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Serum-Free Thymus Transplantation in DiGeorge Anomaly (SerumFree)

Primary Purpose

DiGeorge Anomaly

Status

Terminated

Phase

Phase 1

Locations

Study Type

Interventional

Intervention

Serum Free Thymus Transplantation with Immunosuppression

Serum Free Thymus Transplantation without immunosuppression

About this trial

This is an interventional treatment trial for DiGeorge Anomaly focused on measuring Thymus Transplantation, DiGeorge Anomaly, Athymia, Low T cell numbers, Immunoreconstitution, Immunodeficiency

Eligibility Criteria

undefined - 2 Years (Child)All SexesDoes not accept healthy volunteers

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

Sites / Locations

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Arm Label

Atypical Complete DiGeorge

Typical Complete DiGeorge

Arm Description

Thymus Transplantation with Immunosuppression

Thymus Transplantation without Immunosuppression

Outcomes

Primary Outcome Measures

Survival

Survival at one year post thymus transplantation.

Incidence of graft-versus-host-disease (GVHD).

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.

Graft rejection analysis by biopsy at 2 months post-thymus transplantation.

Secondary Outcome Measures

Incidence of autoimmune disease.

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.

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

Full Information

NCT ID

NCT00849888

First Posted

February 22, 2009

Last Updated

March 21, 2022

Sponsor

Enzyvant Therapeutics GmBH

Collaborators

National Institutes of Health (NIH), National Institute of Allergy and Infectious Diseases (NIAID), Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)

1. Study Identification

Unique Protocol Identification Number

NCT00849888

Brief Title

Serum-Free Thymus Transplantation in DiGeorge Anomaly

Acronym

SerumFree

Official Title

Phase I Serum-Free Cultured Thymus Transplantation in DiGeorge Anomaly, IND9836

Study Type

Interventional

2. Study Status

Record Verification Date

March 2022

Overall Recruitment Status

Terminated

Why Stopped

The sponsor decided to withdraw the study.

Study Start Date

April 2008 (undefined)

Primary Completion Date

February 2011 (Actual)

Study Completion Date

February 2011 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Enzyvant Therapeutics GmBH

Collaborators

National Institutes of Health (NIH), National Institute of Allergy and Infectious Diseases (NIAID), Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)

4. Oversight

Data Monitoring Committee

Yes

5. Study Description

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).

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

DiGeorge Anomaly

Keywords

Thymus Transplantation, DiGeorge Anomaly, Athymia, Low T cell numbers, Immunoreconstitution, Immunodeficiency

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 1

Interventional Study Model

Parallel Assignment

Masking

None (Open Label)

Allocation

Non-Randomized

Enrollment

2 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Atypical Complete DiGeorge

Arm Type

Experimental

Arm Description

Thymus Transplantation with Immunosuppression

Arm Title

Typical Complete DiGeorge

Arm Type

Experimental

Arm Description

Thymus Transplantation without Immunosuppression

Intervention Type

Biological

Intervention Name(s)

Serum Free Thymus Transplantation with Immunosuppression

Other Intervention Name(s)

IND 9836, Thymus Tissue Transplant

Intervention Description

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.

Intervention Type

Other

Intervention Name(s)

Serum Free Thymus Transplantation without immunosuppression

Other Intervention Name(s)

IND 9836, Thymus Tissue Transplant

Intervention Description

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.

Primary Outcome Measure Information:

Title

Survival

Description

Survival at one year post thymus transplantation.

Time Frame

One year post-thymus transplantation.

Title

Incidence of graft-versus-host-disease (GVHD).

Description

Development of graft versus host disease in first year after transplantation associated with T cells from the thymus donor.

Time Frame

One year post-thymus-transplantation.

Title

Thymopoiesis or graft rejection on biopsy.

Description

Graft rejection analysis by biopsy at 2 months post-thymus transplantation.

Time Frame

Two months post-thymus transplantation.

Secondary Outcome Measure Information:

Title

Incidence of autoimmune disease.

Description

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

Time Frame

By two years post-thymus transplantation.

Title

Immune outcomes: T cell development; evaluate T cell numbers, diversity, and function.

Description

Time Frame

One year post-thymus transplantation.

10. Eligibility

Sex

All

Maximum Age & Unit of Time

2 Years

Accepts Healthy Volunteers

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

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

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

Organizational Affiliation

Duke University Medical Center, Pediatrics, Allergy & Immunology

Official's Role

Principal Investigator

12. IPD Sharing Statement

Citations:

PubMed Identifier

17284531

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.

Results Reference

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PubMed Identifier

15100156

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.

Results Reference

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PubMed Identifier

12702512

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.

Results Reference

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PubMed Identifier

18333898

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.

Results Reference

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PubMed Identifier

18155964

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.

Results Reference

background

PubMed Identifier

18424759

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.

Results Reference

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Serum-Free Thymus Transplantation in DiGeorge Anomaly

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