Thymus Transplantation Dose in DiGeorge #932

NCT00576836 | Completed Phase 2 Results DMC FDA Drug

• 9 other identifiers: Pro00016144FDA-FD-R-0026062R01AI047040-11A2R56 Bridge R01AI4704011A15K12HD043494-09R01AI054843R01AI0470403R56AI047040-11A1S1932
• Study Type: interventional
• Target: 7
• Locations: 1 country
• Sites: 1

Brief Summary

One purpose of this study is to determine whether the amount of cultured thymus tissue implanted into DiGeorge anomaly infants has any effect on the immune outcome. Another purpose of this study is to determine whether parental parathyroid transplantation (in addition to cultured thymus tissue implantation (CTTI) can help both the immune and the calcium problems in DiGeorge infants with hypocalcemia. \[Funding Source - FDA Office of Orphan Products Development (OOPD)\]

Conditions

DiGeorge Anomaly; DiGeorge Syndrome; Complete DiGeorge Anomaly; Complete DiGeorge Syndrome

Keywords

Thymus Transplantation; DiGeorge Syndrome; DiGeorge Anomaly; Athymia; Parathyroid Transplantation; Hypocalcemia; Hypoparathyroidism; Low T cell numbers; Immunoreconstitution; Immunodeficiency; Complete DiGeorge; Complete DiGeorge Anomaly; Typical DiGeorge; Cultured Thymus Tissue Implantation (CTTI)

Outcome Measures

Primary Outcomes (1)

• Survival at 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 Outcomes (8)

• Survival at 2 Years Post-CTTI

  2 years post-CTTI

• Immune Reconstitution Efficacy - CD3 T Cells

  1 year post-CTTI

• Immune Reconstitution Efficacy - CD4 T Cells

  1 year post-CTTI

• Immune Reconstitution Efficacy - CD8 T Cells

  1 year post-CTTI

• Immune Reconstitution Efficacy - Naive CD4 T Cells

  1 year post-CTTI

Study Arms (2)

Cultured Thymus Tissue Implantation w Parathyroid Transplant

EXPERIMENTAL

Cultured Thymus Tissue Implantation With Parathyroid Tissue Transplantation. Subjects who were enrolled in this arm underwent cultured thymus tissue implantation with parathyroid transplantation, if eligible. No specific dose was assigned. The thymus tissue dose was the number of grams of cultured thymus tissue divided by the weight of the recipient in kg or per square meter of body surface area of the recipient. There was a one time administration of the cultured thymus tissue and parathyroid tissue.

Other: Cultured Thymus Tissue Implantation with Parathyroid Transplantation

Cultured Thymus Tissue Implantation

EXPERIMENTAL

Cultured Thymus Tissue Implantation. Subjects who were enrolled in this arm underwent cultured thymus tissue implantation (CTTI) only. No specific dose was assigned. The thymus tissue dose was the number of grams of cultured thymus tissue divided by the weight of the recipient in kg or per square meter of body surface area of the recipient. There was a one time administration of the cultured thymus tissue. .

Biological: Cultured Thymus Tissue Implantation (CTTI)

Interventions

Cultured Thymus Tissue Implantation (CTTI) BIOLOGICAL

Thymus tissue (from unrelated donor), thymus donor, and thymus donor's birth mother screened for safety. CTTI was done under general anesthesia. Cultured thymus tissue was implanted into quadriceps. Thymus dose at least 4grams/m2 body surface area (0.2 grams/kg body weight) and not \>18 grams/m2 body surface area (1.0 grams/kg body weight). At time of CTTI, skin biopsy was obtained to look for preexisting T cells. 2-3 months post-CTTI allograft biopsy was done to evaluate for thymopoiesis \& graft rejection. At time of biopsy, skin biopsy done to look for T cell clonal populations. (Allograft biopsy not done if subject medically unstable.) Post-CTTI, subjects followed by immune evaluations, using blood samples.

Also known as: Thymus Tissue for Transplantation, CTTI

Cultured Thymus Tissue Implantation

Cultured Thymus Tissue Implantation with Parathyroid Transplantation OTHER

Parental parathyroid donors screened for eligibility and safety. If both parents meet eligibility criteria, the parathyroid will be harvested from parent who shares the most Human Leukocyte Antigens (HLA) alleles with thymus donor. Parathyroid harvest \& transplant preferably done at same time as CTTI. (If parathyroid transplant cannot be done at same time, then it is done within 3-8 weeks of CTTI.) Parathyroid harvest done under general anesthesia. One parathyroid gland is minced \& placed in quadriceps muscle; there is no dose in mg. No biopsy done of the parathyroid. Parathyroid donors are monitored as outpatients until recipients' discharge. Recipients' calcium and PTH levels are monitored indefinitely.

Also known as: Thymus and Parathyroid Transplant, CTTI and Parathyroid Transplant

Cultured Thymus Tissue Implantation w Parathyroid Transplant

Eligibility Criteria

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

You may qualify if:

• A parent or guardian of the DGS subject signed the consent form.
• Medical screening was completed.
• For a diagnosis of DGS, the subject had to have one of the following:
• Congenital heart disease;
• Hypocalcemia requiring replacement;
• q11.2 hemizygosity or 10p13 hemizygosity;
• CHARGE association or CHD7 mutation;
• A subject with abnormal ears whose mother had diabetes (type I, type II, or gestational).
• To meet the criteria of typical complete DiGeorge Anomaly (cDGA), the subject had to have either:
• Circulating CD3+ T cell count by flow cytometry \< 50/mm3 OR
• Circulating CD3+ T cells that were also positive for Cluster of Differentiation 45RA (CD45RA)+ CD62L+ and were \< 50/mm3 or less than 5% of total T cells.

You may not qualify if:

• Had heart surgery less than 4 weeks prior to projected implant date;
• Heart surgery anticipated within 3 months after the proposed time of implantation;
• Present or past lymphadenopathy;
• Rash associated with T cell infiltration of the dermis and epidermis;
• Rejection by the surgeon or anesthesiologist as surgical candidate;
• Lack of sufficient muscle tissue to accept a transplant of 4 g/m2 body surface area (BSA) or 0.2 g/kg subject bodyweight;
• Had human immunodeficiency virus (HIV) infection;
• Had prior attempts at immune reconstitution, such as bone marrow transplant or previous thymus transplantation;
• Ventilator support or positive pressure support: Subjects had to be off ventilator or other pressure support such as continuous positive airway pressure (CPAP) or bi-level positive airway pressure (BiPAP) support for 2 weeks prior to enrollment. If the subject was enrolled and was placed back on ventilator or pressure support, the subject had to be able to be weaned off and remain off ventilator or pressure support for 2 weeks. If the subject could not be successfully weaned off ventilator or pressure support, the subject was to be withdrawn from the study.
• tests in patient showing: intact parathyroid hormone (PTH) \< 5 pg/ml when ionized calcium \< 1.1 mmol/L
• involved parents
• Parents do not meet enrollment criteria.
• Parent(s) decline to be parathyroid donor(s).
• \> 18 years old
• Answers all questionnaire items and meets safety screening criteria

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)

• 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

• 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, 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

• 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

• 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, 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 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, 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, 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. Thymus transplantation in complete DiGeorge anomaly. Immunol Res. 2009;44(1-3):61-70. doi: 10.1007/s12026-008-8082-5.

  PMID: 19066739 RESULT

• 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 RESULT

• Ciupe SM, Devlin BH, Markert ML, Kepler TB. Quantification of total T-cell receptor diversity by flow cytometry and spectratyping. BMC Immunol. 2013 Aug 6;14:35. doi: 10.1186/1471-2172-14-35.

  PMID: 23914737 RESULT

MeSH Terms

Conditions

DiGeorge Syndrome; Thymic aplasia; Hypocalcemia; Hypoparathyroidism; Immunologic Deficiency Syndromes

Interventions

Transplantation; 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; Calcium Metabolism Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases; Water-Electrolyte Imbalance; Immune System Diseases

Intervention Hierarchy (Ancestors)

Surgical Procedures, Operative; Tissue Extracts; Complex Mixtures

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
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: December 17, 2007
• First Posted: December 19, 2007
• Study Start: September 2, 2004
• Primary Completion: November 1, 2010
• Study Completion: December 31, 2019
• Last Updated: March 25, 2022
• Results First Posted: February 17, 2020

Record last verified: 2022-03

Locations

US (1)