Once-daily Regimen With Envarsus® to Optimize Immunosuppression Management and Outcomes in Kidney Transplant Recipients

• Sponsor: Medical University of South Carolina (Other)
• Overall Status: Completed
• CT.gov ID: NCT02954198
• Collaborator: (none)
• Enrollment: 40
• Location: 1
• Arms: 2
• Actual Duration (Months): 24.8
• Patients Per Site Per Month: 1.6

Study Details

Study Description

Brief Summary

With the availability of well-studied once-daily formulations of tacrolimus, the ability to achieve a true once-daily immunosuppressant regimen along with everolimus and steroids may finally be achievable and have the potential to optimize immunosuppression safety and efficacy in kidney transplantation.

Condition or Disease	Intervention/Treatment	Phase
Immunosuppression	Drug: Tacrolimus; Drug: Prednisone; Drug: Mycophenolate mofetil; Drug: Everolimus	N/A

Detailed Description

A once-daily immunosuppressant regimen comprising of Envarsus-everolimus-prednisone will have 6-month treatment failure rates that are non-inferior to the twice-daily regimen of Envarsus-mycophenolate mofetil-prednisone and will have improved patient-reported adherence.

Study Design

• Study Type: Interventional
• Actual Enrollment: 40 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Once-daily Regimen With Envarsus® to Optimize Immunosuppression Management and Outcomes in Kidney Transplant Recipients
• Actual Study Start Date: Dec 1, 2016
• Actual Primary Completion Date: Dec 27, 2018
• Actual Study Completion Date: Dec 27, 2018

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Tacrolimus + MMF Tacrolimus IR BID (5-12ng/mL) + mycophenolate mofetil 1g BID + prednisone x at least 3 months, then converted to Tacrolimus Daily (5 -12ng/mL) + mycophenolate mofetil 1g BID + prednisone x 6 months	Drug: Tacrolimus; goal trough level 5-12ng/mL; Other Names: Envarsus ; Drug: Prednisone; goal dose 5mg QD; Other Names: Corticosteroids Methylprednisolone ; Drug: Mycophenolate mofetil; goal dose 1g BID
Active Comparator: Envarsus + Everolimus Tacrolimus IR BID (5-12ng/mL) + mycophenolate mofetil 1g BID + prednisone x at least 3 months, then converted to Envarsus Daily (2-5ng/mL) + Everolimus Daily (3-8ng/mL) + prednisone x 6 months	Drug: Tacrolimus; goal trough level 5-12ng/mL; Other Names: Envarsus ; Drug: Prednisone; goal dose 5mg QD; Other Names: Corticosteroids Methylprednisolone ; Drug: Everolimus; goal trough level 3-8ng/mL

Outcome Measures

Primary Outcome Measures

1. Self-reported Medication Adherence From Baseline to 6 Months. [6 months post conversion]

   Percent of subjects reporting high medication adherence at baseline compared to 6 months post-conversion, using the Morisky Medication Adherence scale (MMAS). The MMAS rates medication adherence on a scale of 0 to 8. 0 is high adherence, 1-2 is medium adherence, and greater than or equal to 3 is low adherence.

Secondary Outcome Measures

1. Percent of Participants Experiencing Acute Allograft Rejection [Baseline to 6 months post conversion]

   Estimate the composite of treatment failure rate, defined as acute allograft rejection with a Banff grade 1A or higher, graft loss, or death at six months post-conversion, in patients converted to a once-daily immunosuppressant regimen of Envarsus®, everolimus, and prednisone versus patients converted to a twice-daily regimen of Envarsus®, MMF, and prednisone.

Other Outcome Measures

1. Subject Specific Change on Medication Side Effect Scale [Baseline to 6 months post conversion]

   Examine subject specific change on a validated Medication Side Effect Scale at the time of the conversion versus six months post-conversion, compared between the two arms. Side effect burden scale is from 0 to 180. A lower score is less side effect burden, a higher score is more side effect burden.

2. Percent of Participants Who Experienced Kidney Transplant Graft Loss [Baseline to 6 months post conversion]

   Measure and compare time-to-event analysis between the two arms graft loss (time to event analysis)

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

1. Inclusion criteria

2. Male or female adult (≥18 years old) with a history of solitary kidney transplant within 3 months (±2 months) of transplant with self-reported medication adherence issues, as indicated by a MMAS-8 of at least 1.

3. Patients must be capable of understanding the purposes and risks of the study and have the ability to give written informed consent and be willing to participate and comply with the study.

4. Women of childbearing potential must have a negative pregnancy test within the 48 hours prior to receiving study medication.

5. Women of childbearing potential and sexually active males must be willing to use contraception, as indicated in Section 6 of the protocol. Subjects who are not of reproductive potential (status post bilateral tubal ligation, bilateral oophorectomy, hysterectomy, or vasectomy), not sexually active, whose current partner(s) is not of reproductive potential, or whose sexual activity is exclusively homosexual are eligible without requiring the use of contraception.

6. Exclusion criteria

7. Patients will be excluded if they are pregnant or nursing females or males with a pregnant female partner

8. Recipient of multiple organ transplant

9. Recipient of a non-renal organ

10. Proteinuria > 800 mg/24 hour

11. eGFR < 30 ml/min

12. WBC ≤ 2k/mm3

13. Plt ≤ 50k/mm3

14. Triglycerides > 500 mg/dL

15. HIV positive (HIV ab +)

16. Unable to tolerate oral medications

17. Use of another investigational product within thirty days prior to receiving study medication

18. Acute graft rejection within the past month (Banff 1A or higher) or received an ABO incompatible donor organ.

19. A condition or disorder that, in the opinion of the investigator, may adversely affect the outcome of the study or the safety of the subject

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Medical University of South Carolina	Charleston	South Carolina	United States	29425

Sponsors and Collaborators

• Medical University of South Carolina

Investigators

None specified.

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - May 11, 2017

More Information

Publications

None provided.

• Responsible Party: Medical University of South Carolina
• ClinicalTrials.gov Identifier: NCT02954198
• Other Study ID Numbers: Pro00059602
• First Posted: Nov 3, 2016
• Last Update Posted: Dec 24, 2019
• Last Verified: Dec 1, 2019

• Additional relevant MeSH terms: Mycophenolic Acid; Prednisone; Methylprednisolone; Everolimus; Tacrolimus

Study Results

Participant Flow

Arm/Group Title	Control: Envarsus + MMF	Intervention: Envarsus + Everoliumus
Arm/Group Description	Envarsus Daily (5 -12ng/mL) + mycophenolate mofetil 1g BID + prednisone x 6 months Tacrolimus: goal trough level 5-12ng/mL Prednisone: goal dose 5mg QD Mycophenolate mofetil: goal dose 1g BID	Envarsus Daily (2-5ng/mL) + Everolimus Daily (3-8ng/mL) + prednisone x 6 months Tacrolimus: goal trough level 2-5 ng/mL Prednisone: goal dose 5mg QD Everolimus: goal trough level 3-8ng/mL
Period Title: Overall Study
STARTED	20	20
COMPLETED	20	20
NOT COMPLETED	0	0

Baseline Characteristics

Arm/Group Title	Control: Envarsus + MMF	Intervention: Envarsus + Everoliumus	Total
Arm/Group Description	Envarsus Daily (5 -12ng/mL) + mycophenolate mofetil 1g BID + prednisone x 6 months Tacrolimus: goal trough level 5-12ng/mL Prednisone: goal dose 5mg QD Mycophenolate mofetil: goal dose 1g BID	Envarsus Daily (2-5ng/mL) + Everolimus Daily (3-8ng/mL) + prednisone x 6 months Tacrolimus: goal trough level 2-5 ng/mL Prednisone: goal dose 5mg QD Everolimus: goal trough level 3-8ng/mL	Total of all reporting groups
Overall Participants	20	20	40
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	52.4 (12.9)	50.3 (14.4)	51.3 (13.5)
Sex: Female, Male (Count of Participants)
Female	7 35%	6 30%	13 32.5%
Male	13 65%	14 70%	27 67.5%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	0 0%	0 0%	0 0%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	8 40%	10 50%	18 45%
White	12 60%	10 50%	22 55%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	0 0%	0 0%
Percent of Participants with Medicare Insurance (Count of Participants)
Count of Participants [Participants]	14 70%	16 80%	30 75%
Weight (kg) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg]	89.7 (15.5)	88.3 (14.1)	89.0 (14.6)
Primary Reason for End Stage Renal Disease (Count of Participants)
Diabetes	6 30%	7 35%	13 32.5%
Hypertension	4 20%	5 25%	9 22.5%
Polycystic Kidney Disease	2 10%	2 10%	4 10%
FSGS	3 15%	1 5%	4 10%
IgA Nephropathy	2 10%	1 5%	3 7.5%
Lupus	0 0%	1 5%	1 2.5%
Other	3 15%	3 15%	6 15%

Outcome Measures

1. Primary Outcome

Title	Self-reported Medication Adherence From Baseline to 6 Months.
Description	Percent of subjects reporting high medication adherence at baseline compared to 6 months post-conversion, using the Morisky Medication Adherence scale (MMAS). The MMAS rates medication adherence on a scale of 0 to 8. 0 is high adherence, 1-2 is medium adherence, and greater than or equal to 3 is low adherence.
Time Frame	6 months post conversion

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Control: Envarsus + MMF	Intervention: Envarsus + Everoliumus
Arm/Group Description	Envarsus Daily (5 -12ng/mL) + mycophenolate mofetil 1g BID + prednisone x 6 months Tacrolimus: goal trough level 5-12ng/mL Prednisone: goal dose 5mg QD Mycophenolate mofetil: goal dose 1g BID	Envarsus Daily (2-5ng/mL) + Everolimus Daily (3-8ng/mL) + prednisone x 6 months Tacrolimus: goal trough level 2-5 ng/mL Prednisone: goal dose 5mg QD Everolimus: goal trough level 3-8ng/mL
Measure Participants	20	20
Baseline	80 400%	45 225%
6 months post-conversion	59 295%	47 235%

2. Secondary Outcome

Title	Percent of Participants Experiencing Acute Allograft Rejection
Description	Estimate the composite of treatment failure rate, defined as acute allograft rejection with a Banff grade 1A or higher, graft loss, or death at six months post-conversion, in patients converted to a once-daily immunosuppressant regimen of Envarsus®, everolimus, and prednisone versus patients converted to a twice-daily regimen of Envarsus®, MMF, and prednisone.
Time Frame	Baseline to 6 months post conversion

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Control: Envarsus + MMF	Intervention: Envarsus + Everoliumus
Arm/Group Description	Envarsus Daily (5 -12ng/mL) + mycophenolate mofetil 1g BID + prednisone x 6 months Tacrolimus: goal trough level 5-12ng/mL Prednisone: goal dose 5mg QD Mycophenolate mofetil: goal dose 1g BID	Envarsus Daily (2-5ng/mL) + Everolimus Daily (3-8ng/mL) + prednisone x 6 months Tacrolimus: goal trough level 2-5 ng/mL Prednisone: goal dose 5mg QD Everolimus: goal trough level 3-8ng/mL
Measure Participants	20	20
Count of Participants [Participants]	0 0%	0 0%

3. Other Pre-specified Outcome

Title	Subject Specific Change on Medication Side Effect Scale
Description	Examine subject specific change on a validated Medication Side Effect Scale at the time of the conversion versus six months post-conversion, compared between the two arms. Side effect burden scale is from 0 to 180. A lower score is less side effect burden, a higher score is more side effect burden.
Time Frame	Baseline to 6 months post conversion

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Control: Envarsus + MMF	Intervention: Envarsus + Everoliumus
Arm/Group Description	Envarsus Daily (5 -12ng/mL) + mycophenolate mofetil 1g BID + prednisone x 6 months Tacrolimus: goal trough level 5-12ng/mL Prednisone: goal dose 5mg QD Mycophenolate mofetil: goal dose 1g BID	Envarsus Daily (2-5ng/mL) + Everolimus Daily (3-8ng/mL) + prednisone x 6 months Tacrolimus: goal trough level 2-5 ng/mL Prednisone: goal dose 5mg QD Everolimus: goal trough level 3-8ng/mL
Measure Participants	20	20
Baseline	71 (67)	37 (38)
6 month post-conversion	93 (86)	38 (34)

4. Other Pre-specified Outcome

Title	Percent of Participants Who Experienced Kidney Transplant Graft Loss
Description	Measure and compare time-to-event analysis between the two arms graft loss (time to event analysis)
Time Frame	Baseline to 6 months post conversion

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Control: Envarsus + MMF	Intervention: Envarsus + Everoliumus
Arm/Group Description	Envarsus Daily (5 -12ng/mL) + mycophenolate mofetil 1g BID + prednisone x 6 months Tacrolimus: goal trough level 5-12ng/mL Prednisone: goal dose 5mg QD Mycophenolate mofetil: goal dose 1g BID	Envarsus Daily (2-5ng/mL) + Everolimus Daily (3-8ng/mL) + prednisone x 6 months Tacrolimus: goal trough level 2-5 ng/mL Prednisone: goal dose 5mg QD Everolimus: goal trough level 3-8ng/mL
Measure Participants	20	20
Count of Participants [Participants]	0 0%	0 0%

Adverse Events

Time Frame	6 months from Baseline to end of study.
Arm/Group Title	Control: Envarsus + MMF		Intervention: Envarsus + Everoliumus
Arm/Group Description	Envarsus Daily (5 -12ng/mL) + mycophenolate mofetil 1g BID + prednisone x 6 months Tacrolimus: goal trough level 5-12ng/mL Prednisone: goal dose 5mg QD Mycophenolate mofetil: goal dose 1g BID		Envarsus Daily (2-5ng/mL) + Everolimus Daily (3-8ng/mL) + prednisone x 6 months Tacrolimus: goal trough level 2-5 ng/mL Prednisone: goal dose 5mg QD Everolimus: goal trough level 3-8ng/mL
All Cause Mortality
	Control: Envarsus + MMF		Intervention: Envarsus + Everoliumus
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/20 (0%)		0/20 (0%)
Serious Adverse Events
	Control: Envarsus + MMF		Intervention: Envarsus + Everoliumus
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/20 (5%)		1/20 (5%)
Infections and infestations
JC virus induced Progressive Multifocal Leukoencephalopathy	1/20 (5%)	1	0/20 (0%)	0
Renal and urinary disorders
Perinephric fluid collection	0/20 (0%)	0	1/20 (5%)	1
Other (Not Including Serious) Adverse Events
	Control: Envarsus + MMF		Intervention: Envarsus + Everoliumus
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	8/20 (40%)		9/20 (45%)
Cardiac disorders
Cardiovascular Event	1/20 (5%)	1	1/20 (5%)	1
Immune system disorders
Lymphocele	0/20 (0%)	0	1/20 (5%)	1
Infections and infestations
Cytomegalovirus infection	2/20 (10%)	2	1/20 (5%)	1
BK infection	1/20 (5%)	1	1/20 (5%)	1
Investigations
Neutropenia	1/20 (5%)	1	0/20 (0%)	0
Renal and urinary disorders
Borderline kidney rejection	1/20 (5%)	1	1/20 (5%)	1
Interstitial Fibrosis and Tubular Atrophy	2/20 (10%)	2	2/20 (10%)	2
Graft dysfunction	0/20 (0%)	0	1/20 (5%)	1
Skin and subcutaneous tissue disorders
Diabetic foot ulcer	0/20 (0%)	0	1/20 (5%)	1

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.