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CompletedNCT03289650Updated Apr 10, 2023Results posted

Extended Release Tacrolimus vs. Twice-Daily Tacrolimus

A Phase 3 interventional study of Tacrolimus and Tacrolimus Extended Release Oral Tablet [Envarsus] in End Stage Renal Disease and Rejection of Renal Transplant, sponsored by Lorenzo Gallon. Completed at 1 site in United States. Open to participants aged 18 Years to 65 Years. Per ClinicalTrials.gov, last updated 2023-04-10.

Sponsored by Lorenzo Gallon · Phase 3, Interventional, and Treatment

Phase
Phase 3
Study type
Interventional
Enrollment
29
Allocation
Randomized
Ages
18 Years to 65 Years
Sex
All
01

Study 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.

Read the 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)
02

Conditions studied

  • End Stage Renal Disease
  • Rejection of Renal Transplant

Keywords

  • immunosuppression
03

Who can participate

Ages eligible
18 Years to 65 Years
Sexes eligible
All
Accepts 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.
  1. Subject (recipient) is able to understand the consent form and give written informed consent

Exclusion criteria

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.
04

Study design

Phase
Phase 3
Primary purpose
Treatment
Allocation
Randomized
Intervention model
Parallel assignment
Masking
None (open label)
Enrollment
29 participants (actual)

Study arms

  • Active comparator
    Standard of care tacrolimus twice-daily

    Drug: Tacrolimus

  • Active comparator
    Extended-release tacrolimus once-daily

    Drug: Tacrolimus Extended Release Oral Tablet [Envarsus]

Interventions

  • DrugTacrolimus

    immunosuppressive agent tacrolimus, given twice-daily

  • DrugTacrolimus Extended Release Oral Tablet [Envarsus]

    immunosuppressive agent extended-release tacrolimus, given once daily

    Also known as: LCP-tacro

05

What researchers measure

Primary outcomes

  1. 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

Secondary outcomes

  1. 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

  2. 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

  3. 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

  4. 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

  5. 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

06

Results

Posted Apr 10, 2023
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

Participant flow

Participant flow — Overall Study
MilestoneGroup 1: Control Arm: Standard of Care (SOC) TacrolimusGroup 2: Interventional Arm: Study Related Drug: LCP-Tacrolimus/Envarsus XR (LCP-Tacro/Envarsus XR)
Started1415
Completed1415
Not completed00

Outcome measures

PrimaryChange 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
Reported as:
Mean · mL/min/1.73m^2
Change in Kidney Transplant Function From 2 Weeks Post Transplant Through 12 Months Post Transplant
mL/min/1.73m^2Group 1: Control Arm: Standard of Care (SOC) TacrolimusGroup 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 Transplant2.03 ± 1.71-2.19 ± 1.77
SecondaryChange 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

No measurements were reported for this outcome.

SecondaryNumber 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
Reported as:
Count of participants · Participants
Number of Participants With Acute Rejection at 3 Months and 12 Months Post-Transplant
ParticipantsGroup 1: Control Arm: Standard of Care (SOC) TacrolimusGroup 2: Interventional Arm: Study Related Drug: LCP-Tacrolimus/Envarsus® XR (LCP-Tacro/Envarsus XR)
Acute rejection at 3 months01
Acute rejection at 12 months02
SecondaryNumber 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
Reported as:
Count of participants · Participants
Number of Participants With Graft Loss at 3 Months and 12 Months Post-Transplant
ParticipantsGroup 1: Control Arm: Standard of Care (SOC) TacrolimusGroup 2: Interventional Arm: Study Related Drug: LCP-Tacrolimus/Envarsus XR (LCP-Tacro/Envarsus XR)
Graft Loss at 3 months00
Graft loss at 12 months00
SecondaryNumber 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
Reported as:
Count of participants · Participants
Number of Subjects Deceased at at 3 Months and 12 Months Post-Transplant
ParticipantsGroup 1: Control Arm: Standard of Care (SOC) TacrolimusGroup 2: Interventional Arm: Study Related Drug: LCP-Tacrolimus/Envarsus® XR (LCP-Tacro/Envarsus XR)
Subject Death at 3 months00
Subject Death at 12 months00
SecondaryNumber 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
Reported as:
Count of participants · Participants
Number of Participants With Change in Allograft Immunohistopathology Profile
ParticipantsGroup 1: Control Arm: Standard of Care (SOC) TacrolimusGroup 2: Interventional Arm: Study Related Drug: LCP-Tacrolimus/Envarsus XR (LCP-Tacro/Envarsus XR)
Acute tubular necrosis > moderate >=222
Arteriolar Hyalinosis >= grade 222
isometric vacuolization of tubules01
Arteriolar myocyte vacuolization00
Thrombotic microangiopathy11
Global glomerulosclerosis >grade 212
IFTA > grade 212

Adverse events

Collected over Adverse events were reviewed at 1 year after tranplant. Non-serious events are listed at a 0% frequency threshold.

Adverse event summary by group
GroupDeathsSeriousOther
Standard of Care Tacrolimus Twice-daily0/14 (0%)0/14 (0%)7/14 (50%)
Extended-release Tacrolimus Once-daily0/15 (0%)1/15 (6.7%)5/15 (33.3%)
Most frequent serious events
Most frequent serious events
EventStandard of Care Tacrolimus Twice-dailyExtended-release Tacrolimus Once-daily
HospitalizationsRenal and urinary disorders0/141/15
Most frequent other events
Most frequent other events
EventStandard of Care Tacrolimus Twice-dailyExtended-release Tacrolimus Once-daily
LeukopeniaImmune system disorders4/144/15
BK ViremiaRenal and urinary disorders2/140/15
InfectionsImmune system disorders1/141/15
MalignancyImmune system disorders0/140/15

Baseline characteristics

Age, Continuous
Age, Continuous(years)Standard of Care Tacrolimus Twice-dailyExtended-release Tacrolimus Once-dailyTotal
Mean43.14 ± 12.747.53 ± 16.0445.4 ± 14.4
Sex: Female, Male
Sex: Female, Male(Participants)Standard of Care Tacrolimus Twice-dailyExtended-release Tacrolimus Once-dailyTotal
Female336
Male111223
Race (NIH/OMB)
Race (NIH/OMB)(Participants)Standard of Care Tacrolimus Twice-dailyExtended-release Tacrolimus Once-dailyTotal
American Indian or Alaska Native000
Asian112
Native Hawaiian or Other Pacific Islander000
Black or African American314
White101323
More than one race000
Unknown or Not Reported000
Cause of Kidney Disease
Cause of Kidney Disease(participants)Standard of Care Tacrolimus Twice-dailyExtended-release Tacrolimus Once-dailyTotal
Diabetes347
Glomerulonephritis347
Obstructive Nephropathy202
Congenital123
Others5510
Type of Donor
Type of Donor(Participants)Standard of Care Tacrolimus Twice-dailyExtended-release Tacrolimus Once-dailyTotal
Cadaveric011
Living141428
Panel reactive antibodies (PRA)
Panel reactive antibodies (PRA)(percentage)Standard of Care Tacrolimus Twice-dailyExtended-release Tacrolimus Once-dailyTotal
Major histocompatibility complex class I (MHC-I) antibodies1.93 ± 2.794.20 ± 8.443.1 ± 6.4
Major histocompatibility complex class II (MHC-II) antibodies3.07 ± 5.184.07 ± 9.013.6 ± 7.3
Estimated glomerular filtration rate (eGFR)
Estimated glomerular filtration rate (eGFR)(ml/min/1.73m2)Standard of Care Tacrolimus Twice-dailyExtended-release Tacrolimus Once-dailyTotal
Median52.43 ± 9.2651.77 ± 9.6952.1 ± 10.6
07

Study locations

1 site
  • Northwestern University
    Chicago, Illinois 60611, United States
08

References and documents

Study documents

  • Protocol and statistical analysis plan · Oct 3, 2019
  • Informed consent form · Sep 17, 2019

Documents are hosted by the registry — open the source record to download them.

09

Registry details

Key details

Study ID
NCT03289650
Lead sponsor
Lorenzo Gallon
Responsible party
Lorenzo Gallon (Professor of Medicine, Northwestern University) — Sponsor-investigator
First posted
Sep 21, 2017
Start date
Sep 5, 2017
Primary completion
Feb 23, 2021
Completion
Feb 23, 2021
Results posted
Apr 10, 2023
Last update
Apr 10, 2023

Oversight

Data monitoring committee
No
FDA-regulated drug
Yes
FDA-regulated device
No
View the source record on ClinicalTrials.gov ↗

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