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

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ClinicalTrials.gov Identifier: NCT00579527
Recruitment Status : Active, not recruiting
First Posted : December 24, 2007
Last Update Posted : July 24, 2019
Sponsor:
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

Tracking Information
First Submitted Date  ICMJE December 20, 2007
First Posted Date  ICMJE December 24, 2007
Last Update Posted Date July 24, 2019
Study Start Date  ICMJE March 2006
Actual Primary Completion Date December 2011   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: December 20, 2007)
Safety/toxicity of 3 immunosuppression regimens in subjects undergoing thymus transplantation. Assessment will be survival at 1 year; incidence of fatal, severe, moderate, and disseminated infections; and, incidence of Grade 3 and 4 toxicities. [ Time Frame: 1 year post-transplantation ]
Original Primary Outcome Measures  ICMJE Same as current
Change History Complete list of historical versions of study NCT00579527 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: March 31, 2014)
  • Thymopoiesis: assessment will be done by evaluating thymus graft biopsy tissue post transplantation [ Time Frame: 2 - 3 months post-transplantation ]
  • Development of T cell numbers and function post thymus transplantation using the 3 regimens tested. [ Time Frame: Ongoing ]
  • Efficacy of parental parathyroid transplantation. Number of subjects who are off both calcium and calcitriol supplementation. The time at which calcium supplementation needs to be resumed post parathyroid transplant will also be recorded. [ Time Frame: 1 year post-transplantation ]
Original Secondary Outcome Measures  ICMJE
 (submitted: December 20, 2007)
  • Thymopoiesis: assessment will be done by evaluating thymus graft biopsy tissue post transplantation [ Time Frame: 2 - 3 months post-transplantation ]
  • Development of T cell numbers and function post thymus transplantation using the 3 regimens tested. [ Time Frame: Ongoing ]
  • Efficacy of parental parathyroid transplantation. Number of subjects who are off both calcium and calcitriol supplementation. The time at which calcium supplementation needs to be resumed post parathyroid transplant will also be recorded. [ Time Frame: 1 year post-transplantation & ongoing ]
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Phase I/II Thymus Transplantation With Immunosuppression #950
Official Title  ICMJE Phase I/II Trial of Thymus Transplantation With Immunosuppression, #950
Brief Summary The study purpose is to determine if thymus transplantation with immunosuppression is a safe and effective treatment for atypical complete DiGeorge anomaly. This study will also evaluate whether thymus and parathyroid transplantation with immunosuppression is a safe and effective treatment for atypical complete DiGeorge anomaly and hypoparathyroidism.
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, thymus transplantation 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 design better immunosuppression use for complete DiGeorge anomaly subjects who have some T cells and different T cell function levels. This protocol includes 3 immunosuppression regimens to allow subjects with different T cell function levels to be suppressed adequately.

DiGeorge infants who have successful thymus transplants but remain with hypoparathyroidism 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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Phase 2
Study Design  ICMJE Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • DiGeorge Anomaly
  • Complete DiGeorge Anomaly
  • Complete Atypical DiGeorge Anomaly
  • Complete DiGeorge Syndrome
  • Complete Atypical DiGeorge Syndrome
Intervention  ICMJE
  • Biological: Thymus Tissue for Transplantation
    Potential thymus recipient subjects are screened for eligibility. Thymus donor (unrelated donor), and donor's biological mother are screened for safety. Thymus transplantation is done under general anesthesia in the operating room. Thymus tissue if transplanted into the subject's quadriceps. Two to three months post thymus transplantation, if medically stable, the subject undergoes allograft biopsy. At the time of transplantation and biopsy, a skin biopsy is done. Immunosuppression is weaned as per protocol.
    Other Name: Thymus Tissue Transplant
  • Other: Thymus Tissue and Parental Parathyroid Transplantation
    If the recipient has hypoparathyroidism, and is eligible, the subject may receive both a thymus and parathyroid transplant. If the subject is not eligible the subject will receive only a thymus transplant. For parathyroid transplant, parental parathyroid donors screened. If both parents met criteria, parathyroid harvested from the parent who shares the most HLA alleles with the thymus donor. Parathyroid harvest is done under general anesthesia. One parathyroid gland is minced and placed in quadriceps muscle of 1 leg; there is no dose. No biopsy is done of the parathyroid. Parathyroid donors are monitored as outpatients until recipients' discharge. Recipients' calcium and PTH levels are monitored indefinitely.
    Other Name: Thymus and Parathyroid Transplant
  • Procedure: Blood Draw
    Biological 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 amy be done.
    Other Name: Venipuncture
  • Drug: Rabbit anti-thymocyte globulin
    Three doses of 2 mg/kg IV prior to thymus or thymus and parathyroid transplantation. Each dose is given over 12 hours. RATGAM is usually given on days-5, -4, and -3 prior to thymus or thymus and parathyroid transplantation. Medications (diphenhydramine, steroids, and acetaminophen) are given with rabbit anti-thymocyte globulin.
    Other Name: RATGAM
  • Drug: Cyclosporine
    Csa may be given every 8 to 12 hours orally or IV before and after thymus transplantation or thymus and parathyroid transplantation. The Csa dose is dependant 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 the thymus transplant or the thymus/parathyroid transplant. FK506 dose is dependent on the 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 after thymus or thymus/parathyroid transplantation. Administration and dosage depends on T cell numbers and symptoms. Steroids are weaned as per protocol.
    Other Name: Steroids
  • Drug: Daclizumab
    A single dose of Daclizumab 1 mg/kg IV may be given. 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 thymus transplantation. If Daclizumab is not given before thymus transplantation, and, depending on the T cell numbers and T cell activation, a single dose of Daclizumab may be given 3-5 days after thymus transplantation.
    Other Name: Zenapax
  • 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 IV. MMF may be stopped at 35 days after thymus transplantation or continued for up to six months after thymus transplantation.
    Other Names:
    • MMF
    • CellCept
Study Arms  ICMJE
  • Experimental: #1 Typ & Atyp cDGA w immunosuppression
    Three doses of 2 mg/kg of rabbit anti-thymocyte globulin IV pre thymus transplantation or pre thymus and parathyroid transplantation.
    Interventions:
    • Biological: Thymus Tissue for Transplantation
    • Other: Thymus Tissue and Parental Parathyroid Transplantation
    • Procedure: Blood Draw
    • Drug: Rabbit anti-thymocyte globulin
  • Experimental: #2 Atypical cDGA w immunosuppression
    Pre-thymus or pre thymus & parathyroid transplant cyclosporine (Csa) are started as soon as complete DiGeorge anomaly (cDGA) is diagnosed. Csa 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. Pre-transplant steroids are used is pre-transplant T cells >4,000cumm. Three doses of 2 mg/kg of rabbit anti-thymocyte globulin IV are given pre-thymus transplant or thymus & parathyroid transplant. Medications (diphenhydramine, steroids, and acetaminophen) are given with rabbit anti-thymocyte globulin.
    Interventions:
    • Biological: Thymus Tissue for Transplantation
    • Other: Thymus Tissue and Parental Parathyroid Transplantation
    • Procedure: Blood Draw
    • Drug: Rabbit anti-thymocyte globulin
    • Drug: Cyclosporine
    • Drug: Tacrolimus
    • Drug: Methylprednisolone or Prednisolone
  • Experimental: #3 Atyp cDGA w additional suppression
    Pre-thymus or thymus & parathyroid transplant, cyclosporine (Csa) and steroids are started after complete DiGeorge anomaly (cDGA) is diagnosed. After PHA response is documented >40,000 cpm on suppression, peri-transplant Csa target trough levels are 250-300 ng/ml. (Levels outside of range, dose modified.) If subject cannot tolerate Csa, change to tacrolimus (target trough level 10-15 ng/ml). When trough levels are outside of range, dosing is modified appropriately. Three doses of 2 mg/kg of rabbit anti-thymocyte globulin IV are given pre-transplant. Medications (diphenhydramine, steroids, & acetaminophen) are given with rabbit anti-thymocyte globulin. Daclizumab 1 mg/kg single dose IV and Mycophenolate mofetil 15 mg/kg/dose every 8 hours IV/orally may be given depending on T cell counts.
    Interventions:
    • Biological: Thymus Tissue for Transplantation
    • Procedure: Blood Draw
    • Drug: Rabbit anti-thymocyte globulin
    • Drug: Cyclosporine
    • Drug: Tacrolimus
    • Drug: Methylprednisolone or Prednisolone
    • Drug: Daclizumab
    • Drug: Mycophenolate mofetil
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Active, not recruiting
Actual Enrollment  ICMJE
 (submitted: July 29, 2011)
28
Original Estimated Enrollment  ICMJE
 (submitted: December 20, 2007)
100
Estimated Study Completion Date  ICMJE June 2027
Actual Primary Completion Date December 2011   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Tx 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+, 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

- Must be eligible for 1 of 3 Regimens:

R#1 - Typical DiGeorge with PHA response >5000 cpm and >20 fold response. Must have PHA response <50,000cpm. If PHA response >50,000 pre-tx, subject will move to R#2.

R#2 - Typical DiGeorge with PHA responses >50,000 cpm; or atypical DiGeorge with PHA response <75,000cpm (when not on immunosuppression) or <40,000 cpm to PHA while on immunosuppression.

R#3 - Atypical DiGeorge with PHA responses >75,000cpm while on no immunosuppression or PHA responses >40,000cpm while on immunosuppression pre-tx.

Parathyroid Tx Additional Inclusion:

  • 2 studies 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

Tx 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 acceptable if meet 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.

Biological Mother Inclusion:

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

Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE Child, Adult, Older Adult
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT00579527
Other Study ID Numbers  ICMJE 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
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE Not Provided
Responsible Party M. Louise Markert, Duke University
Study Sponsor  ICMJE M. Louise Markert
Collaborators  ICMJE
  • 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  ICMJE
Principal Investigator: M. Louise Markert, MD, PhD Duke University Medical Center, Pediatrics, Allergy & Immunology
PRS Account Duke University
Verification Date July 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP