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

Study Overview
=================
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.

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

Conditions
-----------------
Renal Transplant

Intervention / Treatment
-----------------
* Drug: Arm 1 Everolimus/Reduced dose tacrolimus


Participation Criteria
=================
Eligibility Criteria
-----------------
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.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm 1 Everolimus/Reduced dose tacrolimus<br>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<br>* Immunosuppression drug intervention<br>* Other names: Prograf® or Hecoria®;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 2 years | 
| 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. | 2 years | 
| 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 | 2 years | 
| Patient Survival | Patient survival is defined as the percentage of patients still surviving at 2 years post baseline visit | 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 2 years | 
| Proteinuria | The number of patients with proteinuria as defined by spot urine protein to creatinine ratio greater than 1.0 | 2 years | 
| 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 | 2 years | 
| Mouth Ulcers | The number of patients with stomatitis/aphthous ulcer | 2 years | 
| 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 | 2 years | 
| 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 | 2 years | 
| Thrombocytopenia | The number of patients with thrombocytopenia as defined by platelet count less than 50 | 2 years | 
| Neurotoxicity | The number of patients with neurotoxicity as evidenced by incidence of new onset seizure activity or tremors | 2 years | 
| 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 | 2 years | 
| Cytomegalovirus | The number of patients with Incidence of cytomegalovirus infection as defined by need for hospitalization | 2 years | 
| Infection Requiring Hospitalization | The number of patients with serious infections as defined by need for hospitalization | 2 years | 
| BK Infection | The number of patients with BK infection as defined by blood titers requiring reduction in immunosuppressive dose | 2 years | 
| 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) | 2 years | 
| Malignancies | The number of patients developing malignancies including post-transplant lymphoproliferative disorders | 2 years | 
| Cardiovascular Complications | The number of patients with cardiovascular complications as indicated by conditions such as dysrhythmias, coronary artery disease requiring intervention or myocardial infarction | 2 years | 
| Development of Donor Specific Antibody | The number of patients with incidence of development of donor specific antibody | 2 years | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Kidney, Renal Transplant, Immunosuppression, Steroid Avoidance, Calcineurin Avoidance, Mammalian Target of Rapamycin (mTOR)