Renal Transplant
Conditions
Keywords
Renal Transplant, Immunosuppression, Steroid Avoidance, Calcineurin Avoidance, Mammalian Target of Rapamycin (mTOR), Kidney
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).
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.
Interventions
DRUGArm 1 Everolimus/Reduced dose tacrolimus
Immunosuppression drug intervention
Sponsors
Novartis Pharmaceuticals
University of Toledo Health Science Campus
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| 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. |
| 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 |
| Patient Survival | 2 years | Patient survival is defined as the percentage of patients still surviving at 2 years post baseline visit |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 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 |
| 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 |
| Thrombocytopenia | 2 years | The number of patients with thrombocytopenia as defined by platelet count less than 50 |
| Neurotoxicity | 2 years | The number of patients with neurotoxicity as evidenced by incidence of new onset seizure activity or tremors |
| 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 |
| Cytomegalovirus | 2 years | The number of patients with Incidence of cytomegalovirus infection as defined by need for hospitalization |
| 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 |
| BK Infection | 2 years | The number of patients with BK infection as defined by blood titers requiring reduction in immunosuppressive dose |
| 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) |
| Malignancies | 2 years | The number of patients developing malignancies including post-transplant lymphoproliferative disorders |
| 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 |
| Development of Donor Specific Antibody | 2 years | The number of patients with incidence of development of donor specific antibody |
| Infection Requiring Hospitalization | 2 years | The number of patients with serious infections as defined by need for hospitalization |
| Proteinuria | 2 years | The number of patients with proteinuria as defined by spot urine protein to creatinine ratio greater than 1.0 |
| 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 |
| Mouth Ulcers | 2 years | The number of patients with stomatitis/aphthous ulcer |
Countries
United States
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 details
50 participants met the inclusion/exclusion criteria and were enrolled in the treatment arm.
Participants by arm
| Arm | Count |
|---|---|
| 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.
Arm 1 Everolimus/Reduced dose tacrolimus: Immunosuppression drug intervention | 50 |
| Total | 50 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Adverse Event | 6 |
| Overall Study | Death | 1 |
Baseline characteristics
| Characteristic | Arm 1 Everolimus/Reduced Dose Tacrolimus |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 13 Participants |
| Age, Categorical Between 18 and 65 years | 37 Participants |
| Age, Continuous | 51.74 years STANDARD_DEVIATION 12.62 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 2 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 48 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 2 Participants |
| Race (NIH/OMB) Black or African American | 7 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 41 Participants |
| Region of Enrollment United States | 50 participants |
| Sex: Female, Male Female | 21 Participants |
| Sex: Female, Male Male | 29 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 1 / 50 |
| other Total, other adverse events | 50 / 50 |
| serious Total, serious adverse events | 18 / 50 |
Outcome results
Primary
Biopsy Proven Acute Rejection
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
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Arm 1 Everolimus/Reduced Dose Tacrolimus | Biopsy Proven Acute Rejection | 1 Participants |
Primary
Graft Survival
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
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Arm 1 Everolimus/Reduced Dose Tacrolimus | Graft Survival | 49 Participants |
Primary
Patient Survival
Patient survival is defined as the percentage of patients still surviving at 2 years post baseline visit
Time frame: 2 years
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Arm 1 Everolimus/Reduced Dose Tacrolimus | Patient Survival | 49 Participants |
Primary
Renal Function
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
Population: Intent to treat population (all participants assigned to treatment arm). Last observation carried forward (LOCF) imputation method
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Arm 1 Everolimus/Reduced Dose Tacrolimus | Renal Function | 65.70 mL/min/1.73 m2 | Standard Deviation 20.04 |
Secondary
BK Infection
The number of patients with BK infection as defined by blood titers requiring reduction in immunosuppressive dose
Time frame: 2 years
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Arm 1 Everolimus/Reduced Dose Tacrolimus | BK Infection | 7 Participants |
Secondary
BK Nephropathy
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
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Arm 1 Everolimus/Reduced Dose Tacrolimus | BK Nephropathy | 0 Participants |
Secondary
Cardiovascular Complications
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
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Arm 1 Everolimus/Reduced Dose Tacrolimus | Cardiovascular Complications | 1 Participants |
Secondary
Cytomegalovirus
The number of patients with Incidence of cytomegalovirus infection as defined by need for hospitalization
Time frame: 2 years
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Arm 1 Everolimus/Reduced Dose Tacrolimus | Cytomegalovirus | 0 Participants |
Secondary
Development of Donor Specific Antibody
The number of patients with incidence of development of donor specific antibody
Time frame: 2 years
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Arm 1 Everolimus/Reduced Dose Tacrolimus | Development of Donor Specific Antibody | 2 Participants |
Secondary
Gastrointestinal Complaints
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
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Arm 1 Everolimus/Reduced Dose Tacrolimus | Gastrointestinal Complaints | 22 Participants |
Secondary
Impaired Glucose Tolerance
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
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Arm 1 Everolimus/Reduced Dose Tacrolimus | Impaired Glucose Tolerance | 14 Participants |
Secondary
Infection Requiring Hospitalization
The number of patients with serious infections as defined by need for hospitalization
Time frame: 2 years
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Arm 1 Everolimus/Reduced Dose Tacrolimus | Infection Requiring Hospitalization | 11 Participants |
Secondary
Leukopenia
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
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Arm 1 Everolimus/Reduced Dose Tacrolimus | Leukopenia | 1 Participants |
Secondary
Lipid Levels
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
Population: 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 | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Arm 1 Everolimus/Reduced Dose Tacrolimus | Lipid Levels | Baseline negative patients with new onset hyperlipidemia | 7 Participants |
| Arm 1 Everolimus/Reduced Dose Tacrolimus | Lipid Levels | Baseline positive patients started on new lipid-lowering medication or needing increase in dose | 19 Participants |
Secondary
Malignancies
The number of patients developing malignancies including post-transplant lymphoproliferative disorders
Time frame: 2 years
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Arm 1 Everolimus/Reduced Dose Tacrolimus | Malignancies | 2 Participants |
Secondary
Mouth Ulcers
The number of patients with stomatitis/aphthous ulcer
Time frame: 2 years
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Arm 1 Everolimus/Reduced Dose Tacrolimus | Mouth Ulcers | 14 Participants |
Secondary
Neurotoxicity
The number of patients with neurotoxicity as evidenced by incidence of new onset seizure activity or tremors
Time frame: 2 years
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Arm 1 Everolimus/Reduced Dose Tacrolimus | Neurotoxicity | 1 Participants |
Secondary
Pneumonitis
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
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Arm 1 Everolimus/Reduced Dose Tacrolimus | Pneumonitis | 3 Participants |
Secondary
Proteinuria
The number of patients with proteinuria as defined by spot urine protein to creatinine ratio greater than 1.0
Time frame: 2 years
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Arm 1 Everolimus/Reduced Dose Tacrolimus | Proteinuria | 7 Participants |
Secondary
Thrombocytopenia
The number of patients with thrombocytopenia as defined by platelet count less than 50
Time frame: 2 years
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Arm 1 Everolimus/Reduced Dose Tacrolimus | Thrombocytopenia | 0 Participants |