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Phase I/II Thymus Transplantation With Immunosuppression #950 (#950)

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ClinicalTrials.gov Identifier: NCT00579527
Recruitment Status : Completed
First Posted : December 24, 2007
Results First Posted : February 17, 2020
Last Update Posted : March 9, 2020
Sponsor:
Collaborators:
National Institutes of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Enzyvant Therapeutics GmbH
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
Information provided by (Responsible Party):
M. Louise Markert, Duke University

Brief Summary:
The study purpose is to determine if cultured thymus tissue implantation (CTTI) (previously described as transplantation) with tailored immunosuppression based on the recipient's pre-implantation T cell population is a safe and effective treatment for complete DiGeorge anomaly. This study will also evaluate whether cultured thymus tissue implantation and parathyroid transplantation with immunosuppression is a safe and effective treatment for complete DiGeorge anomaly and hypoparathyroidism.

Condition or disease Intervention/treatment Phase
DiGeorge Anomaly Complete DiGeorge Anomaly Complete Atypical DiGeorge Anomaly Complete DiGeorge Syndrome Complete Atypical DiGeorge Syndrome Biological: Cultured Thymus Tissue for Implantation (CTTI) Other: Cultured Thymus Tissue Implantation and Parental Parathyroid Transplantation Procedure: Blood Draw Drug: Rabbit anti-thymocyte globulin Drug: Cyclosporine Drug: Tacrolimus Drug: Methylprednisolone or Prednisolone Drug: Daclizumab Drug: Mycophenolate mofetil Phase 1 Phase 2

Detailed Description:

Complete DiGeorge anomaly is a congenital disorder characterized by athymia. Without successful treatment, children remain immunodeficient and usually die by age 2 years. In infants with complete DiGeorge anomaly and no T cells, cultured thymus tissue implantation (CTTI) without immunosuppression resulted in diverse T cell development and good T cell function. Some infants with no thymus have some T cells that presumably developed extrathymically; these T cells can reject a thymus graft.

The purpose of this study is to tailor immunosuppression use for complete DiGeorge anomaly subjects who have some T cells and different T cell function levels. This protocol includes tailored immunosuppression regimens to allow subjects with different T cell function levels to be suppressed adequately.

Patients with complete DiGeorge often have hypoparathyroidism, a life threatening condition. Successful CTTI does not result in improvement of the hypoparathyroidism. The patients must go to the clinic for frequent calcium levels and to the hospital for calcium infusions. These infants are at risk for seizures from low calcium. This study had a parental parathyroid transplant arm for subjects with hypoparathyroidism who require calcium replacement.

Whether or not a subject was enrolled in the parathyroid arm, the immunosuppression regimen the subject received was dependent on the immune findings as stated in the clinical protocol.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 14 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Phase I/II Trial of Thymus Transplantation With Immunosuppression, #950
Actual Study Start Date : December 19, 2005
Actual Primary Completion Date : December 2011
Actual Study Completion Date : December 31, 2017


Arm Intervention/treatment
Experimental: Cultured Thymus Tissue Implantation (CTTI) w/immunosuppression
Patients with complete DiGeorge Anomaly (cDGA) undergo cultured thymus tissue implantation (previously described as transplantation) with tailored immunosuppression based on the subject's pre-implantation T cell numbers and function.
Biological: Cultured Thymus Tissue for Implantation (CTTI)
Potential thymus recipient subjects are screened for eligibility. Thymus donor (unrelated donor), and thymus donor's birth mother are screened for safety. CTTI is done under general anesthesia in the operating room. Cultured thymus tissue is implanted into the subject's quadriceps. Two to three months post CTTI, if medically stable, the subject undergoes allograft biopsy. At the time of implantation and biopsy, a skin biopsy is done. Immunosuppression is weaned as per protocol.
Other Names:
  • Thymus Tissue Transplant
  • CTTI

Procedure: Blood Draw
Birth mothers of Thymus Recipients are asked to participate in the study and undergo phlebotomy to allow 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 (through a central venous catheter) prior to CTTI. Each dose of Rabbit anti-thymocyte globulin (RATGAM) is given over 12 hours. RATGAM is usually given on days-5, -4, and -3 prior to CTTI or CTTI and parathyroid transplantation. Medications (diphenhydramine, steroids, and acetaminophen) are given with rabbit anti-thymocyte globulin.
Other Names:
  • RATGAM
  • thymoglobulin

Drug: Cyclosporine

In addition to RATGAM, subjects with typical cDGA with PHA responses >50,000 cpm, or atypical cDGA with PHA response <75,000cpm (when not on immunosuppression) or <40,000 cpm to PHA while on immunosuppression, are started on cyclosporine (Csa) as soon as cDGA is diagnosed. Csa is continued with target trough levels of 180 to 220 ng/ml. 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 range, dosing is modified appropriately.

Csa may be given every 8 to 12 hours enterally or IV before and after CTTI. 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 tacrolimus is given. Tacrolimus may be given every 8 to 12 hours enterally or IV before and after the CTTI transplant. Tacrolimus dose is dependent on the T cell numbers and the target tacrolimus trough levels. Tacrolimus is weaned as per protocol.
Other Name: FK506

Drug: Methylprednisolone or Prednisolone
Steroids IV or enterally may be given before and after CTTI or CTTI and parathyroid transplantation. Administration and dosage depends on T cell numbers and symptoms. Pre-transplant steroids may be used when pre-transplant T cells >4,000cumm. Steroids are weaned as per protocol.
Other Name: Steroids

Drug: Daclizumab
In addition, subjects with Atypical DiGeorge with PHA responses >75,000cpm while on no immunosuppression or PHA responses >40,000cpm while on immunosuppression, Daclizumab 1 mg/kg single dose IV may be given depending on T cell counts. Administration of Daclizumab depends on T cell numbers and T cell activation. A single dose may be given after the administration of rabbit anti-thymocyte globulin and before CTTI. If Daclizumab is not given before CTTI, and, depending on the T cell numbers and T cell activation, a single dose of Daclizumab may be given 3-5 days after CTTI.
Other Name: Zenapax

Drug: Mycophenolate mofetil
In addition, subjects with Atypical DiGeorge with PHA responses >75,000cpm while on no immunosuppression or PHA responses >40,000cpm while on immunosuppression, Mycophenolate mofetil 15 mg/kg/dose every 8 hours IV or enterally may be given depending on T cell counts. Mycophenolate mofetil may be given if the T cell count remains elevated 5 days after CTTI. If MMF is given, the dose is 15 mg/kg IV. MMF may be stopped at 35 days after CTTI or continued for up to six months after CTTI.
Other Names:
  • MMF
  • CellCept

Experimental: CTTI with Parathyroid Transplantation w/immunosuppression
Patients with complete DiGeorge Anomaly (cDGA) undergoes cultured thymus tissue thymus implantation (previously described as transplantation) with tailored immunosuppression based on the subject's pre-implantation T cell numbers and function. If the patient has hypoparathyroidism, and is eligible, the patient may also receive a parathyroid transplant.
Other: Cultured Thymus Tissue Implantation and Parental Parathyroid Transplantation
For subjects w/ hypoparathyroidism, the subject may receive CTTI and parathyroid transplant. For parathyroid transplant, parental parathyroid donors are screened. Parathyroid is harvested from the parent who shares the most Human Leukocyte Antigens (HLA) alleles with the thymus donor. Parathyroid gland is minced and placed in quadriceps muscle; there is no dose. Parathyroid donors are monitored as outpatients until recipients' discharge. Recipients' calcium and PTH levels are monitored indefinitely. Potential thymus recipient subjects are screened for eligibility. Thymus donor (unrelated donor), and thymus donor's birth mother are screened for safety. CTTI is done under general anesthesia in the operating room. Cultured thymus tissue is implanted into the subject's quadriceps. Two to three months post CTTI, if medically stable, the subject undergoes allograft biopsy. At the time of CTTI and biopsy, a skin biopsy is done. Immunosuppression is weaned as per protocol.
Other Names:
  • Thymus and Parathyroid Transplant
  • CTTI and Parathyroid Transplant

Procedure: Blood Draw
Birth mothers of Thymus Recipients are asked to participate in the study and undergo phlebotomy to allow 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 (through a central venous catheter) prior to CTTI. Each dose of Rabbit anti-thymocyte globulin (RATGAM) is given over 12 hours. RATGAM is usually given on days-5, -4, and -3 prior to CTTI or CTTI and parathyroid transplantation. Medications (diphenhydramine, steroids, and acetaminophen) are given with rabbit anti-thymocyte globulin.
Other Names:
  • RATGAM
  • thymoglobulin

Drug: Cyclosporine

In addition to RATGAM, subjects with typical cDGA with PHA responses >50,000 cpm, or atypical cDGA with PHA response <75,000cpm (when not on immunosuppression) or <40,000 cpm to PHA while on immunosuppression, are started on cyclosporine (Csa) as soon as cDGA is diagnosed. Csa is continued with target trough levels of 180 to 220 ng/ml. 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 range, dosing is modified appropriately.

Csa may be given every 8 to 12 hours enterally or IV before and after CTTI. 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 tacrolimus is given. Tacrolimus may be given every 8 to 12 hours enterally or IV before and after the CTTI transplant. Tacrolimus dose is dependent on the T cell numbers and the target tacrolimus trough levels. Tacrolimus is weaned as per protocol.
Other Name: FK506

Drug: Methylprednisolone or Prednisolone
Steroids IV or enterally may be given before and after CTTI or CTTI and parathyroid transplantation. Administration and dosage depends on T cell numbers and symptoms. Pre-transplant steroids may be used when pre-transplant T cells >4,000cumm. Steroids are weaned as per protocol.
Other Name: Steroids




Primary Outcome Measures :
  1. Survival at 1 Year Post-CTTI [ Time Frame: 1 year post-CTTI ]
    Survival at 1 year post cultured thymus tissue implantation was assessed using the Kaplan Meier Estimated Survival. This mathematical function estimates the survival for a certain length of time.


Secondary Outcome Measures :
  1. Survival at 2 Years Post-CTTI [ Time Frame: 2 years post-CTTI ]
    Survival at 2 years post cultured thymus tissue implantation was assessed using the Kaplan Meier Estimated Survival. This mathematical function estimates the survival for a certain length of time.

  2. Immune Reconstitution Efficacy - Total CD3 T Cells [ Time Frame: 1 year post-CTTI ]
    The development of total CD3 T cells at one year as measured using flow cytometry

  3. Immune Reconstitution Efficacy - Total CD4 T Cells [ Time Frame: 1 year post-CTTI ]
    The development of total CD4 T cells at one year as measured using flow cytometry

  4. Immune Reconstitution Efficacy - Total CD8 T Cells [ Time Frame: 1 year post-CTTI ]
    The development of total CD8 T cells at one year as measured using flow cytometry

  5. Immune Reconstitution Efficacy - Naive CD4 T Cells [ Time Frame: 1 year post-CTTI ]
    The development of total naive CD4 T cells at one year as measured using flow cytometry

  6. Immune Reconstitution Efficacy - Naive CD8 T Cells [ Time Frame: 1 year post-CTTI ]
    The development of total naive CD8 T cells at one year as measured using flow cytometry

  7. Immune Reconstitution Efficacy - Response to Mitogens [ Time Frame: 1 year post-CTTI ]
    Measurement of the T cell proliferative response to the mitogen phytohemagglutin (PHA).

  8. Thymus Allograft Biopsy [ Time Frame: 2 to 3 months post-CTTI ]
    Evidence, on biopsy of the thymus tissue implanted in muscle, that shows the development of new T cells.



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

Thymus Transplantation Inclusion:

  • Must have 1 of following: 22q11 or 10p13 hemizygosity; hypocalcemia requiring replacement; congenital heart defect; CHARGE association or CHD7 mutation; or abnormal ears plus mother w/diabetes (type I, type II, gestational).
  • <50 CD3+ T cells/cumm or <50 CD3+ T cells/cumm that are CD62L+ CD45RA+ (cluster of differentiation 45RA) (naïve phenotype), or <5% of CD3+ count being CD62L+ CD45RA+

Atypical DiGeorge:

  • Must have, or have had, a rash. If rash present, rash biopsy must show T cells in skin. If rash & adenopathy resolved, must have >50/cumm T cells & naive T cell must be <50/cumm or <5% of T cells.

Typical DiGeorge:

  • CD3+ CD45RA+ CD62L+ T cells <50/mm3 or <5% of total T cells

Parathyroid Transplantation Additional Inclusion:

  • 2 studies in recipient which PTH<5 pg/ml when ionized calcium <1.1 mmol/L. Can be done anytime pre-tx; 1 must be done while at Duke Hospital.
  • Parent(s) willing & eligible to be donors

Thymus Transplantation Exclusion:

  • Heart surgery <4 wks pre-tx
  • Heart surgery anticipated w/in 3 months after proposed tx
  • Rejection by surgeon or anesthesiologist as surgical candidate
  • Lack of sufficient muscle tissue to accept transplant of 4 grams/m2 BSA
  • HIV infection
  • Prior attempts at immune reconstitution, such as bone marrow tx or previous thymus tx
  • CMV(>500 copies/ml blood by PCR on 2 tests)
  • Ventilator dependence

Parathyroid Donor Inclusion:

  • >18 years of age
  • Serum calcium in normal range
  • Normal PTH function
  • HLA typing consistent with parentage
  • Not on anticoagulation or can come off
  • Parent chosen will share HLA-DR allele with thymus donor that was not inherited by the recipient. If no HLA matching at all, then either parent is acceptable if the parent meets other criteria.

Parathyroid Donor Exclusion:

  • <18 years old
  • Hypoparathyroidism-low PTH in presence of low serum calcium & high serum phosphate
  • Hyperparathyroidism(or history)-elevated PTH in presence of high serum calcium and low serum phosphate.
  • History of cancer
  • Donor only living involved parent/guardian of recipient
  • Evidence of HIV-1, HIV-2, HTLV-1, HTLV-2, syphilis, hepatitis B, hepatitis C, West Nile virus, or Chagas disease
  • Creutzfeldt Jakob disease (CJD)
  • Elevated liver function studies: AST, ALT, alkaline phosphatase >3x upper normal limit
  • Receipt of xenograft or risk factors for SARS, CJD and/or smallpox exposure. {If CJD risk factors but not active disease, parent may give permission for parathyroid use.}
  • Urine CMV positive
  • Positive CMV IgM
  • Positive IgM anti-EBV VCA
  • On blood thinners and cannot stop for parathyroid donation
  • Elevated PT or PTT (>ULN)
  • Platelets<100,000
  • Positive Toxoplasma IgM
  • Donor will receive a history and physical; may be excluded based on PI's medical judgment.
  • Hemoglobin <9g/dl
  • Infectious head or neck lesion
  • Goiter on ultrasound
  • Abnormal fiberoptic laryngoscopy of vocal cords
  • HLA inconsistent with parentage
  • Pregnancy
  • Positive HSV IgG isn't exclusion; post-tx prophylaxis needed for recipient if donor is HSV IgG+.
  • Positive VZV IgG isn't exclusion; post-tx prophylaxis needed if donor is VZV IgG+.
  • Medical concern of independent otolaryngologist.
  • Concern by medical psychologist/social worker that potential donor isn't competent or does not understand risks.
  • Questionnaire responses can lead to exclusion.

Mother of DiGeorge Inclusion:

• Provides consent to use blood/buccal sample. No exclusions except unwillingness to consent; or, provide blood/buccal sample.


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): NCT00579527


Locations
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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)
Enzyvant Therapeutics GmbH
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
Investigators
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Principal Investigator: M. Louise Markert, MD, PhD Duke University Medical Center, Pediatrics, Allergy & Immunology
Publications of Results:
Other 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.

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Responsible Party: M. Louise Markert, Professor of Pediatrics, Duke University
ClinicalTrials.gov Identifier: NCT00579527    
Other Study ID Numbers: Pro00011583
2R01AI047040-11A2 ( U.S. NIH Grant/Contract )
R56 Bridge R01AI4704011A1 ( Other Grant/Funding Number: [NIH American Recovery and Reinvestment Act (ARRA) of 2009] )
5K12HD043494-09 ( U.S. NIH Grant/Contract )
R01AI047040 ( U.S. NIH Grant/Contract )
R01AI054843 ( U.S. NIH Grant/Contract )
950 ( Other Identifier: Duke )
First Posted: December 24, 2007    Key Record Dates
Results First Posted: February 17, 2020
Last Update Posted: March 9, 2020
Last Verified: February 2020

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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:
DiGeorge Anomaly
Thymus Transplantation
DiGeorge Syndrome
Athymia
Parathyroid Transplantation
Hypocalcemia
Hypoparathyroidism
Low T cell numbers
Immunoreconstitution
Immunodeficiency
Complete DiGeorge Anomaly
Complete Atypical DiGeorge Anomaly
Complete DiGeorge Syndrome
Complete Atypical DiGeorge Syndrome
Cultured Thymus Tissue Implantation (CTTI)
Additional relevant MeSH terms:
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DiGeorge Syndrome
Craniosynostoses
Marfan Syndrome
Arachnodactyly
Congenital Abnormalities
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
Synostosis
Dysostoses
Bone Diseases, Developmental
Bone Diseases
Connective Tissue Diseases
Limb Deformities, Congenital