Role of Everolimus in Highly Sensitized Patients

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

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.

Study Overview

• Status: Completed
• Conditions: Highly-sensitized Kidney Transplant Recipients
• Intervention / Treatment: Drug: everolimus + low-dose tacrolimus

• Study Type: Interventional
• Enrollment (Actual): 20
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • California
    • Los Angeles, California, United States, 90048
      • Cedars-Sinai Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

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

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Joseph Kahwaji, MD, MPH
• Collaborators: Novartis

Study record dates

Study Major Dates

• Study Start: June 1, 2013
• Primary Completion (Actual): January 1, 2016
• Study Completion (Actual): January 19, 2016

Study Registration Dates

• First Submitted: March 4, 2013
• First Submitted That Met QC Criteria: July 29, 2013
• First Posted (Estimate): July 30, 2013

Study Record Updates

• Last Update Posted (Actual): December 7, 2017
• Last Update Submitted That Met QC Criteria: November 3, 2017
• Last Verified: November 1, 2017

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Calcineurin Inhibitors; Tacrolimus; Everolimus
• Other Study ID Numbers: CRAD001AUS200T

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No