Parathyroid and Thymus Transplantation in DiGeorge #931

March 23, 2022 updated by: Enzyvant Therapeutics GmBH

Parathyroid and Thymus Transplantation in DiGeorge Syndrome, #931

This study has three primary purposes: to assess parathyroid function after parathyroid transplantation in infants with Complete DiGeorge syndrome; to assess immune function development after transplantation; and, to assess safety and tolerability of the procedures. This is a Phase 1, single site, open, non-randomized clinical protocol. Enrollment is closed and study intervention is complete for all enrolled subjects; but subjects continue for observation and follow-up. Subjects under 2 years old with complete DiGeorge syndrome (atypical or typical) received thymus transplantation. Subjects received pre-transplant immune suppression with rabbit anti-human-thymocyte-globulin. Subjects with hypoparathyroidism and an eligible parental donor received thymus and parental parathyroid transplantation. A primary hypothesis: Thymus/Parathyroid transplant subjects will need less calcium and/or calcitriol supplementation at 1 year post-transplant as compared to historical controls.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Detailed Description

Detailed: DiGeorge Syndrome is a complex of three problems, 1) cardiac defects, 2) parathyroid deficiency, and 3) absence of the thymus, resulting in profound T-cell deficiency. There is a spectrum of disease in DiGeorge syndrome with respect to all three defects. There is no safe and effective treatment for DiGeorge Syndrome and most patients die by the age of two. For patients with a severe T cell defect, the PI has shown that thymus transplantation is safe and efficacious under other clinical protocols. Subjects with complete typical and atypical DiGeorge syndrome were eligible for this study. Subjects with athymia and profound hypoparathyroidism were eligible for parental parathyroid transplantation in this protocol. DiGeorge syndrome infants, who have successful thymus transplants but have hypoparathyroidism, must go to the clinic for frequent calcium levels and to the hospital for calcium infusions; infants with hypoparathyroidism are at risk for seizures from low calcium. Approximately ½ of infants with profound hypoparathyroidism will develop nephrocalcinosis. Depending on T cell phenotype and function, subjects were given one of two different immunosuppression regimens. Typical complete DiGeorge subjects (with proliferative T cell function < 50,000 cpm) received Thymoglobulin pre-transplantation. Typical complete DiGeorge subjects (with proliferative cell response to PHA > 50,000 cpm) and atypical DiGeorge subjects (with proliferative T cell response to PHA < 75,000 cpm) received Thymoglobulin (pre-transplantation) and cyclosporine (pre-transplantation and post-transplantation). Thymoglobulin was used in part to prevent graft rejection and also to deplete any T cells in the donor parathyroid. Cyclosporine was used to deplete activated T cells in the recipient. For all subjects, acetaminophen, diphenhydramine, and methylprednisolone were given concurrently with the rabbit anti-human thymocyte globulin. The thymus was cultured in standard medium for 10-21 days to deplete mature thymocytes which could cause GVHD. In the operating room, thymus tissue was placed in the quadriceps muscle in one or both legs. The parathyroid donation was preferably done at the same time as the thymus transplantation. Parathyroid tissue was placed in the quadriceps muscle in only one leg, using the same incision as the thymus transplantation. Depending on post-transplant immune status, subjects may have received cyclosporine and steroids.

For 3 months after thymus transplantation, T cells were monitored by flow cytometry approximately every 2-4 weeks. Alternatively, absolute lymphocyte count was used as the maximum possible T cell number. At 2-3 months post-transplant, the subject may have had a thymus allograft biopsy, done under general anesthesia in the operating room. The biopsy was approximately 4 pea-sized (3x3mm) portions of muscle tissue where the thymus transplant had been inserted. Using immunohistochemistry, the biopsy determined thymopoiesis and any graft rejection. The parathyroid was not biopsied because it is very small; doing a biopsy could remove all of the parathyroid tissue. A research skin biopsy (at site of skin incision at the time of transplantation) was done to determine whether T cells were present pre-transplantation. A skin biopsy was also done at the time of thymus graft biopsy to look for clonal T cell populations. For all subjects who developed T cells, post-transplantation pneumocystis prophylaxis was used for approximately 1 year and IV immunoglobulin for approximately 2 years.

Study Type

Interventional

Enrollment (Actual)

25

Phase

  • Phase 1

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United States
    • North Carolina
      • Durham, North Carolina, United States, 27705
        • Duke University Medical Center

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

No older than 2 years (Child)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Transplant Inclusion:

  • Complete DiGeorge syndrome (typical or atypical) - may have DiGeorge as part of 22q11 hemizygosity, CHARGE association, or diabetic embryopathy or they may have no associated syndromes.

  • Must have 1 of following:

    • Circulating CD3+ T cells < 50/mm3; or
    • Circulating CD3+ T cells that also positive for CD45RA and CD62L must be <50/mm3 or must be < 5% of total T cells.
  • Must be <24 months old

  • Laboratory studies must be done w/in 1 month of treatment:

    • Thyroid studies - if abnormal must be on therapy, if recommended by endocrinology:
    • PT and PTT must be <2x upper limits of normal (ULN)
    • Absolute neutrophil count must be >500/mm3
    • Platelet count must be >50,000/mm3
    • AST and ALT must be <5x ULN
    • Creatinine must be <1.5 mg/dl
  • Parents must agree to have infant stay in Durham until thymus biopsy is done 2-3 months post-treatment.
  • Typical subjects must not have a rash with T cells on biopsy nor lymphadenopathy.
  • Atypical subjects have rash with T cells on biopsy; may have lymphadenopathy.
  • PHA proliferative responses must be tested 2x • Atypical: PHA response must be <75,000cpm on 2 tests; test can be done while on immunosuppression.

Additional Criteria for Parathyroid Treatment Inclusion

  • Hypoparathyroidism
  • At least 1 parent must agree to be parathyroid donor
  • Must require calcium supplementation to maintain ionized calcium >1.0 mmol/L. Alternatively, intact PTH must be <lower limit of normal when ionized calcium is <1.2 mmol/L. (Intact PTH measured 2x pre-treatment.)

DiGeorge Treatment Exclusion:

  • Heart surgery conducted <4 weeks pre-treatment
  • Heart surgery anticipated w/in 3 months of treatment
  • Rejection by surgeon or anesthesiologist as surgical candidate
  • Lack of sufficient muscle tissue to accept 0.2gms/kg treatment
  • Prior attempts at immune reconstitution, such as bone marrow treatment or previous thymus treatment
  • Doesn't commit to remaining at Duke until thymus allograft biopsy

Parathyroid Donor Inclusion:

  • Serum calcium in normal range
  • Normal parathyroid hormone function
  • HLA typing must be consistent with parentage.
  • Must not be on anticoagulation or can come off
  • Parent chosen for donation will be the 1 sharing most HLA alleles with thymus donor
  • HLA-DR matching preferred over HLA class I matching. If there no HLA matching at all, then either parent will be acceptable if meets other criteria.
  • Negative for EBV; CMV; HIV-1; Syphilis; West Nile virus; Hepatitis B; Hepatitis C; pregnancy; & evidence of head/neck infection
  • Fiberoptic nasolaryngoscopy shows vocal cords functioning normally.
  • Normal thyroid function
  • No history of cancer
  • The infant-recipient has 2 living involved parents.

Parathyroid Donor Exclusion:

  • Infant recipient doesn't have 2 living involved parents
  • Animal tissue/organ recipient
  • EBV
  • CMV
  • HIV-1
  • Syphilis
  • West Nile virus
  • Hepatitis B
  • Hepatitis C
  • Pregnant
  • Evidence of head/neck infection
  • Vocal cords not functioning normally.
  • Thyroid abnormalities
  • Hyperparathyroidism
  • History of cancer
  • Mad cow disease (positive)
  • SARS(and exposure)
  • Smallpox exposure

Biological Mother of DiGeorge Subjects Inclusions:

Mother must be competent to consent or assent to study participation and willing to provide blood sample. No other inclusion/exclusion.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: N/A
  • Interventional Model: Single Group Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Thymus and Parathyroid transplantation
Thymus/Parathyroid Transplantation in Complete DiGeorge Syndrome Infants
Biological: Thymus/Parathyroid Transplantation
Thymus tissue, thymus donor, mother of thymus donor, & parental parathyroid donor screened for transplant safety. Depending on T cell phenotype & function, subjects were given 1 of 2 immunosuppression regimes. All received rabbit anti thymocyte globulin pretransplantation. Others also received cyclosporine pre & post-transplantation. The thymus dose was over 0.2 grams/kg recipient weight. Thymus transplant occurred in operating room; thymic slices were placed in quadriceps. Parathyroid harvest was done under general anesthesia. One parathyroid gland was minced and placed in quadriceps muscle. There was no dose in mg. An open biopsy of thymus allograft was done 2-3 months post-transplant. Biopsy tissue was examined by immunohistochemistry to evaluate for thymopoiesis & graft rejection.
Other Names:
  • IND 9836, Thymus Tissue

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Efficacy parameter: use of calcium/calcitriol at 1 year post-transplantation.
Time Frame: 1 year after thymus transplantation
Subjects wtih complete DiGeorge anomaly who have received thymus and parathyroid transplants and survived to one year
1 year after thymus transplantation

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Efficacy parameters: ionized calcium
Time Frame: 10-14 months after thymus transplantation
Ionized calcium (normal values are 1.2 - 1.37 mmol/L)
10-14 months after thymus transplantation
Efficacy parameters: CD3 count
Time Frame: 10-14 months after thymus transplantation
CD3 count/mm3
10-14 months after thymus transplantation
Efficacy parameters: CD4 count
Time Frame: 10-14 months after thymus transplantation
CD4 count/mm3
10-14 months after thymus transplantation
Efficacy parameters: CD8 count
Time Frame: 10-14 months after thymus transplantation
CD8 count/mm3
10-14 months after thymus transplantation
Efficacy parameters: naive CD4 count
Time Frame: 10-14 months after thymus transplantation
naive CD4 count/mm3
10-14 months after thymus transplantation
Efficacy parameters: naive CD8 count
Time Frame: 10-14 months after thymus transplantation
naive CD8 count/mm3
10-14 months after thymus transplantation
Efficacy parameters: proliferative response to phytohemagglutinin
Time Frame: approximately 1 year after thymus transplantation (8.9 to 17.8 months after transplantation)
proliferative response to phytohemagglutinin in counts per minute
approximately 1 year after thymus transplantation (8.9 to 17.8 months after transplantation)
Efficacy parameters: proliferative response to tetanus toxoid
Time Frame: approximately 1 year after thymus transplantation (8.9 to 17.8 months after transplantation)
proliferative response to tetanus toxoid in counts per minute
approximately 1 year after thymus transplantation (8.9 to 17.8 months after transplantation)
Efficacy parameters: spectra typing at 1 year post transplantation
Time Frame: approximately 1 year after thymus transplantation (12.1 to 18.0 months after transplantation)
Variability of CD4 T cell receptor beta repertoire as assessed by the Kullback-Leibler divergence (DKL)
approximately 1 year after thymus transplantation (12.1 to 18.0 months after transplantation)

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Enzyvant Therapeutics GmBH

Collaborators

National Institute of Allergy and Infectious Diseases (NIAID)
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
National Institutes of Health (NIH)
Food and Drug Administration (FDA)

Investigators

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

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

January 1, 2005

Primary Completion (Actual)

August 1, 2007

Study Completion (Actual)

December 1, 2019

Study Registration Dates

First Submitted

November 30, 2007

First Submitted That Met QC Criteria

November 30, 2007

First Posted (Estimate)

December 3, 2007

Study Record Updates

Last Update Posted (Actual)

April 4, 2022

Last Update Submitted That Met QC Criteria

March 23, 2022

Last Verified

April 1, 2020

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • Pro00016482
  • R01AI047040 (NIH)
  • R01AI054843 (NIH)
  • 3R56AI047040-11A1S1 (U.S. NIH Grant/Contract)
  • R56 Bridge R01AI4704011A1 (OTHER_GRANT: [NIH American Recovery and Reinvestment Act (ARRA) of 2009])
  • 2R01AI047040-11A2 (U.S. NIH Grant/Contract)
  • 5K12HD043494-09 (U.S. NIH Grant/Contract)
  • FDA-FD-R-002606 (Other Grant/Funding Number: FDA OOPD)
  • #931

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

Yes

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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