Serum-Free Thymus Transplantation in DiGeorge Anomaly - Full Text View

Sponsor:	Duke University
Collaborators:	National Institutes of Health (NIH) FDA Office of Orphan Products Development National Institute of Allergy and Infectious Diseases (NIAID) Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
Information provided by (Responsible Party):	Duke University
ClinicalTrials.gov Identifier:	NCT00849888

Purpose

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.

Condition	Intervention	Phase
DiGeorge Anomaly	Biological: Serum Free Thymus Transplantation with Immunosuppression Other: Serum Free Thymus Transplantation without immunosuppression	Phase I

Study Type:	Interventional
Study Design:	Allocation: Non-Randomized Endpoint Classification: Safety/Efficacy Study Intervention Model: Parallel Assignment Masking: Open Label Primary Purpose: Treatment
Official Title:	Phase I Serum-Free Cultured Thymus Transplantation in DiGeorge Anomaly, IND9836

Resource links provided by NLM:

Genetics Home Reference related topics: 17q21.31 microdeletion syndrome 22q11.2 deletion syndrome Baller-Gerold syndrome Crouzon syndrome tetrasomy 18p

U.S. FDA Resources

Further study details as provided by Duke University:

Primary Outcome Measures:

Survival [ Time Frame: One year post-thymus transplantation. ] [ Designated as safety issue: Yes ]
Survival at one year post thymus transplantation.
Incidence of graft-versus-host-disease (GVHD). [ Time Frame: One year post-thymus-transplantation. ] [ Designated as safety issue: Yes ]
Development of graft versus host disease in first year after transplantation associated with T cells from the thymus donor.
Thymopoiesis or graft rejection on biopsy. [ Time Frame: Two months post-thymus transplantation. ] [ Designated as safety issue: Yes ]
Graft rejection analysis by biopsy at 2 months post-thymus transplantation.

Secondary Outcome Measures:

Incidence of autoimmune disease. [ Time Frame: By two years post-thymus transplantation. ] [ Designated as safety issue: Yes ]
Incidence of autoimmune disease by year 2 after transplantation Cytopenias as assessed by complete blood counts and differential. Thyroid disease as assessed by thyroid function tests
Immune outcomes: T cell development; evaluate T cell numbers, diversity, and function. [ Time Frame: One year post-thymus transplantation. ] [ Designated as safety issue: No ]
Number of naïve CD4 T cells at one year after transplantation Number of total CD4 T cells at one year after transplantation Proliferative response to PHA at one year after transplantation TCRBV diversity by spectratyping measured by DKL score at one year after transplantation

Enrollment:	2
Study Start Date:	April 2008
Study Completion Date:	February 2011
Primary Completion Date:	February 2011 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
Experimental: Atypical Complete DiGeorge Thymus Transplantation with Immunosuppression	Biological: Serum Free Thymus Transplantation with Immunosuppression Cyclosporine pre-transplant (trough 180-220ng/ml) until naive T cells develop. Subjects >4,000/cumm T cells, pre-transplant methylprednisolone or prednisolone 1-2mg/kg/day. All subjects pre-transplant days -5,-4,-3: 3 doses 2mg/kg rabbit anti-thymocyte globulin. Thymus tissue (unrelated donor), donor, & donor's mother screened for safety. Transplant under general anesthesia into quadriceps. First 2 subjects, FBS cultured thymus is transplanted in 1 leg & serum free (SF) in other. After first 2 subjects >10% naïve T cells, 3rd receives only SF thymus. After 3rd subject >10%naive T cells, 4th subject transplanted. Thymus dose 4-18 grams/m2 body surface area. Thymus biopsy 8-12 weeks post-transplant. Skin biopsy at time of transplant & thymus biopsy. Followed by immune evaluations. Other Names: IND 9836 Thymus Tissue Transplant
Experimental: Typical Complete DiGeorge Thymus Transplantation without Immunosuppression	Other: Serum Free Thymus Transplantation without immunosuppression Thymus tissue (unrelated donor), donor, & donor's mother screened for safety. Transplant under general anesthesia into quadriceps. First 2 subjects: FBS cultured thymus transplanted in 1 leg & serum free cultured thymus in other leg. After first 2 subjects have thymopoiesis in serum-free biopsy, >10% naïve T cells, 3rd subject receives only serum free cultured thymus. After 3rd subject >10% naive T cells, 4th subject receives transplant of only serum free cultured thymus. Dose 4-18grams/m2 body surface area. At time of transplant, skin biopsy. Allograft biopsy & skin biopsy done 8 to 12 weeks post-transplant. (Graft biopsy not done if subject medically unstable.) Post-transplant, subjects followed by immune evaluations, using blood samples, for two years. Other Names: IND 9836 Thymus Tissue Transplant

Arms

Assigned Interventions

Experimental: Atypical Complete DiGeorge

Thymus Transplantation with Immunosuppression

Biological: Serum Free Thymus Transplantation with Immunosuppression

Cyclosporine pre-transplant (trough 180-220ng/ml) until naive T cells develop. Subjects >4,000/cumm T cells, pre-transplant methylprednisolone or prednisolone 1-2mg/kg/day. All subjects pre-transplant days -5,-4,-3: 3 doses 2mg/kg rabbit anti-thymocyte globulin. Thymus tissue (unrelated donor), donor, & donor's mother screened for safety. Transplant under general anesthesia into quadriceps. First 2 subjects, FBS cultured thymus is transplanted in 1 leg & serum free (SF) in other. After first 2 subjects >10% naïve T cells, 3rd receives only SF thymus. After 3rd subject >10%naive T cells, 4th subject transplanted. Thymus dose 4-18 grams/m2 body surface area. Thymus biopsy 8-12 weeks post-transplant. Skin biopsy at time of transplant & thymus biopsy. Followed by immune evaluations.

Other Names:

IND 9836
Thymus Tissue Transplant

Experimental: Typical Complete DiGeorge

Thymus Transplantation without Immunosuppression

Other: Serum Free Thymus Transplantation without immunosuppression

Thymus tissue (unrelated donor), donor, & donor's mother screened for safety. Transplant under general anesthesia into quadriceps. First 2 subjects: FBS cultured thymus transplanted in 1 leg & serum free cultured thymus in other leg. After first 2 subjects have thymopoiesis in serum-free biopsy, >10% naïve T cells, 3rd subject receives only serum free cultured thymus. After 3rd subject >10% naive T cells, 4th subject receives transplant of only serum free cultured thymus. Dose 4-18grams/m2 body surface area. At time of transplant, skin biopsy. Allograft biopsy & skin biopsy done 8 to 12 weeks post-transplant. (Graft biopsy not done if subject medically unstable.) Post-transplant, subjects followed by immune evaluations, using blood samples, for two years.

Other Names:

IND 9836
Thymus Tissue Transplant

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

Ages Eligible for Study:	up to 2 Years
Genders Eligible for Study:	Both
Accepts Healthy Volunteers:	No

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

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT00849888

Sponsors and Collaborators

Duke University

National Institutes of Health (NIH)

FDA Office of Orphan Products Development

National Institute of Allergy and Infectious Diseases (NIAID)

Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)

Investigators

Principal Investigator:

M. Louise Markert, M.D., Ph.D

Duke University Medical Center, Pediatrics, Allergy & Immunology

More Information

Publications:

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. Epub 2007 Feb 6.

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. Epub 2004 Apr 20.

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. Epub 2003 Apr 17.

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.

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. Epub 2007 Dec 26.

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.

Responsible Party:	Duke University
ClinicalTrials.gov Identifier:	NCT00849888 History of Changes
Other Study ID Numbers:	Pro0006109, 1R01-FD003528-01, 2R01AI047040-11A2, 5K12HD043494-09, R01AI047040, R01AI054843, R56 Bridge R01AI4704011A1
Study First Received:	February 22, 2009
Last Updated:	February 7, 2012
Health Authority:	United States: Food and Drug Administration

Keywords provided by Duke University:

Thymus Transplantation
DiGeorge Anomaly
Athymia

Low T cell numbers
Immunoreconstitution
Immunodeficiency

Additional relevant MeSH terms:

Congenital Abnormalities
DiGeorge Syndrome
22q11 Deletion Syndrome
Craniofacial Abnormalities
Musculoskeletal Abnormalities
Musculoskeletal Diseases
Heart Defects, Congenital
Cardiovascular Abnormalities
Cardiovascular Diseases

Heart Diseases
Lymphatic Abnormalities
Lymphatic Diseases
Abnormalities, Multiple
Chromosome Disorders
Genetic Diseases, Inborn
Hypoparathyroidism
Parathyroid Diseases
Endocrine System Diseases

ClinicalTrials.gov processed this record on February 09, 2012