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Thymus Transplantation in DiGeorge Syndrome #668

Primary Purpose

DiGeorge Syndrome, Complete Typical DiGeorge Anomaly

Status
Completed
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
Cultured Thymus Tissue for Implantation (CTTI)
Sponsored by
Enzyvant Therapeutics GmBH
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for DiGeorge Syndrome focused on measuring Thymus Transplantation, DiGeorge Syndrome, Athymia, Low T cell numbers, Immunoreconstitution, Primary immunodeficiency, DiGeorge Anomaly, Complete DiGeorge, Typical DiGeorge, Cultured Thymus Tissue Implantation (CTTI)

Eligibility Criteria

undefined - undefined (Child, Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

  • Duke University Medical Center

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Cultured Thymus Tissue Implantation in Complete DiGeorge

Arm Description

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.

Outcomes

Primary Outcome Measures

Survival at 1 Year Post-Cultured Thymus Tissue Implantation (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.

Secondary Outcome Measures

Survival at 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.
Immune Reconstitution Efficacy - Total CD3 T Cells
The development of total CD3 T cells at one year as measured using flow cytometry
Immune Reconstitution Efficacy - Total CD4 T Cells
The development of total CD4 T cells at one year as measured using flow cytometry
Immune Reconstitution Efficacy - Total CD8 T Cells
The development of total CD8 T cells at one year as measured using flow cytometry
Immune Reconstitution Efficacy - Naive CD4 T Cells
The development of naive CD4 T cells at one year as measured using flow cytometry
Immune Reconstitution Efficacy - Naive CD8 T Cells
The development of naive CD8 T cells at one year as measured using flow cytometry
Immune Reconstitution Efficacy - Response to Mitogens
The development of a T cell proliferative response to the mitogen phytohemagglutinin.
Thymus Allograft Biopsy
Evidence, on biopsy of the thymus tissue implanted in muscle, that shows the development of new T cells.

Full Information

First Posted
December 17, 2007
Last Updated
March 23, 2022
Sponsor
Enzyvant Therapeutics GmBH
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)
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1. Study Identification

Unique Protocol Identification Number
NCT00576407
Brief Title
Thymus Transplantation in DiGeorge Syndrome #668
Official Title
Phase II Study of Thymus Transplantation in Complete DiGeorge Syndrome #668
Study Type
Interventional

2. Study Status

Record Verification Date
March 2022
Overall Recruitment Status
Completed
Study Start Date
October 1991 (Actual)
Primary Completion Date
April 2009 (Actual)
Study Completion Date
December 31, 2017 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Enzyvant Therapeutics GmBH
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)

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

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

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
DiGeorge Syndrome, Complete Typical DiGeorge Anomaly
Keywords
Thymus Transplantation, DiGeorge Syndrome, Athymia, Low T cell numbers, Immunoreconstitution, Primary immunodeficiency, DiGeorge Anomaly, Complete DiGeorge, Typical DiGeorge, Cultured Thymus Tissue Implantation (CTTI)

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
26 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Cultured Thymus Tissue Implantation in Complete DiGeorge
Arm Type
Experimental
Arm Description
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.
Intervention Type
Biological
Intervention Name(s)
Cultured Thymus Tissue for Implantation (CTTI)
Other Intervention Name(s)
Thymus Tissue, Thymus Tissue Transplantation, Thymus Transplant, CTTI
Intervention Description
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.
Primary Outcome Measure Information:
Title
Survival at 1 Year Post-Cultured Thymus Tissue Implantation (CTTI)
Description
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.
Time Frame
1 year post-CTTI
Secondary Outcome Measure Information:
Title
Survival at 2 Years Post-CTTI
Description
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.
Time Frame
2 years post-CTTI
Title
Immune Reconstitution Efficacy - Total CD3 T Cells
Description
The development of total CD3 T cells at one year as measured using flow cytometry
Time Frame
1 year post-CTTI
Title
Immune Reconstitution Efficacy - Total CD4 T Cells
Description
The development of total CD4 T cells at one year as measured using flow cytometry
Time Frame
1 year post-CTTI
Title
Immune Reconstitution Efficacy - Total CD8 T Cells
Description
The development of total CD8 T cells at one year as measured using flow cytometry
Time Frame
1 year post-CTTI
Title
Immune Reconstitution Efficacy - Naive CD4 T Cells
Description
The development of naive CD4 T cells at one year as measured using flow cytometry
Time Frame
1 year post-CTTI
Title
Immune Reconstitution Efficacy - Naive CD8 T Cells
Description
The development of naive CD8 T cells at one year as measured using flow cytometry
Time Frame
1 year post-CTTI
Title
Immune Reconstitution Efficacy - Response to Mitogens
Description
The development of a T cell proliferative response to the mitogen phytohemagglutinin.
Time Frame
1 year post-CTTI
Title
Thymus Allograft Biopsy
Description
Evidence, on biopsy of the thymus tissue implanted in muscle, that shows the development of new T cells.
Time Frame
2 to 3 months post-CTTI

10. Eligibility

Sex
All
Accepts Healthy Volunteers
No
Eligibility Criteria
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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
M. Louise Markert, MD, PhD
Organizational Affiliation
Duke University Medical Center, Pediatrics, Allergy & Immunology
Official's Role
Principal Investigator
Facility Information:
Facility Name
Duke University Medical Center
City
Durham
State/Province
North Carolina
ZIP/Postal Code
27710
Country
United States

12. IPD Sharing Statement

Citations:
PubMed Identifier
21565561
Citation
Li B, Li J, Devlin BH, Markert ML. Thymic microenvironment reconstitution after postnatal human thymus transplantation. Clin Immunol. 2011 Sep;140(3):244-59. doi: 10.1016/j.clim.2011.04.004. Epub 2011 Apr 16.
Results Reference
background
PubMed Identifier
20832849
Citation
Chinn IK, Olson JA, Skinner MA, McCarthy EA, Gupton SE, Chen DF, Bonilla FA, Roberts RL, Kanariou MG, Devlin BH, Markert ML. Mechanisms of tolerance to parental parathyroid tissue when combined with human allogeneic thymus transplantation. J Allergy Clin Immunol. 2010 Oct;126(4):814-820.e8. doi: 10.1016/j.jaci.2010.07.016. Epub 2010 Sep 15.
Results Reference
background
PubMed Identifier
23607606
Citation
Chinn IK, Milner JD, Scheinberg P, Douek DC, Markert ML. Thymus transplantation restores the repertoires of forkhead box protein 3 (FoxP3)+ and FoxP3- T cells in complete DiGeorge anomaly. Clin Exp Immunol. 2013 Jul;173(1):140-9. doi: 10.1111/cei.12088.
Results Reference
background
PubMed Identifier
12702512
Citation
Markert ML, Sarzotti M, Ozaki DA, Sempowski GD, Rhein ME, Hale LP, Le Deist F, Alexieff MJ, Li J, Hauser ER, Haynes BF, Rice HE, Skinner MA, Mahaffey SM, Jaggers J, Stein LD, Mill MR. Thymus transplantation in complete DiGeorge syndrome: immunologic and safety evaluations in 12 patients. Blood. 2003 Aug 1;102(3):1121-30. doi: 10.1182/blood-2002-08-2545. Epub 2003 Apr 17.
Results Reference
result
PubMed Identifier
17284531
Citation
Markert ML, Devlin BH, Alexieff MJ, Li J, McCarthy EA, Gupton SE, Chinn IK, Hale LP, Kepler TB, He M, Sarzotti M, Skinner MA, Rice HE, Hoehner JC. Review of 54 patients with complete DiGeorge anomaly enrolled in protocols for thymus transplantation: outcome of 44 consecutive transplants. Blood. 2007 May 15;109(10):4539-47. doi: 10.1182/blood-2006-10-048652. Epub 2007 Feb 6.
Results Reference
result
PubMed Identifier
20236866
Citation
Markert ML, Devlin BH, McCarthy EA. Thymus transplantation. Clin Immunol. 2010 May;135(2):236-46. doi: 10.1016/j.clim.2010.02.007. Epub 2010 Mar 16.
Results Reference
result
Citation
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.
Results Reference
result
PubMed Identifier
18155964
Citation
Chinn IK, Devlin BH, Li YJ, Markert ML. Long-term tolerance to allogeneic thymus transplants in complete DiGeorge anomaly. Clin Immunol. 2008 Mar;126(3):277-81. doi: 10.1016/j.clim.2007.11.009. Epub 2007 Dec 26.
Results Reference
result
PubMed Identifier
18424759
Citation
Markert ML, Li J, Devlin BH, Hoehner JC, Rice HE, Skinner MA, Li YJ, Hale LP. Use of allograft biopsies to assess thymopoiesis after thymus transplantation. J Immunol. 2008 May 1;180(9):6354-64. doi: 10.4049/jimmunol.180.9.6354.
Results Reference
result
PubMed Identifier
18035553
Citation
Hudson LL, Louise Markert M, Devlin BH, Haynes BF, Sempowski GD. Human T cell reconstitution in DiGeorge syndrome and HIV-1 infection. Semin Immunol. 2007 Oct;19(5):297-309. doi: 10.1016/j.smim.2007.10.002. Epub 2007 Nov 26.
Results Reference
result
PubMed Identifier
18557726
Citation
Markert ML, Devlin BH, Chinn IK, McCarthy EA, Li YJ. Factors affecting success of thymus transplantation for complete DiGeorge anomaly. Am J Transplant. 2008 Aug;8(8):1729-36. doi: 10.1111/j.1600-6143.2008.02301.x. Epub 2008 Jun 28.
Results Reference
result
PubMed Identifier
19066739
Citation
Markert ML, Devlin BH, Chinn IK, McCarthy EA. Thymus transplantation in complete DiGeorge anomaly. Immunol Res. 2009;44(1-3):61-70. doi: 10.1007/s12026-008-8082-5.
Results Reference
result
PubMed Identifier
20978268
Citation
Markert ML, Marques JG, Neven B, Devlin BH, McCarthy EA, Chinn IK, Albuquerque AS, Silva SL, Pignata C, de Saint Basile G, Victorino RM, Picard C, Debre M, Mahlaoui N, Fischer A, Sousa AE. First use of thymus transplantation therapy for FOXN1 deficiency (nude/SCID): a report of 2 cases. Blood. 2011 Jan 13;117(2):688-96. doi: 10.1182/blood-2010-06-292490. Epub 2010 Oct 26.
Results Reference
result
Citation
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.
Results Reference
result

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Thymus Transplantation in DiGeorge Syndrome #668

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