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

Sponsors and Collaborators:	Duke University National Institutes of Health (NIH) FDA Office of Orphan Products Development
Information provided by:	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	Other: Serum Free Thymus Transplantation with Immunosuppression Other: Serum Free Thymus Transplantation without immunosuppression	Phase I

Study Type:	Interventional
Study Design:	Treatment, Non-Randomized, Open Label, Parallel Assignment, Safety/Efficacy Study
Official Title:	Phase I Serum-Free Cultured Thymus Transplantation in DiGeorge Anomaly, IND9836

Resource links provided by NLM:

Genetics Home Reference related topics: 22q11.2 deletion syndrome

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 ]
Incidence of graft-versus-host-disease (GVHD). [ Time Frame: One year post-thymus-transplantation. ] [ Designated as safety issue: Yes ]
Thymopoiesis or graft rejection on biopsy. [ Time Frame: Two months post-thymus transplantation. ] [ Designated as safety issue: Yes ]

Secondary Outcome Measures:

Incidence of autoimmune disease. [ Time Frame: By two years post-thymus transplantation. ] [ Designated as safety issue: Yes ]
Immune outcomes: T cell development; evaluate T cell numbers, diversity, and function. [ Time Frame: One year post-thymus transplantation. ] [ Designated as safety issue: No ]

Estimated Enrollment:	25
Study Start Date:	January 2009
Estimated Study Completion Date:	December 2015
Estimated Primary Completion Date:	December 2012 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
Atypical Complete DiGeorge: Experimental Thymus Transplantation with Immunosuppression	Other: Serum Free Thymus Transplantation with Immunosuppression Cyclosporine starting prior to transplant until naive T cells develop. For 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 receive transplant in 2 legs: FBS cultured thymus in 1 leg; & serum free in other. After first 2 subjects >10% naïve T cells, 3rd subject receives only serum free cultured thymus. After 3rd subject >20%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.
Typical Complete DiGeorge: Experimental 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 receive transplant in both legs: FBS cultured thymus in 1 leg; serum free cultured thymus in other leg. After first 2 subjects >10% naïve T cells, 3rd subject receives only serum free cultured thymus. After 3rd subject >20%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 8 to 12 weeks post-transplant. (Allograft biopsy not done if subject medically unstable.) Post-transplant, subjects followed by immune evaluations, using blood samples.

Arms

Assigned Interventions

Atypical Complete DiGeorge: Experimental

Thymus Transplantation with Immunosuppression

Other: Serum Free Thymus Transplantation with Immunosuppression

Cyclosporine starting prior to transplant until naive T cells develop. For 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 receive transplant in 2 legs: FBS cultured thymus in 1 leg; & serum free in other. After first 2 subjects >10% naïve T cells, 3rd subject receives only serum free cultured thymus. After 3rd subject >20%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.

Typical Complete DiGeorge: Experimental

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 receive transplant in both legs: FBS cultured thymus in 1 leg;

serum free cultured thymus in other leg. After first 2 subjects >10% naïve T cells, 3rd subject receives only serum free cultured thymus. After 3rd subject >20%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 8 to 12 weeks post-transplant. (Allograft biopsy not done if subject medically unstable.) Post-transplant, subjects followed by immune evaluations, using blood samples.

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 subjects who will receive immunosuppression and thymus transplantation; and, typical complete DiGeorge subjects who will receive thymus transplantation without immunosuppression. Use of serum free medium would reduce concerns of animal product exposure including the 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
abnormal ears plus diabetic mother

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
Age 16-50

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 in atypical DiGeorge
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

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

Contacts

Contact: M. Louise Markert, M.D., Ph.D.	919-684-6263	marke001@mc.duke.edu
Contact: Elizabeth A. McCarthy, R.N., M.S.N.	919-684-6828	mccar006@mc.duke.edu

Locations

United States, North Carolina
Duke University Medical Center	Recruiting
Durham, North Carolina, United States, 27705
Contact: M. Louise Markert, M.D., Ph.D. 919-684-6263 marke001@mc.duke.edu
Contact: Elizabeth A. McCarthy, R.N., M.S.N. 919-684-6828 mccar006@mc.duke.edu
Principal Investigator: M. Louise Markert, M.D., Ph.D

Sponsors and Collaborators

Duke University

National Institutes of Health (NIH)

FDA Office of Orphan Products Development

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.

Responsible Party:	Duke University Medical Center, Pediatric Allergy & Immunology ( M. Louise Markert, MD, PhD, Director, Laboratory of T Cell Reconstitution; Associate Professor )
Study ID Numbers:	eIRB Pro0006109, R01AI47040, R01AI54843, FD-R-003528-01 (pending)
Study First Received:	February 22, 2009
Last Updated:	February 23, 2009
ClinicalTrials.gov Identifier:	NCT00849888 History of Changes
Health Authority:	United States: Food and Drug Administration

Keywords provided by Duke University:

Thymus Transplantation
DiGeorge Anomaly
Athymia

Low T cell numbers
Immunoreconstitution
Immunodeficiency

Study placed in the following topic categories:

Parathyroid Diseases
22q11.2 Deletion Syndrome
Cyclosporine
Conotruncal Anomaly Face Syndrome
Methylprednisolone
Velocardiofacial Syndrome
Anesthetics
Endocrine System Diseases
Methylprednisolone acetate
Prednisolone acetate

Cyclosporins
DiGeorge Syndrome
Immunologic Deficiency Syndromes
Antilymphocyte Serum
Prednisolone
Hypoparathyroidism
Endocrinopathy
Congenital Abnormalities
Methylprednisolone Hemisuccinate

Additional relevant MeSH terms:

Parathyroid Diseases
Immune System Diseases
Endocrine System Diseases
Hypoparathyroidism

Congenital Abnormalities
Immunologic Deficiency Syndromes
DiGeorge Syndrome

ClinicalTrials.gov processed this record on August 30, 2009