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

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ClinicalTrials.gov Identifier: NCT01624948
Recruitment Status : Completed
First Posted : June 21, 2012
Results First Posted : August 15, 2016
Last Update Posted : August 15, 2016
Sponsor:
Information provided by (Responsible Party):
University of California, San Francisco

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: None (Open Label);   Primary Purpose: Treatment
Condition BK Virus Infection
Interventions Drug: Everolimus
Drug: Mycophenolic acid dose reduction
Enrollment 40
Recruitment Details  
Pre-assignment Details  
Arm/Group Title Everolimus+Tacrolimus/Prednisone Standard of Care: 50% Reduction of Mycophenolic Acid (MPA)
Hide Arm/Group Description

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.

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.

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 BK polyomavirus (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.

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.

Period Title: Overall Study
Started 20 20
Completed 20 20
Not Completed 0 0
Arm/Group Title Everolimus+Tacrolimus/Prednisone Standard of Care: 50% Reduction of Mycophenolic Acid (MPA) Total
Hide Arm/Group Description

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.

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.

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.

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.

Total of all reporting groups
Overall Number of Baseline Participants 20 20 40
Hide Baseline Analysis Population Description
[Not Specified]
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 20 participants 20 participants 40 participants
54.5  (10.3) 49.9  (12.4) 52.18  (11.47)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 20 participants 20 participants 40 participants
Female
7
  35.0%
9
  45.0%
16
  40.0%
Male
13
  65.0%
11
  55.0%
24
  60.0%
Race (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 20 participants 20 participants 40 participants
American Indian or Alaska Native
0
   0.0%
0
   0.0%
0
   0.0%
Asian
8
  40.0%
4
  20.0%
12
  30.0%
Native Hawaiian or Other Pacific Islander
0
   0.0%
0
   0.0%
0
   0.0%
Black or African American
1
   5.0%
1
   5.0%
2
   5.0%
White
11
  55.0%
15
  75.0%
26
  65.0%
More than one race
0
   0.0%
0
   0.0%
0
   0.0%
Unknown or Not Reported
0
   0.0%
0
   0.0%
0
   0.0%
Region of Enrollment  
Measure Type: Number
Unit of measure:  Participants
United States Number Analyzed 20 participants 20 participants 40 participants
20 20 40
Donor Type  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 20 participants 20 participants 40 participants
Living 7 8 15
Standard Deceased 11 10 21
ECD 2 2 4
Transplant Number  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 20 participants 20 participants 40 participants
First 16 17 33
Second 4 3 7
Etiology of End Stage Renal Disease (ESRD)  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 20 participants 20 participants 40 participants
Diabetes 2 4 6
Hypertension 3 3 6
GN 12 11 23
Other 3 2 5
Calculated Panel Reactive Antibodies (cPRA)   [1] 
Mean (Standard Deviation)
Unit of measure:  Percentage of Potential Donors
Number Analyzed 20 participants 20 participants 40 participants
14.4  (28.8) 25.5  (36.3) 19.93  (32.82)
[1]
Measure Description: The Calculated Panel Reactive Antibodies (cPRA) represents the percentage of potential donors that will be preemptively declined due to the presence of one or more unacceptable antigens. CPRA is a computer calculation based upon HLA frequencies derived from the US donor population and the risk they attribute to circulating antibodies in a candidate's serum directed against those specific HLA antigens.
Ureteral Stent at Transplant  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 20 participants 20 participants 40 participants
Ureteral Stent Present 0 2 2
No Ureteral Stent Present 20 18 38
Renal Graft Function   [1] 
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 20 participants 20 participants 40 participants
Delayed Graft Function 6 2 8
Normal Graft Function 14 18 32
[1]
Measure Description: Delayed Graft Function was defined as > or =1 dialysis session during the first week posttransplant
1.Primary Outcome
Title Evidence of Reduction of BK Viruria and/or Clearance of BK Viremia
Hide Description composite outcome of a 50% or greater reduction in BKV urine levels and/or complete clearance of BKV viremia by 3 months after randomization
Time Frame 3 months post-randomization
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Everolimus+Tacrolimus/Prednisone Standard of Care: 50% Reduction of MPA
Hide Arm/Group Description:

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.

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.

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.

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.

Overall Number of Participants Analyzed 20 20
Measure Type: Number
Unit of Measure: participants
11 8
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Everolimus+Tacrolimus/Prednisone, Standard of Care: 50% Reduction of MPA
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.53
Comments [Not Specified]
Method Fisher Exact
Comments [Not Specified]
2.Secondary Outcome
Title Evaluation for the Development of BK Virus Nephropathy or Doubling of BK Viremia Levels
Hide Description 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.
Time Frame 3 months post-randomization
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Everolimus+Tacrolimus/Prednisone Standard of Care: 50% Reduction of MPA
Hide Arm/Group Description:

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.

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.

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.

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.

Overall Number of Participants Analyzed 20 20
Measure Type: Number
Unit of Measure: participants
2 2
3.Secondary Outcome
Title p70S6 Kinase Phosphorylation
Hide Description [Not Specified]
Time Frame 3 months post-randomization
Hide Outcome Measure Data
Hide Analysis Population Description
19 patients enrolled in the immune-monitoring subset; 1 participant did not have a 3-month assay.
Arm/Group Title Reached Primary Endpoint Failed to Reach Primary Endpoint
Hide Arm/Group Description:
>50% reduction of BKV viruria and/or clearance of BKV viremia
[Not Specified]
Overall Number of Participants Analyzed 6 12
Median (95% Confidence Interval)
Unit of Measure: Mean Fluorescence Intensity
5002
(1821 to 8389)
4353
(2676 to 6442)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Reached Primary Endpoint, Failed to Reach Primary Endpoint
Comments Difference in p70S6 kinase phosphorylation as measured by mean fluorescence intensity (MFI) between those patients who reached the primary endpoint and those who did not
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.67
Comments [Not Specified]
Method Wilcoxon (Mann-Whitney)
Comments [Not Specified]
4.Secondary Outcome
Title Cholesterol
Hide Description [Not Specified]
Time Frame 3 months post-randomization
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Everolimus+Tacrolimus/Prednisone Standard of Care: 50% Reduction of MPA
Hide Arm/Group Description:

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.

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.

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.

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.

Overall Number of Participants Analyzed 20 20
Mean (Standard Deviation)
Unit of Measure: mg/dL
212  (56.8) 170  (29.8)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Everolimus+Tacrolimus/Prednisone, Standard of Care: 50% Reduction of MPA
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.01
Comments [Not Specified]
Method Wilcoxon (Mann-Whitney)
Comments [Not Specified]
5.Secondary Outcome
Title Proteinuria
Hide Description [Not Specified]
Time Frame 3 months post-randomization
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Everolimus+Tacrolimus/Prednisone Standard of Care: 50% Reduction of MPA
Hide Arm/Group Description:

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.

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.

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.

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.

Overall Number of Participants Analyzed 20 20
Mean (Standard Deviation)
Unit of Measure: g/g creatinine
0.16  (.1) 0.23  (.21)
6.Secondary Outcome
Title Median Between the Calculated Mean Residual Expression of NFAT-regulated Genes
Hide Description

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.”

Time Frame 3 months post-randomization
Hide Outcome Measure Data
Hide Analysis Population Description
a subset of 19 participants enrolled in the immune-monitoring portion of the study
Arm/Group Title Rejection No Rejection
Hide Arm/Group Description:
Any biopsy-proven rejection episode
No biopsy-proven rejection episode
Overall Number of Participants Analyzed 3 16
Median (95% Confidence Interval)
Unit of Measure: percent residual expression
46.35
(-16 to 94.82)
29.12
(20.83 to 41.34)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Rejection, No Rejection
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.49
Comments [Not Specified]
Method Wilcoxon (Mann-Whitney)
Comments [Not Specified]
Time Frame [Not Specified]
Adverse Event Reporting Description [Not Specified]
 
Arm/Group Title Everolimus+Tacrolimus/Prednisone Standard of Care: 50% Reduction of MPA
Hide Arm/Group Description Everolimus: MPA discontinuation with the addition of Zortress (everolimus) to current regimen of tacrolimus and prednisone; Zortress (everolimus) at a starting dose of 0.75 mg PO b.i.d. (1.5 mg/day). Everolimus whole blood trough levels monitored at pre-specified time points to achieve a range of 3-8 ng/mL. Continue on prednisone and tacrolimus with a target whole blood trough level of 3-6 ng/mL. Mycophenolic acid dose reduction: 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 re-checked. Renal allograft biopsies will be done for cause as clinically indicated.
All-Cause Mortality
Everolimus+Tacrolimus/Prednisone Standard of Care: 50% Reduction of MPA
Affected / at Risk (%) Affected / at Risk (%)
Total   --/--      --/--    
Show Serious Adverse Events Hide Serious Adverse Events
Everolimus+Tacrolimus/Prednisone Standard of Care: 50% Reduction of MPA
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   2/20 (10.00%)      3/20 (15.00%)    
Blood and lymphatic system disorders     
Anemia and shortness of breath  0/20 (0.00%)  0 1/20 (5.00%)  1
Endocrine disorders     
Hyperglycemia  1/20 (5.00%)  1 0/20 (0.00%)  0
Immune system disorders     
Acute Cellular Rejection (Grade 1)  0/20 (0.00%)  0 1/20 (5.00%)  1
Infections and infestations     
CMV Pnemonia/Viremia  0/20 (0.00%)  0 1/20 (5.00%)  1
Sepsis/UTI  0/20 (0.00%)  0 1/20 (5.00%)  1
Renal and urinary disorders     
Hydronephrosis *  1/20 (5.00%)  1 0/20 (0.00%)  0
*
Indicates events were collected by non-systematic assessment
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 0%
Everolimus+Tacrolimus/Prednisone Standard of Care: 50% Reduction of MPA
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   13/20 (65.00%)      9/20 (45.00%)    
Blood and lymphatic system disorders     
Leukopenia  0/20 (0.00%)  0 1/20 (5.00%)  1
Endocrine disorders     
Hyperlipidemia  2/20 (10.00%)  2 0/20 (0.00%)  0
Gastrointestinal disorders     
GI Upset  2/20 (10.00%)  2 0/20 (0.00%)  0
Diarrhea  1/20 (5.00%)  1 2/20 (10.00%)  2
General disorders     
Edema  1/20 (5.00%)  1 0/20 (0.00%)  0
Insomnia  0/20 (0.00%)  0 1/20 (5.00%)  1
Nightsweats  0/20 (0.00%)  0 1/20 (5.00%)  1
Hepatobiliary disorders     
Transaminitis  1/20 (5.00%)  1 0/20 (0.00%)  0
Immune system disorders     
Borderline Rejection  1/20 (5.00%)  1 0/20 (0.00%)  0
Infections and infestations     
UTI  2/20 (10.00%)  2 2/20 (10.00%)  4
BK Viremia allograft nephropathy  2/20 (10.00%)  2 1/20 (5.00%)  1
Herpes Simplex 1 Oral Ulcer  0/20 (0.00%)  0 1/20 (5.00%)  1
CMV Viremia  0/20 (0.00%)  0 1/20 (5.00%)  1
Metabolism and nutrition disorders     
Hyperkalemia  0/20 (0.00%)  0 1/20 (5.00%)  1
Renal and urinary disorders     
Acute kidney injury with chest pain  1/20 (5.00%)  1 0/20 (0.00%)  0
Dysuria  0/20 (0.00%)  0 1/20 (5.00%)  1
Skin and subcutaneous tissue disorders     
Rash  1/20 (5.00%)  1 0/20 (0.00%)  0
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
Results Point of Contact
Layout table for Results Point of Contact information
Name/Title: Allison Webber MD
Organization: UCSF
Phone: 415 353 8382
EMail: allison.webber2@ucsf.edu
Layout table for additonal information
Responsible Party: University of California, San Francisco
ClinicalTrials.gov Identifier: NCT01624948     History of Changes
Other Study ID Numbers: CRAD001AUS184T
First Submitted: June 15, 2012
First Posted: June 21, 2012
Results First Submitted: April 12, 2016
Results First Posted: August 15, 2016
Last Update Posted: August 15, 2016