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: June 5, 2014
Last verified: April 2014
Results First Received: March 3, 2014  
Study Type: Interventional
Study Design: Allocation: Randomized;   Endpoint Classification: Safety/Efficacy Study;   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  
Number of Participants  
[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  
Diabetic status at randomization [2]
[units: Participants]
     
Yes     111     95     206  
No     195     209     404  
[1] Body Mass Index
[2] 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
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  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


No publications provided


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: June 5, 2014
Health Authority: United States: Food and Drug Administration
Canada: Health Canada