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Thymus Transplantation With Immunosuppression (884)

This study is ongoing, but not recruiting participants.
Sponsor:
Collaborators:
Information provided by (Responsible Party):
M. Louise Markert, Duke University Medical Center
ClinicalTrials.gov Identifier:
NCT00579709
First received: December 20, 2007
Last updated: August 21, 2014
Last verified: August 2014
  Purpose

The purpose of this research 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 Intervention Phase
DiGeorge Syndrome
DiGeorge Anomaly
Complete DiGeorge Anomaly
Complete DiGeorge Syndrome
Biological: Thymus Tissue for Transplantation
Phase 1

Study Type: Interventional
Study Design: Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Thymus Transplantation With Immunosuppression, #884

Resource links provided by NLM:


Further study details as provided by Duke University:

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

Secondary Outcome Measures:
  • Use of additional post transplant immunosuppression after that listed in the protocol. [ Time Frame: The post thymus transplantation period ] [ Designated as safety issue: No ]
    Use of additional post transplant immunosuppression after that listed in the protocol.

  • Allograft biopsy used to evaluate graft rejection [ Time Frame: 2 to 4 months post-transplant ] [ Designated as safety issue: No ]
    Evidence of thymus allograft rejection by immunohistochemistry of biopsy

  • CD3 count [ Time Frame: 10 - 14 months post-transplantation ] [ Designated as safety issue: No ]
    CD3 count in cells/mm3

  • Thymopoiesis [ Time Frame: 2-4 months after thymus transplantation ] [ Designated as safety issue: No ]
    Evidence of thymopoiesis in thymus allograft by immunohistochemistry of a biopsy

  • CD4 count [ Time Frame: 10-14 months after thymus transplantation ] [ Designated as safety issue: No ]
    CD4 count in cells/mm3

  • CD8 count [ Time Frame: 10-14 months after thymus transplantation ] [ Designated as safety issue: No ]
    CD8 count in cells/mm3

  • naive CD4 count [ Time Frame: 10-14 months after thymus transplantation ] [ Designated as safety issue: No ]
    naive CD4 count in cells/mm3

  • naive CD8 count [ Time Frame: 10-14 months after thymus transplantation ] [ Designated as safety issue: No ]
    naive CD8 count in cells/mm3


Enrollment: 15
Study Start Date: July 2002
Estimated Study Completion Date: June 2027
Primary Completion Date: December 2006 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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

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.

  Eligibility

Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00579709

Locations
United States, North Carolina
Duke University Medical Center
Durham, North Carolina, United States, 27710
Sponsors and Collaborators
M. Louise Markert
Investigators
Principal Investigator: M. Louise Markert, MD, PhD Duke University Medical Center, Pediatrics, Allergy & Immunology
  More Information

Publications:
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.

Responsible Party: M. Louise Markert, Professor of Pediatrics, Duke University Medical Center
ClinicalTrials.gov Identifier: NCT00579709     History of Changes
Other Study ID Numbers: Pro00013734, R01AI047040, R01AI054843, 3R56AI047040-11A1S1, R56 Bridge R01AI4704011A1, 2R01AI047040-11A2, 5K12HD043494-09, #884
Study First Received: December 20, 2007
Last Updated: August 21, 2014
Health Authority: United States: Food and Drug Administration
United States: Institutional Review Board

Keywords provided by Duke University:
Thymus Transplantation
DiGeorge Anomaly
DiGeorge Syndrome
Athymia
Low T cell numbers
Immunoreconstitution
Immunodeficiency
Complete DiGeorge
Typical DiGeorge
Atypical DiGeorge
Complete DiGeorge Anomaly

Additional relevant MeSH terms:
Congenital Abnormalities
DiGeorge Syndrome
Syndrome
22q11 Deletion Syndrome
Abnormalities, Multiple
Cardiovascular Abnormalities
Cardiovascular Diseases
Chromosome Disorders
Craniofacial Abnormalities
Disease
Endocrine System Diseases
Genetic Diseases, Inborn
Heart Defects, Congenital
Heart Diseases
Hypoparathyroidism
Lymphatic Abnormalities
Lymphatic Diseases
Musculoskeletal Abnormalities
Musculoskeletal Diseases
Parathyroid Diseases
Pathologic Processes

ClinicalTrials.gov processed this record on November 27, 2014