Envarsus XR Compared to Immediate Release Tacrolimus (SIMPLE)

A Prospective, Randomized, Multicenter, Open-Label, Pilot Study to Investigate Medication Adherence & Patient Reported Symptom Occurrence & Interference w/ Daily Life Comparing Envarsus XR® & Immediate Release Tacrolimus in Adult Renal Transplant Recipients (SIMPLE)

The purpose of this study is to compare once-daily tacrolimus extended-release (Envarsus XR®) to twice-daily immediate release tacrolimus to find out if people taking tacrolimus extended release (Envarsus XR®) report fewer side effects, increased medication compliance and higher scores on quality of life assessments compared to people taking twice daily tacrolimus immediate release.

Study Overview

• Status: Active, not recruiting
• Conditions: Kidney Transplant Recipients
• Intervention / Treatment: Drug: Tacrolimus twice daily; Drug: Envarsus XR

Detailed Description

Despite improvement in short-term graft outcomes in organ transplant, transplant patients still have to take on complex medication regimens to achieve current results. Adherence to these complex medications is an important problem in light of the potential risk of acute and chronic rejection and the associated burden of increased hospitalization, cost, and diminished quality of life that results from missed doses and poor overall drug taking. Part of the diminished quality of life is also tied to the bothersome symptoms patient feel after transplant. Most patients experience symptoms that relate to either the overall transplant immunosuppression or medication specific side effects. In the BENEFIT and BENEFIT-EXT trials, >60% of patients reported tiredness and lack of energy as an issue. Sleep problems, mood swings, restlessness, anxiety, depression, and concentration and memory difficulties appeared in approximately 50-60% of patients. In addition to these symptoms, >38% patients also reported numerous others side effects that have been strongly associated with calcineurin-inhibitors such as tacrolimus that include dizziness, muscle cramps, trembling hands, tingling in hands and feet, and headache.

The investigators hypothesize that the use of once-daily Envarsus XR® could decrease some transplant- and tacrolimus-related adverse symptoms and potentially lead to improvement in quality of life and medication adherence when compared to twice-daily tacrolimus. In order to assess this hypothesis, a prospective, multi-center, randomized, open-label, pilot study to investigate medication adherence and patient reported symptom occurrence and interference with daily life comparing once-daily Envarsus XR® and twice-daily immediate release tacrolimus in adult renal transplant recipients (SIMPLE) is being proposed.

• Study Type: Interventional
• Enrollment (Estimated): 240
• Phase: Phase 4

Contacts and Locations

Study Locations

• United States
  • Arizona
    • Phoenix, Arizona, United States, 85054
      • Mayo Clinic Arizona
  • Florida
    • Jacksonville, Florida, United States, 32224
      • Mayo Clinic Florida
  • Minnesota
    • Rochester, Minnesota, United States, 55905
      • Mayo Clinic Rochester

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Patient is an adult (18 years of age or older).
• Patient is a recipient of a deceased or living donor kidney transplant.
• Patient is able to comply with study procedures for the entire length of the study.
• Patient has been informed about the study survey and has signed an informed consent form.

Exclusion Criteria:

• Patient is unable or unwilling to complete study patient reported outcome questionnaires.
• Patient is currently receiving azathioprine
• Patient is currently receiving an mTOR inhibitor (sirolimus, everolimus)
• Patient is currently receiving an belatacept
• Patient has received investigational immunosuppression 1 month prior to transplant or post-transplant
• Patient is in a setting where a professional care taker is responsible for dispensing subject's medication.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Supportive Care
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Tacrolimus twice-daily; Subjects assigned to this arm will take tacrolimus two times daily by mouth, at the clinically prescribed dose.	Drug: Tacrolimus twice daily; Twice daily tacrolimus vs. Envarsus XR
Active Comparator: Envarsus XR; Subjects assigned to this arm will take Envarsus XR one time daily by mouth, at the clinically prescribed dose.	Drug: Envarsus XR; Twice daily tacrolimus vs. Envarsus XR

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
The primary objective of this study is to compare tacrolimus formulations (Envarsus XR® versus twice a day tacrolimus) based on the difference in mean Calcineurin Inhibitor-Related Symptoms (CIRS) severity score.	The CIRS is a questionnaire that assesses five symptoms (from the Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events [PRO-CTCAE]) that have been shown to be associated with calcineurin inhibitors. These symptoms include trembling hands, muscle cramps, muscle weakness, swollen gums, and increased hair growth. Each symptom is based on symptom severity in the last 7 days scaled from 0 (none) - 4 (very severe). The cumulative score ranges from 0-20.	12 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in calcineurin inhibitor-related symptoms as measured by a change in the Calcineurin Inhibitor-Related Symptoms (CIRC) severity score.	The CIRS is a questionnaire that assesses five symptoms (from the Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events [PRO-CTCAE]) that have been shown to be associated with calcineurin inhibitors. These symptoms include trembling hands, muscle cramps, muscle weakness, swollen gums, and increased hair growth. Each symptom is based on symptom severity in the last 7 days scaled from 0 (none) - 4 (very severe). The cumulative score ranges from 0-20.	12 months
Severity of calcineurin inhibitor-related symptoms	Total percent of patients in each treatment group with a severe or very severe score (3 or 4) on any CIRS item	12 months
Change in severity of calcineurin inhibitor-related symptoms	Total percent of patients with a reduction in a CIRS item score from a severe or very severe score (3 to 4) to a mild to moderate (1 or 2) score	From 4 to 12 months
Change in any one calcineurin inhibitor-related symptom	Total percent of patients with a reduction in any single CIRS item by 1 point or greater	From 4 to 12 months.
Change in transplant-related symptoms as measured by the difference in mean transplant-related symptoms (TRS) score.	The TRS is a multi-item questionnaire capturing 15 symptoms (from PRO-CTCAE) that have been shown to be associated with transplant and general health-related quality of life improvement. These symptoms include change in taste, constipation, diarrhea, swelling in arms or legs, palpitations, dry skin, darkening of skin, blurry vision, headache, insomnia, anxiety, sadness, discouraged, increase in appetite, and fatigue. Each symptom is based on symptom severity in the last 7 days and scaled from 0 (none) - 4 (very severe). Some symptoms also have added questions pertaining to frequency and/or interference with daily activities.	12 months post-transplant
Improvement in health-related qualify of life as measured by the PROMIS-29 health profile.	The PROMIS-29 produces individual scores for depression, anxiety, fatigue, pain interference, sleep disturbance, physical function, participation in social roles, and pain intensity. Physical and mental health summary scores will also be calculated.	12 months post-transplant
Change in individual transplant-related symptoms	Captured in the TRS questionnaire (individual TRS items will be classified as improved, worsened, unchanged)	12 months post-transplant
Change in overall tolerability or patient bother due to side effects	Measured by item GP5 ("I am bothered by side effects of treatment") from the FACT-G Questionnaire	12 months post-transplant
Change in mean taking adherence	Defined as the percentage of prescribed doses taken each day	12 months post-transplant
Change in patient medication satisfaction as assessed by question 14 of the Treatment Satisfaction Questionnaire for Medication.	Question 14 of the Treatment Satisfaction Questionnaire for Medication measures medication satisfaction on a 7 item scale ranging from "Extremely Dissatisfied" to "Extremely Satisfied."	12 months post-transplant
Correlation between de novo DSA and degree of taking and timing adherence	Proportion of patients at different adherence thresholds of taking and timing adherences between 4 months and 12 months post transplant will be correlated with the presence or absence of dnDSA by 12 months post-transplant	12 months post-transplant
Adverse events	Number of adverse events reported	12 months post-transplant

Collaborators and Investigators

• Sponsor: Mayo Clinic
• Collaborators: Veloxis Pharmaceuticals
• Investigators: Principal Investigator: Mark Stegall, M.D., Mayo Clinic

Publications and helpful links

General Publications

• Mellon L, Doyle F, Hickey A, Ward KD, de Freitas DG, McCormick PA, O'Connell O, Conlon P. Interventions for increasing immunosuppressant medication adherence in solid organ transplant recipients. Cochrane Database Syst Rev. 2022 Sep 12;9(9):CD012854. doi: 10.1002/14651858.CD012854.pub2.

Helpful Links

• Mayo Clinic Clinical Trials

Study record dates

Study Major Dates

• Study Start (Actual): July 18, 2019
• Primary Completion (Estimated): July 1, 2024
• Study Completion (Estimated): July 1, 2024

Study Registration Dates

• First Submitted: May 22, 2019
• First Submitted That Met QC Criteria: June 6, 2019
• First Posted (Actual): June 7, 2019

Study Record Updates

• Last Update Posted (Estimated): November 22, 2023
• Last Update Submitted That Met QC Criteria: November 21, 2023
• Last Verified: November 1, 2023

More Information

Terms related to this study

• Keywords: kidney transplant; renal transplant; tacrolimus; 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: 19-002678

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

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