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

This study is enrolling participants by invitation only.
Sponsor:
Information provided by (Responsible Party):
University of California, San Francisco
ClinicalTrials.gov Identifier:
NCT01624948
First received: June 15, 2012
Last updated: September 23, 2013
Last verified: September 2013
  Purpose

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.


Condition Intervention Phase
BK Virus Infection
Drug: Everolimus
Drug: Mycophenolic acid dose reduction
Phase 4

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Safety and Efficacy of Mycophenolic Acid Withdrawal With Conversion to Zortress (Everolimus) in Renal Transplant Recipients With BK Virus Infection

Resource links provided by NLM:


Further study details as provided by University of California, San Francisco:

Primary Outcome Measures:
  • Evidence of reduction of BK viruria and/or clearance of BK viremia [ Time Frame: 3 months post-randomization ] [ Designated as safety issue: No ]
    The primary objective of this pilot study is to evaluate whether concentration-controlled Zortress (everolimus) is superior to mycophenolic acid (MPA) on a composite endpoint of >50% reduction of BK viruria and/or clearance of BK viremia at 3-months post-randomization in maintenance renal transplant recipients.


Secondary Outcome Measures:
  • Evaluation for the development of BK virus nephropathy or doubling of BK viremia levels [ Time Frame: Month 1 - Month 4 ] [ Designated as safety issue: Yes ]
    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.

  • Correlation of p70S6 kinase phosphorylation inhibition with BKV replication and correlation of immune monitoring tests with rejection episodes based on BKV infection treatment regimen [ Time Frame: Month 1 - Month 4 ] [ Designated as safety issue: No ]
    We will investigate the correlation between inhibition of p70S6 kinase phosphorylation and BKV replication. Measurement of p70S6 kinase activity has also been used as a biomarker to predict rejection episodes. A whole blood assay based on the measurement of the expression of three NFAT-regulated genes IL-2, interferon gamma, and GM-CSF, has been developed to predict and monitor the biologic effects of calcineurin-based immunosuppression. The level of expression of these genes is correlated with rejections, recurrent infections, and malignancies in patients maintained on CNIs.

  • Evaluation for the development of proteinuria and hyperlipidemia [ Time Frame: Month 1 - Month 4 ] [ Designated as safety issue: Yes ]
    Patients will be monitored for the development of proteinuria and hyperlipidemia, a known side effect of everolimus treatment. An interim analysis will be performed once 50% of subjects have completed the study protocol and patients will have a final visit at month 4 to monitor for adverse events.


Estimated Enrollment: 60
Study Start Date: September 2012
Estimated Study Completion Date: December 2013
Estimated Primary Completion Date: December 2013 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Everolimus+Tacrolimus/Prednisone
This arm (group 1) will undergo 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.
Drug: Everolimus
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.
Other Name: Zortress
Active Comparator: Standard of care: 50% reduction of MPA
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.
Drug: Mycophenolic acid dose reduction
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 Names:
  • CellCept
  • Myfortic

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 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 BUN and Cr, 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 NFAT-regulated genes 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.

  Eligibility

Ages Eligible for Study:   18 Years to 75 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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 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 ALT, 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 eGFR < 40 ml/min
  • Patients who have undergone desensitization
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01624948

Locations
United States, California
University of California, San Francisco
San Francisco, California, United States, 94143
Sponsors and Collaborators
University of California, San Francisco
Investigators
Principal Investigator: David Wojciechowski, DO University of California, San Francisco
  More Information

No publications provided

Responsible Party: University of California, San Francisco
ClinicalTrials.gov Identifier: NCT01624948     History of Changes
Other Study ID Numbers: CRAD001AUS184T
Study First Received: June 15, 2012
Last Updated: September 23, 2013
Health Authority: United States: Institutional Review Board

Keywords provided by University of California, San Francisco:
BK virus
Kidney Transplantation
Immunologic Monitoring

Additional relevant MeSH terms:
Infection
Communicable Diseases
Virus Diseases
Everolimus
Sirolimus
Tacrolimus
Mycophenolate mofetil
Mycophenolic Acid
Prednisone
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Pharmacologic Actions
Anti-Bacterial Agents
Anti-Infective Agents
Therapeutic Uses
Antibiotics, Antineoplastic
Antineoplastic Agents
Antifungal Agents
Anti-Inflammatory Agents
Glucocorticoids
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists
Antineoplastic Agents, Hormonal
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action

ClinicalTrials.gov processed this record on September 30, 2014