Extended Release Tacrolimus vs. Twice-Daily Tacrolimus

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)

• Tacrolimus (Drug): immunosuppressive agent tacrolimus, given twice-daily
• Tacrolimus Extended Release Oral Tablet [Envarsus] (Drug), also known as LCP-tacro: immunosuppressive agent extended-release tacrolimus, given once daily

Primary outcomes

• 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 outcomes

• 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

Sex: All, ages: 18 Years to 65 Years

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.

Participant flow

Outcome results

• Change in Kidney Transplant Function From 2 Weeks Post Transplant Through 12 Months Post Transplant (Primary), Mean, mL/min/1.73m^2: Group 1: Control Arm: Standard of Care (SOC) Tacrolimus 2.03 +/- 1.71; Group 2: Interventional Arm: Study Related Drug: LCP-Tacrolimus/Envarsus XR (LCP-Tacro/Envarsus XR) -2.19 +/- 1.77
• Change in Subpopulations of T Cells From 2 Weeks Post Transplant Through 12 Months Post Transplant (Secondary)
• Number of Participants With Acute Rejection at 3 Months and 12 Months Post-Transplant (Secondary), Count of participants, Participants: Group 1: Control Arm: Standard of Care (SOC) Tacrolimus 0; Group 2: Interventional Arm: Study Related Drug: LCP-Tacrolimus/Envarsus® XR (LCP-Tacro/Envarsus XR) 1
• Number of Participants With Graft Loss at 3 Months and 12 Months Post-Transplant (Secondary), Count of participants, Participants: Group 1: Control Arm: Standard of Care (SOC) Tacrolimus 0; Group 2: Interventional Arm: Study Related Drug: LCP-Tacrolimus/Envarsus XR (LCP-Tacro/Envarsus XR) 0
• Number of Subjects Deceased at at 3 Months and 12 Months Post-Transplant (Secondary), Count of participants, Participants: Group 1: Control Arm: Standard of Care (SOC) Tacrolimus 0; Group 2: Interventional Arm: Study Related Drug: LCP-Tacrolimus/Envarsus® XR (LCP-Tacro/Envarsus XR) 0
• Number of Participants With Change in Allograft Immunohistopathology Profile (Secondary), Count of participants, Participants: Group 1: Control Arm: Standard of Care (SOC) Tacrolimus 2; Group 2: Interventional Arm: Study Related Drug: LCP-Tacrolimus/Envarsus XR (LCP-Tacro/Envarsus XR) 2

Adverse events

Time frame: Adverse events were reviewed at 1 year after tranplant

Serious adverse events by term

Other adverse events by term

Limitations and caveats: The study ran out of funding and as a result the outcome (Change in Subpopulations of T Cells) has not been analyzed. The PI will look for additional funding to complete the analysis

• Study Protocol and Statistical Analysis Plan (PDF, 2019-10-03)
• Informed Consent Form (PDF, 2019-09-17)