Graft Rejection
Conditions
Brief summary
This study is being conducted to determine how safe and effective using an immune cell (b cell) depleting therapy and/or Thymoglobulin is in patients with a kidney transplant who are experiencing certain types of rejection.
Detailed description
The purpose of the study is to determine safety and efficacy of treatment if mixed (cellular and antibody) mediated acute rejection with addition of B-cell depleting therapy to Thymoglobulin in kidney and simultaneous kidney pancreas allograft recipients.
Interventions
DRUGRabbit Antithymocyte Globulin (RATG)
All patients will receive Thymoglobulin dosed based on CD3 count. Patients will be redosed when the CD3 count is ≥ 25. Depending on rejection severity, Thymoglobulin will be given for a maximum of 7-14 days. CD3 levels will be monitored daily.
DRUGRituximab
Rituximab dose of 375 mg/ m2 on day 2. Patients will be premedicated with an antihistamine and acetaminophen prior to dosing per institution standard of care.
DRUGBortezomib
Patient will receive 1.3 mg/m2 via IV push over 3-5 seconds on days 2, 5, 9, and 12. Consolidation course of bortezomib will be dosed at 1.3 mg/m2 IVP X 4 doses administered on days 1, 4, 7 and 10.
DRUGAcetaminophen
Patients will be premedicated with acetaminophen prior to dosing per institution standard of care.
DRUGAntihistamine
Patients will be premedicated with an antihistamine prior to dosing per institution standard of care.
DRUGMethylprednisolone
Methylprednisolone 250 mg with 1st dose of Thymoglobulin. Methylprednisolone 125 mg on treatment day 2 subsequent corticosteroids per institution standard of care; following treatment, corticosteroid therapy will resume at the pre-rejection dose.
Sponsors
University of Cincinnati
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
Each subject must meet all of the following inclusion criteria to be enrolled in the study: * Voluntary written informed consent before performance of any study-related procedure not part of normal medical care, with the understanding that consent may be withdrawn by the subject at any time without prejudice to future medical care. * Female subject is either post-menopausal or surgically sterilized or willing to use two acceptable methods of birth control (i.e., a hormonal contraceptive, intra-uterine device, diaphragm with spermicide, condom with spermicide, or abstinence) for the duration of the study. * Male subject agrees to use an acceptable method for contraception for the duration of the study. * Subject is between 18 and 65 years of age, inclusive. * Subject has a transplant dysfunction indicated by an increase in creatinine of 0.3 mg/dL or 15% (lipase \>3 X ULN for kidney/pancreas recipients) over baseline necessitating an allograft biopsy to assess for allograft rejection. * Presence of light microscopic histologic changes consistent with acute cellular rejection of a Banff 97 (2005 update) grade IA or greater and at least one of the following: * Donor-specific antibody (DSA) positive via Luminex * Presence of C4d in the peritubular capillaries or glomeruli * Subject must have no known contraindications to treatment with bortezomib, boron or mannitol, thymoglobulin, or rituximab. * Recipients of kidney or simultaneous kidney pancreas organ transplant.
Exclusion criteria
Subjects meeting any of the following
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Patients in Each Group With Any of the Following: Rejection Reversal or Recurrent Rejection | 1 year | Rejection Reversal is a return of serum creatinine to within 115% of the baseline value, or histologic reversal occurring within 14 days of initiation of treatment. Recurrent Rejection is histologic evidence of rejection noted on a biopsy specimen obtained up to 3 months after documented rejection reversal. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Renal Allograft Survival | 1 year after rejection treatment | — |
| Mean Serum Creatinine | 7, 14, 28, 60, 90 days and 1 year post therapy initiation | Renal allograft function as determined by change (∆) in Calculated creatinine clearance by Cockcroft-Gault at 7, 14, 28, 60, and 90 days and 1 year post therapy initiation |
| Number of Patients With Allografts With C4d Focal Positive Pretreatment Biopsy | Day 1 | — |
| Number of Patients With Allografts With C4d Diffuse Positive Pretreatment Biopsy | 90 days | — |
| Incidence of Post Transplant Lymphoproliferative Disorder (PTLD) | 1 year | — |
| Incidence of Death | 90 days | — |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Rabbit Antithymocyte Globulin (RATG) RATG
Rabbit Antithymocyte Globulin (RATG): All patients will receive Thymoglobulin dosed based on CD3 count. Patients will be redosed when the CD3 count is ≥ 25. Depending on rejection severity, Thymoglobulin will be given for a maximum of 7-14 days. CD3 levels will be monitored daily.
Rituximab: Rituximab dose of 375 mg/ m2 on day 2. Patients will be premedicated with an antihistamine and acetaminophen prior to dosing per institution standard of care.
Bortezomib: Patient will receive 1.3 mg/m2 via IV push over 3-5 seconds on days 2, 5, 9, and 12. Consolidation course of bortezomib will be dosed at 1.3 mg/m2 IVP X 4 doses administered on days 1, 4, 7 and 10. | 10 |
| RATG/Rituximab Rabbit Antithymocyte Globulin (RATG) + Rituximab
Rituximab: Rituximab dose of 375 mg/ m2 on day 2. Patients will be premedicated with an antihistamine and acetaminophen prior to dosing per institution standard of care. | 9 |
| RATG/Bortezomib Rabbit Antithymocyte Globulin (RATG) + Bortezomib
Bortezomib: Patient will receive 1.3 mg/m2 via IV push over 3-5 seconds on days 2, 5, 9, and 12. Consolidation course of bortezomib will be dosed at 1.3 mg/m2 IVP X 4 doses administered on days 1, 4, 7 and 10. | 10 |
| Total | 29 |
Baseline characteristics
| Characteristic | Rabbit Antithymocyte Globulin (RATG) | RATG/Rituximab | RATG/Bortezomib | Total |
|---|---|---|---|---|
| Age, Continuous | 34.9 years STANDARD_DEVIATION 12.6 | 34.2 years STANDARD_DEVIATION 6.6 | 38.5 years STANDARD_DEVIATION 12.3 | 35.8 years STANDARD_DEVIATION 10.8 |
| Region of Enrollment United States | 10 participants | 9 participants | 10 participants | 29 participants |
| Sex: Female, Male Female | 2 Participants | 4 Participants | 4 Participants | 10 Participants |
| Sex: Female, Male Male | 8 Participants | 5 Participants | 6 Participants | 19 Participants |
| Type of Transplant Deceased Donor Kidney Transplant | 2 participants | 1 participants | 3 participants | 6 participants |
| Type of Transplant Deceased Donor Simultaneous Pancreas/Kidney | 1 participants | 1 participants | 2 participants | 4 participants |
| Type of Transplant Living Donor | 7 participants | 7 participants | 5 participants | 19 participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 10 / 10 | 9 / 9 | 7 / 10 |
| serious Total, serious adverse events | 7 / 10 | 5 / 9 | 7 / 10 |
Outcome results
Primary
Number of Patients in Each Group With Any of the Following: Rejection Reversal or Recurrent Rejection
Rejection Reversal is a return of serum creatinine to within 115% of the baseline value, or histologic reversal occurring within 14 days of initiation of treatment. Recurrent Rejection is histologic evidence of rejection noted on a biopsy specimen obtained up to 3 months after documented rejection reversal.
Time frame: 1 year
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Rabbit Antithymocyte Globulin (RATG) | Number of Patients in Each Group With Any of the Following: Rejection Reversal or Recurrent Rejection | Rejection Recurrence | 0 participants |
| Rabbit Antithymocyte Globulin (RATG) | Number of Patients in Each Group With Any of the Following: Rejection Reversal or Recurrent Rejection | Rejection Reversal | 2 participants |
| RATG/Rituximab | Number of Patients in Each Group With Any of the Following: Rejection Reversal or Recurrent Rejection | Rejection Recurrence | 0 participants |
| RATG/Rituximab | Number of Patients in Each Group With Any of the Following: Rejection Reversal or Recurrent Rejection | Rejection Reversal | 1 participants |
| RATG/Bortezomib | Number of Patients in Each Group With Any of the Following: Rejection Reversal or Recurrent Rejection | Rejection Recurrence | 0 participants |
| RATG/Bortezomib | Number of Patients in Each Group With Any of the Following: Rejection Reversal or Recurrent Rejection | Rejection Reversal | 1 participants |
Secondary
Incidence of Death
Time frame: 90 days
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Rabbit Antithymocyte Globulin (RATG) | Incidence of Death | 0 participants |
| RATG/Rituximab | Incidence of Death | 0 participants |
| RATG/Bortezomib | Incidence of Death | 0 participants |
Secondary
Incidence of Post Transplant Lymphoproliferative Disorder (PTLD)
Time frame: 1 year
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Rabbit Antithymocyte Globulin (RATG) | Incidence of Post Transplant Lymphoproliferative Disorder (PTLD) | 0 participants |
| RATG/Rituximab | Incidence of Post Transplant Lymphoproliferative Disorder (PTLD) | 0 participants |
| RATG/Bortezomib | Incidence of Post Transplant Lymphoproliferative Disorder (PTLD) | 0 participants |
Secondary
Mean Serum Creatinine
Renal allograft function as determined by change (∆) in Calculated creatinine clearance by Cockcroft-Gault at 7, 14, 28, 60, and 90 days and 1 year post therapy initiation
Time frame: 7, 14, 28, 60, 90 days and 1 year post therapy initiation
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Rabbit Antithymocyte Globulin (RATG) | Mean Serum Creatinine | 1 year | 2.19 mg/dL | Standard Deviation 0.84 |
| Rabbit Antithymocyte Globulin (RATG) | Mean Serum Creatinine | 14 days | 3.25 mg/dL | Standard Deviation 1.76 |
| Rabbit Antithymocyte Globulin (RATG) | Mean Serum Creatinine | 60 days | 2.62 mg/dL | Standard Deviation 1.23 |
| Rabbit Antithymocyte Globulin (RATG) | Mean Serum Creatinine | 90 days | 2.48 mg/dL | Standard Deviation 1.18 |
| Rabbit Antithymocyte Globulin (RATG) | Mean Serum Creatinine | 28 days | 2.9 mg/dL | Standard Deviation 1.23 |
| Rabbit Antithymocyte Globulin (RATG) | Mean Serum Creatinine | 7 days | 3.04 mg/dL | Standard Deviation 1.67 |
| RATG/Rituximab | Mean Serum Creatinine | 28 days | 2.35 mg/dL | Standard Deviation 0.9 |
| RATG/Rituximab | Mean Serum Creatinine | 60 days | 2.32 mg/dL | Standard Deviation 0.87 |
| RATG/Rituximab | Mean Serum Creatinine | 7 days | 2.32 mg/dL | Standard Deviation 0.89 |
| RATG/Rituximab | Mean Serum Creatinine | 1 year | 2.07 mg/dL | Standard Deviation 1.1 |
| RATG/Rituximab | Mean Serum Creatinine | 90 days | 2.12 mg/dL | Standard Deviation 1.01 |
| RATG/Rituximab | Mean Serum Creatinine | 14 days | 2.35 mg/dL | Standard Deviation 0.95 |
| RATG/Bortezomib | Mean Serum Creatinine | 14 days | 2.20 mg/dL | Standard Deviation 0.69 |
| RATG/Bortezomib | Mean Serum Creatinine | 90 days | 2.13 mg/dL | Standard Deviation 0.54 |
| RATG/Bortezomib | Mean Serum Creatinine | 7 days | 2.31 mg/dL | Standard Deviation 0.78 |
| RATG/Bortezomib | Mean Serum Creatinine | 1 year | 2.87 mg/dL | Standard Deviation 1.37 |
| RATG/Bortezomib | Mean Serum Creatinine | 28 days | 2.18 mg/dL | Standard Deviation 0.47 |
| RATG/Bortezomib | Mean Serum Creatinine | 60 days | 2.38 mg/dL | Standard Deviation 0.62 |
Secondary
Number of Patients With Allografts With C4d Diffuse Positive Pretreatment Biopsy
Time frame: 90 days
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Rabbit Antithymocyte Globulin (RATG) | Number of Patients With Allografts With C4d Diffuse Positive Pretreatment Biopsy | 3 participants |
| RATG/Rituximab | Number of Patients With Allografts With C4d Diffuse Positive Pretreatment Biopsy | 3 participants |
| RATG/Bortezomib | Number of Patients With Allografts With C4d Diffuse Positive Pretreatment Biopsy | 5 participants |
Secondary
Number of Patients With Allografts With C4d Focal Positive Pretreatment Biopsy
Time frame: Day 1
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Rabbit Antithymocyte Globulin (RATG) | Number of Patients With Allografts With C4d Focal Positive Pretreatment Biopsy | 2 participants |
| RATG/Rituximab | Number of Patients With Allografts With C4d Focal Positive Pretreatment Biopsy | 2 participants |
| RATG/Bortezomib | Number of Patients With Allografts With C4d Focal Positive Pretreatment Biopsy | 4 participants |
Secondary
Renal Allograft Survival
Time frame: 1 year after rejection treatment
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Rabbit Antithymocyte Globulin (RATG) | Renal Allograft Survival | 7 participants |
| RATG/Rituximab | Renal Allograft Survival | 7 participants |
| RATG/Bortezomib | Renal Allograft Survival | 10 participants |