Kidney Transplant RecipientsPhase 4SIMPLENCT03979365
Envarsus XR Compared to Immediate Release Tacrolimus
A Phase 4 study testing Envarsus XR and Tacrolimus twice daily in people with Kidney Transplant Recipients, run by Mayo Clinic at 3 sites in United States.
Trial summary
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… Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Kidney Transplant Recipients
- What is being tested?
- Envarsus XR and Tacrolimus twice daily
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 261 participants
- Where
- 3 sitesUnited States
- Study dates
- 18 Jul 2019to 29 Mar 2022
- Phase
- Phase 4
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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.
Who cannot join
- 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.
Trial locations and contacts
3 sites in 1 country.
United States3 sites
Mayo Clinic Florida
Jacksonville, Florida, 32224
Mayo Clinic Arizona
Phoenix, Arizona, 85054
Mayo Clinic Rochester
Rochester, Minnesota, 55905
About this study
Official title: 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.
Read the 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.
- Conditions
- Kidney Transplant Recipients
- Being tested
- Envarsus XR, Tacrolimus twice daily
- Keywords
- tacrolimus, envarsus xr, renal transplant, kidney transplant
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Envarsus XRDrug
Once daily Envarsus XR
Tacrolimus twice dailyDrug
Twice daily tacrolimus
| Study group | Role | What they receive |
|---|---|---|
| Tacrolimus twice-daily | Active comparator | Subjects assigned to this arm will take tacrolimus two times daily by mouth, at the clinically prescribed dose. Receives: Drug: Tacrolimus twice daily |
| Envarsus XR | Active comparator | Subjects assigned to this arm will take Envarsus XR one time daily by mouth, at the clinically prescribed dose. Receives: Drug: Envarsus XR |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: Baseline; 12 months
Secondary outcomes (12)
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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: Baseline; 12 months
Change in Medication Adherence
Defined as the percentage of prescribed doses taken each day
Measured: 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.
Measured: 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
Measured: 4 months; 12 months
Adverse Events
Number of adverse events reported
Measured: 12 months
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted7 Jun 2019
- Study start18 Jul 2019
- Primary completion29 Mar 2022
- Study completion29 Mar 2022
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for Kidney Transplant RecipientsStudies of the same condition, open and under way.
- More trials run by Mayo ClinicThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 4
- Primary purpose
- Supportive care
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Enrolment
- 261 participants (actual)
Sponsor and investigators
- Lead sponsor
- Mayo Clinic
- Sponsor type
- University, hospital or other
- Collaborators
- Veloxis Pharmaceuticals
- Responsible party
- Principal investigator, Mark Stegall, Mayo Clinic
- Investigators
- Mark Stegall, M.D., Principal investigator, Mayo Clinic
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03979365
- Sponsor's protocol ID
- 19-002678
- Acronym
- SIMPLE
- Status last verified
- Dec 2025
- First submitted
- 22 May 2019
- Last updated
- 18 Dec 2025
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- No
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- No
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.
PubMed 36094829
Study at a glance
From the registry record, last updated by the sponsor on 18 Dec 2025. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- 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)
- ClinicalTrials.gov ID
- NCT03979365
- Acronym / sponsor ID
- SIMPLE / 19-002678
- Conditions
- Kidney Transplant Recipients
- Keywords
- tacrolimus, envarsus xr, renal transplant, kidney transplant
- Phase
- Phase 4
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 261 participants (actual)
- Lead sponsor
- Mayo ClinicUniversity, hospital or other
- Collaborators
- Veloxis Pharmaceuticals
- Study start
- 18 Jul 2019 (actual)
- Primary completion
- 29 Mar 2022 (actual)
- Study completion
- 29 Mar 2022 (actual)
- First posted
- 7 Jun 2019 (actual)
- Results
- Posted 18 Dec 2025
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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
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 design
- Primary purpose
- Supportive care
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Tacrolimus twice-daily | Active comparator | Drug: Tacrolimus twice dailySubjects assigned to this arm will take tacrolimus two times daily by mouth, at the clinically prescribed dose. |
| Envarsus XR | Active comparator | Drug: Envarsus XRSubjects assigned to this arm will take Envarsus XR one time daily by mouth, at the clinically prescribed dose. |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (5 listed)
- 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.
Key exclusion criteria (6 listed)
- 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
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Envarsus XROnce daily Envarsus XR | Drug | Envarsus XR |
| Tacrolimus twice dailyTwice daily tacrolimus | Drug | Tacrolimus twice-daily |
Primary outcome
Mean Change in Calcineurin Inhibitor-related Symptoms Severity Score
Time frame: Baseline; 12 months
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 secondary outcomes
Change in the Severity Score in Each of the Five Individual CIRS Items
Time frame: Baseline; 12 months
Number of Subjects With a Moderately Severe, Severe or Very Severe Score on Any CIRS Item
Time frame: 12 months
Change in the Number of Subjects Who Had a Reduction in Severity of Calcineurin Inhibitor-related Symptoms
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
Time frame: 4 months; 12 months.
Transplant-related Symptoms as Measured by the Difference in Mean Transplant-related Symptoms (TRS) Score.
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.
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
Time frame: Baseline; 12 months
Change in Overall Tolerability or Patient Bother Due to Side Effects
Time frame: Baseline; 12 months
Change in Medication Adherence
Time frame: 12 months
Change in Patient Medication Satisfaction as Assessed by Question 14 of the Treatment Satisfaction Questionnaire for Medication.
Time frame: Baseline; 12 months
Correlation Between de Novo DSA and Degree of Taking and Timing Adherence
Time frame: 4 months; 12 months
Adverse Events
Time frame: 12 months
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 18 Dec 2025.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Derived from this study: PubMed 36094829Mellon 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.
- Mayo Clinic Clinical TrialsLink provided by the sponsor.
- Individual participant dataSharing planned: No
Related trials for Kidney Transplant Recipients
RecruitingPhase 2
A Trial to Evaluate the Safety, Tolerability and Efficacy of AIC263029 in Kidney Transplant Recipients With BKV Infection
BK Virus Infection, BKV Infection
RecruitingPhase 2
A Study to Learn About the Effects of Felzartamab Infusions in Adults With Kidney Transplants Who Have Late Isolated Microvascular Inflammation
Microvascular Inflammation
Active, not recruitingObservational study
Central Blood Pressure and Pulse Wave Velocity in Kidney Transplant Recipients
End Stage Renal Disease
Enrolling by invitationPhase 4
Phenotype Guided Vasoactive Medication During Kidney Transplantation
Kidney Transplant, Fluid Management
RecruitingObservational study
China Glomerulonephritis Kidney Transplant Recipient Cohort: A Prospective Multicenter Observational Study
Glomerulonephritis Kidney Transplant
Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Mark Stegall, M.D. principal investigator
Mayo Clinic
3 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 4 study testing Envarsus XR and Tacrolimus twice daily in people with Kidney Transplant Recipients, run by Mayo Clinic at 3 sites in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 5 inclusion and 6 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 18 Dec 2025. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 3 sites in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 4 studies take place after a treatment is approved, to learn more about its long-term benefits and risks in everyday use.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 18 Dec 2025). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Mean Change in Calcineurin Inhibitor-related Symptoms Severity Score (time frame: Baseline; 12 months). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT03979365, which also lists 1 linked publication.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 18 Dec 2025.