Trial record 12 of 15 for:    Open Studies | "Hypoparathyroidism"

Thymus Transplantation Safety-Efficacy

This study is currently recruiting participants. (see Contacts and Locations)
Verified March 2014 by Duke University
Sponsor:
Collaborators:
Information provided by (Responsible Party):
M. Louise Markert, Duke University Medical Center
ClinicalTrials.gov Identifier:
NCT01220531
First received: September 22, 2010
Last updated: March 31, 2014
Last verified: March 2014
  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, complete DiGeorge 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 Phase
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
Phase 1
Phase 2

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
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 Duke University:

Primary Outcome Measures:
  • Survival [ Time Frame: One-year post-transplantation ] [ Designated as safety issue: Yes ]
    Assess Survival at One Year Post Thymus Transplantation. The primary hypothesis is that greater than 50% of subjects will survive thymus transplantation.


Secondary Outcome Measures:
  • Descriptive Study - Immune Outcomes [ Time Frame: 6 Months & 1 Year Post-Transplantation ] [ Designated as safety issue: No ]
    • Total CD3, CD4, CD8, naïve CD8 TCRαβ, TCRγδ, total B cells and total NK cells at 6 months and 12 months post-transplantation.
    • TCR repertoire as assessed by flow cytometry 12 months post-transplantation.
    • PHA response, a response to CD3 and tetanus toxoid at 12 months post-transplantation.

  • Naive CD 4 T Cell Count [ Time Frame: One Year Post-Transplantation ] [ Designated as safety issue: No ]
    Assess total naïve T cell count at 12 months post-thymus transplantation. The hypothesis is that greater than 50% of subjects will have >100 naïve T cells at one year post-transplantation. An additional hypothesis is that the dose of thymus tissue transplanted will affect the naïve CD4 count at one year.

  • Descriptive Study - GVHD [ Time Frame: 1 Year Post-Transplantation ] [ Designated as safety issue: Yes ]
    • Grade of skin GVHD in the first year post-transplantation.
    • Grades of upper & lower intestinal GVHD in the first year post-transplantation.
    • Grade of liver GVHD in the first year post-transplantation.

  • Descriptive Study - Infections [ Time Frame: 1 Year Post-Transplantation ] [ Designated as safety issue: Yes ]
    Recording and tabulation of infections during the first 12 months post-transplantation including the organism, infection site, and severity.

  • Descriptive Study - Autoimmune Disease [ Time Frame: 1 Year Post-Transplantation ] [ Designated as safety issue: No ]
    Autoimmune disease will be recorded and tabulated in first year post-transplantation.

  • Descriptive Study - Persistent Rashes [ Time Frame: 1 Year Post-Transplantation ] [ Designated as safety issue: No ]
    Description and location of any rashes persisting over 2 weeks will be recorded.

  • Descriptive Study - Thymus Donor T Cell Presence [ Time Frame: 3 Months Post-Transplantation ] [ Designated as safety issue: No ]
    Tabulate the presence of donor T cells in the blood 3 months post-transplantation.

  • Descriptive Study - Other Adverse Events [ Time Frame: 1 Year Post-Transplantation ] [ Designated as safety issue: Yes ]

    Other adverse events possibly, probably and/or definitely transplant-related will be recorded and tabulated.

    • For any cancer, the type of cancer, location and genetic identity.
    • For any granuloma, the location and description.


Estimated Enrollment: 50
Study Start Date: December 2010
Estimated Study Completion Date: December 2016
Estimated Primary Completion Date: December 2016 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: #1: Typical cDGA No Immunosuppression
Subjects receive thymus transplant. Subjects do not receive any pre or post-transplantation immunosuppression.
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
Experimental: #2:Typ & Atyp cDGA Immunosuppression

Group two will receive three doses of 2 mg/kg of rabbit anti-thymocyte globulin IV pre transplantation.

Medications (diphenhydramine, steroids, and acetaminophen) are given with rabbit anti-thymocyte globulin.

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
Experimental: #3: Atypical cDGA Immunosuppression
Pre-transplant cyclosporine (Csa) as soon as complete DiGeorge anomaly is diagnosed. Csa continued with target trough levels of 180 to 220 ng/ml. When trough levels are outside of range, dosing is modified appropriately. If subject cannot tolerate Csa, Csa may be changed to tacrolimus (FK506) with target trough level 7 to 10 ng/ml. When trough levels are outside of this target range, dosing will be modified appropriately. Pre-transplant steroids are used for atypical subjects if pre-transplant T cells >4,000/mm3. Three doses of 2 mg/kg of rabbit anti-thymocyte globulin IV are given pre-transplantation. Medications (diphenhydramine, steroids, and acetaminophen) are given with rabbit anti-thymocyte globulin.
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
Experimental: #4: Atypical cDGA Additional Suppression
Pre-transplant cyclosporine (Csa) and steroids are started after atypical complete DiGeorge anomaly is diagnosed. After PHA response is documented >40,000 cpm on suppression, peri-transplant Csa is maintained at target levels 250 to 300 ng/ml. (When levels outside of range, dose modified.) If subject cannot tolerate Csa then may be changed to tacrolimus (FK506) with target level 10 to 15 ng/ml. When levels are outside of range, dosing is modified. Three doses of 2 mg/kg rabbit anti-thymocyte globulin IV are given pre-transplantation. Medications (diphenhydramine, steroids, and acetaminophen) are given with rabbit anti-thymocyte globulin. Additional immunosuppression: Basiliximab, 5 mg/kg single dose IV; Mycophenolate Mofetil (MMF), 15 mg/kg/dose every 8 hours IV or enteral.
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

Genders Eligible for Study:   Both
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
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: 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 Recruiting
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
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.

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, 5K12HD043494-09
Study First Received: September 22, 2010
Last Updated: March 31, 2014
Health Authority: United States: Food and Drug Administration
United States: Institutional Review Board

Keywords provided by Duke University:
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:
Hypoparathyroidism
Congenital Abnormalities
DiGeorge Syndrome
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
Antilymphocyte Serum
Cyclosporins
Cyclosporine
Mycophenolate mofetil
Tacrolimus
Basiliximab
Mycophenolic Acid
Methylprednisolone acetate
Prednisolone acetate
Methylprednisolone
Methylprednisolone Hemisuccinate
Prednisolone

ClinicalTrials.gov processed this record on August 20, 2014