Phase I/II Thymus Transplantation With Immunosuppression #950
Sponsor
Enzyvant Therapeutics GmBH (Industry)
Overall Status
Completed
CT.gov ID
NCT00579527
Collaborator
National Institutes of Health (NIH) (NIH), National Institute of Allergy and Infectious Diseases (NIAID) (NIH), Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) (NIH)
14
1
2
144.4
0.1
Study Details
Study Description
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.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Phase 1/Phase 2 |
Detailed Description
Complete DiGeorge anomaly is a congenital disorder characterized by athymia. Without successful treatment, children remain immunodeficient and usually die by age 2 years. In infants with complete DiGeorge anomaly and no T cells, cultured thymus tissue implantation (CTTI) without immunosuppression resulted in diverse T cell development and good T cell function. Some infants with no thymus have some T cells that presumably developed extrathymically; these T cells can reject a thymus graft.
The purpose of this study is to tailor immunosuppression use for complete DiGeorge anomaly subjects who have some T cells and different T cell function levels. This protocol includes tailored immunosuppression regimens to allow subjects with different T cell function levels to be suppressed adequately.
Patients with complete DiGeorge often have hypoparathyroidism, a life threatening condition. Successful CTTI does not result in improvement of the hypoparathyroidism. The patients must go to the clinic for frequent calcium levels and to the hospital for calcium infusions. These infants are at risk for seizures from low calcium. This study had a parental parathyroid transplant arm for subjects with hypoparathyroidism who require calcium replacement.
Whether or not a subject was enrolled in the parathyroid arm, the immunosuppression regimen the subject received was dependent on the immune findings as stated in the clinical protocol.
Study Design
Study Type:
Interventional
Actual Enrollment
:
14 participants
Allocation:
Non-Randomized
Intervention Model:
Parallel Assignment
Masking:
None (Open Label)
Primary Purpose:
Treatment
Official Title:
Phase I/II Trial of Thymus Transplantation With Immunosuppression, #950
Actual Study Start Date
:
Dec 19, 2005
Actual Primary Completion Date
:
Dec 1, 2011
Actual Study Completion Date
:
Dec 31, 2017
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: Cultured Thymus Tissue Implantation (CTTI) w/immunosuppression 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)
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.
Other Names:
Procedure: Blood Draw
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.
Other Names:
Drug: Rabbit anti-thymocyte globulin
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.
Other Names:
Drug: Cyclosporine
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.
Other Names:
Drug: Tacrolimus
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.
Other Names:
Drug: Methylprednisolone or Prednisolone
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.
Other Names:
Drug: Daclizumab
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.
Other Names:
Drug: Mycophenolate mofetil
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.
Other Names:
|
| Experimental: CTTI with Parathyroid Transplantation w/immunosuppression 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
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.
Other Names:
Procedure: Blood Draw
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.
Other Names:
Drug: Rabbit anti-thymocyte globulin
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.
Other Names:
Drug: Cyclosporine
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.
Other Names:
Drug: Tacrolimus
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.
Other Names:
Drug: Methylprednisolone or Prednisolone
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.
Other Names:
|
Outcome Measures
Primary Outcome Measures
- Survival at 1 Year Post-CTTI [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.
Secondary Outcome Measures
- Survival at 2 Years Post-CTTI [2 years post-CTTI]
Survival at 2 years 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.
- Immune Reconstitution Efficacy - Total CD3 T Cells [1 year post-CTTI]
The development of total CD3 T cells at one year as measured using flow cytometry
- Immune Reconstitution Efficacy - Total CD4 T Cells [1 year post-CTTI]
The development of total CD4 T cells at one year as measured using flow cytometry
- Immune Reconstitution Efficacy - Total CD8 T Cells [1 year post-CTTI]
The development of total CD8 T cells at one year as measured using flow cytometry
- Immune Reconstitution Efficacy - Naive CD4 T Cells [1 year post-CTTI]
The development of total naive CD4 T cells at one year as measured using flow cytometry
- Immune Reconstitution Efficacy - Naive CD8 T Cells [1 year post-CTTI]
The development of total naive CD8 T cells at one year as measured using flow cytometry
- Immune Reconstitution Efficacy - Response to Mitogens [1 year post-CTTI]
Measurement of the T cell proliferative response to the mitogen phytohemagglutin (PHA).
- Thymus Allograft Biopsy [2 to 3 months post-CTTI]
Evidence, on biopsy of the thymus tissue implanted in muscle, that shows the development of new T cells.
Eligibility Criteria
Criteria
Ages Eligible for Study:
N/A
and Older
Sexes Eligible for Study:
All
Accepts Healthy Volunteers:
No
Thymus Transplantation Inclusion:
-
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
Parathyroid Transplantation Additional Inclusion:
-
2 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
Thymus Transplantation Exclusion:
-
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
Parathyroid Donor Inclusion:
-
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.
Parathyroid Donor Exclusion:
-
<18 years old
-
Hypoparathyroidism-low PTH in presence of low serum calcium & high serum phosphate
-
Hyperparathyroidism(or history)-elevated PTH in presence of high serum calcium and low serum phosphate.
-
History of cancer
-
Donor only living involved parent/guardian of recipient
-
Evidence of HIV-1, HIV-2, HTLV-1, HTLV-2, syphilis, hepatitis B, hepatitis C, West Nile virus, or Chagas disease
-
Creutzfeldt Jakob disease (CJD)
-
Elevated liver function studies: AST, ALT, alkaline phosphatase >3x upper normal limit
-
Receipt of xenograft or risk factors for SARS, CJD and/or smallpox exposure. {If CJD risk factors but not active disease, parent may give permission for parathyroid use.}
-
Urine CMV positive
-
Positive CMV IgM
-
Positive IgM anti-EBV VCA
-
On blood thinners and cannot stop for parathyroid donation
-
Elevated PT or PTT (>ULN)
-
Platelets<100,000
-
Positive Toxoplasma IgM
-
Donor will receive a history and physical; may be excluded based on PI's medical judgment.
-
Hemoglobin <9g/dl
-
Infectious head or neck lesion
-
Goiter on ultrasound
-
Abnormal fiberoptic laryngoscopy of vocal cords
-
HLA inconsistent with parentage
-
Pregnancy
-
Positive HSV IgG isn't exclusion; post-tx prophylaxis needed for recipient if donor is HSV IgG+.
-
Positive VZV IgG isn't exclusion; post-tx prophylaxis needed if donor is VZV IgG+.
-
Medical concern of independent otolaryngologist.
-
Concern by medical psychologist/social worker that potential donor isn't competent or does not understand risks.
-
Questionnaire responses can lead to exclusion.
Mother of DiGeorge Inclusion:
• Provides consent to use blood/buccal sample. No exclusions except unwillingness to consent; or, provide blood/buccal sample.
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Duke University Medical Center | Durham | North Carolina | United States | 27710 |
Sponsors and Collaborators
- Enzyvant Therapeutics GmBH
- 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)
Investigators
- Principal Investigator: M. Louise Markert, MD, PhD, Duke University Medical Center, Pediatrics, Allergy & Immunology
Study Documents (Full-Text)
None provided.More Information
Publications
- 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.
- 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.
- 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.
- 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.
- 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, 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.
- 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, 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. doi: 10.1111/j.1600-0560.2007.00816.x.
Responsible Party:
Enzyvant Therapeutics GmBH
ClinicalTrials.gov Identifier:
NCT00579527
Other Study ID Numbers:
- Pro00011583
- 2R01AI047040-11A2
- R56 Bridge R01AI4704011A1
- 5K12HD043494-09
- R01AI047040
- R01AI054843
- 950
First Posted:
Dec 24, 2007
Last Update Posted:
Mar 25, 2022
Last Verified:
Mar 1, 2022
Studies a U.S. FDA-regulated Drug Product:
Yes
Studies a U.S. FDA-regulated Device Product:
No
Keywords provided by Enzyvant Therapeutics GmBH
Additional relevant MeSH terms:
Study Results
Participant Flow
| Recruitment Details | |
|---|---|
| Pre-assignment Detail | The goal of this study is survival of subjects after cultured thymus tissue implantation (CTTI) regardless of the immunosuppressive regimen or of parathyroid co-transplantation. |
| Arm/Group Title | Cultured Thymus Tissue Implantation w/ Immunosuppression |
|---|---|
| Arm/Group Description | Participants enrolled in cultured thymus tissue implantation (CTTI) with immunosuppression were given immunosuppression based on results of flow cytometry without consideration of whether a parathyroid transplant would be given. No participants were enrolled into Arm 2. No subjects received a parathyroid transplant. No specific dose of cultured thymus tissue was assigned. The dose was the number of grams of cultured thymus tissue divided by the weight of the recipient in kg or per square meter of body surface area of the participant. There was one administration of cultured thymus tissue. The dosage form was cultured thymus tissue. |
| Period Title: Overall Study | |
| STARTED | 14 |
| COMPLETED | 10 |
| NOT COMPLETED | 4 |
Baseline Characteristics
| Arm/Group Title | Cultured Thymus Tissue Implantation With Immunosuppression |
|---|---|
| Arm/Group Description | Participants enrolled into cultured thymus tissue for implantation (previously described as transplantation) with immunosuppression were given immunosuppression based on the subject's pre-implantation T cell number and function. |
| Overall Participants | 14 |
| Age (Count of Participants) | |
| <=18 years |
14
100%
|
| Between 18 and 65 years |
0
0%
|
| >=65 years |
0
0%
|
| Age (days) [Mean (Standard Deviation) ] | |
| Mean (Standard Deviation) [days] |
248
(161)
|
| Sex: Female, Male (Count of Participants) | |
| Female |
5
35.7%
|
| Male |
9
64.3%
|
| Race/Ethnicity, Customized (Count of Participants) | |
| White |
8
57.1%
|
| Black or African American |
3
21.4%
|
| American Indian or Alaska Native |
2
14.3%
|
| More than One Race (Caucasian/Asian) |
1
7.1%
|
| Region of Enrollment (Count of Participants) | |
| United States |
14
100%
|
Outcome Measures
| Title | Survival at 1 Year Post-CTTI |
|---|---|
| Description | 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. |
| Time Frame | 1 year post-CTTI |
Outcome Measure Data
| Analysis Population Description |
|---|
| The study was designed to assess survival, without regard to the immune suppression used. No participants were enrolled into Arm 2. No subjects received a parathyroid transplant. Therefore, results are reported for Arm 1 only. |
| Arm/Group Title | Cultured Thymus Tissue With Immunosuppression |
|---|---|
| Arm/Group Description | Participants enrolled into cultured thymus tissue for Implantation (previously described as transplantation) with immunosuppression were given immunosuppression based on the subject's pre-implantation T cell numbers and function. |
| Measure Participants | 14 |
| Number (95% Confidence Interval) [% of participants who survive to 1 year] |
71
507.1%
|
| Title | Survival at 2 Years Post-CTTI |
|---|---|
| Description | Survival at 2 years 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. |
| Time Frame | 2 years post-CTTI |
Outcome Measure Data
| Analysis Population Description |
|---|
| The study was designed to assess survival, without regard to the immune suppression used. No participants were enrolled into Arm 2. No subjects received a parathyroid transplant. Therefore, results are reported for Arm 1 only. |
| Arm/Group Title | Cultured Thymus Tissue Implantation With Immunosuppression |
|---|---|
| Arm/Group Description | Participants enrolled into Cultured Thymus Tissue Implantation (previously described as transplantation) with immunosuppression were given immunosuppression based on the subject's pre-implantation T cell numbers and function. |
| Measure Participants | 14 |
| Number (95% Confidence Interval) [% of participants who survive to 2 years] |
71
507.1%
|
| Title | Immune Reconstitution Efficacy - Total CD3 T Cells |
|---|---|
| Description | The development of total CD3 T cells at one year as measured using flow cytometry |
| Time Frame | 1 year post-CTTI |
Outcome Measure Data
| Analysis Population Description |
|---|
| Data were only included for the 1 year time point if a CD3 T cell count was performed in relevant time period. The study was designed to assess survival, without regard to the immune suppression used. No participants were enrolled into Arm 2. No subjects received a parathyroid transplant. Therefore, results are reported for Arm 1 only. |
| Arm/Group Title | Cultured Thymus Tissue Implantation With Immunosuppression |
|---|---|
| Arm/Group Description | Participants enrolled into Cultured Thymus Tissue Implantation (previously described as transplantation) with immunosuppression were given immunosuppression based on the subject's pre-implantation T cell numbers and function. |
| Measure Participants | 9 |
| Median (Full Range) [cells/mm3] |
726
|
| Title | Immune Reconstitution Efficacy - Total CD4 T Cells |
|---|---|
| Description | The development of total CD4 T cells at one year as measured using flow cytometry |
| Time Frame | 1 year post-CTTI |
Outcome Measure Data
| Analysis Population Description |
|---|
| Data were only included for the 1 year time point if a CD4 T cell count was performed in relevant time period. The study was designed to assess survival, without regard to the immune suppression used. No participants were enrolled into Arm 2. No subjects received a parathyroid transplant. Therefore, results are reported for Arm 1 only. |
| Arm/Group Title | Cultured Thymus Tissue Implantation With Immunosuppression |
|---|---|
| Arm/Group Description | Participants enrolled into Cultured Thymus Tissue Implantation (previously described as transplantation) with immunosuppression were given immunosuppression based on the subject's pre-implantation T cell numbers and function. |
| Measure Participants | 10 |
| Median (Full Range) [cells/mm3] |
593
|
| Title | Immune Reconstitution Efficacy - Total CD8 T Cells |
|---|---|
| Description | The development of total CD8 T cells at one year as measured using flow cytometry |
| Time Frame | 1 year post-CTTI |
Outcome Measure Data
| Analysis Population Description |
|---|
| Data were only included for the 1 year time point if a CD8 T cell count was performed in relevant time period. The study was designed to assess survival, without regard to the immune suppression used. No participants were enrolled into Arm 2. No subjects received a parathyroid transplant. Therefore, results are reported for Arm 1 only. |
| Arm/Group Title | Cultured Thymus Tissue Implantation With Immunosuppression |
|---|---|
| Arm/Group Description | Participants enrolled into Cultured Thymus Tissue Implantation (previously described as transplantation) with immunosuppression were given immunosuppression based on the subject's pre-implantation T cell numbers and function. |
| Measure Participants | 10 |
| Median (Full Range) [cells/mm3] |
145
|
| Title | Immune Reconstitution Efficacy - Naive CD4 T Cells |
|---|---|
| Description | The development of total naive CD4 T cells at one year as measured using flow cytometry |
| Time Frame | 1 year post-CTTI |
Outcome Measure Data
| Analysis Population Description |
|---|
| Data were only included for the 1 year time point if a T cell count was performed in relevant time period. The study was designed to assess survival, without regard to the immune suppression used. No participants were enrolled into Arm 2. No subjects received a parathyroid transplant. Therefore, results are reported for Arm 1 only. |
| Arm/Group Title | Cultured Thymus Tissue Implantation With Immunosuppression |
|---|---|
| Arm/Group Description | Participants enrolled into Cultured Thymus Tissue Implantation (previously described as transplantation) with immunosuppression were given immunosuppression based on the subject's pre-implantation T cell numbers and function. |
| Measure Participants | 9 |
| Median (Full Range) [cells/mm3] |
156
|
| Title | Immune Reconstitution Efficacy - Naive CD8 T Cells |
|---|---|
| Description | The development of total naive CD8 T cells at one year as measured using flow cytometry |
| Time Frame | 1 year post-CTTI |
Outcome Measure Data
| Analysis Population Description |
|---|
| Data were only included for the 1 year time point if a T cell count was performed in the relevant time period. The study was designed to assess survival, without regard to the immune suppression used. No participants were enrolled into Arm 2. No subjects received a parathyroid transplant. Therefore, results are reported for Arm 1 only. |
| Arm/Group Title | Cultured Thymus Tissue Implantation With Immunosuppression |
|---|---|
| Arm/Group Description | Participants enrolled into Cultured Thymus Tissue Implantation (previously described as transplantation) with immunosuppression were given immunosuppression based on the subject's pre-implantation T cell numbers and function. |
| Measure Participants | 9 |
| Median (Full Range) [cells/mm3] |
37
|
| Title | Immune Reconstitution Efficacy - Response to Mitogens |
|---|---|
| Description | Measurement of the T cell proliferative response to the mitogen phytohemagglutin (PHA). |
| Time Frame | 1 year post-CTTI |
Outcome Measure Data
| Analysis Population Description |
|---|
| Data were only included for the 1 year time point if a testing was performed in the relevant time period. The study was designed to assess survival, without regard to the immune suppression used. No participants were enrolled into Arm 2. No subjects received a parathyroid transplant. Therefore, results are reported for Arm 1 only. |
| Arm/Group Title | Cultured Thymus Tissue Implantation With Immunosuppression |
|---|---|
| Arm/Group Description | Participants enrolled into Cultured Thymus Tissue Implantation (previously described as transplantation) with immunosuppression were given immunosuppression based on the subject's pre-implantation T cell numbers and function. |
| Measure Participants | 8 |
| Median (Full Range) [counts per minute (cpm)] |
139189
|
| Title | Thymus Allograft Biopsy |
|---|---|
| Description | Evidence, on biopsy of the thymus tissue implanted in muscle, that shows the development of new T cells. |
| Time Frame | 2 to 3 months post-CTTI |
Outcome Measure Data
| Analysis Population Description |
|---|
| Data were only included if the participant had a biopsy of the thymus tissue implanted. The study was designed to assess survival, without regard to the immune suppression used. No participants were enrolled into Arm 2. No subjects received a parathyroid transplant. Therefore, results are reported for Arm 1 only. |
| Arm/Group Title | Cultured Thymus Tissue Implantation With Immunosuppression |
|---|---|
| Arm/Group Description | Participants enrolled into Cultured Thymus Tissue Implantation (previously described as transplantation) with immunosuppression were given immunosuppression based on the subject's pre-implantation T cell numbers and function. |
| Measure Participants | 10 |
| Evidence of thymopoiesis |
7
50%
|
| Evidence of rejection |
0
0%
|
| Inconclusive for thymopoiesis |
3
21.4%
|
Adverse Events
| Time Frame | 2 years post-CTTI | |
|---|---|---|
| Adverse Event Reporting Description | Participants enrolled into Cultured Thymus Tissue for Implantation (previously described as transplantation) with immunosuppression were given immunosuppression based on the subject's pre-implantation T cell numbers and function. All adverse events are reported below. | |
| Arm/Group Title | Cultured Thymus Tissue Implantation With Immunosuppression | |
| Arm/Group Description | Participants enrolled into Cultured Thymus Tissue Implantation (previously described as transplantation) with immunosuppression were given immunosuppression based on the subject's pre-implantation T cell numbers and function. All adverse events were combined for this analysis regardless of the immunosuppression used. | |
All Cause Mortality |
||
| Cultured Thymus Tissue Implantation With Immunosuppression | ||
| Affected / at Risk (%) | # Events | |
| Total | 4/14 (28.6%) | |
Serious Adverse Events |
||
| Cultured Thymus Tissue Implantation With Immunosuppression | ||
| Affected / at Risk (%) | # Events | |
| Total | 13/14 (92.9%) | |
| Blood and lymphatic system disorders | ||
| Neutropenia | 2/14 (14.3%) | 2 |
| Disseminated intravascular coagulation | 1/14 (7.1%) | 1 |
| Haemolysis | 1/14 (7.1%) | 1 |
| Thrombocytopenia | 1/14 (7.1%) | 1 |
| Gastrointestinal disorders | ||
| Diarrhoea | 1/14 (7.1%) | 1 |
| Enteritis | 1/14 (7.1%) | 1 |
| Pancreatitis | 1/14 (7.1%) | 1 |
| General disorders | ||
| Pyrexia | 3/14 (21.4%) | 3 |
| Immune system disorders | ||
| Cytokine release syndrome | 3/14 (21.4%) | 3 |
| Hypersensitivity | 1/14 (7.1%) | 1 |
| Systemic immune activation | 1/14 (7.1%) | 1 |
| Infections and infestations | ||
| Device related infection | 11/14 (78.6%) | 34 |
| Cytomegalovirus infection | 2/14 (14.3%) | 2 |
| Cystitis escherichia | 1/14 (7.1%) | 1 |
| Cystitis klebsiella | 1/14 (7.1%) | 1 |
| Enterobacter bacteraemia | 1/14 (7.1%) | 1 |
| Enterococcal bacteraemia | 1/14 (7.1%) | 1 |
| Gastroenteritis rotavirus | 1/14 (7.1%) | 1 |
| Lower respiratory tract infection fungal | 1/14 (7.1%) | 1 |
| Pneumonia haemophilus | 1/14 (7.1%) | 1 |
| Pneumonia moraxella | 1/14 (7.1%) | 1 |
| Respiratory tract infection | 1/14 (7.1%) | 1 |
| Staphylococcal skin infection | 1/14 (7.1%) | 1 |
| Urinary tract infection | 1/14 (7.1%) | 1 |
| Injury, poisoning and procedural complications | ||
| Wound complication | 1/14 (7.1%) | 1 |
| Investigations | ||
| Blood bicarbonate decreased | 1/14 (7.1%) | 1 |
| Metabolism and nutrition disorders | ||
| Feeding intolerance | 1/14 (7.1%) | 1 |
| Hyperkalaemia | 1/14 (7.1%) | 1 |
| Hypoalbuminaemia | 1/14 (7.1%) | 1 |
| Hypocalcaemia | 1/14 (7.1%) | 1 |
| Hyponatraemia | 1/14 (7.1%) | 1 |
| Nervous system disorders | ||
| Hypocalcaemic seizure | 1/14 (7.1%) | 2 |
| Cerebral atrophy | 1/14 (7.1%) | 1 |
| Renal and urinary disorders | ||
| Renal failure | 1/14 (7.1%) | 1 |
| Respiratory, thoracic and mediastinal disorders | ||
| Tachypnoea | 2/14 (14.3%) | 3 |
| Respiratory failure | 1/14 (7.1%) | 3 |
| Chylothorax | 1/14 (7.1%) | 1 |
| Cough | 1/14 (7.1%) | 1 |
| Hypoxia | 1/14 (7.1%) | 1 |
| Skin and subcutaneous tissue disorders | ||
| Granuloma skin | 1/14 (7.1%) | 1 |
| Rash | 1/14 (7.1%) | 1 |
| Vascular disorders | ||
| Thrombosis | 1/14 (7.1%) | 1 |
Other (Not Including Serious) Adverse Events |
||
| Cultured Thymus Tissue Implantation With Immunosuppression | ||
| Affected / at Risk (%) | # Events | |
| Total | 14/14 (100%) | |
| Blood and lymphatic system disorders | ||
| Anaemia | 4/14 (28.6%) | 5 |
| Thrombocytopenia | 3/14 (21.4%) | 3 |
| Neutropenia | 2/14 (14.3%) | 2 |
| Cardiac disorders | ||
| Sinus bradycardia | 3/14 (21.4%) | 4 |
| Sinus tachycardia | 3/14 (21.4%) | 3 |
| Congenital, familial and genetic disorders | ||
| Hydrocele | 1/14 (7.1%) | 1 |
| Endocrine disorders | ||
| Hypothyroidism | 4/14 (28.6%) | 4 |
| Gastrointestinal disorders | ||
| Constipation | 3/14 (21.4%) | 3 |
| Diarrhoea | 2/14 (14.3%) | 2 |
| Gastrooesophageal reflux disease | 2/14 (14.3%) | 2 |
| Ileus | 2/14 (14.3%) | 2 |
| Abdominal distension | 1/14 (7.1%) | 1 |
| Diarrhoea haemorrhagic | 1/14 (7.1%) | 1 |
| Gastric haemorrhage | 1/14 (7.1%) | 1 |
| Haematochezia | 1/14 (7.1%) | 1 |
| Pneumatosis intestinalis | 1/14 (7.1%) | 1 |
| Rectal prolapse | 1/14 (7.1%) | 1 |
| Vomiting | 1/14 (7.1%) | 1 |
| General disorders | ||
| Pyrexia | 4/14 (28.6%) | 5 |
| Injection site reaction | 1/14 (7.1%) | 1 |
| Hepatobiliary disorders | ||
| Cholestasis | 1/14 (7.1%) | 1 |
| Hepatomegaly | 1/14 (7.1%) | 1 |
| Hyperbilirubinaemia | 1/14 (7.1%) | 1 |
| Immune system disorders | ||
| Cytokine release syndrome | 5/14 (35.7%) | 6 |
| Hypersensitivity | 1/14 (7.1%) | 2 |
| Infections and infestations | ||
| Urinary tract infection bacterial | 4/14 (28.6%) | 6 |
| Clostridium difficile colitis | 3/14 (21.4%) | 3 |
| Ear infection | 2/14 (14.3%) | 2 |
| Fungal skin infection | 3/14 (21.4%) | 3 |
| Urinary tract infection enterococcal | 3/14 (21.4%) | 3 |
| Eye infection bacterial | 2/14 (14.3%) | 3 |
| Rhinitis | 1/14 (7.1%) | 1 |
| Oral candidiasis | 1/14 (7.1%) | 2 |
| Urinary tract infection pseudomonal | 1/14 (7.1%) | 2 |
| Cystitis klebsiella | 1/14 (7.1%) | 1 |
| Eye infection | 1/14 (7.1%) | 1 |
| Gastroenteritis adenovirus | 1/14 (7.1%) | 1 |
| Gastrointestinal bacterial infection | 1/14 (7.1%) | 1 |
| Otitis media | 1/14 (7.1%) | 1 |
| Otitis media acute | 1/14 (7.1%) | 1 |
| Pneumonia moraxella | 1/14 (7.1%) | 1 |
| Staphylococcal bacteraemia | 1/14 (7.1%) | 1 |
| Staphylococcal skin infection | 1/14 (7.1%) | 1 |
| Stoma site infection | 1/14 (7.1%) | 1 |
| Urinary tract infection | 1/14 (7.1%) | 1 |
| Urinary tract infection staphylococcal | 1/14 (7.1%) | 1 |
| Viral diarrhoea | 1/14 (7.1%) | 1 |
| Viral upper respiratory tract infection | 1/14 (7.1%) | 1 |
| Wound infection staphylococcal | 1/14 (7.1%) | 1 |
| Injury, poisoning and procedural complications | ||
| Stoma site hypergranulation | 2/14 (14.3%) | 2 |
| Wound dehiscence | 2/14 (14.3%) | 2 |
| Allergic transfusion reaction | 1/14 (7.1%) | 2 |
| Transfusion reaction | 1/14 (7.1%) | 1 |
| Investigations | ||
| Alanine aminotransferase increased | 4/14 (28.6%) | 5 |
| Occult blood positive | 3/14 (21.4%) | 4 |
| Aspartate aminotransferase increased | 3/14 (21.4%) | 3 |
| Blood alkaline phosphatase increased | 2/14 (14.3%) | 3 |
| Blood bicarbonate decreased | 2/14 (14.3%) | 2 |
| Blood chloride decreased | 2/14 (14.3%) | 2 |
| Blood creatinine increased | 2/14 (14.3%) | 2 |
| Blood urea increased | 2/14 (14.3%) | 2 |
| Blood immunoglobulin E increased | 1/14 (7.1%) | 1 |
| Blood triglycerides increased | 1/14 (7.1%) | 1 |
| Protein total decreased | 1/14 (7.1%) | 1 |
| Red blood cell morphology abnormal | 1/14 (7.1%) | 1 |
| Weight decreased | 1/14 (7.1%) | 1 |
| Metabolism and nutrition disorders | ||
| Hypomagnesaemia | 6/14 (42.9%) | 6 |
| Hyperglycaemia | 2/14 (14.3%) | 2 |
| Hypocalcaemia | 2/14 (14.3%) | 2 |
| Hyponatraemia | 2/14 (14.3%) | 2 |
| Disaccharidase deficiency | 1/14 (7.1%) | 1 |
| Feeding intolerance | 1/14 (7.1%) | 1 |
| Fluid retention | 1/14 (7.1%) | 1 |
| Hyperkalaemia | 1/14 (7.1%) | 1 |
| Hypermagnesaemia | 1/14 (7.1%) | 1 |
| Hypoalbuminaemia | 1/14 (7.1%) | 1 |
| Metabolic alkalosis | 1/14 (7.1%) | 1 |
| Nervous system disorders | ||
| Seizure | 2/14 (14.3%) | 2 |
| Hypotonia | 1/14 (7.1%) | 1 |
| Renal and urinary disorders | ||
| Proteinuria | 2/14 (14.3%) | 2 |
| Nephrocalcinosis | 1/14 (7.1%) | 1 |
| Pyelocaliectasis | 1/14 (7.1%) | 1 |
| Renal failure | 1/14 (7.1%) | 1 |
| Reproductive system and breast disorders | ||
| Bilateral breast buds | 1/14 (7.1%) | 1 |
| Ovarian cyst | 1/14 (7.1%) | 1 |
| Respiratory, thoracic and mediastinal disorders | ||
| Tachypnoea | 4/14 (28.6%) | 5 |
| Cough | 3/14 (21.4%) | 3 |
| Hypoxia | 2/14 (14.3%) | 2 |
| Pulmonary oedema | 1/14 (7.1%) | 1 |
| Wheezing | 1/14 (7.1%) | 1 |
| Skin and subcutaneous tissue disorders | ||
| Rash | 4/14 (28.6%) | 5 |
| Dermatitis diaper | 2/14 (14.3%) | 2 |
| Erythema | 2/14 (14.3%) | 2 |
| Seborrhoeic dermatitis | 2/14 (14.3%) | 2 |
| Skin disorder | 1/14 (7.1%) | 2 |
| Alopecia | 1/14 (7.1%) | 1 |
| Dermatitis atopic | 1/14 (7.1%) | 1 |
| Exfoliative rash | 1/14 (7.1%) | 1 |
| Palmar-plantar erythrodysaesthesia syndrome | 1/14 (7.1%) | 1 |
| Rash maculo-papular | 1/14 (7.1%) | 1 |
| Rash papular | 1/14 (7.1%) | 1 |
| Rash pruritic | 1/14 (7.1%) | 1 |
| Skin ulcer | 1/14 (7.1%) | 1 |
| Urticaria | 1/14 (7.1%) | 1 |
| Vascular disorders | ||
| Hypertension | 10/14 (71.4%) | 11 |
| Lymphorrhoea | 1/14 (7.1%) | 1 |
| Thrombosis | 1/14 (7.1%) | 1 |
Limitations/Caveats
[Not Specified]
More Information
Certain Agreements
All Principal Investigators ARE employed by the organization sponsoring the study.
There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
Results Point of Contact
| Name/Title | M. Louise Markert, MD, PhD Professor of Pediatrics and Immunology |
|---|---|
| Organization | Duke University Medical Center |
| Phone | 919-684-6263 |
| marke001@mc.duke.edu |
Responsible Party:
Enzyvant Therapeutics GmBH
ClinicalTrials.gov Identifier:
NCT00579527
Other Study ID Numbers:
- Pro00011583
- 2R01AI047040-11A2
- R56 Bridge R01AI4704011A1
- 5K12HD043494-09
- R01AI047040
- R01AI054843
- 950
First Posted:
Dec 24, 2007
Last Update Posted:
Mar 25, 2022
Last Verified:
Mar 1, 2022