Phase I/II Thymus Transplantation With Immunosuppression #950

NCT00579527 | Completed Phase 1 Results DMC FDA Drug

• 7 other identifiers: Pro000115832R01AI047040-11A2R56 Bridge R01AI4704011A15K12HD043494-09R01AI047040R01AI054843950
• Study Type: interventional
• Target: 14
• Locations: 1 country
• Sites: 1

Brief Summary

The study purpose is to determine if cultured thymus tissue implantation (CTTI) (previously described as transplantation) with tailored immunosuppression based on the recipient's pre-implantation T cell population is a safe and effective treatment for complete DiGeorge anomaly. This study will also evaluate whether cultured thymus tissue implantation and parathyroid transplantation with immunosuppression is a safe and effective treatment for complete DiGeorge anomaly and hypoparathyroidism.

Conditions

DiGeorge Anomaly; Complete DiGeorge Anomaly; Complete Atypical DiGeorge Anomaly; Complete DiGeorge Syndrome; Complete Atypical DiGeorge Syndrome

Keywords

DiGeorge Anomaly; Thymus Transplantation; DiGeorge Syndrome; Athymia; Parathyroid Transplantation; Hypocalcemia; Hypoparathyroidism; Low T cell numbers; Immunoreconstitution; Immunodeficiency; Complete DiGeorge Anomaly; Complete Atypical DiGeorge Anomaly; Complete DiGeorge Syndrome; Complete Atypical DiGeorge Syndrome; Cultured Thymus Tissue Implantation (CTTI)

Outcome Measures

Primary Outcomes (1)

• Survival at 1 Year Post-CTTI

  Survival at 1 year post cultured thymus tissue implantation was assessed using the Kaplan Meier Estimated Survival. This mathematical function estimates the survival for a certain length of time.

  1 year post-CTTI

Secondary Outcomes (8)

• Survival at 2 Years Post-CTTI

  2 years post-CTTI

• Immune Reconstitution Efficacy - Total CD3 T Cells

  1 year post-CTTI

• Immune Reconstitution Efficacy - Total CD4 T Cells

  1 year post-CTTI

• Immune Reconstitution Efficacy - Total CD8 T Cells

  1 year post-CTTI

• Immune Reconstitution Efficacy - Naive CD4 T Cells

  1 year post-CTTI

Study Arms (2)

Cultured Thymus Tissue Implantation (CTTI) w/immunosuppression

EXPERIMENTAL

Patients with complete DiGeorge Anomaly (cDGA) undergo cultured thymus tissue implantation (previously described as transplantation) with tailored immunosuppression based on the subject's pre-implantation T cell numbers and function.

Biological: Cultured Thymus Tissue for Implantation (CTTI); Procedure: Blood Draw; Drug: Rabbit anti-thymocyte globulin; Drug: Cyclosporine; Drug: Tacrolimus; Drug: Methylprednisolone or Prednisolone; Drug: Daclizumab; Drug: Mycophenolate mofetil

CTTI with Parathyroid Transplantation w/immunosuppression

EXPERIMENTAL

Patients with complete DiGeorge Anomaly (cDGA) undergoes cultured thymus tissue thymus implantation (previously described as transplantation) with tailored immunosuppression based on the subject's pre-implantation T cell numbers and function. If the patient has hypoparathyroidism, and is eligible, the patient may also receive a parathyroid transplant.

Other: Cultured Thymus Tissue Implantation and Parental Parathyroid Transplantation; Procedure: Blood Draw; Drug: Rabbit anti-thymocyte globulin; Drug: Cyclosporine; Drug: Tacrolimus; Drug: Methylprednisolone or Prednisolone

Interventions

Cultured Thymus Tissue for Implantation (CTTI) BIOLOGICAL

Potential thymus recipient subjects are screened for eligibility. Thymus donor (unrelated donor), and thymus donor's birth mother are screened for safety. CTTI is done under general anesthesia in the operating room. Cultured thymus tissue is implanted into the subject's quadriceps. Two to three months post CTTI, if medically stable, the subject undergoes allograft biopsy. At the time of implantation and biopsy, a skin biopsy is done. Immunosuppression is weaned as per protocol.

Also known as: Thymus Tissue Transplant, CTTI

Cultured Thymus Tissue Implantation (CTTI) w/immunosuppression

Cultured Thymus Tissue Implantation and Parental Parathyroid Transplantation OTHER

For subjects w/ hypoparathyroidism, the subject may receive CTTI and parathyroid transplant. For parathyroid transplant, parental parathyroid donors are screened. Parathyroid is harvested from the parent who shares the most Human Leukocyte Antigens (HLA) alleles with the thymus donor. Parathyroid gland is minced and placed in quadriceps muscle; there is no dose. Parathyroid donors are monitored as outpatients until recipients' discharge. Recipients' calcium and PTH levels are monitored indefinitely. Potential thymus recipient subjects are screened for eligibility. Thymus donor (unrelated donor), and thymus donor's birth mother are screened for safety. CTTI is done under general anesthesia in the operating room. Cultured thymus tissue is implanted into the subject's quadriceps. Two to three months post CTTI, if medically stable, the subject undergoes allograft biopsy. At the time of CTTI and biopsy, a skin biopsy is done. Immunosuppression is weaned as per protocol.

Also known as: Thymus and Parathyroid Transplant, CTTI and Parathyroid Transplant

CTTI with Parathyroid Transplantation w/immunosuppression

Blood Draw PROCEDURE

Birth mothers of Thymus Recipients are asked to participate in the study and undergo phlebotomy to allow testing of T cell identity in the Complete DiGeorge subjects. If blood is not obtainable then a buccal swab may be done.

Also known as: Venipuncture

CTTI with Parathyroid Transplantation w/immunosuppression; Cultured Thymus Tissue Implantation (CTTI) w/immunosuppression

Rabbit anti-thymocyte globulin DRUG

Three doses of 2 mg/kg IV (through a central venous catheter) prior to CTTI. Each dose of Rabbit anti-thymocyte globulin (RATGAM) is given over 12 hours. RATGAM is usually given on days-5, -4, and -3 prior to CTTI or CTTI and parathyroid transplantation. Medications (diphenhydramine, steroids, and acetaminophen) are given with rabbit anti-thymocyte globulin.

Also known as: RATGAM, thymoglobulin

CTTI with Parathyroid Transplantation w/immunosuppression; Cultured Thymus Tissue Implantation (CTTI) w/immunosuppression

Cyclosporine DRUG

In addition to RATGAM, subjects with typical cDGA with PHA responses \>50,000 cpm, or atypical cDGA with PHA response \<75,000cpm (when not on immunosuppression) or \<40,000 cpm to PHA while on immunosuppression, are started on cyclosporine (Csa) as soon as cDGA is diagnosed. Csa is continued with target trough levels of 180 to 220 ng/ml. If subject cannot tolerate Csa, Csa may be changed to tacrolimus (FK506) with target trough level 7 to 10 ng/ml. When trough levels are outside of range, dosing is modified appropriately. Csa may be given every 8 to 12 hours enterally or IV before and after CTTI. The Csa dose is dependent on T cell numbers and the target Csa trough levels. Csa is weaned as per protocol.

Also known as: Csa

CTTI with Parathyroid Transplantation w/immunosuppression; Cultured Thymus Tissue Implantation (CTTI) w/immunosuppression

Tacrolimus DRUG

If unable to tolerate cyclosporine, then tacrolimus is given. Tacrolimus may be given every 8 to 12 hours enterally or IV before and after the CTTI transplant. Tacrolimus dose is dependent on the T cell numbers and the target tacrolimus trough levels. Tacrolimus is weaned as per protocol.

Also known as: FK506

CTTI with Parathyroid Transplantation w/immunosuppression; Cultured Thymus Tissue Implantation (CTTI) w/immunosuppression

Methylprednisolone or Prednisolone DRUG

Steroids IV or enterally may be given before and after CTTI or CTTI and parathyroid transplantation. Administration and dosage depends on T cell numbers and symptoms. Pre-transplant steroids may be used when pre-transplant T cells \>4,000cumm. Steroids are weaned as per protocol.

Also known as: Steroids

CTTI with Parathyroid Transplantation w/immunosuppression; Cultured Thymus Tissue Implantation (CTTI) w/immunosuppression

Daclizumab DRUG

In addition, subjects with Atypical DiGeorge with PHA responses \>75,000cpm while on no immunosuppression or PHA responses \>40,000cpm while on immunosuppression, Daclizumab 1 mg/kg single dose IV may be given depending on T cell counts. Administration of Daclizumab depends on T cell numbers and T cell activation. A single dose may be given after the administration of rabbit anti-thymocyte globulin and before CTTI. If Daclizumab is not given before CTTI, and, depending on the T cell numbers and T cell activation, a single dose of Daclizumab may be given 3-5 days after CTTI.

Also known as: Zenapax

Cultured Thymus Tissue Implantation (CTTI) w/immunosuppression

Mycophenolate mofetil DRUG

In addition, subjects with Atypical DiGeorge with PHA responses \>75,000cpm while on no immunosuppression or PHA responses \>40,000cpm while on immunosuppression, Mycophenolate mofetil 15 mg/kg/dose every 8 hours IV or enterally may be given depending on T cell counts. Mycophenolate mofetil may be given if the T cell count remains elevated 5 days after CTTI. If MMF is given, the dose is 15 mg/kg IV. MMF may be stopped at 35 days after CTTI or continued for up to six months after CTTI.

Also known as: MMF, CellCept

Cultured Thymus Tissue Implantation (CTTI) w/immunosuppression

Eligibility Criteria

• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• Must have 1 of following: 22q11 or 10p13 hemizygosity; hypocalcemia requiring replacement; congenital heart defect; CHARGE association or CHD7 mutation; or abnormal ears plus mother w/diabetes (type I, type II, gestational).
• \<50 CD3+ T cells/cumm or \<50 CD3+ T cells/cumm that are CD62L+ CD45RA+ (cluster of differentiation 45RA) (naïve phenotype), or \<5% of CD3+ count being CD62L+ CD45RA+
• Atypical DiGeorge:
• Must have, or have had, a rash. If rash present, rash biopsy must show T cells in skin. If rash \& adenopathy resolved, must have \>50/cumm T cells \& naive T cell must be \<50/cumm or \<5% of T cells.
• Typical DiGeorge:
• CD3+ CD45RA+ CD62L+ T cells \<50/mm3 or \<5% of total T cells
• studies in recipient which PTH\<5 pg/ml when ionized calcium \<1.1 mmol/L. Can be done anytime pre-tx; 1 must be done while at Duke Hospital.
• Parent(s) willing \& eligible to be donors

You may not qualify if:

• Heart surgery \<4 wks pre-tx
• Heart surgery anticipated w/in 3 months after proposed tx
• Rejection by surgeon or anesthesiologist as surgical candidate
• Lack of sufficient muscle tissue to accept transplant of 4 grams/m2 BSA
• HIV infection
• Prior attempts at immune reconstitution, such as bone marrow tx or previous thymus tx
• CMV(\>500 copies/ml blood by PCR on 2 tests)
• Ventilator dependence
• \>18 years of age
• Serum calcium in normal range
• Normal PTH function
• HLA typing consistent with parentage
• Not on anticoagulation or can come off
• Parent chosen will share HLA-DR allele with thymus donor that was not inherited by the recipient. If no HLA matching at all, then either parent is acceptable if the parent meets other criteria.
• \<18 years old

Sponsors & Collaborators

• Sumitomo Pharma Switzerland GmbH: lead
• National Institutes of Health (NIH): collaborator
• National Institute of Allergy and Infectious Diseases (NIAID): collaborator
• Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD): collaborator

Study Sites (1)

Duke University Medical Center

Durham, North Carolina, 27710, United States

Location

Related Publications (16)

• 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.

  PMID: 17284531 BACKGROUND

• 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.

  PMID: 15100156 BACKGROUND

• Markert ML and Devlin BH. Thymic reconstitution (in Rich RR, Shearer WT, Fleischer T, Schroeder HW, Weyand CM, Frew A, eds., Clinical Immunology 3rd edn., Elsevier, Edinburgh) p 1253-1262, 2008.

  BACKGROUND

• 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.

  PMID: 18333898 BACKGROUND

• 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.

  PMID: 18155964 BACKGROUND

• Markert ML, Alexieff MJ, Li J, Sarzotti M, Ozaki DA, Devlin BH, Sempowski GD, Rhein ME, Szabolcs P, Hale LP, Buckley RH, Coyne KE, Rice HE, Mahaffey SM, Skinner MA. Complete DiGeorge syndrome: development of rash, lymphadenopathy, and oligoclonal T cells in 5 cases. J Allergy Clin Immunol. 2004 Apr;113(4):734-41. doi: 10.1016/j.jaci.2004.01.766.

  PMID: 15100681 BACKGROUND

• 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.

  PMID: 12702512 BACKGROUND

• Li B, Li J, Devlin BH, Markert ML. Thymic microenvironment reconstitution after postnatal human thymus transplantation. Clin Immunol. 2011 Sep;140(3):244-59. doi: 10.1016/j.clim.2011.04.004. Epub 2011 Apr 16.

  PMID: 21565561 BACKGROUND

• Chinn IK, Olson JA, Skinner MA, McCarthy EA, Gupton SE, Chen DF, Bonilla FA, Roberts RL, Kanariou MG, Devlin BH, Markert ML. Mechanisms of tolerance to parental parathyroid tissue when combined with human allogeneic thymus transplantation. J Allergy Clin Immunol. 2010 Oct;126(4):814-820.e8. doi: 10.1016/j.jaci.2010.07.016. Epub 2010 Sep 15.

  PMID: 20832849 BACKGROUND

• Markert ML, Devlin BH, McCarthy EA. Thymus transplantation. Clin Immunol. 2010 May;135(2):236-46. doi: 10.1016/j.clim.2010.02.007. Epub 2010 Mar 16.

  PMID: 20236866 RESULT

• 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.

  PMID: 18424759 RESULT

• Hudson LL, Louise Markert M, Devlin BH, Haynes BF, Sempowski GD. Human T cell reconstitution in DiGeorge syndrome and HIV-1 infection. Semin Immunol. 2007 Oct;19(5):297-309. doi: 10.1016/j.smim.2007.10.002. Epub 2007 Nov 26.

  PMID: 18035553 RESULT

• Markert ML, Devlin BH, Chinn IK, McCarthy EA, Li YJ. Factors affecting success of thymus transplantation for complete DiGeorge anomaly. Am J Transplant. 2008 Aug;8(8):1729-36. doi: 10.1111/j.1600-6143.2008.02301.x. Epub 2008 Jun 28.

  PMID: 18557726 RESULT

• Markert ML, Devlin BH, McCarthy EA, Chinn IK, Hale LP. Thymus Transplantation in Thymus Gland Pathology: Clinical, Diagnostic, and Therapeutic Features. Eds Lavinin C, Moran CA, Morandi U, Schoenhuber R. Springer-Verlag Italia, Milan, 2008, pp 255-267.

  RESULT

• Markert ML, Devlin BH, Chinn IK, McCarthy EA. Thymus transplantation in complete DiGeorge anomaly. Immunol Res. 2009;44(1-3):61-70. doi: 10.1007/s12026-008-8082-5.

  PMID: 19066739 RESULT

• Chinn IK, Milner JD, Scheinberg P, Douek DC, Markert ML. Thymus transplantation restores the repertoires of forkhead box protein 3 (FoxP3)+ and FoxP3- T cells in complete DiGeorge anomaly. Clin Exp Immunol. 2013 Jul;173(1):140-9. doi: 10.1111/cei.12088.

  PMID: 23607606 RESULT

MeSH Terms

Conditions

DiGeorge Syndrome; Thymic aplasia; Hypocalcemia; Hypoparathyroidism; Immunologic Deficiency Syndromes

Interventions

Drug Implants; Thymus Extracts; Blood Specimen Collection; Phlebotomy; Antilymphocyte Serum; thymoglobulin; Cyclosporine; Cyclosporins; Tacrolimus; Methylprednisolone; Prednisolone; Steroids; Daclizumab; Mycophenolic Acid

Condition Hierarchy (Ancestors)

22q11 Deletion Syndrome; Craniofacial Abnormalities; Musculoskeletal Abnormalities; Musculoskeletal Diseases; Heart Defects, Congenital; Cardiovascular Abnormalities; Cardiovascular Diseases; Heart Diseases; Lymphatic Abnormalities; Lymphatic Diseases; Hemic and Lymphatic Diseases; Abnormalities, Multiple; Congenital Abnormalities; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Chromosome Disorders; Genetic Diseases, Inborn; Parathyroid Diseases; Endocrine System Diseases; Calcium Metabolism Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases; Water-Electrolyte Imbalance; Immune System Diseases

Intervention Hierarchy (Ancestors)

Delayed-Action Preparations; Dosage Forms; Pharmaceutical Preparations; Tissue Extracts; Complex Mixtures; Specimen Handling; Clinical Laboratory Techniques; Diagnostic Techniques and Procedures; Diagnosis; Punctures; Surgical Procedures, Operative; Investigative Techniques; Therapeutics; Immune Sera; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins; Biological Products; Peptides, Cyclic; Macrocyclic Compounds; Polycyclic Compounds; Peptides; Macrolides; Lactones; Organic Chemicals; Pregnadienetriols; Pregnadienes; Pregnanes; Fused-Ring Compounds; Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Caproates; Acids, Acyclic; Carboxylic Acids; Fatty Acids; Lipids

Results Point of Contact

• Title: M. Louise Markert, MD, PhD Professor of Pediatrics and Immunology
• Organization: Duke University Medical Center

marke001@mc.duke.edu

919-684-6263

Study Officials

• M. Louise Markert, MD, PhD

  Duke University Medical Center, Pediatrics, Allergy & Immunology

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: December 20, 2007
• First Posted: December 24, 2007
• Study Start: December 19, 2005
• Primary Completion: December 1, 2011
• Study Completion: December 31, 2017
• Last Updated: March 25, 2022
• Results First Posted: February 17, 2020

Record last verified: 2022-03

Locations

US (1)