Envarsus XR Compared to Immediate Release Tacrolimus

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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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)

Conditions
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Kidney Transplant Recipients

Intervention / Treatment
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* Drug: Envarsus XR
* Drug: Tacrolimus twice daily


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

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

What is the study measuring?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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envarsus xr, tacrolimus, renal transplant, kidney transplant