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: Completed
• 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 (Actual): 261
• 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: 14 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Patient is an adult (18 years of age or older).
• Treatment with Envarsus XR® or immediate-release, twice-daily tacrolimus has been indicated by patient's transplant care team.
• 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
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; Once daily Envarsus XR

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Mean Change in Calcineurin Inhibitor-related Symptoms 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, with higher scores indicating a worse outcome.	Baseline; 12 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in the Severity Score in Each of the Five Individual CIRS Items	The change in the severity score in each of the five individual CIRS items: trembling hands, muscle cramps, muscle weakness, swollen gums, and increased hair growth. 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), with higher scores indicating a worse outcome.	Baseline; 12 months
Number of Subjects With a Moderately Severe, Severe or Very Severe Score on Any CIRS Item	Number of subjects in each treatment group with a moderately severe, severe or very severe score (2, 3 or 4) on any CIRS item. 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, with higher scores indicating a worse outcome.	12 months
Change in the Number of Subjects Who Had a Reduction in Severity of Calcineurin Inhibitor-related Symptoms	The change in the number of subjects 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 months to 12 months.	4 months; 12 months
Change in the Number of Subjects Who Had at Least One Calcineurin Inhibitor-related Symptom Reduced by 1 Point or Greater	The change in the number of subjects with a reduction in any single CIRS item by 1 point or greater from 4 months to 12 months.	4 months; 12 months.
Transplant-related Symptoms as Measured by the Difference in Mean Transplant-related Symptoms (TRS) Score.	The TRS is a 30-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). Total scores range from 0 to 120, with higher scores indicating a worse outcome.	Baseline; 12 months
Change in Health-related Quality of Life (HRQoL), as Measured by the Patient-Reported Outcomes Measurement Information System 29 (PROMIS-29) Health Profile.	The PROMIS-29 questionnaire measures physical and mental health outcomes for patients. Patients responded to 29 questions in seven categories: physical function, pain interference, depressive symptoms, anxiety, ability to participate in social activities, and sleep disturbance. Scores were scaled so that an average healthy person would score 50 points. A higher score represents a worse outcome. Patient questionnaire responses are scored using the PROMIS-29 scoring algorithm. Scores were scaled to a mean of 50 for a healthy reference population with a standard deviation of 10.	Baseline; 12 months
Change in Transplant-related Symptoms as Measured by the Difference in Transplant-related Symptoms (TRS) Score in for Each Individual Symptom	The change in the transplant related symptoms score in each of the fifteen individual TRS items: change in taste, constipation, diarrhea, swelling in arms or legs, palpitations, dry skin, darkening of skin, blurry vision, headache, insomnia, anxiety, sadness, depression, increase in appetite, and fatigue. 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, depression, 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), with higher scores indicating a worse outcome.	Baseline; 12 months
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. FACT-G GP5 is a single-item measure from the Functional Assessment of Cancer Therapy (FACT) scale, specifically designed to assess patient-reported tolerability to cancer treatments. Subjects are asked to rate their level of tolerability on a scale of 0 (not at all bothered) to 4 (very much bothered), with a higher score indicating a worse outcome.	Baseline; 12 months
Change in Medication Adherence	Defined as the percentage of prescribed doses taken each day	12 months
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 0 (Extremely Dissatisfied) to 7 (Extremely Satisfied), with higher scores indicating better satisfaction.	Baseline; 12 months
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	4 months; 12 months
Adverse Events	Number of adverse events reported	12 months

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 (Actual): March 29, 2022
• Study Completion (Actual): March 29, 2022

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): December 18, 2025
• Last Update Submitted That Met QC Criteria: December 5, 2025
• Last Verified: December 1, 2025

More Information

Terms related to this study

• Keywords: kidney transplant; renal transplant; tacrolimus; envarsus xr
• Additional Relevant MeSH Terms: Organic Chemicals; Macrolides; Lactones; 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