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Thymus Transplantation Safety-Efficacy

Expanded access is currently available for this treatment.
Verified May 2017 by M. Louise Markert, Duke University Medical Center
Sponsor:
ClinicalTrials.gov Identifier:
NCT01220531
First Posted: October 14, 2010
Last Update Posted: May 11, 2017
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. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
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)
Enzyvant Therapeutics GmbH
Information provided by (Responsible Party):
M. Louise Markert, Duke University Medical Center
  Purpose

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 T cells, which fight infection. Complete DiGeorge anomaly patients cannot fight infection and are immunodeficient. Without successful treatment, cDGA patients usually die by age 2 years.

Thymus transplantation with and without immunosuppression (drugs given before and after transplantation) has resulted in the development good T cell function in complete DiGeorge anomaly subjects.

This Phase I/II study continues thymus transplantation safety and efficacy research for the treatment of complete DiGeorge anomaly. Eligible participants undergo thymus transplantation and biopsy. Immune function testing is continued for one year post-transplantation.


Condition Intervention
Complete DiGeorge Anomaly DiGeorge Syndrome DiGeorge Anomaly Complete DiGeorge Syndrome Biological: Thymus Tissue for Transplantation Procedure: Blood Draw Drug: Rabbit anti-thymocyte globulin Drug: Cyclosporine Drug: Tacrolimus Drug: Methylprednisolone or Prednisolone Drug: Basiliximab Drug: Mycophenolate mofetil

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

Resource links provided by NLM:


Further study details as provided by M. Louise Markert, Duke University Medical Center:

Study Start Date: December 2010
Estimated Study Completion Date: December 2023
Estimated Primary Completion Date: December 2021 (Final data collection date for primary outcome measure)
Intervention Details:
    Biological: Thymus Tissue for Transplantation
    Potential thymus recipient subjects are screened for eligibility. Thymus tissue (unrelated donor), donor, & donor's mother screened for safety. Thymus transplantation is done under general anesthesia in the operating room. Thymus tissue is transplanted into the subject's quadriceps. Two to three months post-transplantation, if medically stable, the subject undergoes allograft biopsy. At the time of transplantation and biopsy, skin biopsy conducted. Subjects undergo laboratory testing for approximately one year post-transplantation. At year 2 post-transplantation, subjects are contacted for data collection.
    Other Name: Thymus Tissue Transplant
    Procedure: Blood Draw
    Biological Mothers of Thymus Recipients are asked to participate in the study and undergo phlebotomy to allow for testing of T cell identity in the complete DiGeorge subjects. If blood is not obtainable, then a buccal swab may be done.
    Other Name: Venipuncture
    Drug: Rabbit anti-thymocyte globulin
    Three doses of 2 mg/kg IV prior to thymus transplantation. Each dose is given over 12 hours. RATGAM is usually given on days -5, -4, and -3 prior to thymus transplantation.
    Other Name: RATGAM
    Drug: Cyclosporine
    Csa may be given every 8 to 12 hours orally or IV before and after thymus transplantation. 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 to 12 hours orally or IV before and after thymus transplantation. 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 thymus transplantation. Administration and dosage depends on T cell numbers. Steroids are weaned as per protocol.
    Other Name: Steroids
    Drug: Basiliximab
    A single dose of Basiliximab 5 mg/kg IV may be given. Administration of Basiliximab depends on T cell numbers and T cell activation. A single dose of Basiliximab may be given after the administration of rabbit anti-thymocyte globulin and before thymus transplantation. If Basiliximab is not given before thymus transplantation, and, depending on the T cell numbers and T cell activation, a single dose of Basiliximab may be given 3 to 5 days after thymus transplantation.
    Other Name: Simulect
    Drug: Mycophenolate mofetil
    Mycophenolate mofetil may be given if the T cell count remains elevated 5 days after thymus transplantation. 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 thymus transplantation.
    Other Names:
    • MMF
    • CellCept
Detailed Description:

Complete DiGeorge anomaly (cDGA) is a congenital disorder characterized by athymia. Without successful treatment, children remain immunodeficient and usually die by age 2 years. In complete DiGeorge subjects, thymus transplantation with and without immunosuppression has resulted in diverse T cell development and good T cell function. The purpose of this Phase I/II study is to continue thymus transplantation safety and efficacy research for the treatment of complete DiGeorge anomaly. Until thymus transplantation is FDA approved as standard care for DiGeorge anomaly, 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 undergo thymus transplantation and an allograft biopsy. Protocol specified studies continue until approximately one year post-transplantation.

Study participation lasts two years.

  Eligibility

Information from the National Library of Medicine

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Ages Eligible for Study:   Child, Adult, Senior
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Transplant Inclusion:

  • Must have 1 of following: 22q11 or 10p13 hemizygosity; hypocalcemia requiring replacement; congenital heart disease; CHARGE association 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 must have, or have had, a rash.

Group 1

•Typical cDGA whose T cells have a PHA response < 5,000 cpm and < 20 fold PHA response.

Group 2

•Typical cDGA whose T cells have a PHA response >5,000 cpm and <50,000 cpm and >20 fold PHA response

Group 3

  • Typical cDGA whose T cells have PHA response >50,000 cpm
  • Typical cDGA with maternal engraftment
  • Atypical cDGA whose T cells have PHA response <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 >75,000cpm while on no immunosuppression or PHA responses >40,000cpm while on immunosuppression
  • Atypical cDGA with maternal engraftment and group 4 PHA response

Transplant Exclusion:

  • Heart surgery <4 wks pre-transplantation
  • Heart surgery anticipated w/in 3 months after proposed transplantation
  • Rejection by surgeon or anesthesiologist as surgical candidate
  • Lack of sufficient muscle tissue to accept transplant of 4 grams/m2 body surface area
  • HIV infection
  • Prior attempts at immune reconstitution, such as bone marrow transplant or previous thymus transplant
  • CMV on 2 tests for Groups 2, 3, and 4

Biological Mother Inclusion/Exclusion:

• Must be biological mother of thymus recipient

  Contacts and Locations
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
Contact: M. Louise Markert, M.D., Ph.D 919-684-6263 marke001@mc.duke.edu
Contact: Stephanie Gupton, RN, CPNP 919-684-4704 stephanie.gupton@dm.duke.edu

Locations
United States, North Carolina
Duke University Medical Center
Durham, North Carolina, United States, 27701
Contact: M. Louise Markert, M.D., Ph.D    919-684-6263    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)
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
Enzyvant Therapeutics GmbH
Investigators
Principal Investigator: M. Louise Markert, M.D., Ph.D Duke University Medical Center, Pediatrics, Allergy & Immunology
  More Information

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.

Responsible Party: M. Louise Markert, Professor of Pediatrics, Duke University Medical Center
ClinicalTrials.gov Identifier: NCT01220531     History of Changes
Other Study ID Numbers: Pro00025966
2R01AI047040-11A2 ( U.S. NIH Grant/Contract )
5K12HD043494-09 ( U.S. NIH Grant/Contract )
First Submitted: September 22, 2010
First Posted: October 14, 2010
Last Update Posted: May 11, 2017
Last Verified: May 2017

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

Additional relevant MeSH terms:
Syndrome
Congenital Abnormalities
DiGeorge 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
Tacrolimus
Cyclosporins
Cyclosporine
Antilymphocyte Serum
Basiliximab
Thymoglobulin
Mycophenolic Acid
Prednisolone
Methylprednisolone Hemisuccinate