Clincosm LogoSign in Get a demo

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

Sponsor
Novartis Pharmaceuticals (Industry)
Overall Status
Completed
CT.gov ID
NCT01025817
Collaborator
(none)
613
Enrollment
50
Locations
2
Arms
37.9
Duration (Months)
12.3
Patients Per Site
0.3
Patients Per Site Per Month

Study Details

Study Description

Brief Summary

The purpose of this phase 3b study is to compare the safety and efficacy of everolimus with low dose tacrolimus to mycophenolate mofetil with standard dose tacrolimus in kidney transplant recipients.

Condition or Disease Intervention/Treatment Phase
  • Drug: Everolimus and tacrolimus
  • Drug: mycophenolate mofetil and tacrolimus
 Phase 3

Study Design

Study Type:
Interventional
Actual Enrollment :
613 participants
Allocation:
Randomized
Intervention Model:
Parallel Assignment
Masking:
None (Open Label)
Primary Purpose:
Treatment
Official Title:
A 12 Month, Multi-center, Randomized, Open-label Non-inferiority Study Comparing Safety and Efficacy of Concentration-controlled Everolimus With Low Dose Tacrolimus to Mycophenolate Mofetil With Standard Dose Tacrolimus in de Novo Renal Transplant Recipients
Study Start Date :
Jan 1, 2010
Actual Primary Completion Date :
Mar 1, 2013
Actual Study Completion Date :
Mar 1, 2013

Arms and Interventions

Arm Intervention/Treatment
Experimental: Everolimus (EVR) & low dose of tacrolimus

Everolimus (EVR) and tacrolimus 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.

Drug: Everolimus and tacrolimus
Everolimus: Dosage form: 0.75 mg, 0.25 mg, and 0.5 mg tablets Dose: 1.5 mg per day Frequency: 0.75 mg twice daily Tacrolimus: Dose adjusted to maintain specific blood levels
Active Comparator: Mycophenolate mofetil & standard dose tacrolimus

Mycophenolate mofetil and tacrolimus (MMF) treatment arm: 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 decrease in WBC. MMF trough or AUC was not used to adjust dosing. In this group, tacrolimus was initiated according to local practice. 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, target tacrolimus trough level was reduced to 7 - 10 ng/mL. After Month 6, target level of tacrolimus was reduced to 5 - 8 ng/mL.

Drug: mycophenolate mofetil and tacrolimus
Mycophenolate mofetil: - Dose form: 250 mg capsule - Dose: 2g per day - Frequency: 1g twice daily Tacrolimus: - Dose adjusted to maintain specific blood levels
Other Names:
  • Active Comparator Control)

    		•

    Outcome Measures

    Primary Outcome Measures

    1. Number of Participants With Incidence of Composite Efficacy Failure [12 Months]

      Efficacy failure rate used the composite endpoint of: (1) treated biopsy-proven acute rejection (BPAR)*, (2) graft loss**, (3) participant death or(4) loss to follow-up. *A treated BPAR was defined as a biopsy graded IA, IB, IIA, IIB, or III and which was treated with anti-rejection therapy. **Graft loss is defined as when the allograft was presumed lost on the day the participant started dialysis and was not able to subsequently be removed from dialysis.

    Secondary Outcome Measures

    1. Estimated Glomerular Filtration Rate (eGFR) [12 Months]

      Renal function was assessed by estimated Glomerular Filtration Rate (eGFR) using the Modification of Diet in Renal Disease (MDRD) formula. MDRD formula: GFR [mL/min/1.73m˄2] = 186.3*(C˄-1.154)*(A˄-0.203)*G*R. DEFINITIONS: C = serum concentration of creatinine [mg/dL]; A = age [years]; G = 0.742 when gender is female, otherwise G = 1; R = 1.21 when race is black, otherwise R = 1

    2. Number of Participants With Incidence of CMV (Viremia, Syndrome and Disease) [12 Months]

      Participants with incidence of CMV (viremia, syndrome and disease). CMV is cytomegalovirus.

    3. Number of Participants With Incidence Rates of BKV Viremia, BKV Viruria, or BKV Nephropathy [12 Months]

      Participants with Incidence of BKV (viremia, viruria, or nephropathy). BKV is Polyomavirus type BK.

    4. Number of Participants With Incidence of New Onset of Diabetes Mellitus [12 Months]

      Incidence of new onset diabetes mellitus defined as non-diabetic patients before transplantation, who are receiving glucose lowering treatment for more than 30 days post-transplant, or with a random plasma glucose ≥200 mg dL (11.1 mmol/L) with 2 fasting plasma glucose values ≥126 mg/dL (7 mmol/L)

    5. Number of Participants With Incidence of Proteinuria Events [Baseline and 12 Months]

      Number of participants with Incidence of proteinuria events indicating chronic kidney disease

    6. Number of Participants With Incidence of Adverse Events, Serious Adverse Events, and Tacrolimus-associated Adverse Events [12 Months]

      Incidence of adverse events, serious adverse events, and tacrolimus-associated adverse events by System Organ Class

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    18 Years to 70 Years
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No
    Inclusion criteria:

    • Male or female renal recipients 18-70 years of age undergoing kidney transplantation, either primary or re-transplant;

    • Recipient of a cadaveric, deceased donor (including expanded criteria donor organs and deceased donor organs after cardiac death), living unrelated or non-HLA identical living related donor kidney;

    • Graft must be functional (producing greater than or equal to 100 ml of urine within 24 hours after transplantation) at time of randomization.

    Exclusion criteria:

    • Donor organ with a cold ischemic time > 30 hours;

    • Males or females who produce less than 100 ml of urine in the first 24 hours post-transplantation;

    • Males or females who are recipients of ABO incompatible transplants, or T cell, or B cell crossmatch positive transplant;

    • Males or females with severe total hypercholesterolemia or total hypertriglyceridemia (Patients on lipid lowering treatment with controlled hyperlipidemia are acceptable);

    • Males or females who have any surgical or any medical condition, such as severe diarrhea, active peptic ulcer disease, or uncontrolled diabetes mellitus, which in the opinion of the investigator, might alter the absorption, distribution, metabolism and/or excretion of study medication.

    Other protocol related inclusion/exclusion criteria may apply.

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 Novartis Investigative Site Birmingham Alabama United States 35233
    2 Novartis Investigative Site Tucson Arizona United States 85742-5022
    3 Novartis Investigative Site Los Angeles California United States 90033
    4 Novartis Investigative Site Los Angeles California United States 90048
    5 Novartis Investigative Site Los Angeles California United States 90095
    6 Novartis Investigative Site Orange California United States 92868
    7 Novartis Investigative Site Sacramento California United States 95817
    8 Novartis Investigative Site San Diego California United States 92103
    9 Novartis Investigative Site San Diego California United States 92123
    10 Novartis Investigative Site San Francisco California United States 94115
    11 Novartis Investigative Site San Francisco California United States 94143-0780
    12 Novartis Investigative Site Aurora Colorado United States 80045
    13 Novartis Investigative Site Miami Florida United States 33136
    14 Novartis Investigative Site Orlando Florida United States 32804
    15 Novartis Investigative Site Tampa Florida United States 33606
    16 Novartis Investigative Site Chicago Illinois United States 60612
    17 Novartis Investigative Site Chicago Illinois United States 60637
    18 Novartis Investigative Site Baltimore Maryland United States 21201
    19 Novartis Investigative Site Boston Massachusetts United States 02111
    20 Novartis Investigative Site Worcester Massachusetts United States 01655
    21 Novartis Investigative Site Ann Arbor Michigan United States 48109-0331
    22 Novartis Investigative Site Detroit Michigan United States 48202-2689
    23 Novartis Investigative Site Detroit Michigan United States 48236
    24 Novartis Investigative Site Royal Oak Michigan United States 48073
    25 Novartis Investigative Site Minneapolis Minnesota United States 55455
    26 Novartis Investigative Site St. Louis Missouri United States 63110
    27 Novartis Investigative Site Omaha Nebraska United States 68198-3285
    28 Novartis Investigative Site Livingston New Jersey United States 07039
    29 Novartis Investigative Site Buffalo New York United States 14215
    30 Novartis Investigative Site New York New York United States 10032
    31 Novartis Investigative Site Durham North Carolina United States 27710
    32 Novartis Investigative Site Greenville North Carolina United States 27834
    33 Novartis Investigative Site Portland Oregon United States 97239
    34 Novartis Investigative Site Harrisburg Pennsylvania United States 17105-8700
    35 Novartis Investigative Site Charleston South Carolina United States 29425
    36 Novartis Investigative Site Nashville Tennessee United States 37212-3139
    37 Novartis Investigative Site Dallas Texas United States 75246
    38 Novartis Investigative Site Fort Worth Texas United States 76104
    39 Novartis Investigative Site Galveston Texas United States 77555-0144
    40 Novartis Investigative Site Houston Texas United States 77030
    41 Novartis Investigative Site Lubbock Texas United States 79430
    42 Novartis Investigative Site Salt Lake City Utah United States 84132
    43 Novartis Investigative Site Burlington Vermont United States 05401
    44 Novartis Investigative Site Charlottesville Virginia United States 22908
    45 Novartis Investigative Site Norfolk Virginia United States 23507
    46 Novartis Investigative Site Richmond Virginia United States 23298
    47 Novartis Investigative Site Seattle Washington United States 98195
    48 Novartis Investigative Site Spokane Washington United States 99204
    49 Novartis Investigative Site Montreal Quebec Canada H1T 2M4
    50 Novartis Investigative Site Montreal Quebec Canada H2L 4M1

    Sponsors and Collaborators

    • Novartis Pharmaceuticals

    Investigators

    • Study Director: Novartis Pharmaceuticals, Novartis Pharmaceuticals

    Study Documents (Full-Text)

    None provided.

    More Information

    Publications

    None provided.
    Responsible Party:
    Novartis Pharmaceuticals
    ClinicalTrials.gov Identifier:
    NCT01025817
    Other Study ID Numbers:
    • CRAD001AUS92
    First Posted:
    Dec 4, 2009
    Last Update Posted:
    Nov 11, 2015
    Last Verified:
    Oct 1, 2015
    Keywords provided by Novartis Pharmaceuticals
    Kidney transplant
    renal transplant
    immunosuppression
    mycophenolate mofetil
    tacrolimus
    everolimus
    Additional relevant MeSH terms:
    Mycophenolic Acid
    Everolimus
    Tacrolimus

    Study Results

    Participant Flow

    Recruitment Details 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 Detail
    Arm/Group Title Everolimus and Low Dose Tacrolimus Mycophenolate Mofetil and Standard Dose Tacrolimus
    Arm/Group Description 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. 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.
    Period Title: Completed Study Medication
    STARTED 309 304
    COMPLETED 204 232
    NOT COMPLETED 105 72
    Period Title: Completed Study Medication
    STARTED 309 304
    COMPLETED 293 282
    NOT COMPLETED 16 22

    Baseline Characteristics

    Arm/Group Title Everolimus and Low Dose Tacrolimus Mycophenolate Mofetil and Standard Dose Tacrolimus Total
    Arm/Group Description 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. 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 of all reporting groups
    Overall Participants 306 304 610
    Age (Years) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [Years]
    50.00
    (13.34)
    48.4
    (12.91)
    49.2
    (13.14)
    Sex: Female, Male (Count of Participants)
    Female
    101
    33%
    102
    33.6%
    203
    33.3%
    Male
    205
    67%
    202
    66.4%
    407
    66.7%
    Race/Ethnicity, Customized (Number) [Number]
    American Indian or Alaska Native
    3
    1%
    1
    0.3%
    4
    0.7%
    Asian
    17
    5.6%
    11
    3.6%
    28
    4.6%
    Native Hawaiian or Other Pacific Islander
    3
    1%
    1
    0.3%
    4
    0.7%
    Black or African American
    70
    22.9%
    74
    24.3%
    144
    23.6%
    Caucasian
    196
    64.1%
    201
    66.1%
    397
    65.1%
    Other
    17
    5.6%
    16
    5.3%
    33
    5.4%
    BMI (kg/m˄2) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [kg/m˄2]
    27.7
    (5.55)
    28.3
    (5.13)
    28.0
    (5.35)
    Diabetic status at randomization (Number) [Number]
    Yes
    111
    36.3%
    95
    31.3%
    206
    33.8%
    No
    195
    63.7%
    209
    68.8%
    404
    66.2%

    Outcome Measures

    1. Primary Outcome
    Title Number of Participants With Incidence of Composite Efficacy Failure
    Description Efficacy failure rate used the composite endpoint of: (1) treated biopsy-proven acute rejection (BPAR)*, (2) graft loss**, (3) participant death or(4) loss to follow-up. *A treated BPAR was defined as a biopsy graded IA, IB, IIA, IIB, or III and which was treated with anti-rejection therapy. **Graft loss is defined as when the allograft was presumed lost on the day the participant started dialysis and was not able to subsequently be removed from dialysis.
    Time Frame 12 Months

    Outcome Measure Data

    Analysis Population Description
    Full Analysis Set (FAS) consisted of all participants randomized after transplantation
    Arm/Group Title Everolimus and Low Dose Tacrolimus Mycophenolate Mofetil and Standard Dose Tacrolimus
    Arm/Group Description 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. 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.
    Measure Participants 309 304
    Composite Endpoint
    76
    24.8%
    62
    20.4%
    Treated Biopsy-proven Acute rejection (BPAR)
    59
    19.3%
    34
    11.2%
    Graft Loss
    4
    1.3%
    12
    3.9%
    Death
    6
    2%
    5
    1.6%
    Loss to follow up
    9
    2.9%
    17
    5.6%
    2. Secondary Outcome
    Title Estimated Glomerular Filtration Rate (eGFR)
    Description Renal function was assessed by estimated Glomerular Filtration Rate (eGFR) using the Modification of Diet in Renal Disease (MDRD) formula. MDRD formula: GFR [mL/min/1.73m˄2] = 186.3*(C˄-1.154)*(A˄-0.203)*G*R. DEFINITIONS: C = serum concentration of creatinine [mg/dL]; A = age [years]; G = 0.742 when gender is female, otherwise G = 1; R = 1.21 when race is black, otherwise R = 1
    Time Frame 12 Months

    Outcome Measure Data

    Analysis Population Description
    Full Analysis Set (FAS) consisted of all patients randomized after transplantation
    Arm/Group Title Everolimus and Low Dose Tacrolimus Mycophenolate Mofetil and Standard Dose Tacrolimus
    Arm/Group Description 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. 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.
    Measure Participants 309 304
    Mean (Standard Deviation) [mL/min/1.73m˄2]
    63.14
    (22.042)
    63.06
    (19.512)
    3. Secondary Outcome
    Title Number of Participants With Incidence of CMV (Viremia, Syndrome and Disease)
    Description Participants with incidence of CMV (viremia, syndrome and disease). CMV is cytomegalovirus.
    Time Frame 12 Months

    Outcome Measure Data

    Analysis Population Description
    Safety Set (SS) consisted of all randomized participants who received at least 1 dose of study drug and had at least 1 post-baseline safety assessment. The statement that a patient had no adverse events constitutes a safety assessment. Those who received at least 1 dose of drug but had no post-treatment safety data of any kind are excluded from SS.
    Arm/Group Title Everolimus and Low Dose Tacrolimus Mycophenolate Mofetil and Standard Dose Tacrolimus
    Arm/Group Description 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. 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.
    Measure Participants 306 304
    CMV syndrome event
    9
    2.9%
    13
    4.3%
    Lab evidence of CMV Viremia
    7
    2.3%
    10
    3.3%
    CMV Disease
    2
    0.7%
    8
    2.6%
    4. Secondary Outcome
    Title Number of Participants With Incidence Rates of BKV Viremia, BKV Viruria, or BKV Nephropathy
    Description Participants with Incidence of BKV (viremia, viruria, or nephropathy). BKV is Polyomavirus type BK.
    Time Frame 12 Months

    Outcome Measure Data

    Analysis Population Description
    Safety Set (SS) consisted of all randomized participants who received at least 1 dose of study drug and had at least 1 post-baseline safety assessment. The statement that a patient had no adverse events constitutes a safety assessment. Those who received at least 1 dose of drug but had no post-treatment safety data of any kind are excluded from SS
    Arm/Group Title Everolimus and Low Dose Tacrolimus Mycophenolate Mofetil and Standard Dose Tacrolimus
    Arm/Group Description 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. 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.
    Measure Participants 306 304
    Lab evidence of BKV Viremia
    19
    6.2%
    27
    8.9%
    Lab evidence of BKV Viruria
    19
    6.2%
    15
    4.9%
    BKV Disease (Nephropathy)
    5
    1.6%
    5
    1.6%
    5. Secondary Outcome
    Title Number of Participants With Incidence of New Onset of Diabetes Mellitus
    Description Incidence of new onset diabetes mellitus defined as non-diabetic patients before transplantation, who are receiving glucose lowering treatment for more than 30 days post-transplant, or with a random plasma glucose ≥200 mg dL (11.1 mmol/L) with 2 fasting plasma glucose values ≥126 mg/dL (7 mmol/L)
    Time Frame 12 Months

    Outcome Measure Data

    Analysis Population Description
    Safety Set (SS) consisted of all randomized participants who received at least 1 dose of study drug and had at least 1 post-baseline safety assessment. The statement that a patient had no adverse events constitutes a safety assessment. Those who received at least 1 dose of drug but had no post-treatment safety data of any kind are excluded from SS.
    Arm/Group Title Everolimus and Low Dose Tacrolimus Mycophenolate Mofetil and Standard Dose Tacrolimus
    Arm/Group Description 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. 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.
    Measure Participants 306 304
    Any New Onset Diabetes
    25
    8.2%
    22
    7.2%
    randomGlucose≥200mg/dL w/2 fastingGlucose≥126mg/dL
    15
    4.9%
    12
    3.9%
    Concomitant Diabetes medicine for 30 days or more
    13
    4.2%
    14
    4.6%
    6. Secondary Outcome
    Title Number of Participants With Incidence of Proteinuria Events
    Description Number of participants with Incidence of proteinuria events indicating chronic kidney disease
    Time Frame Baseline and 12 Months

    Outcome Measure Data

    Analysis Population Description
    Safety Set (SS) consisted of all randomized participants who received at least 1 dose of study drug and had at least 1 post-baseline safety assessment. The statement that a patient had no adverse events constitutes a safety assessment. Those who received at least 1 dose of drug but had no post-treatment safety data of any kind are excluded from SS
    Arm/Group Title Everolimus and Low Dose Tacrolimus Mycophenolate Mofetil and Standard Dose Tacrolimus
    Arm/Group Description 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. 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.
    Measure Participants 306 304
    Baseline: Proteinuria (>=300 mg/g)
    243
    79.4%
    250
    82.2%
    Month 12, Day 316-450: Proteinuria (>=300 mg/g)
    36
    11.8%
    35
    11.5%
    7. Secondary Outcome
    Title Number of Participants With Incidence of Adverse Events, Serious Adverse Events, and Tacrolimus-associated Adverse Events
    Description Incidence of adverse events, serious adverse events, and tacrolimus-associated adverse events by System Organ Class
    Time Frame 12 Months

    Outcome Measure Data

    Analysis Population Description
    Safety Set (SS) consisted of all randomized participants who received at least 1 dose of study drug and had at least 1 post-baseline safety assessment. The statement that a patient had no adverse events constitutes a safety assessment. Those who received at least 1 dose of drug but had no post-treatment safety data of any kind are excluded from SS
    Arm/Group Title Everolimus and Low Dose Tacrolimus Mycophenolate Mofetil and Standard Dose Tacrolimus
    Arm/Group Description 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. 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.
    Measure Participants 306 304
    Any system organ class
    303
    99%
    302
    99.3%
    Metabolism and nutrition disorders
    266
    86.9%
    263
    86.5%
    Gastrointestinal disorders
    233
    76.1%
    247
    81.3%
    Injury, poisoning and procedural complications
    223
    72.9%
    202
    66.4%
    General disorders &administration site conditions
    199
    65%
    177
    58.2%
    Infections and infestations
    184
    60.1%
    196
    64.5%
    Investigations
    150
    49%
    143
    47%
    Renal and urinary disorders
    141
    46.1%
    160
    52.6%
    Vascular disorders
    131
    42.8%
    121
    39.8%
    Blood and lymphatic system disorders
    130
    42.5%
    163
    53.6%
    Nervous system disorders
    125
    40.8%
    150
    49.3%
    Respiratory, thoracic and mediastinal disorders
    122
    39.9%
    134
    44.1%
    Musculoskeletal and connective tissue disorders
    110
    35.9%
    114
    37.5%
    Skin and subcutaneous tissue disorders
    109
    35.6%
    108
    35.5%
    Psychiatric disorders
    96
    31.4%
    106
    34.9%
    Reproductive system and breast disorders
    56
    18.3%
    40
    13.2%
    Cardiac disorders
    51
    16.7%
    47
    15.5%
    Eye disorders
    26
    8.5%
    36
    11.8%
    Immune system disorders
    13
    4.2%
    11
    3.6%
    Endocrine disorders
    12
    3.9%
    8
    2.6%
    Neoplasms benign,malignant,other incl cysts/polyps
    10
    3.3%
    15
    4.9%
    Ear and labyrinth disorders
    7
    2.3%
    11
    3.6%
    Hepatobiliary disorders
    6
    2%
    3
    1%
    Surgical and medical procedures
    2
    0.7%
    0
    0%
    Congenital, familial and genetic disorders
    0
    0%
    6
    2%
    Social circumstances
    0
    0%
    1
    0.3%

    Adverse Events

    Time Frame
    Adverse Event Reporting Description
    Arm/Group Title Everolimus and Low Dose Tacrolimus Mycophenolate Mofetil and Standard Dose Tacrolimus
    Arm/Group Description 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. 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.
    All Cause Mortality
    Everolimus and Low Dose Tacrolimus Mycophenolate Mofetil and Standard Dose Tacrolimus
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total / (NaN) / (NaN)
    Serious Adverse Events
    Everolimus and Low Dose Tacrolimus Mycophenolate Mofetil and Standard Dose Tacrolimus
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 154/306 (50.3%) 142/304 (46.7%)
    Blood and lymphatic system disorders
    Anaemia 3/306 (1%) 4/304 (1.3%)
    Bandaemia 0/306 (0%) 1/304 (0.3%)
    Febrile neutropenia 2/306 (0.7%) 1/304 (0.3%)
    Haemolytic uraemic syndrome 2/306 (0.7%) 1/304 (0.3%)
    Leukocytosis 1/306 (0.3%) 1/304 (0.3%)
    Leukopenia 0/306 (0%) 3/304 (1%)
    Pancytopenia 0/306 (0%) 1/304 (0.3%)
    Thrombocytopenia 2/306 (0.7%) 0/304 (0%)
    Thrombotic microangiopathy 1/306 (0.3%) 0/304 (0%)
    Cardiac disorders
    Acute myocardial infarction 2/306 (0.7%) 4/304 (1.3%)
    Atrial fibrillation 2/306 (0.7%) 3/304 (1%)
    Bradycardia 1/306 (0.3%) 0/304 (0%)
    Cardiac arrest 1/306 (0.3%) 2/304 (0.7%)
    Cardiac failure congestive 5/306 (1.6%) 0/304 (0%)
    Cardiogenic shock 0/306 (0%) 1/304 (0.3%)
    Coronary artery disease 0/306 (0%) 1/304 (0.3%)
    Myocardial infarction 2/306 (0.7%) 2/304 (0.7%)
    Sinus tachycardia 1/306 (0.3%) 0/304 (0%)
    Congenital, familial and genetic disorders
    Congenital cystic kidney disease 0/306 (0%) 1/304 (0.3%)
    Congenital renal cyst 0/306 (0%) 1/304 (0.3%)
    Gastrointestinal disorders
    Abdominal distension 2/306 (0.7%) 1/304 (0.3%)
    Abdominal hernia 1/306 (0.3%) 0/304 (0%)
    Abdominal pain 2/306 (0.7%) 2/304 (0.7%)
    Abdominal pain upper 1/306 (0.3%) 1/304 (0.3%)
    Aphthous stomatitis 0/306 (0%) 1/304 (0.3%)
    Ascites 0/306 (0%) 1/304 (0.3%)
    Colitis 0/306 (0%) 2/304 (0.7%)
    Constipation 1/306 (0.3%) 1/304 (0.3%)
    Diabetic gastroparesis 2/306 (0.7%) 0/304 (0%)
    Diarrhoea 7/306 (2.3%) 8/304 (2.6%)
    Erosive oesophagitis 1/306 (0.3%) 1/304 (0.3%)
    Gastritis 1/306 (0.3%) 0/304 (0%)
    Gastrointestinal haemorrhage 1/306 (0.3%) 0/304 (0%)
    Gastrointestinal inflammation 1/306 (0.3%) 0/304 (0%)
    Haematochezia 0/306 (0%) 1/304 (0.3%)
    Ileus 1/306 (0.3%) 2/304 (0.7%)
    Impaired gastric emptying 1/306 (0.3%) 1/304 (0.3%)
    Internal hernia 1/306 (0.3%) 0/304 (0%)
    Intra-abdominal haemorrhage 1/306 (0.3%) 0/304 (0%)
    Localised intraabdominal fluid collection 0/306 (0%) 1/304 (0.3%)
    Nausea 7/306 (2.3%) 4/304 (1.3%)
    Neutropenic colitis 0/306 (0%) 1/304 (0.3%)
    Oesophagitis 0/306 (0%) 1/304 (0.3%)
    Oral pain 1/306 (0.3%) 0/304 (0%)
    Pancreatitis 2/306 (0.7%) 0/304 (0%)
    Peptic ulcer 1/306 (0.3%) 0/304 (0%)
    Peritoneal haemorrhage 1/306 (0.3%) 0/304 (0%)
    Retroperitoneal haematoma 1/306 (0.3%) 1/304 (0.3%)
    Small intestinal obstruction 2/306 (0.7%) 1/304 (0.3%)
    Small intestinal perforation 1/306 (0.3%) 0/304 (0%)
    Tongue ulceration 1/306 (0.3%) 0/304 (0%)
    Upper gastrointestinal haemorrhage 0/306 (0%) 1/304 (0.3%)
    Vomiting 8/306 (2.6%) 7/304 (2.3%)
    General disorders
    Asthenia 1/306 (0.3%) 0/304 (0%)
    Chest pain 2/306 (0.7%) 5/304 (1.6%)
    Chills 1/306 (0.3%) 1/304 (0.3%)
    Device malfunction 1/306 (0.3%) 1/304 (0.3%)
    Fatigue 1/306 (0.3%) 0/304 (0%)
    General physical health deterioration 0/306 (0%) 1/304 (0.3%)
    Generalised oedema 1/306 (0.3%) 1/304 (0.3%)
    Hernia 2/306 (0.7%) 1/304 (0.3%)
    Impaired healing 3/306 (1%) 0/304 (0%)
    Irritability 0/306 (0%) 1/304 (0.3%)
    Medical device complication 0/306 (0%) 1/304 (0.3%)
    Oedema 2/306 (0.7%) 0/304 (0%)
    Oedema peripheral 3/306 (1%) 2/304 (0.7%)
    Pyrexia 13/306 (4.2%) 11/304 (3.6%)
    Rebound effect 0/306 (0%) 1/304 (0.3%)
    Sluggishness 0/306 (0%) 1/304 (0.3%)
    Immune system disorders
    Kidney transplant rejection 1/306 (0.3%) 1/304 (0.3%)
    Transplant rejection 1/306 (0.3%) 1/304 (0.3%)
    Infections and infestations
    Adenovirus infection 0/306 (0%) 1/304 (0.3%)
    BK virus infection 1/306 (0.3%) 1/304 (0.3%)
    Bacteraemia 1/306 (0.3%) 4/304 (1.3%)
    Bacterial pyelonephritis 0/306 (0%) 2/304 (0.7%)
    Bronchitis 1/306 (0.3%) 1/304 (0.3%)
    Cellulitis 6/306 (2%) 3/304 (1%)
    Cellulitis of male external genital organ 0/306 (0%) 1/304 (0.3%)
    Cerebral fungal infection 1/306 (0.3%) 0/304 (0%)
    Clostridial infection 3/306 (1%) 3/304 (1%)
    Clostridium difficile colitis 0/306 (0%) 2/304 (0.7%)
    Cystitis 0/306 (0%) 1/304 (0.3%)
    Cytomegalovirus infection 0/306 (0%) 5/304 (1.6%)
    Cytomegalovirus viraemia 1/306 (0.3%) 1/304 (0.3%)
    Device related infection 1/306 (0.3%) 1/304 (0.3%)
    Enterococcal bacteraemia 1/306 (0.3%) 0/304 (0%)
    Escherichia bacteraemia 1/306 (0.3%) 1/304 (0.3%)
    Escherichia sepsis 1/306 (0.3%) 0/304 (0%)
    Escherichia urinary tract infection 2/306 (0.7%) 0/304 (0%)
    Gangrene 2/306 (0.7%) 2/304 (0.7%)
    Gastroenteritis 3/306 (1%) 2/304 (0.7%)
    Gastroenteritis clostridial 1/306 (0.3%) 0/304 (0%)
    Gastroenteritis salmonella 1/306 (0.3%) 0/304 (0%)
    Gastroenteritis viral 3/306 (1%) 3/304 (1%)
    Incision site infection 1/306 (0.3%) 0/304 (0%)
    Infection 0/306 (0%) 1/304 (0.3%)
    Influenza 0/306 (0%) 1/304 (0.3%)
    Lung infection pseudomonal 1/306 (0.3%) 0/304 (0%)
    Mastitis 1/306 (0.3%) 0/304 (0%)
    Meningitis cryptococcal 0/306 (0%) 1/304 (0.3%)
    Metapneumovirus infection 1/306 (0.3%) 0/304 (0%)
    Oral herpes 0/306 (0%) 1/304 (0.3%)
    Osteomyelitis 1/306 (0.3%) 0/304 (0%)
    Peritonitis 1/306 (0.3%) 0/304 (0%)
    Pneumocystis jiroveci pneumonia 1/306 (0.3%) 0/304 (0%)
    Pneumonia 13/306 (4.2%) 7/304 (2.3%)
    Pneumonia bacterial 1/306 (0.3%) 0/304 (0%)
    Pneumonia cryptococcal 0/306 (0%) 1/304 (0.3%)
    Pneumonia cytomegaloviral 0/306 (0%) 1/304 (0.3%)
    Polyomavirus-associated nephropathy 0/306 (0%) 2/304 (0.7%)
    Post procedural cellulitis 1/306 (0.3%) 0/304 (0%)
    Pseudomonal bacteraemia 1/306 (0.3%) 0/304 (0%)
    Pulmonary mycosis 1/306 (0.3%) 0/304 (0%)
    Pyelonephritis 6/306 (2%) 4/304 (1.3%)
    Sepsis 1/306 (0.3%) 2/304 (0.7%)
    Septic shock 1/306 (0.3%) 1/304 (0.3%)
    Sinusitis 1/306 (0.3%) 0/304 (0%)
    Staphylococcal infection 2/306 (0.7%) 1/304 (0.3%)
    Upper respiratory tract infection 0/306 (0%) 1/304 (0.3%)
    Urinary tract infection 22/306 (7.2%) 24/304 (7.9%)
    Urinary tract infection bacterial 1/306 (0.3%) 2/304 (0.7%)
    Urinary tract infection enterococcal 1/306 (0.3%) 0/304 (0%)
    Urinary tract infection pseudomonal 0/306 (0%) 1/304 (0.3%)
    Urinary tract infection staphylococcal 1/306 (0.3%) 0/304 (0%)
    Urosepsis 5/306 (1.6%) 7/304 (2.3%)
    Viraemia 0/306 (0%) 2/304 (0.7%)
    Viral infection 1/306 (0.3%) 1/304 (0.3%)
    Wound infection 4/306 (1.3%) 2/304 (0.7%)
    Injury, poisoning and procedural complications
    Anaemia postoperative 1/306 (0.3%) 0/304 (0%)
    Arteriovenous fistula thrombosis 0/306 (0%) 1/304 (0.3%)
    Complications of transplant surgery 1/306 (0.3%) 0/304 (0%)
    Complications of transplanted kidney 4/306 (1.3%) 4/304 (1.3%)
    Device dislocation 0/306 (0%) 1/304 (0.3%)
    Graft complication 2/306 (0.7%) 1/304 (0.3%)
    Graft dysfunction 9/306 (2.9%) 8/304 (2.6%)
    Graft loss 2/306 (0.7%) 3/304 (1%)
    Graft thrombosis 2/306 (0.7%) 0/304 (0%)
    Hip fracture 0/306 (0%) 1/304 (0.3%)
    Incision site complication 1/306 (0.3%) 0/304 (0%)
    Incision site haemorrhage 0/306 (0%) 1/304 (0.3%)
    Incisional hernia 2/306 (0.7%) 1/304 (0.3%)
    Incisional hernia, obstructive 0/306 (0%) 1/304 (0.3%)
    Limb injury 0/306 (0%) 1/304 (0.3%)
    Medical device complication 1/306 (0.3%) 0/304 (0%)
    Overdose 0/306 (0%) 1/304 (0.3%)
    Patella fracture 1/306 (0.3%) 0/304 (0%)
    Perinephric collection 3/306 (1%) 1/304 (0.3%)
    Perirenal haematoma 3/306 (1%) 1/304 (0.3%)
    Post procedural discharge 1/306 (0.3%) 1/304 (0.3%)
    Post procedural haematoma 0/306 (0%) 1/304 (0.3%)
    Post procedural haemorrhage 1/306 (0.3%) 0/304 (0%)
    Post procedural myocardial infarction 0/306 (0%) 1/304 (0.3%)
    Post procedural urine leak 1/306 (0.3%) 0/304 (0%)
    Procedural pain 0/306 (0%) 1/304 (0.3%)
    Renal haematoma 0/306 (0%) 1/304 (0.3%)
    Seroma 2/306 (0.7%) 2/304 (0.7%)
    Tibia fracture 1/306 (0.3%) 0/304 (0%)
    Toxicity to various agents 0/306 (0%) 2/304 (0.7%)
    Transfusion reaction 1/306 (0.3%) 0/304 (0%)
    Urinary anastomotic leak 1/306 (0.3%) 0/304 (0%)
    Vascular graft complication 1/306 (0.3%) 0/304 (0%)
    Wound complication 1/306 (0.3%) 0/304 (0%)
    Wound dehiscence 3/306 (1%) 1/304 (0.3%)
    Investigations
    Blood creatine increased 1/306 (0.3%) 0/304 (0%)
    Blood creatinine increased 10/306 (3.3%) 14/304 (4.6%)
    Blood glucose increased 0/306 (0%) 1/304 (0.3%)
    Electrocardiogram ST segment elevation 1/306 (0.3%) 0/304 (0%)
    Escherichia test positive 1/306 (0.3%) 0/304 (0%)
    Transaminases increased 2/306 (0.7%) 0/304 (0%)
    Urine output decreased 1/306 (0.3%) 2/304 (0.7%)
    White blood cell count increased 0/306 (0%) 1/304 (0.3%)
    Metabolism and nutrition disorders
    Decreased appetite 1/306 (0.3%) 1/304 (0.3%)
    Dehydration 6/306 (2%) 5/304 (1.6%)
    Diabetes mellitus 2/306 (0.7%) 7/304 (2.3%)
    Diabetic ketoacidosis 1/306 (0.3%) 2/304 (0.7%)
    Fluid overload 6/306 (2%) 1/304 (0.3%)
    Fluid retention 1/306 (0.3%) 0/304 (0%)
    Gout 0/306 (0%) 1/304 (0.3%)
    Hypercalcaemia 1/306 (0.3%) 1/304 (0.3%)
    Hyperglycaemia 2/306 (0.7%) 6/304 (2%)
    Hyperglycaemic hyperosmolar nonketotic syndrome 0/306 (0%) 1/304 (0.3%)
    Hyperkalaemia 3/306 (1%) 6/304 (2%)
    Hyperosmolar state 1/306 (0.3%) 0/304 (0%)
    Hyperphosphataemia 0/306 (0%) 1/304 (0.3%)
    Hypocalcaemia 1/306 (0.3%) 0/304 (0%)
    Hypoglycaemia 0/306 (0%) 2/304 (0.7%)
    Hyponatraemia 1/306 (0.3%) 3/304 (1%)
    Hypophosphataemia 1/306 (0.3%) 0/304 (0%)
    Hypovolaemia 1/306 (0.3%) 1/304 (0.3%)
    Metabolic acidosis 0/306 (0%) 1/304 (0.3%)
    Musculoskeletal and connective tissue disorders
    Arthralgia 0/306 (0%) 1/304 (0.3%)
    Back pain 0/306 (0%) 1/304 (0.3%)
    Flank pain 1/306 (0.3%) 1/304 (0.3%)
    Intervertebral disc protrusion 0/306 (0%) 1/304 (0.3%)
    Pain in extremity 1/306 (0.3%) 1/304 (0.3%)
    Rheumatoid arthritis 0/306 (0%) 1/304 (0.3%)
    Spinal osteoarthritis 0/306 (0%) 1/304 (0.3%)
    Systemic lupus erythematosus 0/306 (0%) 1/304 (0.3%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Bone giant cell tumour benign 1/306 (0.3%) 0/304 (0%)
    Non-small cell lung cancer 0/306 (0%) 1/304 (0.3%)
    Pleural mesothelioma 0/306 (0%) 1/304 (0.3%)
    Renal cancer 0/306 (0%) 1/304 (0.3%)
    Renal cell carcinoma 1/306 (0.3%) 0/304 (0%)
    Renal haemangioma 1/306 (0.3%) 0/304 (0%)
    Squamous cell carcinoma of skin 0/306 (0%) 1/304 (0.3%)
    Nervous system disorders
    Carotid artery stenosis 0/306 (0%) 1/304 (0.3%)
    Cerebrovascular accident 0/306 (0%) 1/304 (0.3%)
    Dysarthria 0/306 (0%) 1/304 (0.3%)
    Embolic stroke 0/306 (0%) 1/304 (0.3%)
    Encephalitis 0/306 (0%) 1/304 (0.3%)
    Encephalopathy 0/306 (0%) 1/304 (0.3%)
    Headache 1/306 (0.3%) 1/304 (0.3%)
    Hypoxic-ischaemic encephalopathy 0/306 (0%) 1/304 (0.3%)
    Neuropathy peripheral 1/306 (0.3%) 0/304 (0%)
    Syncope 1/306 (0.3%) 0/304 (0%)
    Transient ischaemic attack 0/306 (0%) 1/304 (0.3%)
    Tremor 0/306 (0%) 1/304 (0.3%)
    Unresponsive to stimuli 0/306 (0%) 1/304 (0.3%)
    Psychiatric disorders
    Anxiety 0/306 (0%) 1/304 (0.3%)
    Confusional state 1/306 (0.3%) 1/304 (0.3%)
    Disorientation 0/306 (0%) 1/304 (0.3%)
    Mental status changes 3/306 (1%) 3/304 (1%)
    Psychotic disorder 0/306 (0%) 1/304 (0.3%)
    Renal and urinary disorders
    Bladder spasm 0/306 (0%) 1/304 (0.3%)
    Calculus ureteric 1/306 (0.3%) 0/304 (0%)
    Cystitis haemorrhagic 0/306 (0%) 1/304 (0.3%)
    Dysuria 0/306 (0%) 1/304 (0.3%)
    Focal segmental glomerulosclerosis 0/306 (0%) 1/304 (0.3%)
    Haematuria 2/306 (0.7%) 5/304 (1.6%)
    Hydronephrosis 3/306 (1%) 6/304 (2%)
    Hydroureter 0/306 (0%) 1/304 (0.3%)
    Nephrolithiasis 1/306 (0.3%) 0/304 (0%)
    Obstructive uropathy 2/306 (0.7%) 0/304 (0%)
    Pelvi-ureteric obstruction 1/306 (0.3%) 0/304 (0%)
    Proteinuria 1/306 (0.3%) 0/304 (0%)
    Renal aneurysm 1/306 (0.3%) 0/304 (0%)
    Renal artery stenosis 2/306 (0.7%) 2/304 (0.7%)
    Renal artery thrombosis 1/306 (0.3%) 0/304 (0%)
    Renal cyst 1/306 (0.3%) 0/304 (0%)
    Renal cyst ruptured 1/306 (0.3%) 0/304 (0%)
    Renal failure 2/306 (0.7%) 1/304 (0.3%)
    Renal failure acute 7/306 (2.3%) 16/304 (5.3%)
    Renal failure chronic 1/306 (0.3%) 1/304 (0.3%)
    Renal impairment 3/306 (1%) 0/304 (0%)
    Renal injury 1/306 (0.3%) 1/304 (0.3%)
    Renal pain 0/306 (0%) 1/304 (0.3%)
    Renal tubular necrosis 4/306 (1.3%) 2/304 (0.7%)
    Renal vein thrombosis 1/306 (0.3%) 2/304 (0.7%)
    Ureteric stenosis 2/306 (0.7%) 3/304 (1%)
    Urethral stenosis 1/306 (0.3%) 0/304 (0%)
    Urinary bladder haemorrhage 1/306 (0.3%) 0/304 (0%)
    Urinary incontinence 1/306 (0.3%) 4/304 (1.3%)
    Urinary retention 0/306 (0%) 3/304 (1%)
    Urinary tract obstruction 1/306 (0.3%) 1/304 (0.3%)
    Urinoma 2/306 (0.7%) 0/304 (0%)
    Vesicoureteric reflux 0/306 (0%) 1/304 (0.3%)
    Reproductive system and breast disorders
    Benign prostatic hyperplasia 1/306 (0.3%) 0/304 (0%)
    Pelvic haematoma 1/306 (0.3%) 0/304 (0%)
    Prostatitis 1/306 (0.3%) 0/304 (0%)
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory failure 0/306 (0%) 1/304 (0.3%)
    Atelectasis 0/306 (0%) 1/304 (0.3%)
    Cough 1/306 (0.3%) 0/304 (0%)
    Dyspnoea 5/306 (1.6%) 6/304 (2%)
    Hypoxia 3/306 (1%) 0/304 (0%)
    Interstitial lung disease 1/306 (0.3%) 0/304 (0%)
    Lung consolidation 0/306 (0%) 1/304 (0.3%)
    Pleural effusion 1/306 (0.3%) 2/304 (0.7%)
    Pneumonia aspiration 1/306 (0.3%) 0/304 (0%)
    Pneumonitis 2/306 (0.7%) 0/304 (0%)
    Pulmonary embolism 5/306 (1.6%) 1/304 (0.3%)
    Pulmonary hypertension 0/306 (0%) 1/304 (0.3%)
    Pulmonary oedema 7/306 (2.3%) 0/304 (0%)
    Pulmonary toxicity 1/306 (0.3%) 0/304 (0%)
    Respiratory arrest 1/306 (0.3%) 0/304 (0%)
    Respiratory distress 3/306 (1%) 0/304 (0%)
    Respiratory failure 5/306 (1.6%) 1/304 (0.3%)
    Skin and subcutaneous tissue disorders
    Angioedema 1/306 (0.3%) 0/304 (0%)
    Diabetic foot 2/306 (0.7%) 0/304 (0%)
    Erythema 1/306 (0.3%) 0/304 (0%)
    Swelling face 1/306 (0.3%) 0/304 (0%)
    Surgical and medical procedures
    Pyelotomy 1/306 (0.3%) 0/304 (0%)
    Vascular disorders
    Arteriovenous fistula 1/306 (0.3%) 1/304 (0.3%)
    Blood pressure inadequately controlled 1/306 (0.3%) 0/304 (0%)
    Deep vein thrombosis 4/306 (1.3%) 5/304 (1.6%)
    Extremity necrosis 0/306 (0%) 1/304 (0.3%)
    Extrinsic iliac vein compression 1/306 (0.3%) 0/304 (0%)
    Haematoma 1/306 (0.3%) 1/304 (0.3%)
    Haemorrhage 0/306 (0%) 1/304 (0.3%)
    Hypertension 7/306 (2.3%) 3/304 (1%)
    Hypertensive crisis 2/306 (0.7%) 0/304 (0%)
    Hypotension 0/306 (0%) 3/304 (1%)
    Iliac artery thrombosis 0/306 (0%) 1/304 (0.3%)
    Jugular vein thrombosis 2/306 (0.7%) 0/304 (0%)
    Lymphocele 7/306 (2.3%) 4/304 (1.3%)
    Orthostatic hypotension 0/306 (0%) 2/304 (0.7%)
    Peripheral vascular disorder 1/306 (0.3%) 0/304 (0%)
    Superior vena cava syndrome 1/306 (0.3%) 0/304 (0%)
    Thrombophlebitis 2/306 (0.7%) 0/304 (0%)
    Thrombophlebitis superficial 0/306 (0%) 1/304 (0.3%)
    Thrombosis 0/306 (0%) 1/304 (0.3%)
    Venous stenosis 0/306 (0%) 2/304 (0.7%)
    Venous thrombosis limb 0/306 (0%) 1/304 (0.3%)
    Other (Not Including Serious) Adverse Events
    Everolimus and Low Dose Tacrolimus Mycophenolate Mofetil and Standard Dose Tacrolimus
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 302/306 (98.7%) 299/304 (98.4%)
    Blood and lymphatic system disorders
    Anaemia 83/306 (27.1%) 67/304 (22%)
    Leukocytosis 22/306 (7.2%) 31/304 (10.2%)
    Leukopenia 27/306 (8.8%) 65/304 (21.4%)
    Neutropenia 7/306 (2.3%) 24/304 (7.9%)
    Thrombocytopenia 22/306 (7.2%) 16/304 (5.3%)
    Cardiac disorders
    Tachycardia 22/306 (7.2%) 20/304 (6.6%)
    Gastrointestinal disorders
    Abdominal distension 17/306 (5.6%) 22/304 (7.2%)
    Abdominal pain 29/306 (9.5%) 35/304 (11.5%)
    Constipation 119/306 (38.9%) 120/304 (39.5%)
    Diarrhoea 74/306 (24.2%) 122/304 (40.1%)
    Dyspepsia 20/306 (6.5%) 23/304 (7.6%)
    Flatulence 10/306 (3.3%) 19/304 (6.3%)
    Gastrooesophageal reflux disease 18/306 (5.9%) 28/304 (9.2%)
    Nausea 111/306 (36.3%) 134/304 (44.1%)
    Vomiting 45/306 (14.7%) 64/304 (21.1%)
    General disorders
    Fatigue 58/306 (19%) 52/304 (17.1%)
    Oedema 32/306 (10.5%) 28/304 (9.2%)
    Oedema peripheral 113/306 (36.9%) 88/304 (28.9%)
    Pyrexia 41/306 (13.4%) 47/304 (15.5%)
    Infections and infestations
    BK virus infection 32/306 (10.5%) 41/304 (13.5%)
    Nasopharyngitis 13/306 (4.2%) 20/304 (6.6%)
    Upper respiratory tract infection 28/306 (9.2%) 33/304 (10.9%)
    Urinary tract infection 49/306 (16%) 68/304 (22.4%)
    Injury, poisoning and procedural complications
    Graft dysfunction 35/306 (11.4%) 32/304 (10.5%)
    Incision site pain 46/306 (15%) 54/304 (17.8%)
    Procedural pain 93/306 (30.4%) 94/304 (30.9%)
    Investigations
    Blood creatinine increased 49/306 (16%) 41/304 (13.5%)
    Weight increased 20/306 (6.5%) 14/304 (4.6%)
    Metabolism and nutrition disorders
    Decreased appetite 6/306 (2%) 23/304 (7.6%)
    Dehydration 17/306 (5.6%) 18/304 (5.9%)
    Diabetes mellitus 32/306 (10.5%) 30/304 (9.9%)
    Fluid overload 21/306 (6.9%) 23/304 (7.6%)
    Hypercalcaemia 12/306 (3.9%) 17/304 (5.6%)
    Hyperglycaemia 75/306 (24.5%) 81/304 (26.6%)
    Hyperkalaemia 93/306 (30.4%) 81/304 (26.6%)
    Hyperlipidaemia 71/306 (23.2%) 31/304 (10.2%)
    Hyperphosphataemia 23/306 (7.5%) 25/304 (8.2%)
    Hypocalcaemia 46/306 (15%) 40/304 (13.2%)
    Hypoglycaemia 20/306 (6.5%) 23/304 (7.6%)
    Hypokalaemia 56/306 (18.3%) 54/304 (17.8%)
    Hypomagnesaemia 102/306 (33.3%) 124/304 (40.8%)
    Hyponatraemia 11/306 (3.6%) 21/304 (6.9%)
    Hypophosphataemia 108/306 (35.3%) 94/304 (30.9%)
    Metabolic acidosis 35/306 (11.4%) 39/304 (12.8%)
    Vitamin D deficiency 21/306 (6.9%) 25/304 (8.2%)
    Musculoskeletal and connective tissue disorders
    Arthralgia 31/306 (10.1%) 23/304 (7.6%)
    Back pain 21/306 (6.9%) 23/304 (7.6%)
    Muscle spasms 15/306 (4.9%) 20/304 (6.6%)
    Pain in extremity 28/306 (9.2%) 24/304 (7.9%)
    Nervous system disorders
    Dizziness 26/306 (8.5%) 36/304 (11.8%)
    Headache 44/306 (14.4%) 53/304 (17.4%)
    Hypoaesthesia 17/306 (5.6%) 9/304 (3%)
    Tremor 51/306 (16.7%) 86/304 (28.3%)
    Psychiatric disorders
    Anxiety 17/306 (5.6%) 33/304 (10.9%)
    Insomnia 68/306 (22.2%) 71/304 (23.4%)
    Renal and urinary disorders
    Dysuria 24/306 (7.8%) 25/304 (8.2%)
    Haematuria 30/306 (9.8%) 33/304 (10.9%)
    Proteinuria 31/306 (10.1%) 19/304 (6.3%)
    Renal tubular necrosis 20/306 (6.5%) 19/304 (6.3%)
    Urinary retention 17/306 (5.6%) 13/304 (4.3%)
    Respiratory, thoracic and mediastinal disorders
    Cough 28/306 (9.2%) 43/304 (14.1%)
    Dyspnoea 40/306 (13.1%) 49/304 (16.1%)
    Oropharyngeal pain 23/306 (7.5%) 24/304 (7.9%)
    Skin and subcutaneous tissue disorders
    Acne 20/306 (6.5%) 7/304 (2.3%)
    Alopecia 6/306 (2%) 18/304 (5.9%)
    Pruritus 32/306 (10.5%) 32/304 (10.5%)
    Rash 24/306 (7.8%) 12/304 (3.9%)
    Vascular disorders
    Hypertension 64/306 (20.9%) 71/304 (23.4%)
    Hypotension 25/306 (8.2%) 29/304 (9.5%)

    Limitations/Caveats

    HLA mismatches ≥3, everolimus group 261 vs MMF group 240

    More Information

    Certain Agreements

    Principal Investigators are NOT employed by the organization sponsoring the study.

    The terms and conditions of Novartis' agreements with its investigators may vary. However, Novartis does not prohibit any investigator from publishing. Any publications from a single-site are postponed until the publication of the pooled data (i.e., data from all sites) in the clinical trial; or disclosure of the trial results in their entirety.

    Results Point of Contact

    Name/Title Study Director
    Organization Novartis
    Phone +1 (862) 778-8300
    Email
    Responsible Party:
    Novartis Pharmaceuticals
    ClinicalTrials.gov Identifier:
    NCT01025817
    Other Study ID Numbers:
    • CRAD001AUS92
    First Posted:
    Dec 4, 2009
    Last Update Posted:
    Nov 11, 2015
    Last Verified:
    Oct 1, 2015