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    Clinical Trial Results:
    Multicenter, Open-Label, Randomized, 24 Months Follow-up, Two Arm Study to Compare the Cardiovascular Profile in a Regimen With Everolimus + Mycophenolic Acid (MPA) Versus (vs.) a Regimen of CNI+MPA in Maintenance Renal Transplant Recipients (EVITA)

    Summary
    EudraCT number
    		 2009-013780-19
    Trial protocol
    		 ES  
    Global end of trial date
    03 Mar 2014

    Results information
    Results version number
    		 v1(current)
    This version publication date
    01 Apr 2016
    First version publication date
    01 Apr 2016
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    CRAD001AES07
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01169701
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Novartis Pharma AG
    Sponsor organisation address
    CH-4002, Basel, Switzerland,
    Public contact
    Clinical Disclosure Office, Novartis Pharma AG, 41 613241111,
    Scientific contact
    Clinical Disclosure Office, Novartis Pharma AG, 41 613241111,
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    03 Mar 2014
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    03 Mar 2014
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The objective of the study was to compare the cardiovascular profile of an everolimus and mycophenolic acid immunosuppressive regimen with a calcineurin inhibitor and mycophenolic acid regimen in maintenance renal transplant patients.
    Protection of trial subjects
    The study was in compliance with the ethical principles derived from the Declaration of Helsinki and the International Conference on Harmonization (ICH) Good Clinical Practice (GCP) Guidelines. All the local regulatory requirements pertinent to safety of trial subjects were also followed during the conduct of the trial. In addition, the patients’ usual medications were administered throughout the study treatment period, until the final study assessments were completed. Medications necessary to treat infections, rejection episodes and adverse events were permitted but could require termination of the study medication. Concomitant medications which, according to their summary of product characteristics could interfere with tacrolimus (drug interactions) or everolimus, were avoided. In addition, the administration of therapies with medicinal products that potentiate the nephrotoxicity of tacrolimus (amphotericin B, ketoconazole, azapropazone and diclofenac) and therapies that interfere in the pharmacokinetics of tacrolimus, were avoided. All other immunosuppressive medicinal products that were not those specified in the protocol were not permitted, except those required to manage rejection episodes. Calcium channel blockers, or H2 receptor antagonists continuously, for up to four weeks prior to randomisation were accepted. Treatment with steroids was allowed according to the routine clinical practice of the site.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    06 Aug 2010
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Spain: 71
    Worldwide total number of subjects
    71
    EEA total number of subjects
    71
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    65
    From 65 to 84 years
    6
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 This study was conducted at 9 kidney transplant centers in Spain. The enrolment of 80 maintenance renal transplant patients, between 18 and 70 years, who had had a first or second kidney transplant in the last 3 years was anticipated. Eighty patients were enrolled, of which 71 were included in the study.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Tacrolimus plus Mycophenolic Acid (MPA)
    Arm description
    		 Patients continued with the same dose of tacrolimus+MPA as they were on prior to the start of the study (tacrolimus at levels of 4-7 ng/ml). Tacrolimus was administered as either Prograf® (twice a day) or Advagraf® (once daily in the morning) and could not be changed during the study. Mycophenolic acid (MPA) could be administerd as Myfortic® (720-1440 mg/day or 360-1440 mg/day) or Cell-Cept®(1000-2000 mg/day or 500-2000 mg/day).
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Tacrolimus
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Patients in treatment with Prograf® took it twice a day and patients with Advagraf® once daily in the morning. In both cases, administration of the drug was performed in a consistent manner with respect to the time of day and meals. The capsules were administered on an empty stomach or at least 1 hour before, or 2 to 3 hours after the ingestion of food, to achieve maximum absorption.

    Investigational medicinal product name
    Mycophenolic Acid (MPA)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    MFS (Myfortic®): dose 720-1440 mg/day MMF (Cell-Cept®): dose 1000-2000 mg/day Although the following doses of MPA were permitted: MFS (Myfortic®): dose 360-1440 mg/day MMF (Cell-Cept®): dose 500-2000 mg/day

    Arm title
    		 Everolimus
    Arm description
    		 The investigational drug was everolimus (Certican®) for oral administration containing trough levels of 5-8 ng/ml, taken simultaneuously with MPA every 12 hours. Tacrolimus was also administered and are detailed under dose and administration.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Everolimus
    Investigational medicinal product code
    Other name
    Certican®
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Everolimus was taken twice daily simultaneously with MPA every 12 hours. Morning and evening doses were taken before, after or during meals according to the patient’s choice and always in the same way. The starting dose (day 1) of everolimus with tacrolimus was 2 mg in the evening, maintaining full dose of Prograf® in the morning and reducing it to 50% in the evening. In the case of Advagraf®, 75% of the dose was administered in the morning. On Day 2 and 3, 2 mg of everolimus was administered in the morning and 2 mg in the evening, without tacrolimus. On Day 4-5 the everolimus trough levels were determined and adjusted between 5-8 ng/ml. The dose was adjusted by increasing the dose of everolimus if the trough level was less than 5 ng/ml and reducing the dose if the trough level was greater than 8 ng/ml. A follow-up trough level was performed on day 8 to ensure that the level was between 5-8 ng/ml. The same dose of MPA was continued as patient was on prior to starting the study.

    Investigational medicinal product name
    Tacrolimus
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Patients in treatment with Prograf® took it twice a day and patients with Advagraf® once daily in the morning. In both cases, administration of the drug was performed in a consistent manner with respect to the time of day and meals. The capsules were administered on an empty stomach or at least 1 hour before, or 2 to 3 hours after the ingestion of food, to achieve maximum absorption.

    Investigational medicinal product name
    Mycophenolic Acid (MPA)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    MFS (Myfortic®): dose 720-1440 mg/day MMF (Cell-Cept®): dose 1000-2000 mg/day Although the following doses of MPA were permitted: MFS (Myfortic®): dose 360-1440 mg/day MMF (Cell-Cept®): dose 500-2000 mg/day

    Number of subjects in period 1
    		Tacrolimus plus Mycophenolic Acid (MPA) Everolimus
    Started
    36
    35
    Completed
    31
    25
    Not completed
    5
    10
         Consent withdrawn by subject
    1
    3
         Adverse Event
    1
    2
         Death
    -
    1
         Administrative Problems
    -
    1
         Sponsor Decision
    -
    1
         Exclusion Criteria
    2
    -
         Lost to follow-up
    1
    1
         Serious Adverse Event
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Tacrolimus plus Mycophenolic Acid (MPA)
    Reporting group description
    		 Patients continued with the same dose of tacrolimus+MPA as they were on prior to the start of the study (tacrolimus at levels of 4-7 ng/ml). Tacrolimus was administered as either Prograf® (twice a day) or Advagraf® (once daily in the morning) and could not be changed during the study. Mycophenolic acid (MPA) could be administerd as Myfortic® (720-1440 mg/day or 360-1440 mg/day) or Cell-Cept®(1000-2000 mg/day or 500-2000 mg/day).

    Reporting group title
    Everolimus
    Reporting group description
    		 The investigational drug was everolimus (Certican®) for oral administration containing trough levels of 5-8 ng/ml, taken simultaneuously with MPA every 12 hours. Tacrolimus was also administered and are detailed under dose and administration.

    Reporting group values
    		 Tacrolimus plus Mycophenolic Acid (MPA) Everolimus Total
    Number of subjects
    		 36 35 71
    Age categorical
    Units: Subjects
        In utero
    		 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0
        Newborns (0-27 days)
    		 0
        Infants and toddlers (28 days-23 months)
    		 0
        Children (2-11 years)
    		 0
        Adolescents (12-17 years)
    		 0
        Adults (18-64 years)
    		 0
        From 65-84 years
    		 0
        85 years and over
    		 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 49.1 ± 12 47.4 ± 13.2 -
    Gender categorical
    Units: Subjects
        Female
    		 16 13 29
        Male
    		 20 22 42

    End points

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    End points reporting groups
    Reporting group title
    Tacrolimus plus Mycophenolic Acid (MPA)
    Reporting group description
    		 Patients continued with the same dose of tacrolimus+MPA as they were on prior to the start of the study (tacrolimus at levels of 4-7 ng/ml). Tacrolimus was administered as either Prograf® (twice a day) or Advagraf® (once daily in the morning) and could not be changed during the study. Mycophenolic acid (MPA) could be administerd as Myfortic® (720-1440 mg/day or 360-1440 mg/day) or Cell-Cept®(1000-2000 mg/day or 500-2000 mg/day).

    Reporting group title
    Everolimus
    Reporting group description
    		 The investigational drug was everolimus (Certican®) for oral administration containing trough levels of 5-8 ng/ml, taken simultaneuously with MPA every 12 hours. Tacrolimus was also administered and are detailed under dose and administration.

    Primary: Change from baseline in left ventricular mass index (LVMI)

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    End point title
    		 Change from baseline in left ventricular mass index (LVMI)
    End point description
    Change from baseline in left ventricular hypertrophy (LVH) was assessed by echocardiogram where the left ventricular mass index was calculated. The presence of LVM was defined as > 49.2 g/m^2.7 in men and >46.7 g/m^2.7 in women. A negative change from baseline indicates improvement. Analysis population included the Intent to Treat (ITT) analysis set, who had both baseline and month 24 values, were analyzed. The ITT included participants who received at least one dose of study medication and at least one post baseline LVMI value.
    End point type
    Primary
    End point timeframe
    Baseline, Month 24
    End point values
    		 Tacrolimus plus Mycophenolic Acid (MPA) Everolimus
    Number of subjects analysed
    31 [1]
    25 [2]
    Units: g/m^ 2. 7
    arithmetic mean (standard deviation)
        Change from Baseline in LVMI
    -6.071 ± 20.116
    -4.008 ± 17.61
    Notes
    [1] - Intent to Treat (ITT) analysis set
    [2] - Intent to Treat (ITT)
    Statistical analysis title
    		 LV Mass Index by Visit ITT Population-Tacrolimus
    Statistical analysis description
    LVMI was summarised by visit, presenting absolute values and changes with respect to the baseline value. An analysis of repeated measures was also conducted for the LVMI with treatment and the visit considered as fixed factors and LVMI baseline as covariate. The assessment of the primary endpoint was performed by means of the determination of the change in LVM between the visit at 24 months and the baseline visit, between the two treatment groups.
    Comparison groups
    Tacrolimus plus Mycophenolic Acid (MPA) v Everolimus
    Number of subjects included in analysis
    56
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.7753
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -13.45
         upper limit
    		 1.307
    Variability estimate
    Standard deviation
    Statistical analysis title
    		 LV Mass Index by Visit ITT Population-Everolimus
    Statistical analysis description
    LVMI was summarised by visit, presenting absolute values and changes with respect to the baseline value. An analysis of repeated measures was also conducted for the LVMI with treatment and the visit considered as fixed factors and LVMI baseline as covariate. The assessment of the primary endpoint was performed by means of the determination of the change in LVM between the visit at 24 months and the baseline visit, between the two treatment groups.
    Comparison groups
    Everolimus v Tacrolimus plus Mycophenolic Acid (MPA)
    Number of subjects included in analysis
    56
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.7753
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -11.28
         upper limit
    		 3.261
    Variability estimate
    Standard deviation

    Secondary: Pulse Wave Velocity (PWV)

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    End point title
    		 Pulse Wave Velocity (PWV)
    End point description
    Utilizing the SphygmoCor Device, ECG leads placed at the carotid and femoral arteries provided the measure of the pulse wave at that particular arterial location. The distance between the two vascular beds divided by the pulse wave time shift provided a measure of the pulse wave velocity. Participants from the safety analysis set were considered for this analysis. The safety analysis set included participants who received at least one dose of study medication. For each time point, only participants, who had values at both baseline and the given time point, were analyzed for that time point.
    End point type
    Secondary
    End point timeframe
    Month 6, month 24
    End point values
    		 Tacrolimus plus Mycophenolic Acid (MPA) Everolimus
    Number of subjects analysed
    36 [3]
    35 [4]
    Units: m/sec
    arithmetic mean (standard deviation)
        Month 6 (n=31,30)
    7.01 ± 1.62
    7.4 ± 1.62
        Month 24 (n=28,25)
    7.58 ± 1.68
    7.06 ± 1.74
    Notes
    [3] - Safety Analysis Set
    [4] - Safety Analysis Set
    No statistical analyses for this end point

    Secondary: Percentage of Participants with Major Cardiovascular Events (MACE)

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    End point title
    		 Percentage of Participants with Major Cardiovascular Events (MACE)
    End point description
    A major cardiovascular event (MACE) included acute myocardial infarction, insertion or replacement of implantable defibrillator, peripheral vascular disorders, congestive heart failure, coronary artery bypass, other events, percutaneous coronary intervention, and stroke. This secondary endpont examined the percentage of participants with MACE. This included the Intent to Treat (ITT) analysis set: The ITT included participants who received at least one dose of study medication and had at least one post baseline LVMI value.
    End point type
    Secondary
    End point timeframe
    Month 24
    End point values
    		 Tacrolimus plus Mycophenolic Acid (MPA) Everolimus
    Number of subjects analysed
    32 [5]
    28 [6]
    Units: Percentatge of Participants
    number (not applicable)
        Percentage Participants with MACE
    0
    0
    Notes
    [5] - Intent to Treat Population. MACE=major cardiovascular event
    [6] - Intent to Treat Population. MACE=major cardiovascular event
    No statistical analyses for this end point

    Secondary: Renal Function as Measured by Estimated Glomerular Fltration Rate (eGFR)

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    End point title
    		 Renal Function as Measured by Estimated Glomerular Fltration Rate (eGFR)
    End point description
    This secondary endpoint assessesrRenal function as measured by estimated glomerular filtration rate (eGFR). Estimated GFR was calculated using the modification of diet in renal disease (MDRD) formula. Participants from the safety analysis set were considered for this analysis. The safety analysis set included participants who received at least one dose of study medication. For each time point, only participants, who had values at both baseline and the given time point, were analyzed for that time point.
    End point type
    Secondary
    End point timeframe
    Month 6, month 12, month 24
    End point values
    		 Tacrolimus plus Mycophenolic Acid (MPA) Everolimus
    Number of subjects analysed
    36 [7]
    35 [8]
    Units: mL /min/1 .73 m ^ 2
    arithmetic mean (standard deviation)
        Month 6 (n=33,29)
    55.648 ± 11.244
    63.781 ± 18.38
        Month 12 (n=32,28)
    57.757 ± 11.391
    61.225 ± 19.239
        Month 24 (n=31,26)
    57.727 ± 10.498
    60.779 ± 17.023
    Notes
    [7] - Safety Analysis Set
    [8] - Safety Analysis Set
    No statistical analyses for this end point

    Secondary: Percentage of Participants with Biopsy-Proven Acute Rejection (BPAR), Graft Loss, Death, and Lost to Follow Up

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    End point title
    		 Percentage of Participants with Biopsy-Proven Acute Rejection (BPAR), Graft Loss, Death, and Lost to Follow Up
    End point description
    The incidence of biopsy-proven acute rejection (BPAR), graft loss, death, and lost to follow-up events was calculated using relative frequency. The population analyzed was the Intent to Treat (ITT) population. The ITT included participants who received at least one dose of study medication and at least one post baseline LVMI value.
    End point type
    Secondary
    End point timeframe
    Month 24
    End point values
    		 Tacrolimus plus Mycophenolic Acid (MPA) Everolimus
    Number of subjects analysed
    32 [9]
    28 [10]
    Units: Percentage of Participants
    number (not applicable)
        BPAR
    0
    0
        Graft Loss
    0
    0
        Deaths
    0
    0
        Lost to Follow-Up
    3.13
    0
    Notes
    [9] - Intent to Treat Population. BPAR=biopsy-proven acute rejection
    [10] - Intent to Treat Population. BPAR=biopsy-proven acute rejection
    No statistical analyses for this end point

    Secondary: Change from Baseline in Cardiovascular Biomarkers: Troponin I and collagen type 1 C- telopeptide (ICTP)

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    End point title
    		 Change from Baseline in Cardiovascular Biomarkers: Troponin I and collagen type 1 C- telopeptide (ICTP)
    End point description
    This secondary endpoint assesses change from baseline in cardiovascular biomarkers in both treatment arms. Blood samples were collected to analyze Troponin I and collagen type 1 C-telopeptide (ICTP). A negative change from baseline indicates improvement. Participants from the safety analysis set were considered for this analysis. The safety analysis set included participants who received at least one dose of study medication. For each time point, only participants, who had values at both baseline and the given time point, were analyzed for that time point.
    End point type
    Secondary
    End point timeframe
    Baseline, month 6, month 24
    End point values
    		 Tacrolimus plus Mycophenolic Acid (MPA) Everolimus
    Number of subjects analysed
    36 [11]
    35 [12]
    Units: ng/ml
    arithmetic mean (standard deviation)
        Troponin 1, Month 6 (n=27,30)
    0 ± 0.01
    -0.006 ± 0.026
        Troponin 1, Month 24 (n=24,24)
    0.003 ± 0.026
    -0.007 ± 0.018
        ICTP, Month 6 (n=27,30)
    0.049 ± 0.341
    -0.195 ± 0.234
        ICTP, Month 24 (n=24,24)
    -0.035 ± 0.366
    -0.125 ± 0.323
    Notes
    [11] - Safety Analysis Set. ICTP=collagen type 1 C-telopeptide.
    [12] - Safety Analysis Set. ICTP=collagen type 1 C-telopeptide.
    No statistical analyses for this end point

    Secondary: Mean 24 hour Systolic and Diastolic Blood Bressure (Change from Baseline)

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    End point title
    		 Mean 24 hour Systolic and Diastolic Blood Bressure (Change from Baseline)
    End point description
    Mean 24 hour systolic and diastolic blood pressure was measured using ambulatory blood pressure monitoring (ABPM). Participants from the safety analysis set were considered for this analysis. The safety analysis set included participants who received at least one dose of study medication. For each time point, only participants, who had values at both baseline and the given time point, were analyzed for that time point.
    End point type
    Secondary
    End point timeframe
    Baseline, month 6, month 12, month 24
    End point values
    		 Tacrolimus plus Mycophenolic Acid (MPA) Everolimus
    Number of subjects analysed
    31 [13]
    30 [14]
    Units: mmHg
    arithmetic mean (standard deviation)
        Change from Baseline to Month 6 (n=31,29)
    -0.6 ± 9.1
    3.2 ± 8.6
        Change from Baseline to Month 12 (n=28,24)
    2.1 ± 6.9
    2.7 ± 10.4
        Change from Baseline to Month 24 (n=29,24)
    2.2 ± 10.6
    2 ± 8.7
    Notes
    [13] - Safety Analysis Set
    [14] - Safety Analysis Set
    No statistical analyses for this end point

    Secondary: Renal Function Measured by Serum Creatinine

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    End point title
    		 Renal Function Measured by Serum Creatinine
    End point description
    Renal function was measured by serum creatinine. Serum samples were collected to analyze serum creatinine. Participants from the safety analysis set were considered for this analysis. The safety analysis set included participants who received at least one dose of study medication. For each time point, only participants, who had values at both baseline and the given time point, were analyzed for that time point.
    End point type
    Secondary
    End point timeframe
    Month 6, month 12, month 24
    End point values
    		 Tacrolimus plus Mycophenolic Acid (MPA) Everolimus
    Number of subjects analysed
    36 [15]
    35 [16]
    Units: mg/dL
    arithmetic mean (standard deviation)
        Month 6 (n=33,29)
    1.232 ± 0.272
    1.234 ± 0.36
        Month 12 (n=32,28)
    1.231 ± 0.278
    1.256 ± 0.367
        Month 24 (n= 31,26)
    1.217 ± 0.235
    1.26 ± 0.358
    Notes
    [15] - Safety Analysis Set
    [16] - Safety Analysis Set
    No statistical analyses for this end point

    Secondary: Renal Function as Measured by Creatinine Clearance

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    End point title
    		 Renal Function as Measured by Creatinine Clearance
    End point description
    Renal function was measured by creatinine clearance. Creatinine clearance was calculated using the Cockroft-Gault formula. Participants from the safety analysis set were considered for this analysis. The safety analysis set included participants who received at least one dose of study medication. For each time point, only participants, who had values at both baseline and the given time point, were analyzed for that time point.
    End point type
    Secondary
    End point timeframe
    Month 6, month 12, month 24
    End point values
    		 Tacrolimus plus Mycophenolic Acid (MPA) Everolimus
    Number of subjects analysed
    36 [17]
    35 [18]
    Units: mg/min
    arithmetic mean (standard deviation)
        Month 6 (n=29,25)
    64.841 ± 16.163
    76.618 ± 27.708
        Month 12 (n=28,25)
    65.037 ± 15.866
    73.363 ± 25.989
        Month 24 (n=28,24)
    66.933 ± 13.264
    72.91 ± 23.926
    Notes
    [17] - Safety Analysis Set
    [18] - Safety Analsysis Set
    No statistical analyses for this end point

    Secondary: Change from Baseline in the Cardiovascular Biomarker, Glycosylated Hemoglobin (HbA1c)

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    End point title
    		 Change from Baseline in the Cardiovascular Biomarker, Glycosylated Hemoglobin (HbA1c)
    End point description
    Blood samples were collected to analyze HbA1c. A negative change from baseline indicates improvement. Participants from the safety analysis set were considered for this analysis. The safety analysis set included participants who received at least one dose of study medication. For each time point, only participants, who had values at both baseline and the given time point, were analyzed for that time point.
    End point type
    Secondary
    End point timeframe
    Baseline, month 6, month 24
    End point values
    		 Tacrolimus plus Mycophenolic Acid (MPA) Everolimus
    Number of subjects analysed
    36 [19]
    35 [20]
    Units: Percentage of HbA1c
    arithmetic mean (standard deviation)
        Month 6 (n=20,22)
    0.015 ± 0.184
    0.159 ± 0.346
        Month 12 (n=22,20)
    0.045 ± 0.237
    0.185 ± 0.407
    Notes
    [19] - Safety Analysis Set.
    [20] - Safety Analysis Set.
    No statistical analyses for this end point

    Secondary: Change from Baseline in the Cardiovascular Biomarker: Myeloperoxidase (MPO)

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    End point title
    		 Change from Baseline in the Cardiovascular Biomarker: Myeloperoxidase (MPO)
    End point description
    Blood samples were collected to analyze myeloperoxidase (MPO). A negative change from baseline indicates improvement. Participants from the safety analysis set were considered for this analysis. The safety analysis set included participants who received at least one dose of study medication. For each time point, only participants, who had values at both baseline and the given time point, were analyzed for that time point.
    End point type
    Secondary
    End point timeframe
    Baseline, month 6, month 24
    End point values
    		 Tacrolimus plus Mycophenolic Acid (MPA) Everolimus
    Number of subjects analysed
    36 [21]
    35 [22]
    Units: U/mL
    arithmetic mean (standard deviation)
        Month 6 (n=27,30)
    0.433 ± 2.189
    -0.093 ± 1.158
        Month 24 (n=24,24)
    -0.329 ± 0.28
    -0.642 ± 0.972
    Notes
    [21] - Safety Analysis Set
    [22] - Safety Analysis Set.
    No statistical analyses for this end point

    Secondary: Change from Baseline in the Cardiovascular Biomarker, N-terminal Pro-brain Natriuretic Peptide Fraction (NT-proBNP)

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    End point title
    		 Change from Baseline in the Cardiovascular Biomarker, N-terminal Pro-brain Natriuretic Peptide Fraction (NT-proBNP)
    End point description
    Blood samples were collected to analyze N-terminal pro-brain natriuretic peptide fraction (NT-proBNP). A negative change from baseline indicates improvement. Participants from the safety analysis set were considered for this analysis. The safety analysis set included participants who received at least one dose of study medication. For each time point, only participants, who had values at both baseline and the given time point, were analyzed for that time point.
    End point type
    Secondary
    End point timeframe
    Baseline, month 6, month 24
    End point values
    		 Tacrolimus plus Mycophenolic Acid (MPA) Everolimus
    Number of subjects analysed
    36 [23]
    35 [24]
    Units: ng/mL
    arithmetic mean (standard deviation)
        Month 6 (n=27,30)
    21.604 ± 294.82
    -79.1 ± 401.44
        Month 24 (n=24,24)
    -80.2 ± 424.24
    -193.3 ± 590.9
    Notes
    [23] - Safety Analysis Set
    [24] - Safety Analysis Set
    No statistical analyses for this end point

    Secondary: Change from Baseline in the Cardiovascular Biomarker, Type 1 Procollagen Amino-Terminal- Propeptide (PINP)

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    End point title
    		 Change from Baseline in the Cardiovascular Biomarker, Type 1 Procollagen Amino-Terminal- Propeptide (PINP)
    End point description
    Blood samples were collected to analyze Type 1 procollagen amino-terminal- propeptide (PINP). A negative change from baseline indicates improvement. Participants from the safety analysis set were considered for this analysis. The safety analysis set included participants who received at least one dose of study medication. For each time point, only participants, who had values at both baseline and the given time point, were analyzed for that time point.
    End point type
    Secondary
    End point timeframe
    Baseline, month 6, month 24
    End point values
    		 Tacrolimus plus Mycophenolic Acid (MPA) Everolimus
    Number of subjects analysed
    36 [25]
    35 [26]
    Units: ug/L
    arithmetic mean (standard deviation)
        Month 6 (n=27,30)
    -13.82 ± 34.11
    -33.36 ± 33.227
        Month 24 (n=24,24)
    -13.65 ± 40.675
    -28.17 ± 30.381
    Notes
    [25] - Safety Analysis Set
    [26] - Safety Analysis Set
    No statistical analyses for this end point

    Secondary: Change from Baseline in Cardiovascular Biomarkers, C-reactive Protein (CRP)

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    End point title
    		 Change from Baseline in Cardiovascular Biomarkers, C-reactive Protein (CRP)
    End point description
    Blood samples were collected to analyze C-reactive protein (CRP). A negative change from baseline indicates improvement. Participants from the safety analysis set were considered for this analysis. The safety analysis set included participants who received at least one dose of study medication. For each time point, only participants, who had values at both baseline and the given time point, were analyzed for that time point.
    End point type
    Secondary
    End point timeframe
    Baseline, month 6, month 24
    End point values
    		 Tacrolimus plus Mycophenolic Acid (MPA) Everolimus
    Number of subjects analysed
    36 [27]
    35 [28]
    Units: mg/dL
    arithmetic mean (standard deviation)
        Month 6 (n=27,30)
    0.512 ± 2.342
    0.326 ± 1.129
        Month 24 (n=24,24)
    0.1 ± 0.469
    -0.04 ± 1.683
    Notes
    [27] - Safety Analysis Set
    [28] - Safety Analysis Set
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events are collected from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV). All adverse events reported in this record are from date of First Patient First Treatment until Last Patient Last Visit.
    Adverse event reporting additional description
    Consistent with EudraCT disclosure specifications, Novartis has reported under the Serious adverse events field “number of deaths resulting from adverse events” all those deaths, resulting from serious adverse events that are deemed to be causally related to treatment by the investigator.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    17.0
    Reporting groups
    Reporting group title
    Everolimus
    Reporting group description
    		 Everolimus

    Reporting group title
    Tacrolimus
    Reporting group description
    		 Tacrolimus

    Serious adverse events
    		 Everolimus Tacrolimus
    Total subjects affected by serious adverse events
         subjects affected / exposed
    8 / 35 (22.86%)
    5 / 36 (13.89%)
         number of deaths (all causes)
    1
    0
         number of deaths resulting from adverse events
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Basal cell carcinoma
         subjects affected / exposed
    0 / 35 (0.00%)
    1 / 36 (2.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Central nervous system lymphoma
         subjects affected / exposed
    0 / 35 (0.00%)
    1 / 36 (2.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metastatic neoplasm
         subjects affected / exposed
    1 / 35 (2.86%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Surgical and medical procedures
    Arteriovenous fistula operation
         subjects affected / exposed
    1 / 35 (2.86%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Cerebrovascular accident
         subjects affected / exposed
    0 / 35 (0.00%)
    1 / 36 (2.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    0 / 35 (0.00%)
    1 / 36 (2.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune system disorders
    Drug hypersensitivity
         subjects affected / exposed
    1 / 35 (2.86%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    1 / 35 (2.86%)
    1 / 36 (2.78%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Haematuria
         subjects affected / exposed
    1 / 35 (2.86%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal impairment
         subjects affected / exposed
    1 / 35 (2.86%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract obstruction
         subjects affected / exposed
    1 / 35 (2.86%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Oral herpes
         subjects affected / exposed
    1 / 35 (2.86%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    1 / 35 (2.86%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyelonephritis
         subjects affected / exposed
    0 / 35 (0.00%)
    1 / 36 (2.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory syncytial virus infection
         subjects affected / exposed
    1 / 35 (2.86%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Septic shock
         subjects affected / exposed
    1 / 35 (2.86%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urosepsis
         subjects affected / exposed
    1 / 35 (2.86%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Everolimus Tacrolimus
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    24 / 35 (68.57%)
    20 / 36 (55.56%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    5 / 35 (14.29%)
    1 / 36 (2.78%)
         occurrences all number
    5
    1
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    0 / 35 (0.00%)
    2 / 36 (5.56%)
         occurrences all number
    0
    2
    Oedema peripheral
         subjects affected / exposed
    6 / 35 (17.14%)
    3 / 36 (8.33%)
         occurrences all number
    8
    3
    Reproductive system and breast disorders
    Metrorrhagia
         subjects affected / exposed
    2 / 35 (5.71%)
    0 / 36 (0.00%)
         occurrences all number
    2
    0
    Psychiatric disorders
    Depression
         subjects affected / exposed
    2 / 35 (5.71%)
    0 / 36 (0.00%)
         occurrences all number
    2
    0
    Injury, poisoning and procedural complications
    Arteriovenous fistula site complication
         subjects affected / exposed
    2 / 35 (5.71%)
    0 / 36 (0.00%)
         occurrences all number
    3
    0
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    2 / 35 (5.71%)
    0 / 36 (0.00%)
         occurrences all number
    2
    0
    Headache
         subjects affected / exposed
    2 / 35 (5.71%)
    2 / 36 (5.56%)
         occurrences all number
    2
    3
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    3 / 35 (8.57%)
    0 / 36 (0.00%)
         occurrences all number
    3
    0
    Leukopenia
         subjects affected / exposed
    2 / 35 (5.71%)
    0 / 36 (0.00%)
         occurrences all number
    2
    0
    Polycythaemia
         subjects affected / exposed
    2 / 35 (5.71%)
    1 / 36 (2.78%)
         occurrences all number
    2
    1
    Gastrointestinal disorders
    Aphthous stomatitis
         subjects affected / exposed
    3 / 35 (8.57%)
    0 / 36 (0.00%)
         occurrences all number
    3
    0
    Diarrhoea
         subjects affected / exposed
    2 / 35 (5.71%)
    4 / 36 (11.11%)
         occurrences all number
    3
    4
    Skin and subcutaneous tissue disorders
    Acne
         subjects affected / exposed
    2 / 35 (5.71%)
    0 / 36 (0.00%)
         occurrences all number
    2
    0
    Dermatitis
         subjects affected / exposed
    2 / 35 (5.71%)
    0 / 36 (0.00%)
         occurrences all number
    2
    0
    Seborrhoeic dermatitis
         subjects affected / exposed
    0 / 35 (0.00%)
    2 / 36 (5.56%)
         occurrences all number
    0
    3
    Renal and urinary disorders
    Proteinuria
         subjects affected / exposed
    5 / 35 (14.29%)
    0 / 36 (0.00%)
         occurrences all number
    5
    0
    Musculoskeletal and connective tissue disorders
    Osteoporosis
         subjects affected / exposed
    1 / 35 (2.86%)
    2 / 36 (5.56%)
         occurrences all number
    1
    2
    Tendonitis
         subjects affected / exposed
    0 / 35 (0.00%)
    2 / 36 (5.56%)
         occurrences all number
    0
    2
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    0 / 35 (0.00%)
    2 / 36 (5.56%)
         occurrences all number
    0
    2
    Nasopharyngitis
         subjects affected / exposed
    2 / 35 (5.71%)
    0 / 36 (0.00%)
         occurrences all number
    2
    0
    Urinary tract infection
         subjects affected / exposed
    0 / 35 (0.00%)
    2 / 36 (5.56%)
         occurrences all number
    0
    2
    Metabolism and nutrition disorders
    Dyslipidaemia
         subjects affected / exposed
    1 / 35 (2.86%)
    2 / 36 (5.56%)
         occurrences all number
    1
    2
    Hypercalcaemia
         subjects affected / exposed
    1 / 35 (2.86%)
    3 / 36 (8.33%)
         occurrences all number
    1
    3
    Hypercholesterolaemia
         subjects affected / exposed
    2 / 35 (5.71%)
    1 / 36 (2.78%)
         occurrences all number
    2
    1
    Hyperglycaemia
         subjects affected / exposed
    2 / 35 (5.71%)
    2 / 36 (5.56%)
         occurrences all number
    2
    2
    Hypertriglyceridaemia
         subjects affected / exposed
    2 / 35 (5.71%)
    0 / 36 (0.00%)
         occurrences all number
    2
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    25 Mar 2010
    As a result of an exhaustive review with new participants, the exclusion criteria were extended in order to achieve a more defined study population.
    30 Apr 2010
    Changes in the study design (visit windows) were detected and included in this amendment.
    28 Jun 2010
    At the time of purchasing the study medication it was confirmed that not only was it necessary to supply the doses of 0.5 mg and 1 mg Certican but also the 0.25 mg dose. For this reason sections 4.3.1 and 4.4.1 of the protocol were changed.
    02 Feb 2011
    During the course of the study, it was verified that the determination of glycosylated haemoglobin (Hb1Ac) during the Glucose Tolerance Test (OGTT) at 2 hours was not relevant as changes are not appreciable until days or even months; thus it was decided to remove this measurement.

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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