Thymus Transplantation in DiGeorge Syndrome #668

NCT00576407 | Completed Phase 2 Results DMC FDA Drug

• 8 other identifiers: Pro000099552R01AI047040-11A2R56 Bridge R01AI4704011A15K12HD043494-09R01AI0470403R56AI047040-11A1S1R01AI054843#668
• Study Type: interventional
• Target: 26
• Locations: 1 country
• Sites: 1

Brief Summary

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

Conditions

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)

Outcome Measures

Primary Outcomes (1)

• 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.

  1 year post-CTTI

Secondary Outcomes (8)

• Survival at 2 Years Post-CTTI

  2 years post-CTTI

• Immune Reconstitution Efficacy - Total CD3 T Cells

  1 year post-CTTI

• Immune Reconstitution Efficacy - Total CD4 T Cells

  1 year post-CTTI

• Immune Reconstitution Efficacy - Total CD8 T Cells

  1 year post-CTTI

• Immune Reconstitution Efficacy - Naive CD4 T Cells

  1 year post-CTTI

Study Arms (1)

Cultured Thymus Tissue Implantation in Complete DiGeorge

EXPERIMENTAL

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)

Interventions

Cultured Thymus Tissue for Implantation (CTTI) BIOLOGICAL

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.

Also known as: Thymus Tissue, Thymus Tissue Transplantation, Thymus Transplant, CTTI

Cultured Thymus Tissue Implantation in Complete DiGeorge

Eligibility Criteria

• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• 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
• q11 hemizygosity
• p13 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.

You may not qualify if:

• 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

Sponsors & Collaborators

• Sumitomo Pharma Switzerland GmbH: lead
• National Institutes of Health (NIH): collaborator
• National Institute of Allergy and Infectious Diseases (NIAID): collaborator
• Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD): collaborator

Study Sites (1)

Duke University Medical Center

Durham, North Carolina, 27710, United States

Location

Related Publications (14)

• 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.

  PMID: 21565561 BACKGROUND

• 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.

  PMID: 20832849 BACKGROUND

• 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.

  PMID: 23607606 BACKGROUND

• 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.

  PMID: 12702512 RESULT

• 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.

  PMID: 17284531 RESULT

• 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.

  PMID: 20236866 RESULT

• 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.

  RESULT

• 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.

  PMID: 18155964 RESULT

• 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.

  PMID: 18424759 RESULT

• 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.

  PMID: 18035553 RESULT

• 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.

  PMID: 18557726 RESULT

• 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.

  PMID: 19066739 RESULT

• 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.

  PMID: 20978268 RESULT

• 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.

  RESULT

MeSH Terms

Conditions

DiGeorge Syndrome; Thymic aplasia; Primary Immunodeficiency Diseases

Interventions

Drug Implants

Condition Hierarchy (Ancestors)

22q11 Deletion Syndrome; Craniofacial Abnormalities; Musculoskeletal Abnormalities; Musculoskeletal Diseases; Heart Defects, Congenital; Cardiovascular Abnormalities; Cardiovascular Diseases; Heart Diseases; Lymphatic Abnormalities; Lymphatic Diseases; Hemic and Lymphatic Diseases; Abnormalities, Multiple; Congenital Abnormalities; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Chromosome Disorders; Genetic Diseases, Inborn; Hypoparathyroidism; Parathyroid Diseases; Endocrine System Diseases; Immunologic Deficiency Syndromes; Immune System Diseases

Intervention Hierarchy (Ancestors)

Delayed-Action Preparations; Dosage Forms; Pharmaceutical Preparations

Results Point of Contact

• Title: M. Louise Markert, MD, PhD Professor of Pediatrics and Immunology
• Organization: Duke University Medical Center

marke001@mc.duke.edu

919-684-6263

Study Officials

• M. Louise Markert, MD, PhD

  Duke University Medical Center, Pediatrics, Allergy & Immunology

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: December 17, 2007
• First Posted: December 19, 2007
• Study Start: October 1, 1991
• Primary Completion: April 1, 2009
• Study Completion: December 31, 2017
• Last Updated: March 25, 2022
• Results First Posted: February 17, 2020

Record last verified: 2022-03

Locations

US (1)