Thymus Transplantation Dose in DiGeorge #932

Dose Study of Thymus Transplantation in DiGeorge Anomaly, IND 9836, #932.1

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)]

Study Overview

• Status: Completed
• Conditions: DiGeorge Syndrome; DiGeorge Anomaly; Complete DiGeorge Anomaly; Complete DiGeorge Syndrome
• Intervention / Treatment: Other: Cultured Thymus Tissue Implantation with Parathyroid Transplantation; Biological: Cultured Thymus Tissue Implantation (CTTI)

Detailed Description

DiGeorge anomaly is a congenital disorder in which infants are born with defects of the thymus, heart, and parathyroid gland. Complete DiGeorge Anomaly is usually fatal within the first two years of life. This trial evaluates the role of cultured thymus tissue dose in cultured thymus tissue implantation (CTTI) in complete (typical) DiGeorge anomaly infants, and continues safety assessments.

DiGeorge infants who have successful CTTIs but remain with hypoparathyroidism must go to the clinic for frequent calcium levels and to the hospital for calcium infusions; these infants are at risk for seizures from low calcium. Approximately ½ of infants with profound hypoparathyroidism will develop nephrocalcinosis. This protocol had a parental parathyroid transplant arm for complete DiGeorge infants with athymia and profound hypoparathyroidism.

• Study Type: Interventional
• Enrollment (Actual): 7
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • North Carolina
    • Durham, North Carolina, United States, 27710
      • Duke University Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult; Older Adult
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Thymus Transplant Inclusion Criteria:

• 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;
  • 22q11.2 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.

Thymus Transplant Exclusion Criteria:

• 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.

Additional Inclusion Criteria for Parathyroid Transplant Recipient:

• 2 tests in patient showing: intact parathyroid hormone (PTH) < 5 pg/ml when ionized calcium < 1.1 mmol/L
• All inclusion criteria for thymus transplant must be met
• 2 involved parents

Exclusion for Parathyroid Transplant Recipient:

• Parents do not meet enrollment criteria.
• Parent(s) decline to be parathyroid donor(s).

Parental Parathyroid Donor Inclusion:

• > 18 years old
• Answers all questionnaire items and meets safety screening criteria
• Normal serum calcium
• Normal PTH function
• HLA typing consistent with parentage
• Parent chosen for donation will share HLA-DR allele in thymus donor; if not applicable, then either parent will be selected (if meet all other criteria).
• Must not be on anticoagulation or can come off for donation/transplantation

Parental Parathyroid Donor Exclusion:

• Donor is only living involved parent or caretaker of the recipient
• Hypoparathyroidism - low parathyroid hormone (PTH) in presence of low serum calcium and high serum phosphate
• Hyperparathyroidism (or history of) - elevated PTH in presence of high serum calcium and low serum phosphate
• History of cancer
• Evidence of any of following: HIV-1, HIV-2, HTLV-1, HTLV-2, syphilis, hepatitis B, hepatitis C, West Nile virus, or Trypanosoma Cruzi (Chagas disease)
• Elevated AST, ALT, alkaline phosphatase > 3 times upper limit of normal
• History including receipt of a xenograft or risk factors for SARS, Mad Cow - Disease or smallpox. Note: if parent has Mad Cow Disease risk factors (but not active disease), parent(s) may give permission for transplantation.
• CMV positive urine
• Positive CMV IgM antibodies
• Positive IgM anti-EBV VCA
• On blood thinners and cannot stop for the parathyroid donation
• Elevated PT or PTT (> ULN)
• Platelets < 100,000
• Positive Toxoplasma IgM
• The donor will receive a history and physical; may be excluded based on PI's medical judgment
• Hemoglobin < 9 g/dl
• Infectious lesion on head or neck
• Goiter on ultrasound
• Abnormal fiberoptic laryngoscopy of vocal cords
• Pregnancy
• Positive HSV IgG is not an exclusion; however, post transplantation prophylaxis is needed
• Positive VZV IgG is not an exclusion; however, post transplantation prophylaxis is needed
• Medical concern of otolaryngologist
• Concern by medical psychologist or social worker. Parents are interviewed together and separately regarding following areas: medical history; health habits; substance use; relationships and support; education/work history; mental status/psychological history; readiness for donation.
• Questionnaire (safety screening) responses can lead to exclusion.

Biological Mother of DiGeorge Subject Inclusion Criteria:

• Competent to provide consent
• Willing to provide blood for testing (No other inclusion/exclusion for mother)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Cultured Thymus Tissue Implantation w Parathyroid Transplant; 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; 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.; Other Names: Thymus and Parathyroid Transplant; CTTI and Parathyroid Transplant
Experimental: Cultured Thymus Tissue Implantation; 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); 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.; Other Names: CTTI; Thymus Tissue for Transplantation

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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 Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	2 years post-CTTI
Immune Reconstitution Efficacy - CD3 T Cells	The development of total CD3 T cells at one year as measured using flow cytometry	1 year post-CTTI
Immune Reconstitution Efficacy - CD4 T Cells	The development of total CD4 T cells at one year as measured using flow cytometry	1 year post-CTTI
Immune Reconstitution Efficacy - CD8 T Cells	The development of total CD8 T cells at one year as measured using flow cytometry	1 year post-CTTI
Immune Reconstitution Efficacy - Naive CD4 T Cells	The development of naive CD4 T cells at one year as measured using flow cytometry	1 year post-CTTI
Immune Reconstitution Efficacy - Naive CD8 T Cells	The development of naïve CD8 T cells at one year as measured using flow cytometry.	1 year post-CTTI
Immune Reconstitution Efficacy - Response to Mitogens	The development of a T cell proliferative response to the mitogen phytohemagglutinin.	1 year post-CTTI
Thymus Allograft Biopsy	Evidence, on biopsy of the thymus tissue implanted in the recipient muscle, that shows the development of new T cells.	2 to 3 months post-CTTI

Collaborators and Investigators

• 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

General Publications

• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.

Study record dates

Study Major Dates

• Study Start (Actual): September 2, 2004
• Primary Completion (Actual): November 1, 2010
• Study Completion (Actual): December 31, 2019

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: Immunodeficiency; Hypocalcemia; Hypoparathyroidism; Thymus Transplantation; DiGeorge Anomaly; DiGeorge Syndrome; Athymia; Low T cell numbers; Immunoreconstitution; Complete DiGeorge; Typical DiGeorge; Complete DiGeorge Anomaly; Parathyroid Transplantation; Cultured Thymus Tissue Implantation (CTTI)
• Additional Relevant MeSH Terms: Pathologic Processes; Heart Diseases; Cardiovascular Diseases; Lymphatic Diseases; Endocrine System Diseases; Disease; Genetic Diseases, Inborn; Musculoskeletal Diseases; Parathyroid Diseases; Heart Defects, Congenital; Cardiovascular Abnormalities; Craniofacial Abnormalities; Musculoskeletal Abnormalities; Abnormalities, Multiple; Chromosome Disorders; 22q11 Deletion Syndrome; Lymphatic Abnormalities; Hypoparathyroidism; Syndrome; Congenital Abnormalities; DiGeorge Syndrome; Physiological Effects of Drugs; Calcium-Regulating Hormones and Agents; Parathyroid Hormone
• Other Study ID Numbers: Pro00016144; 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); FDA-FD-R-002606 (Other Grant/Funding Number: FDA OOPD); 932 (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