Clinical trial NCT00576836: Thymus Transplantation Dose in DiGeorge #932
Official title: Dose Study of Thymus Transplantation in DiGeorge Anomaly, IND 9836, #932.1
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
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)
Lead sponsor: Sumitomo Pharma Switzerland GmbH
Sponsor class: INDUSTRY
Collaborators: name: National Institutes of Health (NIH)
name: National Institute of Allergy and Infectious Diseases (NIAID)
name: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
First posted: 2007-12-19
Enrollment: 7
Sex: ALL
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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. \[Funding Source - FDA Office of Orphan Products Development (OOPD)\]

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.

Eligibility criteria: 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)

Primary outcomes:
measure: Survival at 1 Year Post-CTTI
timeFrame: 1 year post-CTTI
Secondary outcomes:
measure: Survival at 2 Years Post-CTTI
timeFrame: 2 years post-CTTI
measure: Immune Reconstitution Efficacy - CD3 T Cells
timeFrame: 1 year post-CTTI
measure: Immune Reconstitution Efficacy - CD4 T Cells
timeFrame: 1 year post-CTTI
measure: Immune Reconstitution Efficacy - CD8 T Cells
timeFrame: 1 year post-CTTI
measure: Immune Reconstitution Efficacy - Naive CD4 T Cells
timeFrame: 1 year post-CTTI
measure: Immune Reconstitution Efficacy - Naive CD8 T Cells
timeFrame: 1 year post-CTTI
measure: Immune Reconstitution Efficacy - Response to Mitogens
timeFrame: 1 year post-CTTI
measure: Thymus Allograft Biopsy
timeFrame: 2 to 3 months post-CTTI
Other outcomes:
Locations:
city: Durham
country: United States
facility: Duke University Medical Center
state: North Carolina
Study officials:
affiliation: Duke University Medical Center, Pediatrics, Allergy & Immunology
name: M. Louise Markert, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References:
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
citation: 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.