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.
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
Allocation
RANDOMIZED
Purpose
SUPPORTIVE_CARE
Masking
NONE
Enrollment
261
Once daily Envarsus XR
Twice daily tacrolimus
Mayo Clinic Arizona
Phoenix, Arizona, United States
Mayo Clinic Florida
Jacksonville, Florida, United States
Mayo Clinic Rochester
Rochester, Minnesota, United States
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.
Time frame: Baseline; 12 months
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.
Time frame: 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.
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Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: Baseline; 12 months
Change in Medication Adherence
Defined as the percentage of prescribed doses taken each day
Time frame: 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.
Time frame: 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
Time frame: 4 months; 12 months
Adverse Events
Number of adverse events reported
Time frame: 12 months