Non-inferiority Study of Safety and Efficacy of Everolimus With Low Dose Tacrolimus to Mycophenolate Mofetil With Standard Dose Tacrolimus in Kidney Transplant Recipients

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Novartis ( Novartis Pharmaceuticals )
ClinicalTrials.gov Identifier:
NCT01025817
First received: November 19, 2009
Last updated: October 13, 2015
Last verified: October 2015
Results First Received: March 3, 2014  
Study Type: Interventional
Study Design: Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: Open Label;   Primary Purpose: Treatment
Condition: Kidney Transplant
Interventions: Drug: Everolimus and tacrolimus
Drug: mycophenolate mofetil and tacrolimus

  Participant Flow
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Recruitment Details
Key information relevant to the recruitment process for the overall study, such as dates of the recruitment period and locations

In total 738 participants were screened, and 613 were transplanted and randomized to treatment (n=309 to EVR+Low TAC dose and n=304 to MMF+Std TAC).

EVR=Everolimus and low dose tacrolimus, and MMF=Mycophenolate mofetil and standard dose tacrolimus.


Pre-Assignment Details
Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
No text entered.

Reporting Groups
  Description
Everolimus and Low Dose Tacrolimus Everolimus treatment arm: Therapeutic drug monitoring of everolimus and tacrolimus was mandatory throughout the study. From Day 5 onwards, the everolimus 0.75 mg b.i.d. dose was increased if the trough level was < 3 ng/mL, or reduced if the trough level was > 8 ng/mL. Tacrolimus was initiated according to local practice. In this treatment arm, the tacrolimus dose was adjusted from Day 3 onwards, to a target whole blood trough concentration of 4 ng/mL to 7 ng/mL. From Month 2 until Month 6, the target tacrolimus trough level was 3 ng/mL to 6 ng/mL. After Month 6, the tacrolimus dose was adjusted in order to achieve a target trough level of 2 ng/mL to 5 ng/mL.
Mycophenolate Mofetil and Standard Dose Tacrolimus MMF treatment arm: The MMF dose was initiated at 1 g b.i.d. (2 g/day). Adjustments were to be made for adverse events including, but not limited to, gastrointestinal intolerance and a decrease in WBC. MMF trough or AUC was not used to adjust dosing. In this group, tacrolimus was initiated according to local practice. The tacrolimus dose was adjusted from Day 3 on to achieve a target whole blood trough concentration of 8 ng/mL to 12 ng/mL. From Month 2 until Month 6, the target tacrolimus trough level was reduced to 7 - 10 ng/mL. After Month 6, the target level of tacrolimus was reduced to 5 - 8 ng/mL.

Participant Flow for 2 periods

Period 1:   Completed Study Medication
    Everolimus and Low Dose Tacrolimus   Mycophenolate Mofetil and Standard Dose Tacrolimus
STARTED   309   304 
COMPLETED   204   232 
NOT COMPLETED   105   72 
Adverse Event                66                39 
Protocol Deviation                9                8 
Withdrawal by Subject                8                9 
Administrative problems                7                5 
Unsatisfactory therapeutic effect                7                0 
Abnormal test procedure                4                0 
Graft loss                2                5 
Death                2                2 
Abnormal lab values                0                2 
Subject no longer required study drug                0                1 
Lost to Follow-up                0                1 

Period 2:   Completed Study
    Everolimus and Low Dose Tacrolimus   Mycophenolate Mofetil and Standard Dose Tacrolimus
STARTED   309   304 
COMPLETED   293 [1]   282 [1] 
NOT COMPLETED   16   22 
Withdrawal by Subject                8                16 
Death                6                5 
Missing                2                0 
Lost to Follow-up                0                1 
[1] Completed study phase



  Baseline Characteristics
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Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.

Full Analysis Set (FAS) consisted of all participants randomized after transplantation.

*The discrepancy with the Ns is that there are 613 participants overall and 610 in the safety population.


Reporting Groups
  Description
Everolimus and Low Dose Tacrolimus Everolimus treatment arm: Therapeutic drug monitoring of everolimus and tacrolimus was mandatory throughout the study. From Day 5 onwards, the everolimus 0.75 mg b.i.d. dose was increased if the trough level was < 3 ng/mL, or reduced if the trough level was > 8 ng/mL. Tacrolimus was initiated according to local practice. In this treatment arm, the tacrolimus dose was adjusted from Day 3 onwards, to a target whole blood trough concentration of 4 ng/mL to 7 ng/mL. From Month 2 until Month 6, the target tacrolimus trough level was 3 ng/mL to 6 ng/mL. After Month 6, the tacrolimus dose was adjusted in order to achieve a target trough level of 2 ng/mL to 5 ng/mL.
Mycophenolate Mofetil and Standard Dose Tacrolimus MMF treatment arm: The MMF dose was initiated at 1 g b.i.d. (2 g/day). Adjustments were to be made for adverse events including, but not limited to, gastrointestinal intolerance and a decrease in WBC. MMF trough or AUC was not used to adjust dosing. In this group, tacrolimus was initiated according to local practice. The tacrolimus dose was adjusted from Day 3 on to achieve a target whole blood trough concentration of 8 ng/mL to 12 ng/mL. From Month 2 until Month 6, the target tacrolimus trough level was reduced to 7 - 10 ng/mL. After Month 6, the target level of tacrolimus was reduced to 5 - 8 ng/mL.
Total Total of all reporting groups

Baseline Measures
   Everolimus and Low Dose Tacrolimus   Mycophenolate Mofetil and Standard Dose Tacrolimus   Total 
Overall Participants Analyzed 
[Units: Participants]
 306   304   610 
Age 
[Units: Years]
Mean (Standard Deviation)
 50.00  (13.34)   48.4  (12.91)   49.2  (13.14) 
Gender 
[Units: Participants]
     
Female   101   102   203 
Male   205   202   407 
Race/Ethnicity, Customized 
[Units: Participants]
     
American Indian or Alaska Native   3   1   4 
Asian   17   11   28 
Native Hawaiian or Other Pacific Islander   3   1   4 
Black or African American   70   74   144 
Caucasian   196   201   397 
Other   17   16   33 
BMI [1] 
[Units: Kg/m˄2]
Mean (Standard Deviation)
 27.7  (5.55)   28.3  (5.13)   28.0  (5.35) 
[1] Body Mass Index
Diabetic status at randomization [1] 
[Units: Participants]
     
Yes   111   95   206 
No   195   209   404 
[1] 62 Insulin dependent + 49 Non-insulin dependent = 111 participants who were diabetic at randomization.


  Outcome Measures
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1.  Primary:   Number of Participants With Incidence of Composite Efficacy Failure   [ Time Frame: 12 Months ]

2.  Secondary:   Estimated Glomerular Filtration Rate (eGFR)   [ Time Frame: 12 Months ]

3.  Secondary:   Number of Participants With Incidence of CMV (Viremia, Syndrome and Disease)   [ Time Frame: 12 Months ]

4.  Secondary:   Number of Participants With Incidence Rates of BKV Viremia, BKV Viruria, or BKV Nephropathy   [ Time Frame: 12 Months ]

5.  Secondary:   Number of Participants With Incidence of New Onset of Diabetes Mellitus   [ Time Frame: 12 Months ]

6.  Secondary:   Number of Participants With Incidence of Proteinuria Events   [ Time Frame: Baseline and 12 Months ]

7.  Secondary:   Number of Participants With Incidence of Adverse Events, Serious Adverse Events, and Tacrolimus-associated Adverse Events   [ Time Frame: 12 Months ]


  Serious Adverse Events


  Other Adverse Events


  Limitations and Caveats
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Limitations of the study, such as early termination leading to small numbers of participants analyzed and technical problems with measurement leading to unreliable or uninterpretable data
HLA mismatches ≥3, everolimus group 261 vs MMF group 240


  More Information
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Certain Agreements:  
Principal Investigators are NOT employed by the organization sponsoring the study.
There IS 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.
The agreement is:
unchecked The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.
unchecked The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is more than 60 days but less than or equal to 180 days. The sponsor cannot require changes to the communication and cannot extend the embargo.


Results Point of Contact:  
Name/Title: Study Director
Organization: Novartis
phone: +1 (862) 778-8300



Responsible Party: Novartis ( Novartis Pharmaceuticals )
ClinicalTrials.gov Identifier: NCT01025817     History of Changes
Other Study ID Numbers: CRAD001AUS92
Study First Received: November 19, 2009
Results First Received: March 3, 2014
Last Updated: October 13, 2015