Trial Outcomes & Findings for Envarsus XR Compared to Immediate Release Tacrolimus (NCT NCT03979365)

Results Overview

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.

Recruitment status

COMPLETED

Study phase

PHASE4

Target enrollment

261 participants

Primary outcome timeframe

Baseline; 12 months

Results posted on

2025-12-18

Participant Flow

28 subjects withdrew prior to randomization.

Participant milestones

Participant milestones
Measure	Tacrolimus Twice-daily Subjects assigned to this arm took tacrolimus two times daily by mouth, at the clinically prescribed dose. Tacrolimus twice daily: Twice daily tacrolimus	Envarsus XR Subjects assigned to this arm took Envarsus XR one time daily by mouth, at the clinically prescribed dose. Envarsus XR: Once daily Envarsus XR
Overall Study STARTED	109	124
Overall Study COMPLETED	108	117
Overall Study NOT COMPLETED	1	7

Reasons for withdrawal

Reasons for withdrawal
Measure	Tacrolimus Twice-daily Subjects assigned to this arm took tacrolimus two times daily by mouth, at the clinically prescribed dose. Tacrolimus twice daily: Twice daily tacrolimus	Envarsus XR Subjects assigned to this arm took Envarsus XR one time daily by mouth, at the clinically prescribed dose. Envarsus XR: Once daily Envarsus XR
Overall Study Death	1	3
Overall Study Withdrawal by Subject	0	1
Overall Study Drug Conversion	0	3

Baseline Characteristics

Envarsus XR Compared to Immediate Release Tacrolimus

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Tacrolimus Twice-daily n=109 Participants Subjects assigned to this arm took tacrolimus two times daily by mouth, at the clinically prescribed dose. Tacrolimus twice daily: Twice daily tacrolimus	Envarsus XR n=124 Participants Subjects assigned to this arm took Envarsus XR one time daily by mouth, at the clinically prescribed dose. Envarsus XR: Once daily Envarsus XR	Total n=233 Participants Total of all reporting groups
Age, Continuous	55.97 years STANDARD_DEVIATION 13.38 • n=47 Participants	53.91 years STANDARD_DEVIATION 14.77 • n=41 Participants	54.95 years STANDARD_DEVIATION 14.09 • n=88 Participants
Sex/Gender, Customized Female	45 Participants n=47 Participants	46 Participants n=41 Participants	91 Participants n=88 Participants
Sex/Gender, Customized Male	64 Participants n=47 Participants	77 Participants n=41 Participants	141 Participants n=88 Participants
Sex/Gender, Customized Unknown	0 Participants n=47 Participants	1 Participants n=41 Participants	1 Participants n=88 Participants
Race/Ethnicity, Customized Hispanic or Latino	0 Participants n=47 Participants	5 Participants n=41 Participants	5 Participants n=88 Participants
Race/Ethnicity, Customized White	91 Participants n=47 Participants	86 Participants n=41 Participants	177 Participants n=88 Participants
Race/Ethnicity, Customized African American or Black	11 Participants n=47 Participants	31 Participants n=41 Participants	42 Participants n=88 Participants
Race/Ethnicity, Customized Asian	3 Participants n=47 Participants	1 Participants n=41 Participants	4 Participants n=88 Participants
Race/Ethnicity, Customized American Indian or Alaska Native	2 Participants n=47 Participants	0 Participants n=41 Participants	2 Participants n=88 Participants
Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islander	2 Participants n=47 Participants	0 Participants n=41 Participants	2 Participants n=88 Participants
Race/Ethnicity, Customized Unknown	0 Participants n=47 Participants	1 Participants n=41 Participants	1 Participants n=88 Participants
Region of Enrollment United States	109 participants n=47 Participants	124 participants n=41 Participants	233 participants n=88 Participants

PRIMARY outcome

Timeframe: Baseline; 12 months

Population: 20 subjects in the Tacrolimus arm and 45 subjects in the Envarsus arm did not complete the CIRS questionnaire at the 12-month mark, therefore no data exists for those 65 subjects.

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.

Outcome measures

Outcome measures
Measure	Tacrolimus Twice-daily n=88 Participants Subjects assigned to this arm took tacrolimus two times daily by mouth, at the clinically prescribed dose. Tacrolimus twice daily: Twice daily tacrolimus	Envarsus XR n=72 Participants Subjects assigned to this arm took Envarsus XR one time daily by mouth, at the clinically prescribed dose. Envarsus XR: Once daily Envarsus XR
Mean Change in Calcineurin Inhibitor-related Symptoms Severity Score	-2.977 score on a scale Standard Deviation 14.053	-3.139 score on a scale Standard Deviation 14.846

SECONDARY outcome

Timeframe: Baseline; 12 months

Population: 20 subjects in the Tac arm and 45 subjects in the Envarsus arm didn't complete the CIRS questionnaire at the 12-month mark, therefore no data exists for those 65 subjects. 1 subject in the Tac arm and 1 in the Envarsus arm didn't complete the muscle weakness section of the questionnaire. 1 subject in the Tac arm didn't complete the swollen gums section of the questionnaire. 2 subjects in the Tac arm and 1 in the Envarsus arm didn't complete the hair growth section of the questionnaire.

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.

Outcome measures

Outcome measures
Measure	Tacrolimus Twice-daily n=88 Participants Subjects assigned to this arm took tacrolimus two times daily by mouth, at the clinically prescribed dose. Tacrolimus twice daily: Twice daily tacrolimus	Envarsus XR n=72 Participants Subjects assigned to this arm took Envarsus XR one time daily by mouth, at the clinically prescribed dose. Envarsus XR: Once daily Envarsus XR
Change in the Severity Score in Each of the Five Individual CIRS Items Trembling Hands	0 score on a scale Interval -1.0 to 1.0	0 score on a scale Interval -1.0 to 1.0
Change in the Severity Score in Each of the Five Individual CIRS Items Muscle Cramps	0 score on a scale Interval 0.0 to 0.0	0 score on a scale Interval 0.0 to 0.0
Change in the Severity Score in Each of the Five Individual CIRS Items Muscle Weakness	0 score on a scale Interval -1.0 to 0.0	0 score on a scale Interval -1.0 to 1.0
Change in the Severity Score in Each of the Five Individual CIRS Items Swollen Gums	0 score on a scale Interval 0.0 to 0.0	0 score on a scale Interval 0.0 to 0.0
Change in the Severity Score in Each of the Five Individual CIRS Items Increased Hair Growth	0 score on a scale Interval 0.0 to 0.0	0 score on a scale Interval 0.0 to 0.0

SECONDARY outcome

Timeframe: 12 months

Population: 20 subjects in the Tacrolimus arm and 45 subjects in the Envarsus arm did not complete the CIRS questionnaire at the 12-month mark, therefore no data exists for those 65 subjects.

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.

Outcome measures

Outcome measures
Measure	Tacrolimus Twice-daily n=88 Participants Subjects assigned to this arm took tacrolimus two times daily by mouth, at the clinically prescribed dose. Tacrolimus twice daily: Twice daily tacrolimus	Envarsus XR n=72 Participants Subjects assigned to this arm took Envarsus XR one time daily by mouth, at the clinically prescribed dose. Envarsus XR: Once daily Envarsus XR
Number of Subjects With a Moderately Severe, Severe or Very Severe Score on Any CIRS Item	18 Participants	28 Participants

SECONDARY outcome

Timeframe: 4 months; 12 months

Population: 29 subjects in the Tacrolimus arm and 54 subjects in the Envarsus arm did not complete the CIRS questionnaire at the 4-month mark, therefore no data exists for those 83 subjects. 2 subjects in the Tacrolimus arm only filled out a portion of the survey at the 4-month mark, due to this those two subjects were not included in the analysis for this outcome as a change in reduction of symptoms from very severe/severe to mild/moderate could not be calculated.

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.

Outcome measures

Outcome measures
Measure	Tacrolimus Twice-daily n=77 Participants Subjects assigned to this arm took tacrolimus two times daily by mouth, at the clinically prescribed dose. Tacrolimus twice daily: Twice daily tacrolimus	Envarsus XR n=63 Participants Subjects assigned to this arm took Envarsus XR one time daily by mouth, at the clinically prescribed dose. Envarsus XR: Once daily Envarsus XR
Change in the Number of Subjects Who Had a Reduction in Severity of Calcineurin Inhibitor-related Symptoms	8 Participants	8 Participants

SECONDARY outcome

Timeframe: 4 months; 12 months.

Population: 29 subjects in the Tacrolimus arm and 54 subjects in the Envarsus arm did not complete the CIRS questionnaire at the 4-month mark, therefore no data exists for those 83 subjects.

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.

Outcome measures

Outcome measures
Measure	Tacrolimus Twice-daily n=79 Participants Subjects assigned to this arm took tacrolimus two times daily by mouth, at the clinically prescribed dose. Tacrolimus twice daily: Twice daily tacrolimus	Envarsus XR n=63 Participants Subjects assigned to this arm took Envarsus XR one time daily by mouth, at the clinically prescribed dose. Envarsus XR: Once daily Envarsus XR
Change in the Number of Subjects Who Had at Least One Calcineurin Inhibitor-related Symptom Reduced by 1 Point or Greater	43 Participants	30 Participants

SECONDARY outcome

Timeframe: Baseline; 12 months

Population: 20 subjects in the Tacrolimus arm and 45 subjects in the Envarsus arm did not complete the TRS questionnaire at the 12-month mark, therefore no data exists for those 65 subjects.

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.

Outcome measures

Outcome measures
Measure	Tacrolimus Twice-daily n=88 Participants Subjects assigned to this arm took tacrolimus two times daily by mouth, at the clinically prescribed dose. Tacrolimus twice daily: Twice daily tacrolimus	Envarsus XR n=72 Participants Subjects assigned to this arm took Envarsus XR one time daily by mouth, at the clinically prescribed dose. Envarsus XR: Once daily Envarsus XR
Transplant-related Symptoms as Measured by the Difference in Mean Transplant-related Symptoms (TRS) Score.	-1.375 score on a scale Standard Deviation 9.882	-1.069 score on a scale Standard Deviation 8.421

SECONDARY outcome

Timeframe: Baseline; 12 months

Population: 36 subjects in the Tacrolimus arm and 56 subjects in the Envarsus arm did not complete the PROMIS-29 questionnaire at the 12-month mark, therefore no data exists for those 92 subjects.

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.

Outcome measures

Outcome measures
Measure	Tacrolimus Twice-daily n=72 Participants Subjects assigned to this arm took tacrolimus two times daily by mouth, at the clinically prescribed dose. Tacrolimus twice daily: Twice daily tacrolimus	Envarsus XR n=61 Participants Subjects assigned to this arm took Envarsus XR one time daily by mouth, at the clinically prescribed dose. Envarsus XR: Once daily Envarsus XR
Change in Health-related Quality of Life (HRQoL), as Measured by the Patient-Reported Outcomes Measurement Information System 29 (PROMIS-29) Health Profile.	-10 score on a scale Interval -22.0 to 1.0	-20 score on a scale Interval -32.0 to -5.0

SECONDARY outcome

Timeframe: Baseline; 12 months

Population: 20 in Tac arm,45 in XR arm didn't complete TRS at 12months,therefore no data exists for the 65 subjects.1 in XR arm didn't complete taste/palpitation/headache/insomnia/fatigue sections.1 in Tac arm didn't complete appetite/swelling/palpitation/fatigue/anxiety/depression section.3 in XR arm didn't complete diarrhea/depression/sadness sections.2 in Tac arm didn't complete vision/sadness sections.3 in Tac arm didn't complete headache section.8 in Tac arm,7 in XR arm didn't complete darkskin section

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.

Outcome measures

Outcome measures
Measure	Tacrolimus Twice-daily n=88 Participants Subjects assigned to this arm took tacrolimus two times daily by mouth, at the clinically prescribed dose. Tacrolimus twice daily: Twice daily tacrolimus	Envarsus XR n=72 Participants Subjects assigned to this arm took Envarsus XR one time daily by mouth, at the clinically prescribed dose. Envarsus XR: Once daily Envarsus XR
Change in Transplant-related Symptoms as Measured by the Difference in Transplant-related Symptoms (TRS) Score in for Each Individual Symptom Taste Change	0 score on a scale Interval 0.0 to 0.0	0 score on a scale Interval -1.0 to 0.0
Change in Transplant-related Symptoms as Measured by the Difference in Transplant-related Symptoms (TRS) Score in for Each Individual Symptom Appetite	0 score on a scale Interval 0.0 to 0.0	0 score on a scale Interval -1.0 to 1.0
Change in Transplant-related Symptoms as Measured by the Difference in Transplant-related Symptoms (TRS) Score in for Each Individual Symptom Constipation	0 score on a scale Interval -1.0 to 0.0	0 score on a scale Interval -1.0 to 0.0
Change in Transplant-related Symptoms as Measured by the Difference in Transplant-related Symptoms (TRS) Score in for Each Individual Symptom Diarrhea	0 score on a scale Interval -1.0 to 0.0	0 score on a scale Interval -1.0 to 0.0
Change in Transplant-related Symptoms as Measured by the Difference in Transplant-related Symptoms (TRS) Score in for Each Individual Symptom Swelling	0 score on a scale Interval 0.0 to 0.0	0 score on a scale Interval -2.0 to 1.0
Change in Transplant-related Symptoms as Measured by the Difference in Transplant-related Symptoms (TRS) Score in for Each Individual Symptom Palpitations	0 score on a scale Interval 0.0 to 0.0	0 score on a scale Interval -2.0 to 0.0
Change in Transplant-related Symptoms as Measured by the Difference in Transplant-related Symptoms (TRS) Score in for Each Individual Symptom Dry Skin	0 score on a scale Interval -1.0 to 0.0	0 score on a scale Interval -1.0 to 0.0
Change in Transplant-related Symptoms as Measured by the Difference in Transplant-related Symptoms (TRS) Score in for Each Individual Symptom Darker Skin	0 score on a scale Interval 0.0 to 0.0	0 score on a scale Interval 0.0 to 0.0
Change in Transplant-related Symptoms as Measured by the Difference in Transplant-related Symptoms (TRS) Score in for Each Individual Symptom Blurry Vision	0 score on a scale Interval 0.0 to 0.0	0 score on a scale Interval 0.0 to 0.0
Change in Transplant-related Symptoms as Measured by the Difference in Transplant-related Symptoms (TRS) Score in for Each Individual Symptom Headache	0 score on a scale Interval -1.0 to 1.0	0 score on a scale Interval -1.0 to 2.0
Change in Transplant-related Symptoms as Measured by the Difference in Transplant-related Symptoms (TRS) Score in for Each Individual Symptom Insomnia	-1 score on a scale Interval -2.0 to 0.0	0 score on a scale Interval -2.0 to 1.0
Change in Transplant-related Symptoms as Measured by the Difference in Transplant-related Symptoms (TRS) Score in for Each Individual Symptom Fatigue	-1 score on a scale Interval -2.0 to 0.0	-1 score on a scale Interval -2.0 to 0.0
Change in Transplant-related Symptoms as Measured by the Difference in Transplant-related Symptoms (TRS) Score in for Each Individual Symptom Anxiety	0 score on a scale Interval 0.0 to 0.0	0 score on a scale Interval -2.0 to 0.0
Change in Transplant-related Symptoms as Measured by the Difference in Transplant-related Symptoms (TRS) Score in for Each Individual Symptom Depression	0 score on a scale Interval 0.0 to 0.0	0 score on a scale Interval 0.0 to 0.0
Change in Transplant-related Symptoms as Measured by the Difference in Transplant-related Symptoms (TRS) Score in for Each Individual Symptom Sadness	0 score on a scale Interval 0.0 to 0.0	0 score on a scale Interval 0.0 to 1.0

SECONDARY outcome

Timeframe: Baseline; 12 months

Population: 21 subjects in the Tacrolimus arm and 45 subjects in the Envarsus arm did not complete the FACT-G questionnaire at the 12-month mark, therefore no data exists for those 66 subjects.

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.

Outcome measures

Outcome measures
Measure	Tacrolimus Twice-daily n=87 Participants Subjects assigned to this arm took tacrolimus two times daily by mouth, at the clinically prescribed dose. Tacrolimus twice daily: Twice daily tacrolimus	Envarsus XR n=72 Participants Subjects assigned to this arm took Envarsus XR one time daily by mouth, at the clinically prescribed dose. Envarsus XR: Once daily Envarsus XR
Change in Overall Tolerability or Patient Bother Due to Side Effects	0 score on a scale Interval -1.0 to 0.0	0 score on a scale Interval -1.0 to 0.0

SECONDARY outcome

Timeframe: 12 months

Population: Data for this outcome measure were not collected in either treatment arm. The electronic data capture system was configured incorrectly and did not include the fields required to record medication adherence. As a result, the study team was unable to collect adherence data for any participants.

Defined as the percentage of prescribed doses taken each day

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: Baseline; 12 months

Population: 99 subjects in the Tacrolimus arm and 116 subjects in the Envarsus arm did not complete the Treatment Satisfaction questionnaire at the 12-month mark, therefore no data exists for those 215 subjects.

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.

Outcome measures

Outcome measures
Measure	Tacrolimus Twice-daily n=9 Participants Subjects assigned to this arm took tacrolimus two times daily by mouth, at the clinically prescribed dose. Tacrolimus twice daily: Twice daily tacrolimus	Envarsus XR n=1 Participants Subjects assigned to this arm took Envarsus XR one time daily by mouth, at the clinically prescribed dose. Envarsus XR: Once daily Envarsus XR
Change in Patient Medication Satisfaction as Assessed by Question 14 of the Treatment Satisfaction Questionnaire for Medication.	0 score on a scale Interval -1.0 to 1.0	1 score on a scale Interval 1.0 to 1.0

SECONDARY outcome

Timeframe: 4 months; 12 months

Population: Data for this outcome measure were not collected in either treatment arm. The electronic data capture system was configured incorrectly and did not include the fields required to record correlation between de novo DSA and degree of taking and timing adherence. As a result, the study team was unable to collect correlation between de novo DSA and degree of taking and timing adherence data on any participant.

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

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: 12 months

Number of adverse events reported

Outcome measures

Outcome measures
Measure	Tacrolimus Twice-daily n=109 Participants Subjects assigned to this arm took tacrolimus two times daily by mouth, at the clinically prescribed dose. Tacrolimus twice daily: Twice daily tacrolimus	Envarsus XR n=124 Participants Subjects assigned to this arm took Envarsus XR one time daily by mouth, at the clinically prescribed dose. Envarsus XR: Once daily Envarsus XR
Adverse Events	0 events	0 events

Adverse Events

Tacrolimus Twice-daily

Serious events: 0 serious events

Other events: 0 other events

Deaths: 1 deaths

Envarsus XR

Serious events: 0 serious events

Other events: 0 other events

Deaths: 3 deaths

Serious adverse events

Adverse event data not reported

Other adverse events

Adverse event data not reported

Additional Information

Mark Stegall, M.D.

Mayo Clinic

Phone: 507-266-4505

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place