Envarsus on the Effect of Total Tacrolimus Dose/Trough Level Ratio on Renal Function (eGFR) in Kidney Transplantation

To Understand the Impact of Immunosuppression Using Once-per-day Envarsus XR on the Effect of Total Tacrolimus Dose/Trough Level Ratio on Renal Function (eGFR) in Kidney Transplantation

This is a one year, prospective, randomized, open-label trial examining once versus twice daily tacrolimus dosing regimen using two preparations, extended-release Tacrolimus (Envarsus XR) versus twice daily Tacrolimus (Prograf). It will examine kidney function between the two groups using estimated glomerular filtration rate (eGFR) and also examine one-year kidney outcomes, including graft loss and patient death. Patients will be followed for up to 1 year during the open-label study period.

Study Overview

• Status: Active, not recruiting
• Conditions: Renal Transplant Rejection; Kidney Transplant Failure and Rejection
• Intervention / Treatment: Drug: Tacrolimus; Drug: Tacrolimus Extended Release Oral Tablet

Detailed Description

Despite lower rates of acute rejection and short-term improvements in patient and graft survival, the rate of late allograft loss following kidney transplantation has remained unchanged. Achievement of therapeutic, minimally toxic, tacrolimus concentrations early (within 30 days), after transplantation, is known to be important since achieving it has been associated with a lowered risk of acute rejection. The investigators hypothesize that using extended release tacrolimus (Envarsus XR, Veloxis), will provide more stable, more effective, and less toxic levels of tacrolimus in renal allograft recipients. Therefore, the investigators propose to analyze the impact of the blood concentration normalized by the dose (C/D ratio) on kidney function after renal transplantation in experimental group that will be treated with Envarsus XR and the standard of care (SOC) group treated with twice a day tacrolimus.

• Study Type: Interventional
• Enrollment (Actual): 50
• Phase: Phase 4

Contacts and Locations

Study Locations

• United States
  • New York
    • New York, New York, United States, 10032
      • Columbia University Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 80 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Kidney transplant patient ≥ 18 years and ≤ 80 years old
2. Institutional Review Board (IRB) approved written Informed Consent and privacy language must be obtained from the subject or legally authorized representative prior to any study-related procedures (including withdrawal of prohibited medication, if applicable).

3. Recipient of a de novo kidney from a living or deceased donor.

   a. If deceased donor, a Kidney Donor Profile Index (KDPI) ≤ 85% are eligible for enrollment.

4. Willingness to comply with study protocol.
5. Previous kidney transplants will be permitted. Patients who are receiving a secondary transplant and who previously received Envarsus or who are currently on Envarsus as a component of maintenance immunosuppression and re-listed for transplant will be eligible to enroll in this study and will be randomized at the time of transplant to either cohort.
6. Subject agrees not to participate in another study while on treatment.

7. Female subject must be either:

   1. Of non-child-bearing potential,

      • Post-menopausal (defined as at least 1 year without any menses) prior to screening, or
      • Documented surgically sterile or status post-hysterectomy

   2. Or, if of childbearing potential,

      • Agree not to try to become pregnant during the study and for 90 days after the final study drug administration
      • And have a negative serum or urine pregnancy test within 7 days prior to transplant procedure
      • And, if heterosexually active, agree to consistently use two forms of highly effective birth control (at least one of which must be a barrier method) which includes consistent and correct usage of established oral contraception, established intrauterine device or intrauterine system , or barrier methods of contraception: condom or occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam/gel/film/cream/suppository, starting at screening and throughout the study period and for 90 days after the final study drug administration.

Exclusion Criteria:

1. Patient is known to have a positive test for latent tuberculosis (TB) and has not previously received adequate anti-microbial therapy or would require TB prophylaxis after transplant.
2. Uncontrolled concomitant infection or any unstable medical condition that could interfere with study objectives.
3. Significant liver disease, defined as having, during the past 28 days, consistently elevated aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase (SGOT)) and/or alanine aminotransferase (ALT) (serum glutamic-pyruvic transaminase (SPGT)) levels greater than 3 times the upper value of the normal range of the investigational site.
4. Patient who will be maintained on a non-tacrolimus-based maintenance immunosuppressive regimen following his/her transplant procedure.
5. Patient currently taking, having taken within 30 days, or who will be maintained on an mechanistic target of rapamycin (mTOR) inhibitor following his/her transplant procedure.
6. Use of an investigational study drug in the 30 days prior to the transplant procedure.
7. Contraindication or hypersensitivity to drugs or any of their components that constitute the immunosuppression regimen.
8. Known infection or seropositivity for HIV (HBsAg and Hepatitis C (HCV) positivity with negative viral load permitted).
9. Focal segmental glomerulosclerosis.
10. Subject has a current malignancy or history of malignancy (within the past 2 years), except non-metastatic basal or squamous cell carcinoma of the skin or carcinoma-in- situ of the cervix that has been successfully treated.
11. Recipient of multi-organ kidney transplants.
12. Recipient of an en bloc, adult or pediatric deceased donor kidney
13. Any condition which, in the investigator's opinion, makes the subject unsuitable for study participation.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: PREVENTION
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: NONE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
ACTIVE_COMPARATOR: Tacrolimus, Immediate release; Tacrolimus (immediate-release) will be administered twice daily per clinical judgment of supervising physician (dosing and monitoring in accordance with center protocol) to a minimum whole blood tacrolimus concentration of at least 8 ng/mL.	Drug: Tacrolimus; Tacrolimus immediate-release, oral; 0.5 mg, 1 mg, 5 mg capsules will be administered twice daily per clinical judgment of supervising physician; Other Names: Prograf
EXPERIMENTAL: Envarsus XR; Envarsus XR (Tacrolimus Extended Release Oral Tablet) will be administered once daily at initial weight-based dose of 0.12 mg/kg. Dosing and monitoring thereafter predicated on clinical judgment to a minimum whole blood tacrolimus concentration of at least 8 ng/mL. When possible, patients will receive their daily dose of Envarsus using the fewest number of pills possible.	Drug: Tacrolimus Extended Release Oral Tablet; Tacrolimus, extended-release, oral (Envarsus); 0.75 mg, 1 mg, 4 mg tablets will be administered once daily at initial weight-based dose of 0.12 mg/kg.; Other Names: Envarsus XR

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
C/D Ratio	Calculation of the daily trough level over the average daily total tacrolimus dose delivered either by ENVARSUS or by SOC twice a day Tacrolimus will be performed monthly throughout the study.	Every Month for up to 1 year

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Estimated Glomerular Filtration Rate (eGRF)	Estimated glomerular filtration rate (eGFR) will be calculated at day 7 and months 1, 3, 6, and 12 using the Modification of Diet in Renal Disease (4 variable - MDRD) criteria.	At day 7 and months 1, 3, 6, 12
Patient Survival Rate	Patient survival is any subject that is known to be alive at the study conclusion.	Every Month for up to 1 year
Graft Survival Rate	Graft survival is defined as any subject that does not fit the following definition of graft loss: subject death, re-transplantation, transplant nephrectomy, or return to dialysis for a period of ≥6 weeks by study end.	Every Month for up to 1 year
Number of Serious Adverse Events	Compare and summarize serious adverse events (AEs) between study groups	Through study completion, an average of 1 year
Rate of Acute Rejection	For study purposes, diagnoses of rejection require biopsy confirmation.	Every Month for up to 1 year

Collaborators and Investigators

• Sponsor: Columbia University
• Collaborators: Veloxis Pharmaceuticals
• Investigators: Principal Investigator: Mark Hardy, MD, Columbia University

Study record dates

Study Major Dates

• Study Start (ACTUAL): July 26, 2018
• Primary Completion (ACTUAL): July 17, 2020
• Study Completion (ANTICIPATED): July 1, 2021

Study Registration Dates

• First Submitted: January 29, 2018
• First Submitted That Met QC Criteria: April 26, 2018
• First Posted (ACTUAL): April 30, 2018

Study Record Updates

• Last Update Posted (ACTUAL): January 29, 2021
• Last Update Submitted That Met QC Criteria: January 26, 2021
• Last Verified: January 1, 2021

More Information

Terms related to this study

• Keywords: Tacrolimus; Kidney Transplantation; Envarsus XR
• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Immunosuppressive Agents; Immunologic Factors; Calcineurin Inhibitors; Tacrolimus
• Other Study ID Numbers: AAAR6805

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No