Safety and Efficacy Study of Everolimus to Treat BK Virus Infection in Kidney Transplant Recipients

Safety and Efficacy of Mycophenolic Acid Withdrawal With Conversion to Zortress (Everolimus) in Renal Transplant Recipients With BK Virus Infection

This study is examining the safety and efficacy of converting anti-rejection therapy from mycophenolic acid (MPA) to Zortress (everolimus) in renal transplant recipients with BK virus infection. The study will also determine if immune monitoring tests can detect an association between BK virus infection and transplant rejection episodes, based on the specific BKV infection treatment regimen. The investigators hypothesize that an anti-rejection regimen with Zortress (everolimus) and tacrolimus + prednisone will be superior to a standard regimen of reduced dose MPA and tacrolimus + prednisone in patients who have undergone renal transplantation and have active BKV infections.

This is a pilot study designed as a single center, randomized, open-label trial study comparing the safety and efficacy of MPA discontinuation with the addition of Zortress (everolimus) versus standard immunosuppression reduction in adult patients who have undergone a renal transplant and who have evidence of BKV infection. All kidney transplant recipients at University of California, San Francisco (UCSF) are screened for BKV in the urine and plasma at months 1, 3, 6, 9, and 12 post-transplantation. The presence of viruria > 1 million copies/mL and/or viremia prompts a 50% reduction in the MPA dose as well as monthly monitoring of BKV in the urine and plasma. Renal transplant patients found to have BK viruria > 1 million copies/mL and/or viremia > 500 copies/mL on any screening lab will be eligible for enrollment. Before any study-related evaluations are performed, the patient must give written informed consent. Once consent is obtained, patients will be randomized in consecutive blocks of 10, such that there will be 5 patients allocated to each group for each block. Only the study coordinator will have access to the block sequences. Patients will be randomized to one of two groups: group 1 will undergo MPA discontinuation with the addition of Zortress (everolimus) to their current regimen of tacrolimus and prednisone; group 2 will undergo a 50% dose reduction in MPA and continue with tacrolimus and prednisone. The two groups will be as follows: All patients in group 1 will undergo discontinuation of MPA and will receive Zortress (everolimus) at a starting dose of 0.75 mg PO b.i.d. (1.5 mg/day). Everolimus whole blood trough levels will be monitored at pre-specified time points to achieve a range of 3-8 ng/mL. Group 1 patients will continue on prednisone and tacrolimus with a target whole blood trough level of 3-6 ng/mL. Group 2 patients will continue with tacrolimus (target trough level of 6-10 ng/mL), prednisone, and undergo a 50% reduction of the MPA dose. At months 1, 2, and 3 post-randomization urine and plasma BKV levels will be re-checked. Renal allograft biopsies will be done for cause as clinically indicated. Tacrolimus trough levels are lower in the Zortress (everolimus) arm in order to minimize any potential nephrotoxicity with this drug combination as well as minimize the risk of over-immunosuppression. In all patients, routine transplant monitoring labs will be performed monthly as part of standard of care including a measurement of blood urea nitrogen (BUN) and creatinine (Cr), complete blood count (CBC), tacrolimus trough levels, urine protein excretion and fasting lipids. During the 3 month treatment period patients will be seen in clinic at baseline and months 1, 2, and 3 for follow-up. The assessment to address the primary objective will be performed at the end of the treatment period (Month 3). An interim analysis will be performed once 50% enrollment is reached. In a sub-group of patients (30 patients total; 15 in group 1 and 15 in group 2) using our whole-blood assay measuring p70S6 kinase phosphorylation, the investigators will investigate the correlation between inhibition of p70S6 kinase phosphorylation with BKV replication. Finally, by measuring both p70S6 phosphorylation inhibition as well as expression of the nuclear factor of activated T cells (NFAT)-regulated genes Interleukin (IL)-2, interferon gamma and GM-CSF, the investigators will correlate rejection episodes in patients maintained on lower immunosuppression alone versus those on a Zortress (everolimus) -based regimen. As patients are assigned to their intervention group based on the randomization scheme they will be offered enrollment in this sub-group analysis. All patients will be sequentially enrolled in the sub-group analysis until the 30 subject goal is reached with 15 subjects per group.

This arm (group 1) will undergo mycophenolic acid (MPA) discontinuation with the addition of Zortress (everolimus) to their current regimen of tacrolimus and prednisone; All patients in group 1 will receive Zortress (everolimus) at a starting dose of 0.75 mg PO b.i.d. (1.5 mg/day). Everolimus whole blood trough levels will be monitored at pre-specified time points to achieve a range of 3-8 ng/mL. Group 1 patients will continue on prednisone and tacrolimus with a target whole blood trough level of 3-6 ng/mL.

This arm (group 2) patients will continue with tacrolimus (target trough level of 6-10 ng/mL), prednisone, and undergo a 50% reduction of the MPA dose, which is the standard immunosuppression treatment for renal transplant recipients with evidence of BKV infection. At months 1, 2, and 3 post-randomization urine and plasma BKV levels will be re-checked. Renal allograft biopsies will be done for cause as clinically indicated.

Everolimus will be administered orally at a starting dose of 0.75 mg PO b.i.d. (1.5 mg/day). Everolimus whole blood trough levels will be monitored at pre-specified time points to achieve a range of 3-8 ng/mL. Group 1 patients will continue on prednisone and tacrolimus with a target whole blood trough level of 3-6 ng/mL.

Group 2 patients will undergo a 50% reduction of the mycophenolic acid (MPA) dose, and continue with tacrolimus (target trough level of 6-10 ng/mL), and prednisone.

composite outcome of a 50% or greater reduction in BKV urine levels and/or complete clearance of BKV viremia by 3 months after randomization

A doubling of BK viremia levels or the development of BKV nephropathy in subjects enrolled in the experimental study arm will prompt a conversion to standard care therapy. We will closely monitor BKV levels in the urine and blood and assess renal function monthly, as per our usual standard of care. Based on BKV results as well as renal function, as assessed by serum Cr, biopsies may be done for cause. Patients will have a final visit at month 4 to monitor for adverse events.

Measurement of the expression of three NFAT-regulated genes IL-2, interferon gamma, and GM-CSF, to predict a rejection episode. The residual gene expression after Tacrolimus intake was calculated as T1.5/T0*100, where T0 is the adjusted number of transcripts at Tacrolimus pre-dose level and T1.5 is the number of transcripts 1.5 hours after drug intake. For all three genes the residual expression was averaged and presented as "MRE of NFAT-regulated genes."

Inclusion Criteria: Male or female renal transplant recipients 18-75 years of age (primary or re-transplant) Recipients of cadaveric, living unrelated or living related donor kidney Baseline immunosuppression (IS) consisting of tacrolimus, MPA, and prednisone Patients with BK viruria ≥ 1 million copies/mL and/or viremia (> 500 copies/mL) found on routine BKV screening. Patients who have given written informed consent to participate in the study Exclusion Criteria: Patients who are ABO incompatible transplants Patients with an abnormal liver profile such as Alanine Aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase, or total bilirubin > 3x ULN at the time of randomization Patients with severe total hypercholesterolemia (> 350 mg/dL) or total hypertriglyceridemia (> 500 mg/dL). Patients on lipid lowering drugs with controlled hyperlipidemia are acceptable. Patients with a platelet count < 100,000/mm3 at randomization Patients with an ANC < 1,500/mm3 or WBC < 4.5mm3 Patients with a known hypersensitivity to the study drug or to drugs of similar chemical classes. Patients being treated with drugs (other than tacrolimus) that are potent inducers or inhibitors of cytochrome P4503A4 Patients who have any surgical or medical condition, such as severe diarrhea, active peptic ulcer disease, or uncontrolled DM, which, in the opinion of the investigators, might significantly alter the absorption, distribution, metabolism and/or excretion of study medication. 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 urine human chorionic gonadotrophin laboratory test 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. The two methods can be a double barrier method or a barrier method plus a hormonal method. Adequate barrier methods of contraception include: diaphragm, condom (by the partner), intrauterine device (copper or hormonal), sponge or spermicide. Hormonal contraceptives include any marketed contraceptive agent that includes an estrogen and/or a progestational agent. Reliable contraception should be maintained throughout the study and for 7 days after study drug discontinuation. Women are considered post-menopausal and not of child bearing potential if they have had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g. age appropriate, history of vasomotor symptoms) or six months of spontaneous amenorrhea with serum FSH levels > 40 mIU/mL and estradiol < 20 pg/mL] or have had surgical bilateral oophorectomy (with or without hysterectomy) at least six weeks ago. In the case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment is she considered not of child bearing potential. Patients with baseline urine protein excretion > 500mg/day Patients with Estimated Glomerular Filtration Rate (eGFR) < 40 ml/min Patients who have undergone desensitization