Evaluation of Calcineurin-inhibitor Reduction With Conversion at 2 Months to Everolimus/Reduced Tacrolimus in Renal Transplant Recipients Following Campath® Induction

• Sponsor: University of Toledo Health Science Campus (Other)
• Overall Status: Completed
• CT.gov ID: NCT01935128
• Collaborator: Novartis Pharmaceuticals (Industry)
• Enrollment: 55
• Location: 1
• Arm: 1
• Actual Duration (Months): 83.9
• Patients Per Site Per Month: 0.7

Study Details

Study Description

Brief Summary

The purpose of this study is to evaluate whether conversion to everolimus (Zortress®), allowing the elimination or reduction of calcineurin inhibitors, will reduce nephrotoxicity (measured by increased creatinine clearance) and lengthen overall graft (kidney transplant) survival (measured by 2-3 year graft survival).

Condition or Disease	Intervention/Treatment	Phase
Renal Transplant	Drug: Arm 1 Everolimus/Reduced dose tacrolimus	Phase 4

Detailed Description

The purpose of this study is to evaluate whether conversion to everolimus (Zortress®), allowing the elimination or reduction of calcineurin inhibitors, will reduce nephrotoxicity (measured by increased creatinine clearance) and lengthen overall graft (kidney transplant) survival (measured by 2-3 year graft survival). Among the worst of the long-term effects of chronic immunosuppression are the nephrotoxicity (toxic to kidney cells) of the calcineurin inhibitors and the myriad complications of steroids. This protocol evaluates the elimination or reduction of calcineurin inhibitors in a protocol that has already successfully eliminated the long-term use of steroids. A considerable need remains for safer therapeutic agents that inhibit T-cell activation (a white blood cell that attacks foreign cells as part of the immune response) via a calcineurin independent or reduced-dose mechanism of action.

Study Design

• Study Type: Interventional
• Actual Enrollment: 55 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A 24-month, Single Center, Pilot, Open Label, Controlled Trial to Evaluate the Efficacy and Safety of Calcineurin-inhibitor Reduction With Conversion at 2 Months to Reduced Dose Tacrolimus/Everolimus in Adult Renal Transplant Recipients Following Campath® Induction and Steroid Avoidance
• Actual Study Start Date: Jul 3, 2013
• Actual Primary Completion Date: Jul 1, 2020
• Actual Study Completion Date: Jul 1, 2020

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Arm 1 Everolimus/Reduced dose tacrolimus In this arm, the myfortic® will be weaned off quickly and everolimus (Zortress®) initiated to achieve a target level of 3-8 ng/ml with a mean of 6 ng/ml. Once achieving a therapeutic dose of everolimus (Zortress®) the tacrolimus (Prograf® or Hecoria®) dose will be reduced a target level of 3-5 ng/ml.	Drug: Arm 1 Everolimus/Reduced dose tacrolimus; Immunosuppression drug intervention; Other Names: Zortress® Prograf® or Hecoria®

Outcome Measures

Primary Outcome Measures

1. Renal Function [2 years]

   Renal function in patients will be assessed using glomerular filtration rate (GFR) as measured by the Modified Diet Renal Disease (MDRD) estimation. Glomerular filtration is the process by which the kidneys filter the blood, removing excess wastes and fluids. Glomerular filtration rate (GFR) is a calculation that determines how well the blood is filtered by the kidneys, which is one way to measure remaining kidney function. GFR is also used to find the stage of chronic kidney disease. Glomerular filtration rate is usually calculated using a mathematical formula that compares a person's size, age, sex, and race to serum creatinine levels. The higher the GFR number, the better the kidney function; the lower the GFR number, the worse the kidney function. A GFR of 60 or higher is in the normal range. A GFR below 60 may mean kidney disease. A GFR of 15 or lower may mean kidney failure.

2. Graft Survival [2 years]

   Graft survival is defined as the percentage of kidney transplants still functioning at 2 years post baseline visit . One patient died of natural causes at 12 months with a functioning graft.

3. Biopsy Proven Acute Rejection [2 years]

   The percentage of patients with a treated biopsy-proven acute rejection (a co-primary endpoint) within the 2 year study time period

4. Patient Survival [2 years]

   Patient survival is defined as the percentage of patients still surviving at 2 years post baseline visit

Secondary Outcome Measures

1. Impaired Glucose Tolerance [2 years]

   The number of patients with impaired glucose tolerance as indicated by fasting blood glucose levels, Hemoglobin A1C (HgbA1C) levels and the need for hypoglycemic medications

2. Proteinuria [2 years]

   The number of patients with proteinuria as defined by spot urine protein to creatinine ratio greater than 1.0

3. Lipid Levels [2 years]

   The number of patients with hyperlipidemia as defined by the development of new onset hyperlipidemia in the baseline negative patients and the number of baseline positive patients who required starting a new lipid-lowering medication or an increase in dose of their lipid-lowering medication over the course of the study

4. Mouth Ulcers [2 years]

   The number of patients with stomatitis/aphthous ulcer

5. Gastrointestinal Complaints [2 years]

   The number of patients with gastrointestinal complaints as indicated by abdominal pain, nausea, vomiting or diarrhea not accounted for by a specific episode of illness such as gastroenteritis

6. Leukopenia [2 years]

   The number of patients with leukopenia as indicated by white blood cell count less than 1.0, absolute neutrophil count less than 500 or the need for exogenous granulocyte stimulating factor administration

7. Thrombocytopenia [2 years]

   The number of patients with thrombocytopenia as defined by platelet count less than 50

8. Neurotoxicity [2 years]

   The number of patients with neurotoxicity as evidenced by incidence of new onset seizure activity or tremors

9. Pneumonitis [2 years]

   The number of patients with pneumonitis as demonstrated by lung inflammation symptoms such as shortness of breath and/or cough requiring clinical intervention and management

10. Cytomegalovirus [2 years]

    The number of patients with Incidence of cytomegalovirus infection as defined by need for hospitalization

11. Infection Requiring Hospitalization [2 years]

    The number of patients with serious infections as defined by need for hospitalization

12. BK Infection [2 years]

    The number of patients with BK infection as defined by blood titers requiring reduction in immunosuppressive dose

13. BK Nephropathy [2 years]

    The number of patients with BK nephropathy as defined by biopsy. Note that biopsies were not required as part of the study but were only done as part of the patient's standard of care if rejection was suspected (i.e. if the serum creatinine increased by 25% and was not associated with elevated tacrolimus levels or clinical signs of dehydration/illness to account for elevated creatinine)

14. Malignancies [2 years]

    The number of patients developing malignancies including post-transplant lymphoproliferative disorders

15. Cardiovascular Complications [2 years]

    The number of patients with cardiovascular complications as indicated by conditions such as dysrhythmias, coronary artery disease requiring intervention or myocardial infarction

16. Development of Donor Specific Antibody [2 years]

    The number of patients with incidence of development of donor specific antibody

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• Male or female renal allograft recipients at least 18 years old.

• Patients who have given written informed consent to participate in the study. If consent cannot be expressed in writing, it must be formally documented and witnessed, ideally via an independent trusted witness.

• Patient who has received a kidney transplant from a deceased or living unrelated-/related donor.

• Recipient of a kidney allograft with a cold ischemia time (CIT) < 36 hours.

• Female patients must have a negative pregnancy test prior to study enrollment.

• Patients on calcineurin inhibitor(s) (CNI) (tacrolimus and myfortic®) without steroid maintenance following Campath® induction.

• Patients with an acceptable allograft function defined by a serum creatinine < 2.5 mg/dL (250 μmol/L) and an actual estimated glomerular filtration rate (eGFR) (Modification of diet in renal disease equation 4, MDRD4) ≥ 30 mL/min/1.73m2 (without renal replacement therapy).

• No evidence of rejection since the time of transplantation.

Exclusion Criteria:

• Recipient of ABO incompatible allograft or a positive cross-match.

• Patient who is human immunodeficiency virus (HIV) positive.

• Patient who received an allograft from a Hepatitis B surface Antigen (HBsAg) or a Hepatitis C Virus (HCV) positive donor.

• HBsAg and/or a HCV positive patient with evidence of elevated liver function tests (LFTs) (Alanine transaminase/Aspartate transaminase [ALT/AST] levels ≥ 2.5 times upper limit of normal [ULN]). Viral serology results obtained within 6 months prior to randomization are acceptable.

• Patient with severe restrictive (total lung capacity [TLC] < 50%) or obstructive pulmonary (forced expiratory volume in one second [FEV1] < 50) disorders.

• Patient with severe allergy requiring acute (within 4 weeks of baseline) or chronic treatment that would prevent patient from potential exposure to everolimus, or with hypersensitivity to drugs similar to everolimus (e.g. macrolides).

• Patients with a known hypersensitivity/contraindication to any of the immunosuppressants or their classes, or to any of the excipients.

• Patient with severe hypercholesterolemia (> 300 mg/dL) or hypertriglyceridemia (> 400 mg/dL) that cannot be controlled despite lipid lowering therapy.

• Patient with white blood cell (WBC) count ≤ 1,000 /mm3 (and absolute neutrophil count [ANC] of <500) or a platelet count ≤ 50,000 /mm3.

• History of malignancy of any organ system, treated or untreated, within the past 5 years, regardless of whether there is evidence of local recurrence or metastases. (Localized basal cell carcinoma of the skin at any time, or small (less than 4 cm) or low-grade renal cancers, bladder cancers, or treated prostate cancer with no evidence of disease after 2 years are allowable)

• Graft loss.

• Patient on renal replacement therapy.

• Patient who experienced biopsy proven rejection.

• Proteinuria > 1 g/day (as calculated from the urinary protein-to-creatinine ratio).

• Patients with recurrence of Focal Segmental Glomerulosclerosis (FSGS).

• Patient who has a current severe systemic infection according to the investigator judgment requiring continued therapy that would interfere with the objectives of the study.

• Patients with ongoing wound healing problems, clinically significant infection requiring continued therapy or other severe surgical complication in the opinion of the investigator.

• Presence of intractable immunosuppressant complications or side effects.

• Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female after conception and until the termination of gestation, confirmed by a positive serum human chorionic gonadotrophin laboratory test (>5 mIU/mL)

• Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, including women whose career, lifestyle, or sexual orientation precludes intercourse with a male partner and women whose partners have been sterilized by vasectomy or other means, UNLESS they are using two birth control methods.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Toledo, Health Science Campus	Toledo	Ohio	United States	43614

Sponsors and Collaborators

• University of Toledo Health Science Campus
• Novartis Pharmaceuticals

Investigators

• Principal Investigator: Michael Rees, MD, PhD, University of Toledo, HSC

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Feb 5, 2018

More Information

Publications

None provided.

• Responsible Party: Michael A. Rees, MD, PhD, Principal Investigator, University of Toledo Health Science Campus
• ClinicalTrials.gov Identifier: NCT01935128
• Other Study ID Numbers: Everolimus
• First Posted: Sep 4, 2013
• Last Update Posted: May 26, 2022
• Last Verified: May 1, 2022

• Keywords provided by Michael A. Rees, MD, PhD, Principal Investigator, University of Toledo Health Science Campus: Renal Transplant; Immunosuppression; Steroid Avoidance; Calcineurin Avoidance; Mammalian Target of Rapamycin (mTOR); Kidney
• Additional relevant MeSH terms: Everolimus; Tacrolimus

Study Results

Participant Flow

Recruitment Details	Participants were recruited following renal transplantation at a single transplant center. Participants were recruited between 2 and 6 months post-transplant. Date of first enrollment was July 3, 2013 and date of last enrollment was July 6, 2018.
Pre-assignment Detail	50 participants met the inclusion/exclusion criteria and were enrolled in the treatment arm.

Arm/Group Title	Arm 1 Everolimus/Reduced Dose Tacrolimus
Arm/Group Description	In this arm, the myfortic® will be weaned off quickly and everolimus (Zortress®) initiated to achieve a target level of 3-8 ng/ml with a mean of 6 ng/ml. Once achieving a therapeutic dose of everolimus (Zortress®) the tacrolimus (Prograf® or Hecoria®) dose will be reduced a target level of 3-5 ng/ml. Arm 1 Everolimus/Reduced dose tacrolimus: Immunosuppression drug intervention
Period Title: Overall Study
STARTED	50
COMPLETED	43
NOT COMPLETED	7

Baseline Characteristics

Arm/Group Title	Arm 1 Everolimus/Reduced Dose Tacrolimus
Arm/Group Description	In this arm, the myfortic® will be weaned off quickly and everolimus (Zortress®) initiated to achieve a target level of 3-8 ng/ml with a mean of 6 ng/ml. Once achieving a therapeutic dose of everolimus (Zortress®) the tacrolimus (Prograf® or Hecoria®) dose will be reduced a target level of 3-5 ng/ml. Arm 1 Everolimus/Reduced dose tacrolimus: Immunosuppression drug intervention
Overall Participants	50
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	37 74%
>=65 years	13 26%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	51.74 (12.62)
Sex: Female, Male (Count of Participants)
Female	21 42%
Male	29 58%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	2 4%
Not Hispanic or Latino	48 96%
Unknown or Not Reported	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	2 4%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	7 14%
White	41 82%
More than one race	0 0%
Unknown or Not Reported	0 0%
Region of Enrollment (participants) [Number]
United States	50 100%

Outcome Measures

1. Primary Outcome

Title	Renal Function
Description	Renal function in patients will be assessed using glomerular filtration rate (GFR) as measured by the Modified Diet Renal Disease (MDRD) estimation. Glomerular filtration is the process by which the kidneys filter the blood, removing excess wastes and fluids. Glomerular filtration rate (GFR) is a calculation that determines how well the blood is filtered by the kidneys, which is one way to measure remaining kidney function. GFR is also used to find the stage of chronic kidney disease. Glomerular filtration rate is usually calculated using a mathematical formula that compares a person's size, age, sex, and race to serum creatinine levels. The higher the GFR number, the better the kidney function; the lower the GFR number, the worse the kidney function. A GFR of 60 or higher is in the normal range. A GFR below 60 may mean kidney disease. A GFR of 15 or lower may mean kidney failure.
Time Frame	2 years

Outcome Measure Data

Analysis Population Description

Intent to treat population (all participants assigned to treatment arm). Last observation carried forward (LOCF) imputation method

Arm/Group Title	Arm 1 Everolimus/Reduced Dose Tacrolimus
Arm/Group Description	In this arm, the myfortic® will be weaned off quickly and everolimus (Zortress®) initiated to achieve a target level of 3-8 ng/ml with a mean of 6 ng/ml. Once achieving a therapeutic dose of everolimus (Zortress®) the tacrolimus (Prograf® or Hecoria®) dose will be reduced a target level of 3-5 ng/ml. Arm 1 Everolimus/Reduced dose tacrolimus: Immunosuppression drug intervention
Measure Participants	50
Mean (Standard Deviation) [mL/min/1.73 m2]	65.70 (20.04)

2. Primary Outcome

Title	Graft Survival
Description	Graft survival is defined as the percentage of kidney transplants still functioning at 2 years post baseline visit . One patient died of natural causes at 12 months with a functioning graft.
Time Frame	2 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Arm 1 Everolimus/Reduced Dose Tacrolimus
Arm/Group Description	In this arm, the myfortic® will be weaned off quickly and everolimus (Zortress®) initiated to achieve a target level of 3-8 ng/ml with a mean of 6 ng/ml. Once achieving a therapeutic dose of everolimus (Zortress®) the tacrolimus (Prograf® or Hecoria®) dose will be reduced a target level of 3-5 ng/ml. Arm 1 Everolimus/Reduced dose tacrolimus: Immunosuppression drug intervention
Measure Participants	50
Count of Participants [Participants]	49 98%

3. Primary Outcome

Title	Biopsy Proven Acute Rejection
Description	The percentage of patients with a treated biopsy-proven acute rejection (a co-primary endpoint) within the 2 year study time period
Time Frame	2 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Arm 1 Everolimus/Reduced Dose Tacrolimus
Arm/Group Description	In this arm, the myfortic® will be weaned off quickly and everolimus (Zortress®) initiated to achieve a target level of 3-8 ng/ml with a mean of 6 ng/ml. Once achieving a therapeutic dose of everolimus (Zortress®) the tacrolimus (Prograf® or Hecoria®) dose will be reduced a target level of 3-5 ng/ml. Arm 1 Everolimus/Reduced dose tacrolimus: Immunosuppression drug intervention
Measure Participants	50
Count of Participants [Participants]	1 2%

4. Primary Outcome

Title	Patient Survival
Description	Patient survival is defined as the percentage of patients still surviving at 2 years post baseline visit
Time Frame	2 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Arm 1 Everolimus/Reduced Dose Tacrolimus
Arm/Group Description	In this arm, the myfortic® will be weaned off quickly and everolimus (Zortress®) initiated to achieve a target level of 3-8 ng/ml with a mean of 6 ng/ml. Once achieving a therapeutic dose of everolimus (Zortress®) the tacrolimus (Prograf® or Hecoria®) dose will be reduced a target level of 3-5 ng/ml. Arm 1 Everolimus/Reduced dose tacrolimus: Immunosuppression drug intervention
Measure Participants	50
Count of Participants [Participants]	49 98%

5. Secondary Outcome

Title	Impaired Glucose Tolerance
Description	The number of patients with impaired glucose tolerance as indicated by fasting blood glucose levels, Hemoglobin A1C (HgbA1C) levels and the need for hypoglycemic medications
Time Frame	2 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Arm 1 Everolimus/Reduced Dose Tacrolimus
Arm/Group Description	In this arm, the myfortic® will be weaned off quickly and everolimus (Zortress®) initiated to achieve a target level of 3-8 ng/ml with a mean of 6 ng/ml. Once achieving a therapeutic dose of everolimus (Zortress®) the tacrolimus (Prograf® or Hecoria®) dose will be reduced a target level of 3-5 ng/ml. Arm 1 Everolimus/Reduced dose tacrolimus: Immunosuppression drug intervention
Measure Participants	50
Count of Participants [Participants]	14 28%

6. Secondary Outcome

Title	Proteinuria
Description	The number of patients with proteinuria as defined by spot urine protein to creatinine ratio greater than 1.0
Time Frame	2 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Arm 1 Everolimus/Reduced Dose Tacrolimus
Arm/Group Description	In this arm, the myfortic® will be weaned off quickly and everolimus (Zortress®) initiated to achieve a target level of 3-8 ng/ml with a mean of 6 ng/ml. Once achieving a therapeutic dose of everolimus (Zortress®) the tacrolimus (Prograf® or Hecoria®) dose will be reduced a target level of 3-5 ng/ml. Arm 1 Everolimus/Reduced dose tacrolimus: Immunosuppression drug intervention
Measure Participants	50
Count of Participants [Participants]	7 14%

7. Secondary Outcome

Title	Lipid Levels
Description	The number of patients with hyperlipidemia as defined by the development of new onset hyperlipidemia in the baseline negative patients and the number of baseline positive patients who required starting a new lipid-lowering medication or an increase in dose of their lipid-lowering medication over the course of the study
Time Frame	2 years

Outcome Measure Data

Analysis Population Description

The overall number of participants analyzed was 50. This population was split into participants who were negative for hyperlipidemia at baseline and developed new onset hyperlipidemia (10) identified in Row 1 and participants who were baseline positive for hyperlipidemia but who required a new lipid-lowering medication or an increase in the dose of their lipid-lowering medication over the course of the study (40) as identified in Row 2.

Arm/Group Title	Arm 1 Everolimus/Reduced Dose Tacrolimus
Arm/Group Description	In this arm, the myfortic® will be weaned off quickly and everolimus (Zortress®) initiated to achieve a target level of 3-8 ng/ml with a mean of 6 ng/ml. Once achieving a therapeutic dose of everolimus (Zortress®) the tacrolimus (Prograf® or Hecoria®) dose will be reduced a target level of 3-5 ng/ml. Arm 1 Everolimus/Reduced dose tacrolimus: Immunosuppression drug intervention
Measure Participants	50
Baseline negative patients with new onset hyperlipidemia	7 14%
Baseline positive patients started on new lipid-lowering medication or needing increase in dose	19 38%

8. Secondary Outcome

Title	Mouth Ulcers
Description	The number of patients with stomatitis/aphthous ulcer
Time Frame	2 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Arm 1 Everolimus/Reduced Dose Tacrolimus
Arm/Group Description	In this arm, the myfortic® will be weaned off quickly and everolimus (Zortress®) initiated to achieve a target level of 3-8 ng/ml with a mean of 6 ng/ml. Once achieving a therapeutic dose of everolimus (Zortress®) the tacrolimus (Prograf® or Hecoria®) dose will be reduced a target level of 3-5 ng/ml. Arm 1 Everolimus/Reduced dose tacrolimus: Immunosuppression drug intervention
Measure Participants	50
Count of Participants [Participants]	14 28%

9. Secondary Outcome

Title	Gastrointestinal Complaints
Description	The number of patients with gastrointestinal complaints as indicated by abdominal pain, nausea, vomiting or diarrhea not accounted for by a specific episode of illness such as gastroenteritis
Time Frame	2 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Arm 1 Everolimus/Reduced Dose Tacrolimus
Arm/Group Description	In this arm, the myfortic® will be weaned off quickly and everolimus (Zortress®) initiated to achieve a target level of 3-8 ng/ml with a mean of 6 ng/ml. Once achieving a therapeutic dose of everolimus (Zortress®) the tacrolimus (Prograf® or Hecoria®) dose will be reduced a target level of 3-5 ng/ml. Arm 1 Everolimus/Reduced dose tacrolimus: Immunosuppression drug intervention
Measure Participants	50
Count of Participants [Participants]	22 44%

10. Secondary Outcome

Title	Leukopenia
Description	The number of patients with leukopenia as indicated by white blood cell count less than 1.0, absolute neutrophil count less than 500 or the need for exogenous granulocyte stimulating factor administration
Time Frame	2 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Arm 1 Everolimus/Reduced Dose Tacrolimus
Arm/Group Description	In this arm, the myfortic® will be weaned off quickly and everolimus (Zortress®) initiated to achieve a target level of 3-8 ng/ml with a mean of 6 ng/ml. Once achieving a therapeutic dose of everolimus (Zortress®) the tacrolimus (Prograf® or Hecoria®) dose will be reduced a target level of 3-5 ng/ml. Arm 1 Everolimus/Reduced dose tacrolimus: Immunosuppression drug intervention
Measure Participants	50
Count of Participants [Participants]	1 2%

11. Secondary Outcome

Title	Thrombocytopenia
Description	The number of patients with thrombocytopenia as defined by platelet count less than 50
Time Frame	2 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Arm 1 Everolimus/Reduced Dose Tacrolimus
Arm/Group Description	In this arm, the myfortic® will be weaned off quickly and everolimus (Zortress®) initiated to achieve a target level of 3-8 ng/ml with a mean of 6 ng/ml. Once achieving a therapeutic dose of everolimus (Zortress®) the tacrolimus (Prograf® or Hecoria®) dose will be reduced a target level of 3-5 ng/ml. Arm 1 Everolimus/Reduced dose tacrolimus: Immunosuppression drug intervention
Measure Participants	50
Count of Participants [Participants]	0 0%

12. Secondary Outcome

Title	Neurotoxicity
Description	The number of patients with neurotoxicity as evidenced by incidence of new onset seizure activity or tremors
Time Frame	2 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Arm 1 Everolimus/Reduced Dose Tacrolimus
Arm/Group Description	In this arm, the myfortic® will be weaned off quickly and everolimus (Zortress®) initiated to achieve a target level of 3-8 ng/ml with a mean of 6 ng/ml. Once achieving a therapeutic dose of everolimus (Zortress®) the tacrolimus (Prograf® or Hecoria®) dose will be reduced a target level of 3-5 ng/ml. Arm 1 Everolimus/Reduced dose tacrolimus: Immunosuppression drug intervention
Measure Participants	50
Count of Participants [Participants]	1 2%

13. Secondary Outcome

Title	Pneumonitis
Description	The number of patients with pneumonitis as demonstrated by lung inflammation symptoms such as shortness of breath and/or cough requiring clinical intervention and management
Time Frame	2 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Arm 1 Everolimus/Reduced Dose Tacrolimus
Arm/Group Description	In this arm, the myfortic® will be weaned off quickly and everolimus (Zortress®) initiated to achieve a target level of 3-8 ng/ml with a mean of 6 ng/ml. Once achieving a therapeutic dose of everolimus (Zortress®) the tacrolimus (Prograf® or Hecoria®) dose will be reduced a target level of 3-5 ng/ml. Arm 1 Everolimus/Reduced dose tacrolimus: Immunosuppression drug intervention
Measure Participants	50
Count of Participants [Participants]	3 6%

14. Secondary Outcome

Title	Cytomegalovirus
Description	The number of patients with Incidence of cytomegalovirus infection as defined by need for hospitalization
Time Frame	2 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Arm 1 Everolimus/Reduced Dose Tacrolimus
Arm/Group Description	In this arm, the myfortic® will be weaned off quickly and everolimus (Zortress®) initiated to achieve a target level of 3-8 ng/ml with a mean of 6 ng/ml. Once achieving a therapeutic dose of everolimus (Zortress®) the tacrolimus (Prograf® or Hecoria®) dose will be reduced a target level of 3-5 ng/ml. Arm 1 Everolimus/Reduced dose tacrolimus: Immunosuppression drug intervention
Measure Participants	50
Count of Participants [Participants]	0 0%

15. Secondary Outcome

Title	Infection Requiring Hospitalization
Description	The number of patients with serious infections as defined by need for hospitalization
Time Frame	2 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Arm 1 Everolimus/Reduced Dose Tacrolimus
Arm/Group Description	In this arm, the myfortic® will be weaned off quickly and everolimus (Zortress®) initiated to achieve a target level of 3-8 ng/ml with a mean of 6 ng/ml. Once achieving a therapeutic dose of everolimus (Zortress®) the tacrolimus (Prograf® or Hecoria®) dose will be reduced a target level of 3-5 ng/ml. Arm 1 Everolimus/Reduced dose tacrolimus: Immunosuppression drug intervention
Measure Participants	50
Count of Participants [Participants]	11 22%

16. Secondary Outcome

Title	BK Infection
Description	The number of patients with BK infection as defined by blood titers requiring reduction in immunosuppressive dose
Time Frame	2 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Arm 1 Everolimus/Reduced Dose Tacrolimus
Arm/Group Description	In this arm, the myfortic® will be weaned off quickly and everolimus (Zortress®) initiated to achieve a target level of 3-8 ng/ml with a mean of 6 ng/ml. Once achieving a therapeutic dose of everolimus (Zortress®) the tacrolimus (Prograf® or Hecoria®) dose will be reduced a target level of 3-5 ng/ml. Arm 1 Everolimus/Reduced dose tacrolimus: Immunosuppression drug intervention
Measure Participants	50
Count of Participants [Participants]	7 14%

17. Secondary Outcome

Title	BK Nephropathy
Description	The number of patients with BK nephropathy as defined by biopsy. Note that biopsies were not required as part of the study but were only done as part of the patient's standard of care if rejection was suspected (i.e. if the serum creatinine increased by 25% and was not associated with elevated tacrolimus levels or clinical signs of dehydration/illness to account for elevated creatinine)
Time Frame	2 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Arm 1 Everolimus/Reduced Dose Tacrolimus
Arm/Group Description	In this arm, the myfortic® will be weaned off quickly and everolimus (Zortress®) initiated to achieve a target level of 3-8 ng/ml with a mean of 6 ng/ml. Once achieving a therapeutic dose of everolimus (Zortress®) the tacrolimus (Prograf® or Hecoria®) dose will be reduced a target level of 3-5 ng/ml. Arm 1 Everolimus/Reduced dose tacrolimus: Immunosuppression drug intervention
Measure Participants	50
Count of Participants [Participants]	0 0%

18. Secondary Outcome

Title	Malignancies
Description	The number of patients developing malignancies including post-transplant lymphoproliferative disorders
Time Frame	2 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Arm 1 Everolimus/Reduced Dose Tacrolimus
Arm/Group Description	In this arm, the myfortic® will be weaned off quickly and everolimus (Zortress®) initiated to achieve a target level of 3-8 ng/ml with a mean of 6 ng/ml. Once achieving a therapeutic dose of everolimus (Zortress®) the tacrolimus (Prograf® or Hecoria®) dose will be reduced a target level of 3-5 ng/ml. Arm 1 Everolimus/Reduced dose tacrolimus: Immunosuppression drug intervention
Measure Participants	50
Count of Participants [Participants]	2 4%

19. Secondary Outcome

Title	Cardiovascular Complications
Description	The number of patients with cardiovascular complications as indicated by conditions such as dysrhythmias, coronary artery disease requiring intervention or myocardial infarction
Time Frame	2 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Arm 1 Everolimus/Reduced Dose Tacrolimus
Arm/Group Description	In this arm, the myfortic® will be weaned off quickly and everolimus (Zortress®) initiated to achieve a target level of 3-8 ng/ml with a mean of 6 ng/ml. Once achieving a therapeutic dose of everolimus (Zortress®) the tacrolimus (Prograf® or Hecoria®) dose will be reduced a target level of 3-5 ng/ml. Arm 1 Everolimus/Reduced dose tacrolimus: Immunosuppression drug intervention
Measure Participants	50
Count of Participants [Participants]	1 2%

20. Secondary Outcome

Title	Development of Donor Specific Antibody
Description	The number of patients with incidence of development of donor specific antibody
Time Frame	2 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Arm 1 Everolimus/Reduced Dose Tacrolimus
Arm/Group Description	In this arm, the myfortic® will be weaned off quickly and everolimus (Zortress®) initiated to achieve a target level of 3-8 ng/ml with a mean of 6 ng/ml. Once achieving a therapeutic dose of everolimus (Zortress®) the tacrolimus (Prograf® or Hecoria®) dose will be reduced a target level of 3-5 ng/ml. Arm 1 Everolimus/Reduced dose tacrolimus: Immunosuppression drug intervention
Measure Participants	50
Count of Participants [Participants]	2 4%

Adverse Events

Time Frame	2 years
Arm/Group Title	Arm 1 Everolimus/Reduced Dose Tacrolimus
Arm/Group Description	In this arm, the myfortic® will be weaned off quickly and everolimus (Zortress®) initiated to achieve a target level of 3-8 ng/ml with a mean of 6 ng/ml. Once achieving a therapeutic dose of everolimus (Zortress®) the tacrolimus (Prograf® or Hecoria®) dose will be reduced a target level of 3-5 ng/ml. Arm 1 Everolimus/Reduced dose tacrolimus: Immunosuppression drug intervention
All Cause Mortality
	Arm 1 Everolimus/Reduced Dose Tacrolimus
	Affected / at Risk (%)	# Events
Total	1/50 (2%)
Serious Adverse Events
	Arm 1 Everolimus/Reduced Dose Tacrolimus
	Affected / at Risk (%)	# Events
Total	18/50 (36%)
Gastrointestinal disorders
Rectal hemorrhage	1/50 (2%)	2
General disorders
Pyrexia	4/50 (8%)	5
Immune system disorders
Kidney transplant rejection	1/50 (2%)	1
Infections and infestations
Influenza A	1/50 (2%)	1
Gastroenteritis	1/50 (2%)	1
Endocarditis	1/50 (2%)	1
Urosepsis	1/50 (2%)	1
Urinary tract infection	1/50 (2%)	1
Nasal abscess	1/50 (2%)	1
Injury, poisoning and procedural complications
Vascular pseudoaneurysm	1/50 (2%)	1
Metabolism and nutrition disorders
Diabetes mellitus	1/50 (2%)	1
Psychiatric disorders
Depression suicidal	1/50 (2%)	1
Renal and urinary disorders
Acute kidney injury	1/50 (2%)	1
Respiratory, thoracic and mediastinal disorders
Dyspnea	3/50 (6%)	3
Surgical and medical procedures
Parathyroid gland excision	1/50 (2%)	1
Nephrectomy	2/50 (4%)	2
Vascular disorders
Venous thrombosis	4/50 (8%)	4
Other (Not Including Serious) Adverse Events
	Arm 1 Everolimus/Reduced Dose Tacrolimus
	Affected / at Risk (%)	# Events
Total	50/50 (100%)
Blood and lymphatic system disorders
Erythrocytosis	8/50 (16%)	8
Leukopenia	9/50 (18%)	12
Worsening leukopenia	2/50 (4%)	3
Eye disorders
Visual acuity reduced	4/50 (8%)	4
Gastrointestinal disorders
Nausea	9/50 (18%)	9
Vomiting	8/50 (16%)	8
Diarrhea	18/50 (36%)	25
Abdominal pain	8/50 (16%)	8
Abdominal distention	3/50 (6%)	3
Stomach upset	7/50 (14%)	7
Gastroenteritis	3/50 (6%)	3
Stomatitis	14/50 (28%)	18
General disorders
Edema, limb	23/50 (46%)	30
Fatigue	12/50 (24%)	14
Worsening fatigue	3/50 (6%)	3
Pyrexia	9/50 (18%)	9
Chills	7/50 (14%)	9
Generalized body aches	4/50 (8%)	4
Hepatobiliary disorders
Hepatic enzyme increased	13/50 (26%)	14
Immune system disorders
Donor specific antibody positive	2/50 (4%)	2
Infections and infestations
Upper respiratory tract infection	31/50 (62%)	52
Urinary tract infection	9/50 (18%)	19
Herpes zoster	5/50 (10%)	5
Cellulitis	3/50 (6%)	3
Investigations
Weight gain	25/50 (50%)	33
Weight loss	11/50 (22%)	12
BK viremia	3/50 (6%)	3
Metabolism and nutrition disorders
Hyperlipidemia	14/50 (28%)	14
Worsening hyperlipidemia	18/50 (36%)	20
Diabetes mellitus	3/50 (6%)	3
Worsening diabetes mellitus	4/50 (8%)	4
Hyperglycemia	3/50 (6%)	4
Hypokalemia	2/50 (4%)	3
Excessive thirst	3/50 (6%)	5
Musculoskeletal and connective tissue disorders
Low back pain	4/50 (8%)	5
Chest pain	2/50 (4%)	2
Flank pain	2/50 (4%)	2
Nervous system disorders
Dizziness	4/50 (8%)	4
Headache	8/50 (16%)	11
Worsening headache	3/50 (6%)	3
Psychiatric disorders
Depression	3/50 (6%)	3
Worsening depression	2/50 (4%)	2
Mental concentration difficulty	3/50 (6%)	3
Insomnia	5/50 (10%)	5
Renal and urinary disorders
Blood creatinine increased	8/50 (16%)	9
Proteinuria	11/50 (22%)	12
Worsening proteinuria	7/50 (14%)	8
Hyponatremia	3/50 (6%)	3
Hematuria	7/50 (14%)	7
Respiratory, thoracic and mediastinal disorders
Cough	14/50 (28%)	16
Sinus congestion	8/50 (16%)	10
Rhinorrhea	6/50 (12%)	7
Dyspnea	4/50 (8%)	4
Dyspnea exertional	3/50 (6%)	3
Worsening dyspnea	3/50 (6%)	3
Skin and subcutaneous tissue disorders
Fungal skin infection	4/50 (8%)	5
Rash, acneiform	7/50 (14%)	8
Worsening rash, acneiform	3/50 (6%)	4
Rash, generalized	3/50 (6%)	3
Vascular disorders
Hypertension	10/50 (20%)	13
Worsening hypertension	9/50 (18%)	9

Limitations/Caveats

The study is limited by early discontinuation of the 2nd arm in this parallel group study due to safety concerns. All 5 patients with tacrolimus elimination developed donor specific antibodies against DQ-beta HLA antigens and were excluded from study analysis. Protocol section notes enrollment of 55 patients. Results for only 50 patients Due to small sample size, study is not powered to achieve statistical significance. Statistical significance also impaired without the 2nd arm of the study.

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.