884: Thymus Transplantation With Immunosuppression

Sponsor
Enzyvant Therapeutics GmBH (Industry)
Overall Status
Completed
CT.gov ID
NCT00579709
Collaborator
National Institutes of Health (NIH) (NIH), National Institute of Allergy and Infectious Diseases (NIAID) (NIH), Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) (NIH)
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Study Details

Study Description

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
  • 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.

Study Design

Study Type:
Interventional
Actual Enrollment :
15 participants
Allocation:
N/A
Intervention Model:
Single Group Assignment
Masking:
None (Open Label)
Primary Purpose:
Treatment
Official Title:
Thymus Transplantation With Immunosuppression, #884
Study Start Date :
Jul 1, 2002
Actual Primary Completion Date :
Dec 1, 2006
Actual Study Completion Date :
Dec 1, 2019

Arms and Interventions

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
  • Outcome Measures

    Primary Outcome Measures

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

    Secondary Outcome Measures

    1. Use of additional post transplant immunosuppression after that listed in the protocol. [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 [2 to 4 months post-transplant]

      Evidence of thymus allograft rejection by immunohistochemistry of biopsy

    3. CD3 count [10 - 14 months post-transplantation]

      CD3 count in cells/mm3

    4. Thymopoiesis [2-4 months after thymus transplantation]

      Evidence of thymopoiesis in thymus allograft by immunohistochemistry of a biopsy

    5. CD4 count [10-14 months after thymus transplantation]

      CD4 count in cells/mm3

    6. CD8 count [10-14 months after thymus transplantation]

      CD8 count in cells/mm3

    7. naive CD4 count [10-14 months after thymus transplantation]

      naive CD4 count in cells/mm3

    8. naive CD8 count [10-14 months after thymus transplantation]

      naive CD8 count in cells/mm3

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    N/A and Older
    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

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 Duke University Medical Center Durham North Carolina United States 27710

    Sponsors and Collaborators

    • Enzyvant Therapeutics GmBH
    • 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)

    Investigators

    • Principal Investigator: M. Louise Markert, MD, PhD, Duke University Medical Center, Pediatrics, Allergy & Immunology

    Study Documents (Full-Text)

    None provided.

    More Information

    Publications

    Responsible Party:
    Enzyvant Therapeutics GmBH
    ClinicalTrials.gov Identifier:
    NCT00579709
    Other Study ID Numbers:
    • Pro00013734
    • R01AI047040
    • R01AI054843
    • 3R56AI047040-11A1S1
    • R56 Bridge R01AI4704011A1
    • 2R01AI047040-11A2
    • 5K12HD043494-09
    • #884
    First Posted:
    Dec 24, 2007
    Last Update Posted:
    Apr 4, 2022
    Last Verified:
    Mar 1, 2022
    Studies a U.S. FDA-regulated Drug Product:
    Yes
    Studies a U.S. FDA-regulated Device Product:
    No
    Keywords provided by Enzyvant Therapeutics GmBH
    Additional relevant MeSH terms:

    Study Results

    No Results Posted as of Apr 4, 2022