Pulse Wave Velocity, Tacrolimus Time in Therapeutic Range and CV in African American Kidney Transplants (PTAAK)

• ClinicalTrials.gov Identifier: NCT03841097
• Recruitment Status: Recruiting
• First Posted: February 15, 2019
• Last Update Posted: January 15, 2021
• Sponsor: Roy D. Bloom, MD
• Collaborator: Veloxis Pharmaceuticals
• Information provided by (Responsible Party): Roy D. Bloom, MD, University of Pennsylvania

Study Description

Brief Summary:

The primary purpose of this study is to evaluate the pulse wave velocity and vascular compliance measurements at the beginning and the end of the study while the participants are taking either extended release tacrolimus tablets (known by brand name Envarsus XR®, and also referred to as LCPT in this study) given once-daily each morning after transplantation or immediate release tacrolimus capsules (also known by brand name Prograf® or abbreviation IR-TAC in this study) that are administered twice-daily 12 hours apart after kidney transplantation. Pulse wave velocity and vascular compliance measurements are two non-invasive tests that are used to evaluate how well the blood vessels adapt to each heartbeat. The secondary purpose is to look at the effectiveness and safety of LCPT given once-daily compared to IR-TAC given twice-daily 12 hours apart after kidney transplantation.

Condition or disease	Intervention/treatment	Phase
Kidney Transplant; Complications	Drug: Extended Release Tacrolimus Tablets; Drug: Immediate Release Tacrolimus Capsule	Phase 4

Detailed Description:

There are several medicines that are given to kidney transplant patients to prevent the body's immune system from rejecting (not accepting) the transplanted kidney. Frequently, more than one medicine is used at the same time to prevent rejection after kidney transplant. Some of the medicines currently used are IR-TAC, Mycophenolate mofetil (MMF), Mycophenolate sodium (MPS), and corticosteroids. IR-TAC is currently approved by the Food and Drug Administration (FDA) under the trade name of Prograf® or equivalent generic versions to prevent rejection in kidney transplant recipients. IR-TAC is taken twice daily (12 hours apart), and the dose is adjusted by the transplant provider to keep the level of tacrolimus in the blood from being too low or too high.

LCPT is a tablet containing the same active ingredient that is in IR-TAC but LCPT has been designed to release tacrolimus over a longer period of time so that it only has to be taken once a day in the morning. The dose of it is also adjusted by the transplant provider to keep the level of tacrolimus in the blood from being too low or too high. It has been approved by the FDA for prevention of rejection in kidney transplant recipients in combination with other medications to prevent rejection after kidney transplant.

In this study, the participants will be randomly assigned by chance (like flipping a coin) to receive either IR-TAC or LCPT from the time of transplant-on. Approximately half (30) of the study participants will be given IR-TAC and half will be given LCPT. Both the study participants and the transplant providers will know which medication that the participants are receiving. The participants will remain in the study for up to 12 months during which time they will be seen for monthly clinic visits, and complete labs per the standard of care.

Additionally, the study investigators will take an additional blood sample to further find out how the body absorbs and breaks down the medication tacrolimus. Participants will also undergo non-invasive pulse wave velocity and vascular compliance measurements within 3 days of post transplant, then 1 month and 12 months after transplant. Pulse wave velocity and vascular compliance measurements are two non-invasive tests that are used to evaluate how well the blood vessels adapt to each heartbeat. All participants will also be taking either Mycophenolate mofetil (MMF) or Mycophenolate sodium (MPS) and corticosteroids to prevent rejection. These procedures will help the investigators to look at the effectiveness and safety of LCPT compared to IR-TAC after kidney transplant.

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 60 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase IV, Prospective, Randomized, Open-label, Comparative Analysis, Single-center Study of Pulse Wave Velocity Evaluation, Tacrolimus TTR and Co-efficient of Tacrolimus Variation of African American Kidney Recipients Receiving Standard of Care Immediate Release Tacrolimus Capsules or Extended Release Tacrolimus Tablets
• Actual Study Start Date: November 11, 2019
• Estimated Primary Completion Date: December 2022
• Estimated Study Completion Date: April 2023

Arms and Interventions

Arm	Intervention/treatment
Active Comparator: Extended Release Tacrolimus Tablets; Dosed once daily in the morning and started at a dose of 0.14 mg/kg/day by the first day after kidney transplant (post-operative day 1). This medication will be given with rabbit antithymocyte globulin (rATG) induction, oral mycophenolate mofetil (MMF) and oral steroids to help prevent rejection. These medications will be ordered per standard of care both inpatient and outpatient.	Drug: Extended Release Tacrolimus Tablets; The primary objective is to assess the change in pulse wave velocity (PWV) and vascular compliance measurements from baseline to 12 months after transplant in kidney recipient subjects on LCPT compared to those on IR-Tac.; Other Names: LCPT; Envarsus XR®
Active Comparator: Immediate Release Tacrolimus Capsules; Dosed twice daily 12 hours apart and started at a dose of 0.1mg/kg/day by the first day after kidney transplant (post-operative day 1). This medication will be given with rabbit antithymocyte globulin (rATG) induction, oral mycophenolate mofetil (MMF) and oral steroids to help prevent rejection. These medications will be ordered per standard of care both inpatient and outpatient.	Drug: Immediate Release Tacrolimus Capsule; The primary objective is to assess the change in pulse wave velocity (PWV) and vascular compliance measurements from baseline to 12 months after transplant in kidney recipient subjects on LCPT compared to those on IR-Tac.; Other Names: IR-TAC; Prograf®

Outcome Measures

Primary Outcome Measures :

1. Assess Change in Pulse Wave Velocity [ Time Frame: baseline and month 12 post transplant ]
   To assess the change in PWV measurements (m/sec) from baseline to 12 months after transplant in kidney recipient subjects on LCPT compared to those on IR-Tac.
2. Assess Change in Vascular Compliance measurements [ Time Frame: baseline and month 12 post transplant ]
   To assess the change in vascular compliance using central blood pressure (mmHg) from baseline to 12 months after transplant in kidney recipient subjects on LCPT compared to those on IR-Tac.
3. Assess Change in Vascular Compliance [ Time Frame: baseline and month 12 post transplant ]
   To assess the change in vascular compliance using Augmentation Index (ratio) from baseline to 12 months after transplant in kidney recipient subjects on LCPT compared to those on IR-Tac.

Secondary Outcome Measures :

1. Assess Change in Pulse Wave Velocity measurements [ Time Frame: baseline and 1 month post transplant ]
   To assess the change in PWV measurements (m/sec) from baseline to 1 month after transplant in kidney recipient subjects on LCPT compared to those on IR-Tac.
2. Assess Change in Vascular Compliance measurements [ Time Frame: baseline and 1 month post transplant ]

   To assess the change in vascular compliance using central blood pressure (mmHg) from baseline to 1 month after transplant in kidney recipient subjects on LCPT compared to those on IR-Tac.

   Augmentation Index (ratio) measurements from baseline to 1 month after transplant in kidney recipient subjects on LCPT compared to those on IR-Tac.

3. Assess Change in Vascular Compliance [ Time Frame: baseline and 1 month post transplant ]

   To assess the change in vascular compliance using Augmentation Index (ratio) from baseline to 1 month after transplant in kidney recipient subjects on LCPT compared to those on IR-Tac.

   Augmentation Index (ratio) measurements from baseline to 1 month after transplant in kidney recipient subjects on LCPT compared to those on IR-Tac.

4. Compare Percent of Kidney Recipients with Tacrolimus Time in Therapeutic Range [ Time Frame: 1 year ]
   To compare % of kidney recipient subjects with Tacrolimus time in therapeutic range (TTR) < 60% or < 75% by 12 months: (TTR will be defined as trough level between 8-12 ug/L between week 1 after transplant-month 5, and 6-9 ug/L between months 6-12 after transplant) in subjects on LCPT compared to those on IR-Tac.
5. Compare the variability of Tacrolimus levels between LCPT and IR-Tac [ Time Frame: First 12 months ]
   To compare the variability of Tacrolimus levels between LCPT and IR-Tac using coefficient of variation (CV); high Tacrolimus CV will be defined > 40% during the first 12 months after transplant in kidney recipient subjects on LCPT compared to those on IR-Tac.
6. Compare steady-state mg/kg Tacrolimus dosing requirements [ Time Frame: At baseline ]
   To compare steady-state mg/kg Tacrolimus dosing requirements to reach initial therapeutic troughs (defined as 8-12 ug/L) in kidney recipient subjects on LCPT compared to those on IR-Tac by CYP3A5*1 expressers vs. CYP3A5*1 non-expressers.
7. Compare Tacrolimus-related medication adherence [ Time Frame: at months 1,2,3,6 and 12 ]
   To compare Tacrolimus-related medication adherence (measured by patient report of missed doses at transplant nephrology visits) in all kidney recipient subjects on LCPT compared to those on IR-Tac.
8. Compare mean systolic and arterial blood pressure [ Time Frame: at baseline and 12 months post-transplant ]
   To compare mean systolic and arterial blood pressure in all kidney recipient subjects on LCPT compared to those on IR-Tac.
9. Compare anti-hypertensive medication use [ Time Frame: at baseline and 12 months post-transplant ]
   To compare anti-hypertensive medication use in all kidney recipient subjects on LCPT compared to those on IR-Tac.
10. Compare mean diastolic and arterial blood pressure [ Time Frame: at baseline and 12 months post-transplant ]
    To compare mean diastolic and arterial blood pressure in all kidney recipient subjects on LCPT compared to those on IR-Tac.
11. Compare estimated glomerular filtration rate (eGFR) measured by the Modification of Diet in Renal Disease (MDRD) formula [ Time Frame: At 6 months and 12 months post- transplant ]
    To compare estimated glomerular filtration rate (eGFR) via Modification of Diet in Renal Disease (MDRD) 4 calculation in all kidney recipient subjects on LCPT compared to those on IR-Tac.
12. Compare hemoglobin A1C values [ Time Frame: Post- transplant at months 3, 6, and 12 ]
    To compare the occurrence of a new diagnosis pre-diabetes (as documented in the electronic health record) and hemoglobin A1C values in all non-diabetic kidney transplant subjects on LCPT compared to those on IR-Tac.
13. Compare the incidence of development of donor specific antibodies [ Time Frame: At months 1, 3, 6 and 12 post- transplant ]
    To compare the incidence of development of donor specific antibodies (DSA) in all kidney recipient subjects on LCPT compared to those on IR-Tac.
14. Compare the incidence of development of BK virus [ Time Frame: At months 1, 3, 6, and 12 post- transplant ]
    To compare the incidence of development of BK virus (defined as BKV > 2.5 log copies/mL) in all kidney recipient subjects on LCPT compared to those on IR-Tac.
15. Compare the incidence of serious adverse events [ Time Frame: At months 6 and 12 post- transplant ]
    To compare the incidence of serious adverse events (SAEs) (including infections resulting in hospitalization, development of biopsy proven cellular and antibody mediated rejection by Banff criteria when biopsy performed for clinical indications, graft loss and patient death) in all kidney recipient subjects on LCPT compared to those on IR-Tac.

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 75 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

• Subjects who are African American (Self-reported patients of Black African descent who live in the United States)
• Subjects receiving a first or second deceased donor or living donor kidney transplant at the Hospital of the University of Pennsylvania
• Subjects whose concurrent immunosuppression at the time of transplant will be (generic or brand formulation) Mycophenolate mofetil (MMF, CellCept®) or mycophenolic sodium (MPS, Myfortic®), prednisone and induction with rabbit-antithymocyte globulin (Thymoglobulin®)

Exclusion Criteria:

• Subjects who are greater than 75 years old
• Subjects who are not self-described as being of Black African descent and living in the United States
• Subjects who are recipients of organ transplants other than kidney
• Subjects who are recipients of third time or more kidney transplants
• Subjects who are HIV positive at the time of pre-transplant screening
• Subjects with recurrent focal segmental glomerulosclerosis (FSGS)

Contacts and Locations

Contacts

Contact: Jennifer Trofe-Clark, Pharm D; 215-614-4274; Jennifer.Trofe-Clark@uphs.upenn.edu

Locations

United States, Pennsylvania

Hospital of the University of Pennsylvania; Recruiting

Philadelphia, Pennsylvania, United States, 19104

Contact: Jennifer Trofe-Clark, Pharm D 215-614-4274 jennifer.trofe-clark@uphs.upenn.edu

Sponsors and Collaborators

Roy D. Bloom, MD

Veloxis Pharmaceuticals

Investigators

• Principal Investigator: Roy D Bloom, MD; University of Pennsylvania

More Information

• Responsible Party: Roy D. Bloom, MD, Principal Investigator, Professor of Medicine, and Medical Director of the Penn Kidney Transplant Program, University of Pennsylvania
• ClinicalTrials.gov Identifier: NCT03841097
• Other Study ID Numbers: 832046
• First Posted: February 15, 2019
• Last Update Posted: January 15, 2021
• Last Verified: January 2021

• 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

Keywords provided by Roy D. Bloom, MD, University of Pennsylvania:

Renal; Transplant; Pulse wave velocity

Additional relevant MeSH terms:

Tacrolimus; Immunosuppressive Agents; Immunologic Factors; Physiological Effects of Drugs; Calcineurin Inhibitors; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action