Role of Everolimus in Highly Sensitized Patients

Study Overview
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Brief Summary
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A growing number of patients on the kidney transplant waiting list are broadly human leukocyte antigen (HLA) sensitized (HS). These patients are unlikely to have a compatible donor. Therefore they wait longer and have increased morbidity and mortality. Desensitization with intravenous immune globulin (IVIG) and rituximab with alemtuzumab induction improves transplant rates and achieves good allograft outcomes. However, HS patients are at risk for viral infections after transplant. We have previously shown an increased incidence of BKV infections after desensitization with HS patients having higher peak viral loads. Cytomegalovirus (CMV) and polyomavirus BK (BKV) infections place HS renal transplant recipients at particular risk. Allograft rejection is associated with both CMV and BKV infection. This is of particular concern for HS patients as they are at an increased risk of rejection at baseline. Furthermore, the frequent development of leukopenia after transplantation often requires the CMV prophylactic agent to be discontinued along with lowering immunosuppression. This increases the risk of CMV infection and allograft rejection. Everolimus was approved for rejection prophylaxis in combination with calcineurin inhibitors (CNI). CNI used in the study that led to drug's approval was cyclosporine. There are several trials nearing it's completion that utilize low dose tacrolimus instead. In 2012 Novartis published data from several trials showing superior outcomes using everolimus + low dose tacrolimus. This combination is currently approved in EU. It is also a combination that is standard of care (SOC) at our center for patients on everolimus. This study aims to demonstrate that use of everolimus as part of a maintenance immunosuppression regimen may decrease viral infections without lowering overall immunosuppression thus improving allograft function and survival.

Official Title
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A Prospective, Pilot Trial to Evaluate Safety and Tolerability of Everolimus for the Prevention of BK and CMV Viremia in HLA Sensitized Kidney Transplant Recipients

Conditions
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Highly-sensitized Kidney Transplant Recipients

Intervention / Treatment
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* Drug: everolimus + low-dose tacrolimus


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Recipient of a deceased or living donor kidney allograft Patients must have undergone desensitization with IVIG and rituximab with or without plasma exchange prior to transplant or be administered IVIG and rituximab peri-operatively. Age 18 and over Able to understand and provide informed consent Exclusion Criteria: Recipients of a dual simultaneous kidney/liver, kidney/heart, kidney/lung transplant 2. Pregnant or lactating females 3. Patients with a platelet count < 100,000/mm3 at time of randomization 4. Patients with an absolute neutrophil count < 1,500/mm3 or a white blood cell count of <3,000/mm3 at time of randomization 5. Patients who have an abnormal liver profile such as ALT, AST, Alkaline Phosphatase, or total bilirubin > 3 times the upper limit of normal (ULN) at time of randomization 6. Patients with severe total hypercholesterolemia (> 350 mg/dL; > 9 mmol/L) or total hypertriglyceridemia (> 500 mg/dL; > 5.6 mmol/L). Patients on lipid lowering treatment with controlled hyperlipidemia are acceptable. 7. History of hypersensitivity to any of the study drugs or to drugs of similar chemical classes 8. Patients being treated with drugs that are strong inducers or inhibitors of cytochrome P450 3A4 9. Patients with a clinically significant systemic infection within 30 days prior to transplant 9 10. Patients who have any surgical or medical condition, such as severe diarrhea, active peptic ulcer disease, or uncontrolled diabetes mellitus, which in the opinion of the investigator, might significantly alter the absorption, distribution, metabolism and/or excretion of study medication. 11. Patients with a history of coagulopathy or medical condition that would require long-term anticoagulation therapy after transplantation, unless the condition would permit a two week interruption in therapy before and after allograft biopsy. (Treatment with low dose aspirin is allowed.) 12. Women of childbearing potential who are either pregnant, lactating, planning to become pregnant during this trial, or with a positive serum or urine pregnancy test. Women of childbearing potential must be willing to agree to contraceptive practices.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: everolimus + low-dose tacrolimus<br>Patients receiving everolimus will be on low dose tacrolimus. | Drug: everolimus + low-dose tacrolimus<br>* Patients are supplied everolimus (Zortress) + prograf<br>* Other names: zortress + prograf;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The Number of Polyoma BK Viremia Patients | Patients will be monitored at regular interval for the development of Polyomavirus Viremia. | 12 months | 
| The Number of CMV Viremia | The number of patients with CMV viremia | 12 Months | 
| Incidence of Antibody Mediated Rejection (ABMR) | Protocol biopsies were obtained at T0 and 6 months post transplant. | 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of Cell Mediated Rejection (CMR) | Patients will be monitored for any episodes of CMR. | 6 months |