fold above background or >5,000 cpm, whichever is higher, or response can be < this.
  • Circulating CD3+ T cells >50/mm3 but CD45RA+CD62L+CD3+ T cells <50/mm or <5% of CD3 count, whichever is higher (must be done 2x)
  • Immunoscope with >40% oligoclonal TCRBV families. A 2nd test per sponsor discretion if T cell numbers increase or activation status changes.
  • If TREC done pre-tx must have TRECs <100 per 100,000 CD3+ cells.

Typical Diagnosis:

  • Circulating CD3+ CD45RA+ CD62L+ T cells and <50/mm3 or <5% of total T cells
  • PHA response >20 fold above background or >5,000 cpm, whichever is higher.
  • 2 studies must show similar immunological findings qualify for this study.
  • TRECs, if done, should be <100/100,000 CD3 cells

Transplant Exclusion:

  • Heart surgery <4 weeks pre-tx date
  • Heart surgery anticipated w/in 3 months of proposed tx
  • Rejection by surgeon or anesthesiologist as surgical candidates
  • Lack of sufficient muscle tissue to accept 0.2 grams/kg transplant

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 identifier (NCT number): NCT00579709

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United States, North Carolina
Duke University Medical Center
Durham, North Carolina, United States, 27710
Sponsors and Collaborators
M. Louise Markert
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)
Enzyvant Therapeutics GmbH
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Principal Investigator: M. Louise Markert, MD, PhD Duke University Medical Center, Pediatrics, Allergy & Immunology

Publications of Results:
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, 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.

Other Publications:
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Responsible Party: M. Louise Markert, Professor of Pediatrics, Duke University Identifier: NCT00579709     History of Changes
Other Study ID Numbers: Pro00013734
R01AI047040 ( U.S. NIH Grant/Contract )
R01AI054843 ( U.S. NIH Grant/Contract )
3R56AI047040-11A1S1 ( U.S. NIH Grant/Contract )
R56 Bridge R01AI4704011A1 ( Other Identifier: NIH American Recovery and Reinvestment Act (ARRA) of 2009 )
2R01AI047040-11A2 ( U.S. NIH Grant/Contract )
5K12HD043494-09 ( U.S. NIH Grant/Contract )
First Posted: December 24, 2007    Key Record Dates
Last Update Posted: July 12, 2018
Last Verified: July 2018

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by M. Louise Markert, Duke University:
Thymus Transplantation
DiGeorge Anomaly
DiGeorge Syndrome
Low T cell numbers
Complete DiGeorge
Typical DiGeorge
Atypical DiGeorge
Complete DiGeorge Anomaly

Additional relevant MeSH terms:
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Congenital Abnormalities
DiGeorge Syndrome
Marfan Syndrome
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
Parathyroid Diseases
Endocrine System Diseases
Bone Diseases, Developmental
Bone Diseases
Connective Tissue Diseases
Limb Deformities, Congenital