Role of Everolimus in Highly Sensitized Patients
Condition: Highly-sensitized Kidney Transplant Recipients
Intervention: everolimus + low-dose tacrolimus
Intervention description: Patients are supplied everolimus (Zortress) + prograf
Intervention MeSH terms: Everolimus; Tacrolimus
Phase: Phase 2
Study type: Interventional
Primary purpose: Prevention
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 20.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No

Summary:

      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.
    

Eligibility criteria:

        Inclusion Criteria:

          1. Recipient of a deceased or living donor kidney allograft

          2. 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.

          3. Age 18 and over

          4. 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.