Thymus Transplantation in DiGeorge Syndrome #668

March 23, 2022 updated by: Enzyvant Therapeutics GmBH

Phase II Study of Thymus Transplantation in Complete DiGeorge Syndrome #668

The study purpose is to determine whether cultured thymus tissue implantation (CTTI) is effective in treating typical complete DiGeorge syndrome.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Detailed Description

There is no safe and effective treatment for DiGeorge syndrome and most patients die by the age of two. Complete DiGeorge syndrome is characterized by very low T cell or very low naïve T cell numbers. In this study, typical complete DiGeorge syndrome subjects underwent human postnatal cultured thymus tissue implantation (CTTI). Thymus tissue that would otherwise be discarded was processed and then implanted into complete DiGeorge subjects in the operating room. At the time of CTTI, a skin biopsy may have been obtained to look for any preexisting T cells. After CTTI, subjects were followed by routine research immune evaluations, using blood samples obtained approximately every 2-4 weeks. At approximately 2-3 months post-CTTI subjects underwent an open biopsy of the allograft. The biopsy was done under general anesthesia in the operating room. At the time of the graft biopsy, another skin biopsy was obtained to look for clonal populations of T cells.

The protocol aims include: assessing thymopoiesis in the allograft biopsy; assessing immunoreconstitution of complete DiGeorge syndrome subjects after postnatal allogeneic cultured thymus tissue implantation; assessing minimally invasive methods of assessing thymopoiesis (flow cytometry and polymerase chain reaction (PCR); assessing pre-implant T cells which do not proliferate in response to mitogens (focusing on NK-T cells); and, assessing cultured thymus tissue implantation safety and toxicity.

Study Type

Interventional

Enrollment (Actual)

26

Phase

  • Phase 2

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, 27710
        • 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

  • Child
  • Adult
  • Older Adult

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Inclusion Criteria:

  • The subject's parent(s) signed the ICF.

  • For a diagnosis of DiGeorge Syndrome (DGS), the subject had one of the following:

    • Heart defect
    • Hypoparathyroidism
    • 22q11 hemizygosity
    • 10p13 hemizygosity
    • Coloboma, heart defect, choanal atresia, growth and development retardation, genital hypoplasia, ear anomalies/ deafness CHARGE association mutation (CHD7 deletion);
    • PHA proliferative responses less than 20-fold above background.
  • Subjects with typical Complete DiGeorge Anomaly (cDGA) had to have one of the following on 2 separate occasions:

  • Circulating CD3+ T cells by flow cytometry < 50/mm3 or PHA < 20-fold over background

    • If CD3+ were > 50/mm3, then CD45RA+ (cluster of differentiation 45RA) CD62L+ had to be < 50/mm3
    • Or T cell receptor rearrangement excision circles (TRECs) by PCR had to be < 100 per 100,000 CD3+ cells.

  • Subjects with atypical cDGA had to have both of the following with 2 studies each:

    • Circulating CD3+ T cells by flow cytometry > 500/mm3 and CD45RA+ CD62L+ CD3+ T cells < 50/mm3 and TRECs less than 100 per 100,000 CD3+ cells.
    • T cell proliferative response to PHA more than 20-fold over background. Circulating CD3+ T cells by flow cytometry > 500/mm3 and CD45RA+ CD62L+ CD3+ T cells < 50/mm3 and TRECs less than 100 per 100,000 CD3+ cells.
    • T cell proliferative response to PHA more than 20-fold over background. While T cell response to PHA might have been seen, eligible subjects were to have no T cell proliferative response to antigens (less than 20-fold response) and were to have serious clinical problems related to immunodeficiency, such as opportunistic infection or failure to thrive.

Exclusion Criteria:

  • Subjects on ventilators, with tracheostomies, with cytomegalovirus (CMV) infections, or requiring ongoing steroids could still be enrolled, but their data were to be analyzed separately
  • Subjects who had heart surgery < 4 weeks prior to transplant
  • Heart surgery anticipated within 3 months of the proposed time of transplantation
  • Ongoing parenteral steroid therapy between enrollment and transplantation
  • Present or past lymphadenopathy
  • Rash associated with T cell infiltration of the dermis and epidermis
  • Rejection by the surgeon or anesthesiologist as surgical candidates
  • Lack of sufficient muscle tissue to accept a transplant of 4 g/m2 body surface area (BSA) of the recipient
  • Prior attempts at immune reconstitution, such as bone marrow transplantation or previous thymus transplantation
  • Human immunodeficiency virus (HIV) infection

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: Cultured Thymus Tissue Implantation in Complete DiGeorge

Participants with Complete DiGeorge Syndrome, who were eligible, received cultured thymus tissue implantation (CTTI).

No specific dose was assigned. There was a one time administration of the cultured thymus tissue.
Biological: Cultured Thymus Tissue for Implantation (CTTI)
Cultured thymus tissue for implantation (CTTI) (previously described as transplantation) is done using allogeneic cultured postnatal tissue from unrelated thymus donors. Thymus tissue, the thymus donor, & thymus donor's birth mother were screened for safety. Approximately 2-3 weeks post-harvest thymus slices were implanted into the recipient's quadriceps. Dose was number of grams of cultured thymus tissue divided by the recipient's weight in kilograms. Minimum dose was 4 g/m2. Maximum dose 18g/m2. At time of CTTI, a skin biopsy was obtained to look for preexisting T cells. 2-3 months post-CTTI allograft biopsy to evaluate for thymopoiesis & graft rejection. At time of biopsy, skin biopsy done to look for T cell clonal populations. Post-CTTI, subjects followed by routine research immune evaluations, using blood samples for approximately 2 years.
Other Names:
  • CTTI
  • Thymus Tissue
  • Thymus Tissue Transplantation
  • Thymus Transplant

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Survival at 1 Year Post-Cultured Thymus Tissue Implantation (CTTI)
Time Frame: 1 year post-CTTI
Survival at 1 year post CTTI was assessed using the Kaplan Meier Estimated Survival. This mathematical function estimates the survival for a certain length of time.
1 year post-CTTI

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
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
1 year post-CTTI
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
1 year post-CTTI
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
1 year post-CTTI
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.
2 to 3 months post-CTTI
Survival at 2 Years Post-CTTI
Time Frame: 2 years post-CTTI
Survival at 2 years post CTTI was assessed using the Kaplan Meier Estimated Survival. This mathematical function estimates the survival for a certain length of time.
2 years post-CTTI
Immune Reconstitution Efficacy - Naive CD4 T Cells
Time Frame: 1 year post-CTTI
The development of naive CD4 T cells at one year as measured using flow cytometry
1 year post-CTTI
Immune Reconstitution Efficacy - Response to Mitogens
Time Frame: 1 year post-CTTI
The development of a T cell proliferative response to the mitogen phytohemagglutinin.
1 year post-CTTI
Immune Reconstitution Efficacy - Naive CD8 T Cells
Time Frame: 1 year post-CTTI
The development of naive CD8 T cells at one year as measured using flow cytometry
1 year post-CTTI

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)

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 (Actual)

October 1, 1991

Primary Completion (Actual)

April 1, 2009

Study Completion (Actual)

December 31, 2017

Study Registration Dates

First Submitted

December 17, 2007

First Submitted That Met QC Criteria

December 18, 2007

First Posted (Estimate)

December 19, 2007

Study Record Updates

Last Update Posted (Actual)

March 25, 2022

Last Update Submitted That Met QC Criteria

March 23, 2022

Last Verified

March 1, 2022

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • Pro00009955
  • 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 (NIH)
  • 5K12HD043494-09 (NIH)
  • #668 (Other Identifier: Duke)

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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