End Stage Renal Disease, Rejection of Renal Transplant
Conditions
Keywords
immunosuppression
Brief summary
The overall aim of the study is to prospectively investigate the impact of two maintenance calcineurin inhibitor immunosuppressive regimens: once-daily extended release tacrolimus and twice-daily tacrolimus on subpopulations of T and B cells and alloreactive T cells as well as on renal allograft function.
Detailed description
Kidney transplantation is the treatment of choice for most patients with end-stage renal disease. Lifelong immunosuppressive therapies are required to prevent organ rejection. However, long term exposure to immunosuppressive therapy after kidney transplantation can place patients at risk for multiple adverse events. The optimal immunosuppressive therapy is not well established. Tacrolimus, a calcineurin inhibitor (CNI) is highly effective in preventing acute rejection after organ transplantation (2). It is used as part of the immunosuppression regimen for the majority of kidney and liver transplant recipients (3). However, treatment with current formulation of Tacrolimus generates high peaks and low troughs in drug concentrations in the blood. It is known that high exposure to CNI is associated with renal toxicities and adverse events (4). New once-daily dosage formulations are now developed with the hope of minimizing side effects while maintaining excellent outcomes (5-8). LCP-Tacro (Envarsus® XR, Veloxis Pharmaceuticals), a new once-daily formulation of tacrolimus, was approved by the FDA in 2015 for conversion from twice-daily tacrolimus in kidney transplant recipients. It is a prolonged-release tacrolimus formulation, utilizing a MeltDose drug delivery technology designed to improve the bioavailability of drugs with low water solubility (1). Recent clinical data demonstrated that once-daily LCP-Tacro has improved pharmacokinetic bioavailability, rapid achievement of therapeutic trough levels, less fluctuation and swing in whole blood concentration, non-inferior efficacy and similar safety, with lower tacrolimus dose than other tacrolimus formulations. The target population is adult recipients of immediately functioning living and deceased donor renal allografts. Immediate function will be defined as the absence of the need for hemodialysis in the first week following renal transplantation. Prospective randomized single center open label study of 2 groups of kidney transplant patients * Group 1 : standard of care (SOC) control group will receive tacrolimus twice-daily (n=25) * Group 2 : LCP-Tacro (Envarsus® XR) group will receive LCPT tablets once daily (n=25)
Interventions
DRUGTacrolimus
immunosuppressive agent tacrolimus, given twice-daily
immunosuppressive agent extended-release tacrolimus, given once daily
Sponsors
Lorenzo Gallon
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
1\. Patients who are males or females aged 18-65 years. 2. Use of the following induction medications: basiliximab and rituximab. 2. Donors aged 18-65 years. 3. No prior organ transplant 4. Patients who are single-organ recipients (kidney only). 5. Women who are of childbearing potential must have a negative serum pregnancy test before transplantation and agree to use a medically acceptable method of contraception throughout the treatment period. 6\. Subject (recipient) is able to understand the consent form and give written informed consent
Exclusion criteria
1. Delayed graft function (please see above). 2. Known sensitivity or contraindication to alemtuzumab, Envarsus® XR, tacrolimus or MMF. 3. Use of the following induction medications: basiliximab and rituximab 4. Patient with significant or active infection. 5. Patients with a positive flow cytometric crossmatch using donor lymphocytes and recipient serum. 6. Patients with PRA \> 40% 7. Patients with current or historic donor specific antibodies 8. Body Mass Index (BMI) of \< 18 or \> 35 9. Patients who are pregnant or nursing mothers. 10. Patients whose life expectancy is severely limited by diseases other than renal disease. 11. Ongoing active substance abuse, drug or alcohol. 12. Major ongoing psychiatric illness or recent history of noncompliance. 13. Significant cardiovascular disease (e.g.): * Significant non-correctable coronary artery disease; * Ejection fraction below 30%; * History of recent myocardial infarction. 14. Malignancy within 3 years, excluding non-melanoma skin cancers. 15. Serologic evidence of infection with HIV or HBVs-Ag positive. 16. Patients with a screening/baseline total white blood cell count \< 4,000/mm3; platelet count \< 100,000/mm3; triglyceride \> 400 mg/dl; total cholesterol \> 300 mg/dl. 17. Investigational drug within 30 days prior to transplant surgery. 18. Anti-T cell therapy within 30 days prior to transplant surgery. 19. Diagnosis of atypical-Hemolytic Uremic Syndrome (aHUS). 20. Subjects transplanted with a Hepatitis C NAT-positive kidney.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Kidney Transplant Function From 2 Weeks Post Transplant Through 12 Months Post Transplant | 2 weeks post transplant through 12 months post transplant | change in the mean eGFR from the baseline (2 weeks post transplant), 3 months (post transplant) , and 12 months (post transplant). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Subpopulations of T Cells From 2 Weeks Post Transplant Through 12 Months Post Transplant | Measured at 2 weeks post transplant, 3 months post transplant, 12 months post transplant | Blood, urine and kidney tissue analysis via serial flow cytometric immunophenotyping (includes regulatory T and B cell populations as well as immune functions). |
| Number of Participants With Acute Rejection at 3 Months and 12 Months Post-Transplant | Measured at 3 months post transplant, 12 months post transplant | Acute rejection of kidney transplant is determined via biopsy. |
| Number of Participants With Graft Loss at 3 Months and 12 Months Post-Transplant | Measured at 3 months post transplant, 12 months post transplant | Graft loss is determined via biopsy. |
| Number of Subjects Deceased at at 3 Months and 12 Months Post-Transplant | Through 12 months post transplant | Subject survival status is continually monitored via routine follow-up visits. |
| Number of Participants With Change in Allograft Immunohistopathology Profile | Measured at 3 months post transplant, 12 months post transplant | Tissue analysis via immunohistopathological staining and microscopic examination Moderate acute tubular necrosis =\> presence of focal coagulative necrosis or infarction on histopathologic examination Arteriolar hyalinosis grade 2 means: Replacement of degenerated smooth muscle cells by hyaline deposits in more than 1 arteriole, without circumferential involvement Global glomerulosclerosis \>grade 2, means glomerulosclerosis affecting more than 50% of glomeruli in the biopsy sample IFTA : Interstitial fibrosis and tubular atrophy: Inflammation in 26% to 50% of scarred cortical parenchyma |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Standard of Care Tacrolimus Twice-daily Tacrolimus: immunosuppressive agent tacrolimus, given twice-daily | 14 |
| Extended-release Tacrolimus Once-daily Tacrolimus Extended Release Oral Tablet \[Envarsus\]: immunosuppressive agent extended-release tacrolimus, given once daily | 15 |
| Total | 29 |
Baseline characteristics
| Characteristic | Standard of Care Tacrolimus Twice-daily | Extended-release Tacrolimus Once-daily | Total |
|---|---|---|---|
| Age, Continuous | 43.14 years STANDARD_DEVIATION 12.7 | 47.53 years STANDARD_DEVIATION 16.04 | 45.4 years STANDARD_DEVIATION 14.4 |
| Cause of Kidney Disease Congenital | 1 participants | 2 participants | 3 participants |
| Cause of Kidney Disease Diabetes | 3 participants | 4 participants | 7 participants |
| Cause of Kidney Disease Glomerulonephritis | 3 participants | 4 participants | 7 participants |
| Cause of Kidney Disease Obstructive Nephropathy | 2 participants | 0 participants | 2 participants |
| Cause of Kidney Disease Others | 5 participants | 5 participants | 10 participants |
| Estimated glomerular filtration rate (eGFR) | 52.43 ml/min/1.73m2 STANDARD_DEVIATION 9.26 | 51.77 ml/min/1.73m2 STANDARD_DEVIATION 9.69 | 52.1 ml/min/1.73m2 STANDARD_DEVIATION 10.6 |
| Panel reactive antibodies (PRA) Major histocompatibility complex class II (MHC-II) antibodies | 3.07 percentage STANDARD_DEVIATION 5.18 | 4.07 percentage STANDARD_DEVIATION 9.01 | 3.6 percentage STANDARD_DEVIATION 7.3 |
| Panel reactive antibodies (PRA) Major histocompatibility complex class I (MHC-I) antibodies | 1.93 percentage STANDARD_DEVIATION 2.79 | 4.20 percentage STANDARD_DEVIATION 8.44 | 3.1 percentage STANDARD_DEVIATION 6.4 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 1 Participants | 2 Participants |
| Race (NIH/OMB) Black or African American | 3 Participants | 1 Participants | 4 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 10 Participants | 13 Participants | 23 Participants |
| Sex: Female, Male Female | 3 Participants | 3 Participants | 6 Participants |
| Sex: Female, Male Male | 11 Participants | 12 Participants | 23 Participants |
| Type of Donor Cadaveric | 0 Participants | 1 Participants | 1 Participants |
| Type of Donor Living | 14 Participants | 14 Participants | 28 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 14 | 0 / 15 |
| other Total, other adverse events | 7 / 14 | 5 / 15 |
| serious Total, serious adverse events | 0 / 14 | 1 / 15 |
Outcome results
Primary
Change in Kidney Transplant Function From 2 Weeks Post Transplant Through 12 Months Post Transplant
change in the mean eGFR from the baseline (2 weeks post transplant), 3 months (post transplant) , and 12 months (post transplant).
Time frame: 2 weeks post transplant through 12 months post transplant
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Group 1: Control Arm: Standard of Care (SOC) Tacrolimus | Change in Kidney Transplant Function From 2 Weeks Post Transplant Through 12 Months Post Transplant | 2.03 mL/min/1.73m^2 | Standard Error 1.71 |
| Group 2: Interventional Arm: Study Related Drug: LCP-Tacrolimus/Envarsus XR (LCP-Tacro/Envarsus XR) | Change in Kidney Transplant Function From 2 Weeks Post Transplant Through 12 Months Post Transplant | -2.19 mL/min/1.73m^2 | Standard Error 1.77 |
Secondary
Change in Subpopulations of T Cells From 2 Weeks Post Transplant Through 12 Months Post Transplant
Blood, urine and kidney tissue analysis via serial flow cytometric immunophenotyping (includes regulatory T and B cell populations as well as immune functions).
Time frame: Measured at 2 weeks post transplant, 3 months post transplant, 12 months post transplant
Population: Secondary outcome data will not be reported because support to collect secondary data was not present
Secondary
Number of Participants With Acute Rejection at 3 Months and 12 Months Post-Transplant
Acute rejection of kidney transplant is determined via biopsy.
Time frame: Measured at 3 months post transplant, 12 months post transplant
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Group 1: Control Arm: Standard of Care (SOC) Tacrolimus | Number of Participants With Acute Rejection at 3 Months and 12 Months Post-Transplant | Acute rejection at 3 months | 0 Participants |
| Group 1: Control Arm: Standard of Care (SOC) Tacrolimus | Number of Participants With Acute Rejection at 3 Months and 12 Months Post-Transplant | Acute rejection at 12 months | 0 Participants |
| Group 2: Interventional Arm: Study Related Drug: LCP-Tacrolimus/Envarsus XR (LCP-Tacro/Envarsus XR) | Number of Participants With Acute Rejection at 3 Months and 12 Months Post-Transplant | Acute rejection at 3 months | 1 Participants |
| Group 2: Interventional Arm: Study Related Drug: LCP-Tacrolimus/Envarsus XR (LCP-Tacro/Envarsus XR) | Number of Participants With Acute Rejection at 3 Months and 12 Months Post-Transplant | Acute rejection at 12 months | 2 Participants |
Secondary
Number of Participants With Change in Allograft Immunohistopathology Profile
Tissue analysis via immunohistopathological staining and microscopic examination Moderate acute tubular necrosis =\> presence of focal coagulative necrosis or infarction on histopathologic examination Arteriolar hyalinosis grade 2 means: Replacement of degenerated smooth muscle cells by hyaline deposits in more than 1 arteriole, without circumferential involvement Global glomerulosclerosis \>grade 2, means glomerulosclerosis affecting more than 50% of glomeruli in the biopsy sample IFTA : Interstitial fibrosis and tubular atrophy: Inflammation in 26% to 50% of scarred cortical parenchyma
Time frame: Measured at 3 months post transplant, 12 months post transplant
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Group 1: Control Arm: Standard of Care (SOC) Tacrolimus | Number of Participants With Change in Allograft Immunohistopathology Profile | Acute tubular necrosis > moderate >=2 | 2 Participants |
| Group 1: Control Arm: Standard of Care (SOC) Tacrolimus | Number of Participants With Change in Allograft Immunohistopathology Profile | Arteriolar Hyalinosis >= grade 2 | 2 Participants |
| Group 1: Control Arm: Standard of Care (SOC) Tacrolimus | Number of Participants With Change in Allograft Immunohistopathology Profile | isometric vacuolization of tubules | 0 Participants |
| Group 1: Control Arm: Standard of Care (SOC) Tacrolimus | Number of Participants With Change in Allograft Immunohistopathology Profile | Arteriolar myocyte vacuolization | 0 Participants |
| Group 1: Control Arm: Standard of Care (SOC) Tacrolimus | Number of Participants With Change in Allograft Immunohistopathology Profile | Thrombotic microangiopathy | 1 Participants |
| Group 1: Control Arm: Standard of Care (SOC) Tacrolimus | Number of Participants With Change in Allograft Immunohistopathology Profile | Global glomerulosclerosis >grade 2 | 1 Participants |
| Group 1: Control Arm: Standard of Care (SOC) Tacrolimus | Number of Participants With Change in Allograft Immunohistopathology Profile | IFTA > grade 2 | 1 Participants |
| Group 2: Interventional Arm: Study Related Drug: LCP-Tacrolimus/Envarsus XR (LCP-Tacro/Envarsus XR) | Number of Participants With Change in Allograft Immunohistopathology Profile | IFTA > grade 2 | 2 Participants |
| Group 2: Interventional Arm: Study Related Drug: LCP-Tacrolimus/Envarsus XR (LCP-Tacro/Envarsus XR) | Number of Participants With Change in Allograft Immunohistopathology Profile | Acute tubular necrosis > moderate >=2 | 2 Participants |
| Group 2: Interventional Arm: Study Related Drug: LCP-Tacrolimus/Envarsus XR (LCP-Tacro/Envarsus XR) | Number of Participants With Change in Allograft Immunohistopathology Profile | Arteriolar myocyte vacuolization | 0 Participants |
| Group 2: Interventional Arm: Study Related Drug: LCP-Tacrolimus/Envarsus XR (LCP-Tacro/Envarsus XR) | Number of Participants With Change in Allograft Immunohistopathology Profile | Thrombotic microangiopathy | 1 Participants |
| Group 2: Interventional Arm: Study Related Drug: LCP-Tacrolimus/Envarsus XR (LCP-Tacro/Envarsus XR) | Number of Participants With Change in Allograft Immunohistopathology Profile | Arteriolar Hyalinosis >= grade 2 | 2 Participants |
| Group 2: Interventional Arm: Study Related Drug: LCP-Tacrolimus/Envarsus XR (LCP-Tacro/Envarsus XR) | Number of Participants With Change in Allograft Immunohistopathology Profile | Global glomerulosclerosis >grade 2 | 2 Participants |
| Group 2: Interventional Arm: Study Related Drug: LCP-Tacrolimus/Envarsus XR (LCP-Tacro/Envarsus XR) | Number of Participants With Change in Allograft Immunohistopathology Profile | isometric vacuolization of tubules | 1 Participants |
Secondary
Number of Participants With Graft Loss at 3 Months and 12 Months Post-Transplant
Graft loss is determined via biopsy.
Time frame: Measured at 3 months post transplant, 12 months post transplant
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Group 1: Control Arm: Standard of Care (SOC) Tacrolimus | Number of Participants With Graft Loss at 3 Months and 12 Months Post-Transplant | Graft Loss at 3 months | 0 Participants |
| Group 1: Control Arm: Standard of Care (SOC) Tacrolimus | Number of Participants With Graft Loss at 3 Months and 12 Months Post-Transplant | Graft loss at 12 months | 0 Participants |
| Group 2: Interventional Arm: Study Related Drug: LCP-Tacrolimus/Envarsus XR (LCP-Tacro/Envarsus XR) | Number of Participants With Graft Loss at 3 Months and 12 Months Post-Transplant | Graft Loss at 3 months | 0 Participants |
| Group 2: Interventional Arm: Study Related Drug: LCP-Tacrolimus/Envarsus XR (LCP-Tacro/Envarsus XR) | Number of Participants With Graft Loss at 3 Months and 12 Months Post-Transplant | Graft loss at 12 months | 0 Participants |
Secondary
Number of Subjects Deceased at at 3 Months and 12 Months Post-Transplant
Subject survival status is continually monitored via routine follow-up visits.
Time frame: Through 12 months post transplant
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Group 1: Control Arm: Standard of Care (SOC) Tacrolimus | Number of Subjects Deceased at at 3 Months and 12 Months Post-Transplant | Subject Death at 3 months | 0 Participants |
| Group 1: Control Arm: Standard of Care (SOC) Tacrolimus | Number of Subjects Deceased at at 3 Months and 12 Months Post-Transplant | Subject Death at 12 months | 0 Participants |
| Group 2: Interventional Arm: Study Related Drug: LCP-Tacrolimus/Envarsus XR (LCP-Tacro/Envarsus XR) | Number of Subjects Deceased at at 3 Months and 12 Months Post-Transplant | Subject Death at 3 months | 0 Participants |
| Group 2: Interventional Arm: Study Related Drug: LCP-Tacrolimus/Envarsus XR (LCP-Tacro/Envarsus XR) | Number of Subjects Deceased at at 3 Months and 12 Months Post-Transplant | Subject Death at 12 months | 0 Participants |