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
Sponsored by
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
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
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
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
Time Frame
One year post-thymus transplantation.
10. Eligibility
Sex
All
Maximum Age & Unit of Time
2 Years
Accepts Healthy Volunteers
No
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
background
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
background
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
background
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
background
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
background
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Serum-Free Thymus Transplantation in DiGeorge Anomaly
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