Safety and Efficacy Study of Everolimus to Treat BK Virus Infection in Kidney Transplant Recipients
Condition: BK Virus Infection
MeSH terms: Infections; Communicable Diseases; Virus Diseases
Study type: Interventional
Phase: Phase 4

Summary: 
      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.
    

Detailed description: 
      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.
    

Intervention name(s): Everolimus; Mycophenolic acid dose reduction
Intervention type(s): Drug; Drug
Intervention description(s): 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.
Other intervention name(s): Zortress; CellCept; Myfortic
Intervention MeSH terms: Mycophenolic Acid; Everolimus
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: BK virus; Kidney Transplantation; Immunologic Monitoring