Clinical trial NCT00849888: Serum-Free Thymus Transplantation in DiGeorge Anomaly
Official title: Phase I Serum-Free Cultured Thymus Transplantation in DiGeorge Anomaly, IND9836
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE1
Conditions: DiGeorge Anomaly
Keywords: Thymus Transplantation
DiGeorge Anomaly
Athymia
Low T cell numbers
Immunoreconstitution
Immunodeficiency
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: 2009-02-24
Enrollment: 2
Sex: ALL
Maximum age (years): 2
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The study purpose is to determine if thymus tissue cultured in a serum-free (SF) solution is a safe and effective treatment for atypical and typical complete DiGeorge anomaly. \[Funding Source - FDA OOPD\]

Detailed description: Complete DiGeorge anomaly is a congenital disorder characterized by athymia. Without successful treatment, patients remain immunodeficient and usually die by age 2 years. In "typical" complete DiGeorge subjects who have no T cells, thymus transplantation without immunosuppression has resulted in diverse T cell development and good T cell function. In "atypical" complete DiGeorge subjects who have no thymus, a rash, and some T cells that presumably developed extrathymically, thymus transplantation with immunosuppression has resulted in diverse T cell development and good T cell function. Thus far, thymus transplantation studies have used thymus cultured in fetal bovine serum (FBS medium). This protocol's purpose is to determine whether transplanted thymus cultured in serum free medium can safely support thymopoiesis and T cell reconstitution as does FBS medium cultured thymus tissue in DiGeorge anomaly subjects. This protocol includes 2 arms: atypical DiGeorge subjects who will receive immunosuppression and thymus transplantation; and, typical complete DiGeorge subjects who will receive thymus transplantation without immunosuppression. Serum free medium use would reduce concerns of animal product exposure including potential exposure to bovine spongiform encephalopathy(BSE).

Eligibility criteria: Thymus Recipients Inclusion:

Complete DiGeorge anomaly diagnosis

Must have one of following:

* congenital heart disease
* hypocalcemia requiring replacement
* 22q11 or 10p13 hemizygous
* CHARGE

Atypical Arm:

* Must have, or have had, rash. If rash present, skin biopsy must show T cells. If rash resolved, must have \>50/cumm T cells; \& \<50/cumm naive T cells or \<5% total
* PHA response must be \<40000 counts per minute(cpm) on immunosuppression; or, \<75000cpm off immunosuppression. PHA test must be done 2x
* CD45RA+CD62L+ CD3+ T cells must be \<50/mm3; or, \<5% of total CD3. Test must be done 2x

Typical Arm:

* PHA response \<20 fold or \<5,000cpm
* Circulating CD3+CD45RA+CD62L+T cells \<50/mm3 or \<5% total T cells
* 2 tests of T cells \& PHA response must show similar results

Biological Mother Inclusion:

-Must be recipient's biological mother

Thymus Recipient Exclusion:

* Heart surgery \<4 weeks pre-transplant or within 3 months post-transplant
* Rejection by surgeon or anesthesiologist as surgical candidates
* Lack of sufficient muscle tissue to accept transplant
* Medical condition does not allow to undergo a biopsy
* HIV
* CMV(\>500 copies/ml blood by PCR on 2 tests)
* Ventilator dependence
* GVHD
* Maternal T cells \>20% of total T cells
* Prior immune reconstitution attempts (e.g., BMT, prior thymus transplant)
* Hypoparathyroidism meeting criteria for combined thymus/parathyroid transplant \& parents desiring it
* RSV or parainfluenza virus
* Enterovirus or Adenovirus in stool

Biological Mother Exclusion:

-Unwillingness to sign consent or provide blood/buccal samples

Primary outcomes:
measure: Survival
timeFrame: One year post-thymus transplantation.
measure: Incidence of graft-versus-host-disease (GVHD).
timeFrame: One year post-thymus-transplantation.
measure: Thymopoiesis or graft rejection on biopsy.
timeFrame: Two months post-thymus transplantation.
Secondary outcomes:
measure: Incidence of autoimmune disease.
timeFrame: By two years post-thymus transplantation.
measure: Immune outcomes: T cell development; evaluate T cell numbers, diversity, and function.
timeFrame: One year post-thymus transplantation.
Other outcomes:
Locations:
Study officials:
affiliation: Duke University Medical Center, Pediatrics, Allergy & Immunology
name: M. Louise Markert, M.D., Ph.D
role: PRINCIPAL_INVESTIGATOR
References:
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, 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.
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: 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.
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, 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.