Parathyroid and Thymus Transplantation in DiGeorge #931

NCT00566488 | Completed Phase 1 DMC FDA Drug

• 9 other identifiers: Pro00016482R01AI0470405K12HD043494-09R01AI054843FDA-FD-R-0026062R01AI047040-11A2R56 Bridge R01AI4704011A13R56AI047040-11A1S1#931
• Study Type: interventional
• Target: 25
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

DiGeorge Syndrome; Hypoparathyroidism; Complete DiGeorge Syndrome

Keywords

Thymus Transplantation; Parathyroid Transplantation; DiGeorge Syndrome; Hypoparathyroidism; Athymia

Outcome Measures

Primary Outcomes (1)

• Efficacy parameter: use of calcium/calcitriol at 1 year post-transplantation.

  Subjects wtih complete DiGeorge anomaly who have received thymus and parathyroid transplants and survived to one year

  1 year after thymus transplantation

Secondary Outcomes (9)

• Efficacy parameters: ionized calcium

  10-14 months after thymus transplantation

• Efficacy parameters: CD3 count

  10-14 months after thymus transplantation

• Efficacy parameters: CD4 count

  10-14 months after thymus transplantation

• Efficacy parameters: CD8 count

  10-14 months after thymus transplantation

• Efficacy parameters: naive CD4 count

  10-14 months after thymus transplantation

Study Arms (1)

Thymus and Parathyroid transplantation

EXPERIMENTAL

Thymus/Parathyroid Transplantation in Complete DiGeorge Syndrome Infants

Biological: Thymus/Parathyroid Transplantation

Interventions

Thymus/Parathyroid Transplantation BIOLOGICAL

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.

Also known as: IND 9836, Thymus Tissue

Thymus and Parathyroid transplantation

Eligibility Criteria

• Age: Up to 24 Months
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17)

You may qualify if:

• 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.

You may not qualify if:

• 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
• 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

Sponsors & Collaborators

• Sumitomo Pharma Switzerland GmbH: lead
• Food and Drug Administration (FDA): collaborator
• 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, 27705, United States

Location

Related Publications (15)

• 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 BACKGROUND

• 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 BACKGROUND

• Selim MA, Markert ML, Burchette JL, Herman CM, Turner JW. The cutaneous manifestations of atypical complete DiGeorge syndrome: a histopathologic and immunohistochemical study. J Cutan Pathol. 2008 Apr;35(4):380-5. doi: 10.1111/j.1600-0560.2007.00816.x.

  PMID: 18333898 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 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, 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, 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

• 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

• 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, 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

• 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 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

• 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, Alexieff MJ, Li J, Sarzotti M, Ozaki DA, Devlin BH, Sedlak DA, Sempowski GD, Hale LP, Rice HE, Mahaffey SM, Skinner MA. Postnatal thymus transplantation with immunosuppression as treatment for DiGeorge syndrome. Blood. 2004 Oct 15;104(8):2574-81. doi: 10.1182/blood-2003-08-2984. Epub 2004 Apr 20.

  PMID: 15100156 RESULT

MeSH Terms

Conditions

DiGeorge Syndrome; Hypoparathyroidism; Thymic aplasia

Interventions

Thymus Extracts

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; Parathyroid Diseases; Endocrine System Diseases

Intervention Hierarchy (Ancestors)

Tissue Extracts; Complex Mixtures

Study Officials

• M. Louise Markert, MD, PhD

  Duke University Medical Center, Pediatrics, Allergy & Immunology

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: November 30, 2007
• First Posted: December 3, 2007
• Study Start: January 1, 2005
• Primary Completion: August 1, 2007
• Study Completion: December 1, 2019
• Last Updated: April 4, 2022

Record last verified: 2020-04

Locations

US (1)