NOCTET: Nordic Everolimus (Certican) Trial in Heart and Lung Transplantation

Sponsor
Novartis Pharmaceuticals (Industry)
Overall Status
Completed
CT.gov ID
NCT00377962
Collaborator
(none)
282
6
2
50
47
0.9

Study Details

Study Description

Brief Summary

This study investigated whether initiation of everolimus together with reduction of calcineurin inhibitors (CNI) in maintenance heart or lung transplant patients with renal impairment would improve renal function.

Condition or Disease Intervention/Treatment Phase
Phase 4

Study Design

Study Type:
Interventional
Actual Enrollment :
282 participants
Allocation:
Randomized
Intervention Model:
Parallel Assignment
Masking:
None (Open Label)
Primary Purpose:
Prevention
Official Title:
Nordic Everolimus (Certican) Trial in Heart and Lung Transplantation: Results at 24 Months
Study Start Date :
Dec 1, 2005
Actual Primary Completion Date :
Feb 1, 2010
Actual Study Completion Date :
Feb 1, 2010

Arms and Interventions

Arm Intervention/Treatment
Experimental: Everolimus + CNI reduction

Everolimus (3-8 ng/mL) + CNI reduction ± MPA/AZA ± steroids. Everolimus 0.75-1.5 mg twice daily. Dose adjusted to target blood concentration in the range 3-8 ng/mL. CNI reduction (reduced 50-70%): target of achieving a cyclosporine A (CsA) trough level < 75 ng/mL or a tacrolimus trough level < 4 ng/mL. MPA was reduced by 25%,upon CNI reduction. If participants were treated with AZA ( alternative to MPA) no dose reduction was needed. Steroid treatment was according to local practice.

Drug: Everolimus
0.75-1.5 mg twice daily. At the week 1 visit and thereafter, the dose was adjusted to target blood concentration in the range 3-8 ng/mL.
Other Names:
  • Certican
  • Drug: Calcineurin inhibitors (CNI)
    Calcineurin inhibitors include cyclosporine, pimecrolimus, and tacrolimus.

    Drug: Steroids
    Steroid treatment was according to local practice. If steroids were given, the baseline dose of prednisone or equivalent was to be kept unchanged for all treatment groups for the total study duration, unless a medical condition dictated a change.

    Active Comparator: Control

    CNI ± MPA/AZA ± steroids. In the standard CNI arm, all immunosuppressants including mycophenolic acid (MPA) and azathioprine (AZA) continued unchanged as per local practice. Steroid treatment was according to local practice.

    Drug: Mycophenolic acid (MPA)/azathioprine (AZA)
    In the standard CNI arm, all immunosuppressants including (MPA) and azathioprine (AZA) continued unchanged as per local practice.
    Other Names:
  • Neoral®/Prograf®
  • Drug: Calcineurin inhibitors (CNI)
    Calcineurin inhibitors include cyclosporine, pimecrolimus, and tacrolimus.

    Drug: Steroids
    Steroid treatment was according to local practice. If steroids were given, the baseline dose of prednisone or equivalent was to be kept unchanged for all treatment groups for the total study duration, unless a medical condition dictated a change.

    Outcome Measures

    Primary Outcome Measures

    1. Change in Measured Glomerular Filtration Rate (mGFR) From Baseline to Month 12 [Baseline to Month 12]

      Renal function was assessed by determining the measured glomerular filtration rate (mGFR) using creatinine ethylenediamine tetraacetic acid (Cr-EDTA) clearance or an equivalent method. A positive change score indicates improved renal function.

    Secondary Outcome Measures

    1. Change in Measured Glomerular Filtration Rate (mGFR) From Baseline to End of Study (Month 24) [Baseline to end of study (Month 24)]

      Renal function was assessed by determining the measured glomerular filtration rate (mGFR) using creatinine ethylenediamine tetraacetic acid (Cr-EDTA) clearance or an equivalent method. A positive change score indicates improved renal function.

    2. Change in Serum Creatinine From Baseline to End of Study (Month 24) [Baseline to end of study (Month 24)]

      Renal function was assessed by determining serum creatinine using standard laboratory methods. A positive change score indicates improved renal function.

    3. Number of Patients With Biopsy-proven Acute Rejection From Month 12 to End of Study (Month 24) [Month 12 to end of study (Month 24)]

      Biopsy-proved acute rejection was defined as a treated acute rejection confirmed by biopsy, graded locally according to the International Society for Heart & Lung Transplantation (ISHLT) criteria. A treated acute rejection was defined as an acute rejection clinically suspected, whether biopsy-proven or not, which had been treated and confirmed by the investigator according to the response to therapy.

    4. Number of Patients Who Died and Number of Patients With Graft Loss From Month 12 to End of Study (Month 24) [Month 12 to end of study (Month 24)]

      Number of patients not alive and number of patients with loss of their graft.

    5. Number of Patients in Need of Dialysis From Month 12 to End of Study (Month 24) [Month 12 to end of study (Month 24)]

    6. Change in Forced Expiratory Volume in 1 Second (FEV1) From Baseline to End of Study (Month 24) in the Lung Transplant Subgroup [Baseline to end of study (Month 24)]

      Forced expiratory volume in 1 second (FEV1) was measured by spirometry conducted according to internationally accepted standards. FEV1 is the volume delivered in the first second of a forced vital capacity (FVC) maneuver. A positive change score indicates improved lung function.

    7. Change in Forced Vital Capacity (FVC) From Baseline to End of Study (Month 24) in the Lung Transplant Subgroup [Baseline to end of study (Month 24)]

      Forced vital capacity (FVC) was measured by spirometry conducted according to internationally accepted standards. FVC is the volume delivered during an expiration made as forcefully and completely as possible starting from full inspiration. A positive change score indicates improved lung function.

    8. Change in Left Ventricular Function (Diameter and Thickness Parameters) From Baseline to End of Study (Month 24) in the Heart Transplant Subgroup [Baseline to end of study (Month 24)]

      Left ventricular function was assessed by echocardiography which was performed according to local routine practice. Echocardiography parameters were left ventricular end diastolic diameter (LVEDD), left ventricular end systolic diameter (LVESD), interventricular septal wall thickness (IVSTd), and posterior wall thickness (PWTd). A positive change score indicates improved left ventricular function.

    9. Change in Left Ventricular Function (Filling and Ejection Fraction Parameters) From Baseline to End of Study (Month 24) in the Heart Transplant Subgroup [Baseline to end of study (Month 24)]

      Left ventricular function was assessed by echocardiography which was performed according to local routine practice. Echocardiography parameters were filling fraction (FF) and ejection fraction (EF). A positive change score indicates improved left ventricular function.

    10. Mean Days of Hospitalization From Baseline to End of Study (Month 24) [Baseline to end of study (Month 24)]

    11. Number of Patients Discontinued From the Study Due to Adverse Events From Month 12 to End of Study (Month 24) [Month 12 to end of study (Month 24)]

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    18 Years to 65 Years
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No
    Inclusion criteria:
    • Patients who have undergone a heart or lung transplantation more than 12 months ago.

    • Patients receiving Neoral® or Prograf®.

    • Patients with a measured or calculated glomerular filtration rate (GFR) > 20 and < 70 mL/min/1.73m2. For patients with a GFR > 60 and < 70 mL/min/1.73m2, a deteriorated renal function since the time of transplantation must be documented by at least one post-transplant GFR level that is > 10% above the GFR level at the time of inclusion.

    • Patients willing and capable of giving written informed consent for study participation and able to participate in the study for 12 months.

    • Females of potential childbearing age must have a negative serum pregnancy test within 7 days prior to enrollment. Effective contraception must be used during the trial and for 6 weeks following discontinuation of the study medication, even where there has been a history of infertility.

    Exclusion criteria:
    • Patients who are recipients of multiple organ transplants.

    • Patients with measured GFR < 20 mL/min/1.73m2 or > 70 mL/min/1.73m2.

    • Patients with a treated acute rejection episode within the last 3 months.

    • Patients with a platelet count of < 50,000/mm3 or with a white blood cell count of ≤ 2,500/mm3 or with a hemoglobin value < 8 g/dL.

    • Presence of severe hypercholesterolemia (≥ 8.0 mmol/L) or hypertriglyceridemia (≥ 6.0 mmol/L) despite conventional lipid lowering treatment.

    • Patients currently treated or who have been treated with a mammalian target of rapamycin (mTOR) inhibitor.

    • Patients who have received an investigational drug within 4 weeks.

    • Patients who are human immunodeficiency virus positive or who have a current severe systemic infection requiring continued therapy according to investigator judgment.

    • Present use of any immunosuppressive drugs other than Neoral®/Prograf®, mycophenolic acid/azathioprine (MPA/AZA), and/or steroids.

    • Patients with a known hypersensitivity to drugs similar to everolimus.

    • Symptoms of significant mental illness which, in the opinion of the investigator, may interfere with the patient's ability to comply with the protocol. History of drug or alcohol abuse within 1 year of baseline.

    • Inability to cooperate or communicate with the investigator.

    • Patients with any past (within the last 5 years) or present malignancy other than excised squamous or basal cell carcinoma.

    • Females of childbearing potential that are planning to become pregnant, who are pregnant and/or lactating, or who are unwilling to use effective means of contraception.

    • Patients with a planned coronary revascularization or patients who have experienced a major adverse cardiovascular event (MACE) within the last 3 months.

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 Novartis Investigative Site Arhus Denmark DK-8200
    2 Novartis Investigative Site Copenhagen Denmark 2100
    3 Novartis Investigative Site Oslo Norway
    4 Novartis Investigative Site Goteborg Sweden 413 45
    5 Novartis Investigative Site Linkoping Sweden 581 85
    6 Novartis Investigative Site Lund Sweden 22185

    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:
    NCT00377962
    Other Study ID Numbers:
    • CRAD001AIC01
    First Posted:
    Sep 19, 2006
    Last Update Posted:
    Jul 30, 2020
    Last Verified:
    Jul 1, 2020
    Individual Participant Data (IPD) Sharing Statement:
    Undecided
    Plan to Share IPD:
    Undecided
    Keywords provided by Novartis Pharmaceuticals
    Additional relevant MeSH terms:

    Study Results

    Participant Flow

    Recruitment Details This was a 12-month study in maintenance heart and lung transplant patients with a follow-up period of an additional 12 months. Results to 24 months are presented. Patients were randomized to continue their current calcineurin inhibitors (CNI) based regimen or to start everolimus with reduction of CNI blood levels.
    Pre-assignment Detail
    Arm/Group Title Everolimus + CNI Reduction Control
    Arm/Group Description Everolimus (3-8 ng/mL) + CNI reduction ± MPA/AZA ± steroids. Everolimus 0.75-1.5 mg twice daily. Dose adjusted to target blood concentration in the range 3-8 ng/mL. CNI reduction (reduced 50-70%): target of achieving a cyclosporine A (CsA) trough level < 75 ng/mL or a tacrolimus trough level < 4 ng/mL. MPA was reduced by 25%,upon CNI reduction. If participants were treated with AZA ( alternative to MPA) no dose reduction was needed. Steroid treatment was according to local practice CNI ± MPA/AZA ± steroids. In the standard CNI arm, all immunosuppressants including mycophenolic acid (MPA) and azathioprine (AZA) continued unchanged as per local practice. Steroid treatment was according to local practice.
    Period Title: Core Study: 0-12 Months
    STARTED 140 142
    COMPLETED 112 133
    NOT COMPLETED 28 9
    Period Title: Core Study: 0-12 Months
    STARTED 108 127
    COMPLETED 98 123
    NOT COMPLETED 10 4

    Baseline Characteristics

    Arm/Group Title Everolimus + CNI Reduction Control Total
    Arm/Group Description Everolimus (3-8 ng/mL) + CNI reduction ± MPA/AZA ± steroids. Everolimus 0.75-1.5 mg twice daily. Dose adjusted to target blood concentration in the range 3-8 ng/mL. CNI reduction (reduced 50-70%): target of achieving a cyclosporine A (CsA) trough level < 75 ng/mL or a tacrolimus trough level < 4 ng/mL. MPA was reduced by 25%,upon CNI reduction. If participants were treated with AZA ( alternative to MPA) no dose reduction was needed. Steroid treatment was according to local practice CNI ± MPA/AZA ± steroids. In the standard CNI arm, all immunosuppressants including mycophenolic acid (MPA) and azathioprine (AZA) continued unchanged as per local practice. Steroid treatment was according to local practice. Total of all reporting groups
    Overall Participants 140 142 282
    Age (years) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [years]
    59.2
    (9.5)
    56.4
    (10.7)
    57.8
    (9.96)
    Sex: Female, Male (Count of Participants)
    Female
    37
    26.4%
    40
    28.2%
    77
    27.3%
    Male
    103
    73.6%
    102
    71.8%
    205
    72.7%

    Outcome Measures

    1. Primary Outcome
    Title Change in Measured Glomerular Filtration Rate (mGFR) From Baseline to Month 12
    Description Renal function was assessed by determining the measured glomerular filtration rate (mGFR) using creatinine ethylenediamine tetraacetic acid (Cr-EDTA) clearance or an equivalent method. A positive change score indicates improved renal function.
    Time Frame Baseline to Month 12

    Outcome Measure Data

    Analysis Population Description
    Intent-to-treat (ITT) population: All randomized patients who were given at least 1 dose of study drug and had at least 1 post-baseline assessment.
    Arm/Group Title Everolimus + CNI Reduction Control
    Arm/Group Description Everolimus (3-8 ng/mL) + CNI reduction ± MPA/AZA ± steroids. Everolimus 0.75-1.5 mg twice daily. Dose adjusted to target blood concentration in the range 3-8 ng/mL. CNI reduction (reduced 50-70%): target of achieving a cyclosporine A (CsA) trough level < 75 ng/mL or a tacrolimus trough level < 4 ng/mL. MPA was reduced by 25%,upon CNI reduction. If participants were treated with AZA ( alternative to MPA) no dose reduction was needed. Steroid treatment was according to local practice CNI ± MPA/AZA ± steroids. In the standard CNI arm, all immunosuppressants including mycophenolic acid (MPA) and azathioprine (AZA) continued unchanged as per local practice. Steroid treatment was according to local practice.
    Measure Participants 114 132
    Baseline
    48.6
    (15.1)
    48.0
    (13.2)
    Month 12
    53.2
    (15.7)
    47.5
    (16.1)
    Change from Baseline
    4.6
    (10.4)
    -0.5
    (9.0)
    2. Secondary Outcome
    Title Change in Measured Glomerular Filtration Rate (mGFR) From Baseline to End of Study (Month 24)
    Description Renal function was assessed by determining the measured glomerular filtration rate (mGFR) using creatinine ethylenediamine tetraacetic acid (Cr-EDTA) clearance or an equivalent method. A positive change score indicates improved renal function.
    Time Frame Baseline to end of study (Month 24)

    Outcome Measure Data

    Analysis Population Description
    Intent-to-treat (ITT) population: All randomized patients who were given at least 1 dose of study drug and had at least 1 post-baseline assessment.
    Arm/Group Title Everolimus + CNI Reduction Control
    Arm/Group Description Everolimus (3-8 ng/mL) + CNI reduction ± MPA/AZA ± steroids. Everolimus 0.75-1.5 mg twice daily. Dose adjusted to target blood concentration in the range 3-8 ng/mL. CNI reduction (reduced 50-70%): target of achieving a cyclosporine A (CsA) trough level < 75 ng/mL or a tacrolimus trough level < 4 ng/mL. MPA was reduced by 25%,upon CNI reduction. If participants were treated with AZA ( alternative to MPA) no dose reduction was needed. Steroid treatment was according to local practice CNI ± MPA/AZA ± steroids. In the standard CNI arm, all immunosuppressants including mycophenolic acid (MPA) and azathioprine (AZA) continued unchanged as per local practice. Steroid treatment was according to local practice.
    Measure Participants 103 119
    Month 0
    49.3
    (14.7)
    49.1
    (13.0)
    Month 24
    52.5
    (16.4)
    46.8
    (15.2)
    Change
    3.2
    (12.3)
    -2.4
    (9.0)
    3. Secondary Outcome
    Title Change in Serum Creatinine From Baseline to End of Study (Month 24)
    Description Renal function was assessed by determining serum creatinine using standard laboratory methods. A positive change score indicates improved renal function.
    Time Frame Baseline to end of study (Month 24)

    Outcome Measure Data

    Analysis Population Description
    Intent-to-treat (ITT) population: All randomized patients who were given at least 1 dose of study drug and had at least 1 post-baseline assessment.
    Arm/Group Title Everolimus + CNI Reduction Control
    Arm/Group Description Everolimus (3-8 ng/mL) + CNI reduction ± MPA/AZA ± steroids. Everolimus 0.75-1.5 mg twice daily. Dose adjusted to target blood concentration in the range 3-8 ng/mL. CNI reduction (reduced 50-70%): target of achieving a cyclosporine A (CsA) trough level < 75 ng/mL or a tacrolimus trough level < 4 ng/mL. MPA was reduced by 25%,upon CNI reduction. If participants were treated with AZA ( alternative to MPA) no dose reduction was needed. Steroid treatment was according to local practice CNI ± MPA/AZA ± steroids. In the standard CNI arm, all immunosuppressants including mycophenolic acid (MPA) and azathioprine (AZA) continued unchanged as per local practice. Steroid treatment was according to local practice.
    Measure Participants 114 132
    Month 0
    126
    (30)
    129
    (29)
    Month 24
    126
    (64)
    132
    (37)
    Change
    0
    (53)
    3
    (23)
    4. Secondary Outcome
    Title Number of Patients With Biopsy-proven Acute Rejection From Month 12 to End of Study (Month 24)
    Description Biopsy-proved acute rejection was defined as a treated acute rejection confirmed by biopsy, graded locally according to the International Society for Heart & Lung Transplantation (ISHLT) criteria. A treated acute rejection was defined as an acute rejection clinically suspected, whether biopsy-proven or not, which had been treated and confirmed by the investigator according to the response to therapy.
    Time Frame Month 12 to end of study (Month 24)

    Outcome Measure Data

    Analysis Population Description
    Intent-to-treat (ITT) population: All randomized patients who were given at least 1 dose of study drug and had at least 1 post-baseline assessment.
    Arm/Group Title Everolimus + CNI Reduction Control
    Arm/Group Description Everolimus (3-8 ng/mL) + CNI reduction ± MPA/AZA ± steroids. Everolimus 0.75-1.5 mg twice daily. Dose adjusted to target blood concentration in the range 3-8 ng/mL. CNI reduction (reduced 50-70%): target of achieving a cyclosporine A (CsA) trough level < 75 ng/mL or a tacrolimus trough level < 4 ng/mL. MPA was reduced by 25%,upon CNI reduction. If participants were treated with AZA ( alternative to MPA) no dose reduction was needed. Steroid treatment was according to local practice CNI ± MPA/AZA ± steroids. In the standard CNI arm, all immunosuppressants including mycophenolic acid (MPA) and azathioprine (AZA) continued unchanged as per local practice. Steroid treatment was according to local practice.
    Measure Participants 108 127
    Number [Participants]
    6
    4.3%
    5
    3.5%
    5. Secondary Outcome
    Title Number of Patients Who Died and Number of Patients With Graft Loss From Month 12 to End of Study (Month 24)
    Description Number of patients not alive and number of patients with loss of their graft.
    Time Frame Month 12 to end of study (Month 24)

    Outcome Measure Data

    Analysis Population Description
    Intent-to-treat (ITT) population: All randomized patients who were given at least 1 dose of study drug and had at least 1 post-baseline assessment.
    Arm/Group Title Everolimus + CNI Reduction Control
    Arm/Group Description Everolimus (3-8 ng/mL) + CNI reduction ± MPA/AZA ± steroids. Everolimus 0.75-1.5 mg twice daily. Dose adjusted to target blood concentration in the range 3-8 ng/mL. CNI reduction (reduced 50-70%): target of achieving a cyclosporine A (CsA) trough level < 75 ng/mL or a tacrolimus trough level < 4 ng/mL. MPA was reduced by 25%,upon CNI reduction. If participants were treated with AZA ( alternative to MPA) no dose reduction was needed. Steroid treatment was according to local practice CNI ± MPA/AZA ± steroids. In the standard CNI arm, all immunosuppressants including mycophenolic acid (MPA) and azathioprine (AZA) continued unchanged as per local practice. Steroid treatment was according to local practice.
    Measure Participants 108 127
    Death
    3
    2.1%
    0
    0%
    Graft Loss
    0
    0%
    0
    0%
    6. Secondary Outcome
    Title Number of Patients in Need of Dialysis From Month 12 to End of Study (Month 24)
    Description
    Time Frame Month 12 to end of study (Month 24)

    Outcome Measure Data

    Analysis Population Description
    The intent-to-treat (ITT) population consisted of all patients as randomized, who were given at least one dose of study drug and had at least one post-baseline assessment. (Extension study)
    Arm/Group Title Everolimus + CNI Reduction Control
    Arm/Group Description Everolimus (3-8 ng/mL) + CNI reduction ± MPA/AZA ± steroids. Everolimus 0.75-1.5 mg twice daily. Dose adjusted to target blood concentration in the range 3-8 ng/mL. CNI reduction (reduced 50-70%): target of achieving a cyclosporine A (CsA) trough level < 75 ng/mL or a tacrolimus trough level < 4 ng/mL. MPA was reduced by 25%,upon CNI reduction. If participants were treated with AZA ( alternative to MPA) no dose reduction was needed. Steroid treatment was according to local practice CNI ± MPA/AZA ± steroids. In the standard CNI arm, all immunosuppressants including mycophenolic acid (MPA) and azathioprine (AZA) continued unchanged as per local practice. Steroid treatment was according to local practice.
    Measure Participants 108 127
    Number [Participants]
    0
    0%
    2
    1.4%
    7. Secondary Outcome
    Title Change in Forced Expiratory Volume in 1 Second (FEV1) From Baseline to End of Study (Month 24) in the Lung Transplant Subgroup
    Description Forced expiratory volume in 1 second (FEV1) was measured by spirometry conducted according to internationally accepted standards. FEV1 is the volume delivered in the first second of a forced vital capacity (FVC) maneuver. A positive change score indicates improved lung function.
    Time Frame Baseline to end of study (Month 24)

    Outcome Measure Data

    Analysis Population Description
    Patients in the lung transplant subgroup of the intent-to-treat (ITT) population which included all randomized patients who were given at least 1 dose of study drug and had at least 1 post-baseline assessment.
    Arm/Group Title Everolimus + CNI Reduction Control
    Arm/Group Description Everolimus (3-8 ng/mL) + CNI reduction ± MPA/AZA ± steroids. Everolimus 0.75-1.5 mg twice daily. Dose adjusted to target blood concentration in the range 3-8 ng/mL. CNI reduction (reduced 50-70%): target of achieving a cyclosporine A (CsA) trough level < 75 ng/mL or a tacrolimus trough level < 4 ng/mL. MPA was reduced by 25%,upon CNI reduction. If participants were treated with AZA ( alternative to MPA) no dose reduction was needed. Steroid treatment was according to local practice CNI ± MPA/AZA ± steroids. In the standard CNI arm, all immunosuppressants including mycophenolic acid (MPA) and azathioprine (AZA) continued unchanged as per local practice. Steroid treatment was according to local practice.
    Measure Participants 36 40
    Mean (Standard Deviation) [Liters]
    -0.2
    (0.2)
    -0.1
    (0.2)
    8. Secondary Outcome
    Title Change in Forced Vital Capacity (FVC) From Baseline to End of Study (Month 24) in the Lung Transplant Subgroup
    Description Forced vital capacity (FVC) was measured by spirometry conducted according to internationally accepted standards. FVC is the volume delivered during an expiration made as forcefully and completely as possible starting from full inspiration. A positive change score indicates improved lung function.
    Time Frame Baseline to end of study (Month 24)

    Outcome Measure Data

    Analysis Population Description
    Patients in the lung transplant subgroup of the intent-to-treat (ITT) population which included all randomized patients who were given at least 1 dose of study drug and had at least 1 post-baseline assessment.
    Arm/Group Title Everolimus + CNI Reduction Control
    Arm/Group Description Everolimus (3-8 ng/mL) + CNI reduction ± MPA/AZA ± steroids. Everolimus 0.75-1.5 mg twice daily. Dose adjusted to target blood concentration in the range 3-8 ng/mL. CNI reduction (reduced 50-70%): target of achieving a cyclosporine A (CsA) trough level < 75 ng/mL or a tacrolimus trough level < 4 ng/mL. MPA was reduced by 25%,upon CNI reduction. If participants were treated with AZA ( alternative to MPA) no dose reduction was needed. Steroid treatment was according to local practice CNI ± MPA/AZA ± steroids. In the standard CNI arm, all immunosuppressants including mycophenolic acid (MPA) and azathioprine (AZA) continued unchanged as per local practice. Steroid treatment was according to local practice.
    Measure Participants 36 40
    Mean (Standard Deviation) [Liters]
    -0.2
    (0.3)
    -0.1
    (0.4)
    9. Secondary Outcome
    Title Change in Left Ventricular Function (Diameter and Thickness Parameters) From Baseline to End of Study (Month 24) in the Heart Transplant Subgroup
    Description Left ventricular function was assessed by echocardiography which was performed according to local routine practice. Echocardiography parameters were left ventricular end diastolic diameter (LVEDD), left ventricular end systolic diameter (LVESD), interventricular septal wall thickness (IVSTd), and posterior wall thickness (PWTd). A positive change score indicates improved left ventricular function.
    Time Frame Baseline to end of study (Month 24)

    Outcome Measure Data

    Analysis Population Description
    Patients in the heart transplant subgroup of the intent-to-treat (ITT) population which included all randomized patients who were given at least 1 dose of study drug and had at least 1 post-baseline assessment.
    Arm/Group Title Everolimus + CNI Reduction Control
    Arm/Group Description Everolimus (3-8 ng/mL) + CNI reduction ± MPA/AZA ± steroids. Everolimus 0.75-1.5 mg twice daily. Dose adjusted to target blood concentration in the range 3-8 ng/mL. CNI reduction (reduced 50-70%): target of achieving a cyclosporine A (CsA) trough level < 75 ng/mL or a tacrolimus trough level < 4 ng/mL. MPA was reduced by 25%,upon CNI reduction. If participants were treated with AZA ( alternative to MPA) no dose reduction was needed. Steroid treatment was according to local practice CNI ± MPA/AZA ± steroids. In the standard CNI arm, all immunosuppressants including mycophenolic acid (MPA) and azathioprine (AZA) continued unchanged as per local practice. Steroid treatment was according to local practice.
    Measure Participants 56 73
    LVEDD
    -0.1
    (0.8)
    -0.0
    (0.4)
    LVESD
    0.1
    (0.7)
    0.1
    (0.6)
    IVSTd
    -0.4
    (2.4)
    -0.1
    (1.2)
    PWTd
    -0.5
    (2.1)
    -0.1
    (1.1)
    10. Secondary Outcome
    Title Change in Left Ventricular Function (Filling and Ejection Fraction Parameters) From Baseline to End of Study (Month 24) in the Heart Transplant Subgroup
    Description Left ventricular function was assessed by echocardiography which was performed according to local routine practice. Echocardiography parameters were filling fraction (FF) and ejection fraction (EF). A positive change score indicates improved left ventricular function.
    Time Frame Baseline to end of study (Month 24)

    Outcome Measure Data

    Analysis Population Description
    Patients in the heart transplant subgroup of the intent-to-treat (ITT) population which included all randomized patients who were given at least 1 dose of study drug and had at least 1 post-baseline assessment.
    Arm/Group Title Everolimus + CNI Reduction Control
    Arm/Group Description Everolimus (3-8 ng/mL) + CNI reduction ± MPA/AZA ± steroids. Everolimus 0.75-1.5 mg twice daily. Dose adjusted to target blood concentration in the range 3-8 ng/mL. CNI reduction (reduced 50-70%): target of achieving a cyclosporine A (CsA) trough level < 75 ng/mL or a tacrolimus trough level < 4 ng/mL. MPA was reduced by 25%,upon CNI reduction. If participants were treated with AZA ( alternative to MPA) no dose reduction was needed. Steroid treatment was according to local practice CNI ± MPA/AZA ± steroids. In the standard CNI arm, all immunosuppressants including mycophenolic acid (MPA) and azathioprine (AZA) continued unchanged as per local practice. Steroid treatment was according to local practice.
    Measure Participants 59 71
    EF
    -0.6
    (8.5)
    0.1
    (7.9)
    FF
    0
    (1)
    0
    (1)
    11. Secondary Outcome
    Title Mean Days of Hospitalization From Baseline to End of Study (Month 24)
    Description
    Time Frame Baseline to end of study (Month 24)

    Outcome Measure Data

    Analysis Population Description
    Intent-to-treat (ITT) population: All randomized patients who were given at least 1 dose of study drug and had at least 1 post-baseline assessment.
    Arm/Group Title Everolimus + CNI Reduction Control
    Arm/Group Description Everolimus (3-8 ng/mL) + CNI reduction ± MPA/AZA ± steroids. Everolimus 0.75-1.5 mg twice daily. Dose adjusted to target blood concentration in the range 3-8 ng/mL. CNI reduction (reduced 50-70%): target of achieving a cyclosporine A (CsA) trough level < 75 ng/mL or a tacrolimus trough level < 4 ng/mL. MPA was reduced by 25%,upon CNI reduction. If participants were treated with AZA ( alternative to MPA) no dose reduction was needed. Steroid treatment was according to local practice CNI ± MPA/AZA ± steroids. In the standard CNI arm, all immunosuppressants including mycophenolic acid (MPA) and azathioprine (AZA) continued unchanged as per local practice. Steroid treatment was according to local practice.
    Measure Participants 108 127
    Mean (Standard Deviation) [Days]
    8.5
    (7.4)
    16.2
    (19.3)
    12. Secondary Outcome
    Title Number of Patients Discontinued From the Study Due to Adverse Events From Month 12 to End of Study (Month 24)
    Description
    Time Frame Month 12 to end of study (Month 24)

    Outcome Measure Data

    Analysis Population Description
    Intent-to-treat (ITT) population: All randomized patients who were given at least 1 dose of study drug and had at least 1 post-baseline assessment.
    Arm/Group Title Everolimus + CNI Reduction Control
    Arm/Group Description Everolimus (3-8 ng/mL) + CNI reduction ± MPA/AZA ± steroids. Everolimus 0.75-1.5 mg twice daily. Dose adjusted to target blood concentration in the range 3-8 ng/mL. CNI reduction (reduced 50-70%): target of achieving a cyclosporine A (CsA) trough level < 75 ng/mL or a tacrolimus trough level < 4 ng/mL. MPA was reduced by 25%,upon CNI reduction. If participants were treated with AZA ( alternative to MPA) no dose reduction was needed. Steroid treatment was according to local practice CNI ± MPA/AZA ± steroids. In the standard CNI arm, all immunosuppressants including mycophenolic acid (MPA) and azathioprine (AZA) continued unchanged as per local practice. Steroid treatment was according to local practice.
    Measure Participants 108 127
    Total discontinued due to AE(s)
    8
    5.7%
    0
    0%
    Pulmonary embolism
    2
    1.4%
    0
    0%
    Skin problems
    1
    0.7%
    0
    0%
    Hypercholesterolemia
    1
    0.7%
    0
    0%
    Stroke
    1
    0.7%
    0
    0%
    Muscular pain
    1
    0.7%
    0
    0%
    Diarrhea
    1
    0.7%
    0
    0%
    Edema
    1
    0.7%
    0
    0%

    Adverse Events

    Time Frame 24 months
    Adverse Event Reporting Description Safety population stratified by sub groups (heart patients and lung patients) and duration of core study and extension study.
    Arm/Group Title Control: 12 Month Heart Everolimus + CNI Reduction: 12 Month Heart Control: 12 Month Lung Everolimus+CNI Reduction: 12 Month Lung Control: 24 Month Heart Everolimus + CNI Reduction: 24 Month Heart Control: 24 Month Lung Everolimus + CNI Reduction: 24 Month Lung
    Arm/Group Description Subgroup of "Control" group with heart patients at 12 months. CNI ± MPA/AZA ± steroids. In the standard CNI arm, all immunosuppressants including mycophenolic acid (MPA) and azathioprine (AZA) continued unchanged as per local practice. Steroid treatment was according to local practice. Subgroup of "everolimus + CNI reduction" group with heart patients at 12 months. Everolimus (3-8 ng/mL) + CNI reduction ± MPA/AZA ± steroids. Everolimus 0.75-1.5 mg twice daily. Dose adjusted to target blood concentration in the range 3-8 ng/mL. CNI reduction (reduced 50-70%): target of achieving a cyclosporine A (CsA) trough level < 75 ng/mL or a tacrolimus trough level < 4 ng/mL. MPA was reduced by 25%, upon CNI reduction. If participants were treated with AZA ( alternative to MPA) no dose reduction was needed. Steroid treatment was according to local practice. Subgroup of "control" group with lung patients at 12 months. CNI ± MPA/AZA ± steroids. In the standard CNI arm, all immunosuppressants including mycophenolic acid (MPA) and azathioprine (AZA) continued unchanged as per local practice. Steroid treatment was according to local practice. Subgroup of "everolimus + CNI reduction" group with lung patients at 12 months. Everolimus (3-8 ng/mL) + CNI reduction ± MPA/AZA ± steroids. Everolimus 0.75-1.5 mg twice daily. Dose adjusted to target blood concentration in the range 3-8 ng/mL. CNI reduction (reduced 50-70%): target of achieving a cyclosporine A (CsA) trough level < 75 ng/mL or a tacrolimus trough level < 4 ng/mL. MPA was reduced by 25%, upon CNI reduction. If participants were treated with AZA ( alternative to MPA) no dose reduction was needed. Steroid treatment was according to local practice. Subgroup of "Control" group with heart patients at 24 months. CNI ± MPA/AZA ± steroids. In the standard CNI arm, all immunosuppressants including mycophenolic acid (MPA) and azathioprine (AZA) continued unchanged as per local practice. Steroid treatment was according to local practice. Subgroup of "everolimus + CNI reduction" group with heart patients at 24 months. Everolimus (3-8 ng/mL) + CNI reduction ± MPA/AZA ± steroids. Everolimus 0.75-1.5 mg twice daily. Dose adjusted to target blood concentration in the range 3-8 ng/mL. CNI reduction (reduced 50-70%): target of achieving a cyclosporine A (CsA) trough level < 75 ng/mL or a tacrolimus trough level < 4 ng/mL. MPA was reduced by 25%, upon CNI reduction. If participants were treated with AZA ( alternative to MPA) no dose reduction was needed. Steroid treatment was according to local practice. Subgroup of "Control" group with lung patients at 24 months. CNI ± MPA/AZA ± steroids. In the standard CNI arm, all immunosuppressants including mycophenolic acid (MPA) and azathioprine (AZA) continued unchanged as per local practice. Steroid treatment was according to local practice. Subgroup of "everolimus + CNI reduction" group with lung patients at 24 months. Everolimus (3-8 ng/mL) + CNI reduction ± MPA/AZA ± steroids. Everolimus 0.75-1.5 mg twice daily. Dose adjusted to target blood concentration in the range 3-8 ng/mL. CNI reduction (reduced 50-70%): target of achieving a cyclosporine A (CsA) trough level < 75 ng/mL or a tacrolimus trough level < 4 ng/mL. MPA was reduced by 25%, upon CNI reduction. If participants were treated with AZA ( alternative to MPA) no dose reduction was needed. Steroid treatment was according to local practice.
    All Cause Mortality
    Control: 12 Month Heart Everolimus + CNI Reduction: 12 Month Heart Control: 12 Month Lung Everolimus+CNI Reduction: 12 Month Lung Control: 24 Month Heart Everolimus + CNI Reduction: 24 Month Heart Control: 24 Month Lung Everolimus + CNI Reduction: 24 Month Lung
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total / (NaN) / (NaN) / (NaN) / (NaN) / (NaN) / (NaN) / (NaN) / (NaN)
    Serious Adverse Events
    Control: 12 Month Heart Everolimus + CNI Reduction: 12 Month Heart Control: 12 Month Lung Everolimus+CNI Reduction: 12 Month Lung Control: 24 Month Heart Everolimus + CNI Reduction: 24 Month Heart Control: 24 Month Lung Everolimus + CNI Reduction: 24 Month Lung
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 23/96 (24%) 40/94 (42.6%) 17/46 (37%) 25/46 (54.3%) 31/86 (36%) 25/69 (36.2%) 21/41 (51.2%) 16/39 (41%)
    Blood and lymphatic system disorders
    Anaemia NOS 0/96 (0%) 0/94 (0%) 0/46 (0%) 1/46 (2.2%) 0/86 (0%) 0/69 (0%) 0/41 (0%) 0/39 (0%)
    Cardiac disorders
    Angina pectoris 0/96 (0%) 1/94 (1.1%) 0/46 (0%) 0/46 (0%) 0/86 (0%) 0/69 (0%) 0/41 (0%) 0/39 (0%)
    Aortic valve stenosis 0/96 (0%) 1/94 (1.1%) 0/46 (0%) 0/46 (0%) 1/86 (1.2%) 1/69 (1.4%) 1/41 (2.4%) 0/39 (0%)
    Atrial fibrillation 1/96 (1%) 0/94 (0%) 0/46 (0%) 0/46 (0%) 0/86 (0%) 1/69 (1.4%) 0/41 (0%) 0/39 (0%)
    Atrial flutter 0/96 (0%) 0/94 (0%) 1/46 (2.2%) 0/46 (0%) 1/86 (1.2%) 0/69 (0%) 1/41 (2.4%) 0/39 (0%)
    Atrial tachycardia 0/96 (0%) 0/94 (0%) 0/46 (0%) 0/46 (0%) 1/86 (1.2%) 0/69 (0%) 0/41 (0%) 0/39 (0%)
    Cardiac failure NOS 1/96 (1%) 1/94 (1.1%) 0/46 (0%) 0/46 (0%) 1/86 (1.2%) 0/69 (0%) 0/41 (0%) 0/39 (0%)
    Coronary artery atheroma haemorrhage 1/96 (1%) 0/94 (0%) 0/46 (0%) 0/46 (0%) 0/86 (0%) 0/69 (0%) 0/41 (0%) 0/39 (0%)
    Coronary artery disease NOS 1/96 (1%) 1/94 (1.1%) 0/46 (0%) 0/46 (0%) 1/86 (1.2%) 1/69 (1.4%) 0/41 (0%) 0/39 (0%)
    Oedema NOS 0/96 (0%) 3/94 (3.2%) 0/46 (0%) 0/46 (0%) 1/86 (1.2%) 1/69 (1.4%) 0/41 (0%) 0/39 (0%)
    Pulmonary oedema NOS 0/96 (0%) 0/94 (0%) 0/46 (0%) 0/46 (0%) 0/86 (0%) 0/69 (0%) 1/41 (2.4%) 0/39 (0%)
    Right ventricular failure 0/96 (0%) 0/94 (0%) 0/46 (0%) 0/46 (0%) 1/86 (1.2%) 0/69 (0%) 0/41 (0%) 0/39 (0%)
    Supraventricular tachycardia 0/96 (0%) 0/94 (0%) 0/46 (0%) 0/46 (0%) 1/86 (1.2%) 0/69 (0%) 0/41 (0%) 0/39 (0%)
    Endocrine disorders
    Hyperthyroidism 0/96 (0%) 0/94 (0%) 0/46 (0%) 0/46 (0%) 0/86 (0%) 0/69 (0%) 1/41 (2.4%) 0/39 (0%)
    Gastrointestinal disorders
    Abdominal pain NOS 0/96 (0%) 1/94 (1.1%) 0/46 (0%) 0/46 (0%) 0/86 (0%) 0/69 (0%) 0/41 (0%) 0/39 (0%)
    Acute abdomen 0/96 (0%) 0/94 (0%) 0/46 (0%) 0/46 (0%) 1/86 (1.2%) 1/69 (1.4%) 0/41 (0%) 0/39 (0%)
    Appendicitis 0/96 (0%) 1/94 (1.1%) 0/46 (0%) 0/46 (0%) 0/86 (0%) 0/69 (0%) 0/41 (0%) 0/39 (0%)
    Diarrhoea NOS 0/96 (0%) 2/94 (2.1%) 1/46 (2.2%) 0/46 (0%) 1/86 (1.2%) 1/69 (1.4%) 0/41 (0%) 0/39 (0%)
    Diverticulitis NOS 0/96 (0%) 1/94 (1.1%) 1/46 (2.2%) 0/46 (0%) 0/86 (0%) 0/69 (0%) 1/41 (2.4%) 0/39 (0%)
    Food poisoning NOS 1/96 (1%) 0/94 (0%) 0/46 (0%) 0/46 (0%) 0/86 (0%) 0/69 (0%) 0/41 (0%) 0/39 (0%)
    Gastric ulcer 0/96 (0%) 0/94 (0%) 0/46 (0%) 0/46 (0%) 1/86 (1.2%) 0/69 (0%) 0/41 (0%) 0/39 (0%)
    Gastric ulcer perforation 0/96 (0%) 0/94 (0%) 0/46 (0%) 0/46 (0%) 0/86 (0%) 0/69 (0%) 1/41 (2.4%) 0/39 (0%)
    Gastrointestinal haemorrhage NOS 0/96 (0%) 0/94 (0%) 0/46 (0%) 1/46 (2.2%) 0/86 (0%) 0/69 (0%) 0/41 (0%) 0/39 (0%)
    Ileus 0/96 (0%) 0/94 (0%) 0/46 (0%) 0/46 (0%) 0/86 (0%) 1/69 (1.4%) 0/41 (0%) 0/39 (0%)
    Inguinal hernia NOS 0/96 (0%) 1/94 (1.1%) 0/46 (0%) 0/46 (0%) 0/86 (0%) 1/69 (1.4%) 0/41 (0%) 0/39 (0%)
    Nausea 0/96 (0%) 1/94 (1.1%) 0/46 (0%) 0/46 (0%) 0/86 (0%) 0/69 (0%) 0/41 (0%) 0/39 (0%)
    Pancreatitis NOS 1/96 (1%) 0/94 (0%) 0/46 (0%) 0/46 (0%) 0/86 (0%) 0/69 (0%) 0/41 (0%) 0/39 (0%)
    Peptic ulcer 0/96 (0%) 1/94 (1.1%) 0/46 (0%) 0/46 (0%) 0/86 (0%) 0/69 (0%) 0/41 (0%) 0/39 (0%)
    Rectal disorder NOS 0/96 (0%) 0/94 (0%) 1/46 (2.2%) 0/46 (0%) 0/86 (0%) 0/69 (0%) 0/41 (0%) 0/39 (0%)
    Vomiting NOS 0/96 (0%) 2/94 (2.1%) 0/46 (0%) 0/46 (0%) 0/86 (0%) 0/69 (0%) 0/41 (0%) 0/39 (0%)
    General disorders
    Chest pain 0/96 (0%) 0/94 (0%) 0/46 (0%) 0/46 (0%) 1/86 (1.2%) 1/69 (1.4%) 0/41 (0%) 0/39 (0%)
    Compartment syndrome 0/96 (0%) 0/94 (0%) 0/46 (0%) 0/46 (0%) 0/86 (0%) 1/69 (1.4%) 0/41 (0%) 0/39 (0%)
    Death NOS 0/96 (0%) 0/94 (0%) 0/46 (0%) 0/46 (0%) 1/86 (1.2%) 0/69 (0%) 0/41 (0%) 1/39 (2.6%)
    Fatigue 0/96 (0%) 0/94 (0%) 0/46 (0%) 0/46 (0%) 1/86 (1.2%) 0/69 (0%) 0/41 (0%) 0/39 (0%)
    Haemorrhage NOS 0/96 (0%) 1/94 (1.1%) 0/46 (0%) 0/46 (0%) 0/86 (0%) 0/69 (0%) 0/41 (0%) 0/39 (0%)
    Malaise 0/96 (0%) 0/94 (0%) 0/46 (0%) 0/46 (0%) 0/86 (0%) 0/69 (0%) 1/41 (2.4%) 0/39 (0%)
    Pain NOS 0/96 (0%) 1/94 (1.1%) 0/46 (0%) 0/46 (0%) 0/86 (0%) 0/69 (0%) 0/41 (0%) 0/39 (0%)
    Pyrexia 1/96 (1%) 3/94 (3.2%) 0/46 (0%) 0/46 (0%) 0/86 (0%) 0/69 (0%) 0/41 (0%) 0/39 (0%)
    Hepatobiliary disorders
    Cholelithiasis 1/96 (1%) 0/94 (0%) 0/46 (0%) 0/46 (0%) 0/86 (0%) 0/69 (0%) 0/41 (0%) 0/39 (0%)
    Immune system disorders
    Graft rejection 1/96 (1%) 0/94 (0%) 0/46 (0%) 0/46 (0%) 1/86 (1.2%) 0/69 (0%) 0/41 (0%) 0/39 (0%)
    Heart transplant rejection 0/96 (0%) 1/94 (1.1%) 0/46 (0%) 0/46 (0%) 1/86 (1.2%) 0/69 (0%) 0/41 (0%) 0/39 (0%)
    Hypersensitivity NOS 0/96 (0%) 1/94 (1.1%) 0/46 (0%) 1/46 (2.2%) 0/86 (0%) 0/69 (0%) 0/41 (0%) 0/39 (0%)
    Infections and infestations
    Brain abscess NOS 0/96 (0%) 0/94 (0%) 0/46 (0%) 0/46 (0%) 0/86 (0%) 0/69 (0%) 1/41 (2.4%) 0/39 (0%)
    Bronchitis NOS 0/96 (0%) 1/94 (1.1%) 0/46 (0%) 0/46 (0%) 0/86 (0%) 0/69 (0%) 1/41 (2.4%) 0/39 (0%)
    Bronchitis acute NOS 0/96 (0%) 0/94 (0%) 2/46 (4.3%) 0/46 (0%) 0/86 (0%) 0/69 (0%) 1/41 (2.4%) 1/39 (2.6%)
    Cholecystitis acute NOS 0/96 (0%) 1/94 (1.1%) 0/46 (0%) 0/46 (0%) 0/86 (0%) 0/69 (0%) 0/41 (0%) 0/39 (0%)
    Cystitis NOS 0/96 (0%) 0/94 (0%) 0/46 (0%) 1/46 (2.2%) 0/86 (0%) 0/69 (0%) 0/41 (0%) 0/39 (0%)
    Cytomegalovirus infection 0/96 (0%) 0/94 (0%) 0/46 (0%) 0/46 (0%) 1/86 (1.2%) 0/69 (0%) 0/41 (0%) 0/39 (0%)
    Ear infection NOS 0/96 (0%) 0/94 (0%) 0/46 (0%) 0/46 (0%) 0/86 (0%) 1/69 (1.4%) 0/41 (0%) 0/39 (0%)
    Epididymitis NOS 0/96 (0%) 1/94 (1.1%) 0/46 (0%) 0/46 (0%) 0/86 (0%) 0/69 (0%) 0/41 (0%) 0/39 (0%)
    Erysipelas 1/96 (1%) 0/94 (0%) 0/46 (0%) 0/46 (0%) 1/86 (1.2%) 1/69 (1.4%) 0/41 (0%) 0/39 (0%)
    Gastroenteritis NOS 2/96 (2.1%) 0/94 (0%) 0/46 (0%) 0/46 (0%) 2/86 (2.3%) 2/69 (2.9%) 0/41 (0%) 0/39 (0%)
    Herpes simplex 0/96 (0%) 0/94 (0%) 0/46 (0%) 0/46 (0%) 0/86 (0%) 1/69 (1.4%) 0/41 (0%) 0/39 (0%)
    Herpes zoster 0/96 (0%) 2/94 (2.1%) 0/46 (0%) 0/46 (0%) 0/86 (0%) 1/69 (1.4%) 0/41 (0%) 1/39 (2.6%)
    Infection NOS 0/96 (0%) 1/94 (1.1%) 1/46 (2.2%) 0/46 (0%) 1/86 (1.2%) 0/69 (0%) 0/41 (0%) 0/39 (0%)
    Influenza 0/96 (0%) 0/94 (0%) 1/46 (2.2%) 0/46 (0%) 1/86 (1.2%) 0/69 (0%) 1/41 (2.4%) 1/39 (2.6%)
    Lobar pneumonia NOS 0/96 (0%) 1/94 (1.1%) 0/46 (0%) 0/46 (0%) 0/86 (0%) 0/69 (0%) 0/41 (0%) 0/39 (0%)
    Localised infection 1/96 (1%) 0/94 (0%) 0/46 (0%) 0/46 (0%) 0/86 (0%) 0/69 (0%) 0/41 (0%) 0/39 (0%)
    Lower respiratory tract infection NOS 0/96 (0%) 1/94 (1.1%) 0/46 (0%) 0/46 (0%) 0/86 (0%) 0/69 (0%) 0/41 (0%) 1/39 (2.6%)
    Nasopharyngitis 1/96 (1%) 0/94 (0%) 0/46 (0%) 0/46 (0%) 0/86 (0%) 1/69 (1.4%) 0/41 (0%) 0/39 (0%)
    Pneumonia NOS 3/96 (3.1%) 7/94 (7.4%) 3/46 (6.5%) 6/46 (13%) 2/86 (2.3%) 0/69 (0%) 7/41 (17.1%) 5/39 (12.8%)
    Pneumonia aspergilla 0/96 (0%) 0/94 (0%) 0/46 (0%) 1/46 (2.2%) 0/86 (0%) 0/69 (0%) 0/41 (0%) 0/39 (0%)
    Pseudomonas aeruginosa infection NOS 0/96 (0%) 0/94 (0%) 0/46 (0%) 2/46 (4.3%) 0/86 (0%) 0/69 (0%) 0/41 (0%) 0/39 (0%)
    Pyelonephritis NOS 0/96 (0%) 0/94 (0%) 0/46 (0%) 0/46 (0%) 0/86 (0%) 1/69 (1.4%) 0/41 (0%) 0/39 (0%)
    Sepsis NOS 1/96 (1%) 0/94 (0%) 0/46 (0%) 0/46 (0%) 1/86 (1.2%) 0/69 (0%) 0/41 (0%) 0/39 (0%)
    Sinusitis NOS 0/96 (0%) 1/94 (1.1%) 0/46 (0%) 0/46 (0%) 0/86 (0%) 1/69 (1.4%) 0/41 (0%) 0/39 (0%)
    Upper respiratory tract infection NOS 0/96 (0%) 1/94 (1.1%) 1/46 (2.2%) 1/46 (2.2%) 2/86 (2.3%) 0/69 (0%) 0/41 (0%) 0/39 (0%)
    Urinary tract infection NOS 1/96 (1%) 3/94 (3.2%) 1/46 (2.2%) 0/46 (0%) 1/86 (1.2%) 2/69 (2.9%) 0/41 (0%) 0/39 (0%)
    Injury, poisoning and procedural complications
    Animal bite 0/96 (0%) 0/94 (0%) 0/46 (0%) 0/46 (0%) 0/86 (0%) 0/69 (0%) 0/41 (0%) 1/39 (2.6%)
    Forearm fracture 0/96 (0%) 0/94 (0%) 1/46 (2.2%) 0/46 (0%) 0/86 (0%) 0/69 (0%) 0/41 (0%) 0/39 (0%)
    Fracture NOS 0/96 (0%) 0/94 (0%) 0/46 (0%) 0/46 (0%) 1/86 (1.2%) 0/69 (0%) 0/41 (0%) 0/39 (0%)
    Hand fracture 1/96 (1%) 0/94 (0%) 0/46 (0%) 0/46 (0%) 0/86 (0%) 0/69 (0%) 0/41 (0%) 0/39 (0%)
    Head injury 1/96 (1%) 0/94 (0%) 0/46 (0%) 0/46 (0%) 0/86 (0%) 0/69 (0%) 0/41 (0%) 0/39 (0%)
    Leg fracture 1/96 (1%) 0/94 (0%) 0/46 (0%) 0/46 (0%) 0/86 (0%) 0/69 (0%) 1/41 (2.4%) 0/39 (0%)
    Radius fracture 0/96 (0%) 0/94 (0%) 1/46 (2.2%) 0/46 (0%) 0/86 (0%) 0/69 (0%) 0/41 (0%) 0/39 (0%)
    Investigations
    Arteriogram coronary 2/96 (2.1%) 0/94 (0%) 0/46 (0%) 0/46 (0%) 1/86 (1.2%) 1/69 (1.4%) 0/41 (0%) 0/39 (0%)
    Biopsy lung 0/96 (0%) 0/94 (0%) 0/46 (0%) 1/46 (2.2%) 0/86 (0%) 0/69 (0%) 0/41 (0%) 0/39 (0%)
    Blood creatinine increased 0/96 (0%) 0/94 (0%) 0/46 (0%) 1/46 (2.2%) 0/86 (0%) 0/69 (0%) 0/41 (0%) 0/39 (0%)
    Lung function abnormal 0/96 (0%) 0/94 (0%) 0/46 (0%) 0/46 (0%) 0/86 (0%) 0/69 (0%) 1/41 (2.4%) 0/39 (0%)
    Lung function decreased 0/96 (0%) 0/94 (0%) 0/46 (0%) 1/46 (2.2%) 0/86 (0%) 0/69 (0%) 0/41 (0%) 0/39 (0%)
    Lymphocyte morphology NOS abnormal 0/96 (0%) 0/94 (0%) 0/46 (0%) 0/46 (0%) 1/86 (1.2%) 0/69 (0%) 0/41 (0%) 0/39 (0%)
    Pericardial drainage 0/96 (0%) 1/94 (1.1%) 0/46 (0%) 0/46 (0%) 0/86 (0%) 0/69 (0%) 0/41 (0%) 0/39 (0%)
    Weight decreased 0/96 (0%) 1/94 (1.1%) 0/46 (0%) 0/46 (0%) 0/86 (0%) 0/69 (0%) 0/41 (0%) 0/39 (0%)
    Metabolism and nutrition disorders
    Gout 0/96 (0%) 1/94 (1.1%) 0/46 (0%) 0/46 (0%) 0/86 (0%) 0/69 (0%) 0/41 (0%) 0/39 (0%)
    Malnutrition NOS 0/96 (0%) 0/94 (0%) 0/46 (0%) 0/46 (0%) 0/86 (0%) 0/69 (0%) 0/41 (0%) 1/39 (2.6%)
    Musculoskeletal and connective tissue disorders
    Arthritis NOS 0/96 (0%) 0/94 (0%) 0/46 (0%) 0/46 (0%) 0/86 (0%) 1/69 (1.4%) 0/41 (0%) 0/39 (0%)
    Back pain 1/96 (1%) 1/94 (1.1%) 0/46 (0%) 1/46 (2.2%) 0/86 (0%) 0/69 (0%) 0/41 (0%) 0/39 (0%)
    Bursitis 1/96 (1%) 0/94 (0%) 0/46 (0%) 0/46 (0%) 0/86 (0%) 0/69 (0%) 0/41 (0%) 0/39 (0%)
    Intervertebral disc prolapse 0/96 (0%) 0/94 (0%) 0/46 (0%) 0/46 (0%) 1/86 (1.2%) 0/69 (0%) 0/41 (0%) 0/39 (0%)
    Localised osteoarthritis 1/96 (1%) 0/94 (0%) 0/46 (0%) 0/46 (0%) 0/86 (0%) 0/69 (0%) 0/41 (0%) 0/39 (0%)
    Muscle atrophy 0/96 (0%) 1/94 (1.1%) 0/46 (0%) 0/46 (0%) 0/86 (0%) 0/69 (0%) 0/41 (0%) 0/39 (0%)
    Myalgia 0/96 (0%) 0/94 (0%) 0/46 (0%) 0/46 (0%) 0/86 (0%) 1/69 (1.4%) 0/41 (0%) 0/39 (0%)
    Neck pain 0/96 (0%) 0/94 (0%) 0/46 (0%) 1/46 (2.2%) 0/86 (0%) 0/69 (0%) 0/41 (0%) 0/39 (0%)
    Sciatica 1/96 (1%) 0/94 (0%) 0/46 (0%) 0/46 (0%) 0/86 (0%) 0/69 (0%) 0/41 (0%) 0/39 (0%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Basal cell carcinoma 0/96 (0%) 0/94 (0%) 0/46 (0%) 0/46 (0%) 1/86 (1.2%) 1/69 (1.4%) 2/41 (4.9%) 0/39 (0%)
    Benign adrenal neoplasm NOS 0/96 (0%) 0/94 (0%) 0/46 (0%) 0/46 (0%) 0/86 (0%) 1/69 (1.4%) 0/41 (0%) 0/39 (0%)
    Bowen's disease 0/96 (0%) 1/94 (1.1%) 0/46 (0%) 0/46 (0%) 0/86 (0%) 0/69 (0%) 0/41 (0%) 0/39 (0%)
    Breast cancer female NOS 0/96 (0%) 0/94 (0%) 1/46 (2.2%) 0/46 (0%) 0/86 (0%) 0/69 (0%) 0/41 (0%) 0/39 (0%)
    Carcinoma NOS 0/96 (0%) 1/94 (1.1%) 0/46 (0%) 0/46 (0%) 0/86 (0%) 0/69 (0%) 0/41 (0%) 0/39 (0%)
    Lip neoplasm malignant stage unspecified 0/96 (0%) 0/94 (0%) 1/46 (2.2%) 0/46 (0%) 0/86 (0%) 0/69 (0%) 0/41 (0%) 0/39 (0%)
    Lung cancer stage unspecified (exc metas 1/96 (1%) 1/94 (1.1%) 0/46 (0%) 0/46 (0%) 1/86 (1.2%) 0/69 (0%) 0/41 (0%) 0/39 (0%)
    Malignant melanoma stage IV 0/96 (0%) 0/94 (0%) 0/46 (0%) 0/46 (0%) 0/86 (0%) 0/69 (0%) 1/41 (2.4%) 0/39 (0%)
    Prostate cancer NOS 0/96 (0%) 1/94 (1.1%) 0/46 (0%) 0/46 (0%) 0/86 (0%) 1/69 (1.4%) 0/41 (0%) 0/39 (0%)
    Skin carcinoma NOS 0/96 (0%) 0/94 (0%) 1/46 (2.2%) 1/46 (2.2%) 0/86 (0%) 1/69 (1.4%) 0/41 (0%) 0/39 (0%)
    Squamous cell carcinoma 3/96 (3.1%) 1/94 (1.1%) 1/46 (2.2%) 1/46 (2.2%) 0/86 (0%) 0/69 (0%) 1/41 (2.4%) 2/39 (5.1%)
    Squamous cell carcinoma of skin 0/96 (0%) 0/94 (0%) 0/46 (0%) 1/46 (2.2%) 1/86 (1.2%) 0/69 (0%) 0/41 (0%) 0/39 (0%)
    Nervous system disorders
    Burning sensation NOS 0/96 (0%) 0/94 (0%) 1/46 (2.2%) 0/46 (0%) 0/86 (0%) 0/69 (0%) 0/41 (0%) 0/39 (0%)
    Cerebrovascular accident NOS 0/96 (0%) 0/94 (0%) 0/46 (0%) 0/46 (0%) 0/86 (0%) 1/69 (1.4%) 0/41 (0%) 0/39 (0%)
    Dizziness (exc vertigo) 0/96 (0%) 2/94 (2.1%) 0/46 (0%) 0/46 (0%) 0/86 (0%) 0/69 (0%) 0/41 (0%) 0/39 (0%)
    Epilepsy NOS 0/96 (0%) 0/94 (0%) 0/46 (0%) 0/46 (0%) 1/86 (1.2%) 0/69 (0%) 0/41 (0%) 0/39 (0%)
    Haemorrhagic stroke 0/96 (0%) 0/94 (0%) 0/46 (0%) 0/46 (0%) 1/86 (1.2%) 0/69 (0%) 0/41 (0%) 0/39 (0%)
    Migraine NOS 0/96 (0%) 0/94 (0%) 0/46 (0%) 0/46 (0%) 0/86 (0%) 1/69 (1.4%) 0/41 (0%) 0/39 (0%)
    Monoparesis 1/96 (1%) 0/94 (0%) 0/46 (0%) 0/46 (0%) 0/86 (0%) 0/69 (0%) 0/41 (0%) 0/39 (0%)
    Restless leg syndrome 1/96 (1%) 0/94 (0%) 0/46 (0%) 0/46 (0%) 0/86 (0%) 0/69 (0%) 0/41 (0%) 0/39 (0%)
    Syncope 0/96 (0%) 1/94 (1.1%) 0/46 (0%) 0/46 (0%) 1/86 (1.2%) 1/69 (1.4%) 0/41 (0%) 0/39 (0%)
    Syncope aggravated 0/96 (0%) 0/94 (0%) 1/46 (2.2%) 0/46 (0%) 0/86 (0%) 0/69 (0%) 0/41 (0%) 0/39 (0%)
    Psychiatric disorders
    Confusion 0/96 (0%) 1/94 (1.1%) 0/46 (0%) 0/46 (0%) 0/86 (0%) 0/69 (0%) 0/41 (0%) 0/39 (0%)
    Renal and urinary disorders
    Fluid retention 0/96 (0%) 1/94 (1.1%) 0/46 (0%) 0/46 (0%) 0/86 (0%) 0/69 (0%) 0/41 (0%) 0/39 (0%)
    Nephropathy NOS 0/96 (0%) 0/94 (0%) 0/46 (0%) 0/46 (0%) 1/86 (1.2%) 0/69 (0%) 0/41 (0%) 0/39 (0%)
    Oliguria 0/96 (0%) 1/94 (1.1%) 0/46 (0%) 0/46 (0%) 0/86 (0%) 0/69 (0%) 0/41 (0%) 0/39 (0%)
    Renal failure NOS 0/96 (0%) 2/94 (2.1%) 0/46 (0%) 0/46 (0%) 1/86 (1.2%) 0/69 (0%) 0/41 (0%) 0/39 (0%)
    Renal impairment NOS 0/96 (0%) 0/94 (0%) 0/46 (0%) 0/46 (0%) 0/86 (0%) 0/69 (0%) 0/41 (0%) 1/39 (2.6%)
    Reproductive system and breast disorders
    Benign prostatic hyperplasia 0/96 (0%) 1/94 (1.1%) 0/46 (0%) 0/46 (0%) 0/86 (0%) 0/69 (0%) 0/41 (0%) 0/39 (0%)
    Ovarian cyst 0/96 (0%) 0/94 (0%) 0/46 (0%) 0/46 (0%) 0/86 (0%) 0/69 (0%) 0/41 (0%) 1/39 (2.6%)
    Uterine prolapse 0/96 (0%) 0/94 (0%) 0/46 (0%) 1/46 (2.2%) 0/86 (0%) 0/69 (0%) 0/41 (0%) 0/39 (0%)
    Respiratory, thoracic and mediastinal disorders
    Asthma NOS 0/96 (0%) 1/94 (1.1%) 0/46 (0%) 0/46 (0%) 0/86 (0%) 0/69 (0%) 0/41 (0%) 0/39 (0%)
    Bronchostenosis 0/96 (0%) 0/94 (0%) 0/46 (0%) 1/46 (2.2%) 0/86 (0%) 0/69 (0%) 0/41 (0%) 0/39 (0%)
    Cough 0/96 (0%) 1/94 (1.1%) 1/46 (2.2%) 0/46 (0%) 0/86 (0%) 0/69 (0%) 0/41 (0%) 0/39 (0%)
    Dyspnoea NOS 2/96 (2.1%) 2/94 (2.1%) 0/46 (0%) 1/46 (2.2%) 2/86 (2.3%) 1/69 (1.4%) 1/41 (2.4%) 0/39 (0%)
    Epistaxis 0/96 (0%) 1/94 (1.1%) 0/46 (0%) 0/46 (0%) 0/86 (0%) 0/69 (0%) 0/41 (0%) 0/39 (0%)
    Excessive bronchial secretion 0/96 (0%) 0/94 (0%) 0/46 (0%) 0/46 (0%) 0/86 (0%) 0/69 (0%) 2/41 (4.9%) 0/39 (0%)
    Haemoptysis 1/96 (1%) 0/94 (0%) 0/46 (0%) 1/46 (2.2%) 0/86 (0%) 0/69 (0%) 0/41 (0%) 0/39 (0%)
    Mediastinal emphysema 0/96 (0%) 0/94 (0%) 0/46 (0%) 0/46 (0%) 0/86 (0%) 0/69 (0%) 1/41 (2.4%) 0/39 (0%)
    Obliterative bronchiolitis 0/96 (0%) 0/94 (0%) 1/46 (2.2%) 2/46 (4.3%) 0/86 (0%) 0/69 (0%) 6/41 (14.6%) 1/39 (2.6%)
    Pleuritic pain 0/96 (0%) 0/94 (0%) 1/46 (2.2%) 0/46 (0%) 0/86 (0%) 0/69 (0%) 0/41 (0%) 0/39 (0%)
    Pneumothorax NOS 1/96 (1%) 0/94 (0%) 0/46 (0%) 0/46 (0%) 0/86 (0%) 0/69 (0%) 0/41 (0%) 1/39 (2.6%)
    Pulmonary fibrosis 0/96 (0%) 0/94 (0%) 0/46 (0%) 1/46 (2.2%) 0/86 (0%) 0/69 (0%) 0/41 (0%) 0/39 (0%)
    Respiratory distress 0/96 (0%) 0/94 (0%) 0/46 (0%) 0/46 (0%) 1/86 (1.2%) 0/69 (0%) 1/41 (2.4%) 0/39 (0%)
    Respiratory failure (exc neonatal) 0/96 (0%) 0/94 (0%) 1/46 (2.2%) 0/46 (0%) 0/86 (0%) 0/69 (0%) 0/41 (0%) 0/39 (0%)
    Skin and subcutaneous tissue disorders
    Angioneurotic oedema 0/96 (0%) 1/94 (1.1%) 0/46 (0%) 0/46 (0%) 0/86 (0%) 0/69 (0%) 0/41 (0%) 0/39 (0%)
    Dermatitis NOS 0/96 (0%) 1/94 (1.1%) 0/46 (0%) 0/46 (0%) 0/86 (0%) 0/69 (0%) 0/41 (0%) 0/39 (0%)
    Diabetic foot ulcer 1/96 (1%) 0/94 (0%) 0/46 (0%) 0/46 (0%) 0/86 (0%) 0/69 (0%) 0/41 (0%) 0/39 (0%)
    Surgical and medical procedures
    Angioplasty 0/96 (0%) 0/94 (0%) 0/46 (0%) 0/46 (0%) 0/86 (0%) 2/69 (2.9%) 0/41 (0%) 0/39 (0%)
    Cholecystectomy 0/96 (0%) 0/94 (0%) 0/46 (0%) 0/46 (0%) 1/86 (1.2%) 0/69 (0%) 0/41 (0%) 0/39 (0%)
    Facial lesion excision 0/96 (0%) 1/94 (1.1%) 0/46 (0%) 0/46 (0%) 0/86 (0%) 0/69 (0%) 0/41 (0%) 0/39 (0%)
    Hip arthroplasty 0/96 (0%) 1/94 (1.1%) 0/46 (0%) 0/46 (0%) 1/86 (1.2%) 0/69 (0%) 0/41 (0%) 0/39 (0%)
    Leg amputation 0/96 (0%) 0/94 (0%) 0/46 (0%) 0/46 (0%) 1/86 (1.2%) 0/69 (0%) 0/41 (0%) 0/39 (0%)
    Operation NOS 0/96 (0%) 0/94 (0%) 0/46 (0%) 0/46 (0%) 1/86 (1.2%) 0/69 (0%) 0/41 (0%) 0/39 (0%)
    Suture removal 0/96 (0%) 0/94 (0%) 0/46 (0%) 0/46 (0%) 0/86 (0%) 0/69 (0%) 1/41 (2.4%) 0/39 (0%)
    Vascular disorders
    Arterial stenosis NOS 0/96 (0%) 0/94 (0%) 0/46 (0%) 0/46 (0%) 1/86 (1.2%) 0/69 (0%) 0/41 (0%) 0/39 (0%)
    Arteriosclerosis 0/96 (0%) 0/94 (0%) 0/46 (0%) 0/46 (0%) 0/86 (0%) 1/69 (1.4%) 0/41 (0%) 0/39 (0%)
    Cerebral artery thrombosis 0/96 (0%) 0/94 (0%) 0/46 (0%) 0/46 (0%) 1/86 (1.2%) 0/69 (0%) 0/41 (0%) 0/39 (0%)
    Hypertension aggravated 0/96 (0%) 0/94 (0%) 0/46 (0%) 0/46 (0%) 0/86 (0%) 1/69 (1.4%) 0/41 (0%) 0/39 (0%)
    Intracranial haemorrhage NOS 0/96 (0%) 0/94 (0%) 0/46 (0%) 1/46 (2.2%) 0/86 (0%) 0/69 (0%) 0/41 (0%) 0/39 (0%)
    Phlebitis NOS 0/96 (0%) 0/94 (0%) 0/46 (0%) 1/46 (2.2%) 0/86 (0%) 0/69 (0%) 0/41 (0%) 0/39 (0%)
    Postural hypotension 0/96 (0%) 0/94 (0%) 0/46 (0%) 0/46 (0%) 0/86 (0%) 0/69 (0%) 1/41 (2.4%) 0/39 (0%)
    Pulmonary embolism 1/96 (1%) 1/94 (1.1%) 2/46 (4.3%) 2/46 (4.3%) 1/86 (1.2%) 2/69 (2.9%) 1/41 (2.4%) 1/39 (2.6%)
    Pulmonary hypertension NOS 0/96 (0%) 0/94 (0%) 0/46 (0%) 1/46 (2.2%) 0/86 (0%) 0/69 (0%) 0/41 (0%) 0/39 (0%)
    Subarachnoid haemorrhage NOS 0/96 (0%) 0/94 (0%) 1/46 (2.2%) 0/46 (0%) 0/86 (0%) 0/69 (0%) 0/41 (0%) 0/39 (0%)
    Transient ischaemic attack 1/96 (1%) 1/94 (1.1%) 0/46 (0%) 0/46 (0%) 1/86 (1.2%) 1/69 (1.4%) 1/41 (2.4%) 0/39 (0%)
    Venous thrombosis NOS 0/96 (0%) 1/94 (1.1%) 0/46 (0%) 0/46 (0%) 0/86 (0%) 0/69 (0%) 0/41 (0%) 0/39 (0%)
    Venous thrombosis deep limb 1/96 (1%) 2/94 (2.1%) 0/46 (0%) 0/46 (0%) 1/86 (1.2%) 1/69 (1.4%) 0/41 (0%) 1/39 (2.6%)
    Other (Not Including Serious) Adverse Events
    Control: 12 Month Heart Everolimus + CNI Reduction: 12 Month Heart Control: 12 Month Lung Everolimus+CNI Reduction: 12 Month Lung Control: 24 Month Heart Everolimus + CNI Reduction: 24 Month Heart Control: 24 Month Lung Everolimus + CNI Reduction: 24 Month Lung
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 48/96 (50%) 75/94 (79.8%) 33/46 (71.7%) 42/46 (91.3%) 33/86 (38.4%) 29/69 (42%) 21/41 (51.2%) 27/39 (69.2%)
    Blood and lymphatic system disorders
    Leucopenia NOS 0/96 (0%) 8/94 (8.5%) 0/46 (0%) 8/46 (17.4%) 1/86 (1.2%) 1/69 (1.4%) 0/41 (0%) 1/39 (2.6%)
    Cardiac disorders
    Oedema NOS 10/96 (10.4%) 24/94 (25.5%) 3/46 (6.5%) 14/46 (30.4%) 9/86 (10.5%) 4/69 (5.8%) 2/41 (4.9%) 5/39 (12.8%)
    Congenital, familial and genetic disorders
    Epidermal naevus 0/96 (0%) 0/94 (0%) 0/46 (0%) 0/46 (0%) 0/86 (0%) 0/69 (0%) 0/41 (0%) 2/39 (5.1%)
    Gastrointestinal disorders
    Abdominal pain upper 1/96 (1%) 1/94 (1.1%) 1/46 (2.2%) 3/46 (6.5%) 1/86 (1.2%) 0/69 (0%) 3/41 (7.3%) 0/39 (0%)
    Diarrhoea NOS 4/96 (4.2%) 15/94 (16%) 3/46 (6.5%) 7/46 (15.2%) 0/86 (0%) 4/69 (5.8%) 1/41 (2.4%) 3/39 (7.7%)
    Gastritis NOS 1/96 (1%) 1/94 (1.1%) 1/46 (2.2%) 0/46 (0%) 0/86 (0%) 0/69 (0%) 0/41 (0%) 2/39 (5.1%)
    Mouth ulceration 0/96 (0%) 1/94 (1.1%) 0/46 (0%) 5/46 (10.9%) 0/86 (0%) 0/69 (0%) 0/41 (0%) 0/39 (0%)
    Nausea 1/96 (1%) 4/94 (4.3%) 1/46 (2.2%) 2/46 (4.3%) 2/86 (2.3%) 1/69 (1.4%) 1/41 (2.4%) 2/39 (5.1%)
    General disorders
    Fall 2/96 (2.1%) 0/94 (0%) 0/46 (0%) 2/46 (4.3%) 0/86 (0%) 0/69 (0%) 0/41 (0%) 2/39 (5.1%)
    Fatigue 5/96 (5.2%) 6/94 (6.4%) 2/46 (4.3%) 2/46 (4.3%) 0/86 (0%) 0/69 (0%) 1/41 (2.4%) 0/39 (0%)
    Pyrexia 6/96 (6.3%) 1/94 (1.1%) 2/46 (4.3%) 0/46 (0%) 0/86 (0%) 1/69 (1.4%) 1/41 (2.4%) 0/39 (0%)
    Infections and infestations
    Bronchitis NOS 0/96 (0%) 5/94 (5.3%) 3/46 (6.5%) 2/46 (4.3%) 0/86 (0%) 0/69 (0%) 2/41 (4.9%) 2/39 (5.1%)
    Infection NOS 0/96 (0%) 3/94 (3.2%) 1/46 (2.2%) 0/46 (0%) 3/86 (3.5%) 2/69 (2.9%) 2/41 (4.9%) 2/39 (5.1%)
    Influenza 5/96 (5.2%) 2/94 (2.1%) 2/46 (4.3%) 1/46 (2.2%) 1/86 (1.2%) 2/69 (2.9%) 0/41 (0%) 1/39 (2.6%)
    Nasopharyngitis 15/96 (15.6%) 18/94 (19.1%) 12/46 (26.1%) 11/46 (23.9%) 12/86 (14%) 7/69 (10.1%) 7/41 (17.1%) 8/39 (20.5%)
    Pneumonia NOS 5/96 (5.2%) 3/94 (3.2%) 2/46 (4.3%) 5/46 (10.9%) 1/86 (1.2%) 0/69 (0%) 0/41 (0%) 3/39 (7.7%)
    Upper respiratory tract infection NOS 1/96 (1%) 2/94 (2.1%) 6/46 (13%) 9/46 (19.6%) 2/86 (2.3%) 2/69 (2.9%) 4/41 (9.8%) 6/39 (15.4%)
    Urinary tract infection NOS 0/96 (0%) 3/94 (3.2%) 3/46 (6.5%) 4/46 (8.7%) 1/86 (1.2%) 1/69 (1.4%) 2/41 (4.9%) 3/39 (7.7%)
    Investigations
    Blood creatinine increased 2/96 (2.1%) 1/94 (1.1%) 0/46 (0%) 0/46 (0%) 0/86 (0%) 1/69 (1.4%) 0/41 (0%) 2/39 (5.1%)
    Metabolism and nutrition disorders
    Hypercholesterolaemia 4/96 (4.2%) 0/94 (0%) 3/46 (6.5%) 6/46 (13%) 1/86 (1.2%) 2/69 (2.9%) 0/41 (0%) 2/39 (5.1%)
    Hypokalaemia 0/96 (0%) 1/94 (1.1%) 1/46 (2.2%) 4/46 (8.7%) 0/86 (0%) 0/69 (0%) 0/41 (0%) 2/39 (5.1%)
    Musculoskeletal and connective tissue disorders
    Arthralgia 5/96 (5.2%) 6/94 (6.4%) 2/46 (4.3%) 3/46 (6.5%) 0/86 (0%) 1/69 (1.4%) 1/41 (2.4%) 1/39 (2.6%)
    Arthritis NOS 1/96 (1%) 0/94 (0%) 0/46 (0%) 3/46 (6.5%) 0/86 (0%) 1/69 (1.4%) 0/41 (0%) 1/39 (2.6%)
    Myalgia 3/96 (3.1%) 7/94 (7.4%) 1/46 (2.2%) 1/46 (2.2%) 2/86 (2.3%) 0/69 (0%) 0/41 (0%) 0/39 (0%)
    Pain in limb 1/96 (1%) 5/94 (5.3%) 0/46 (0%) 1/46 (2.2%) 2/86 (2.3%) 1/69 (1.4%) 0/41 (0%) 0/39 (0%)
    Nervous system disorders
    Headache NOS 7/96 (7.3%) 7/94 (7.4%) 3/46 (6.5%) 5/46 (10.9%) 1/86 (1.2%) 0/69 (0%) 0/41 (0%) 1/39 (2.6%)
    Respiratory, thoracic and mediastinal disorders
    Cough 3/96 (3.1%) 5/94 (5.3%) 3/46 (6.5%) 3/46 (6.5%) 0/86 (0%) 3/69 (4.3%) 1/41 (2.4%) 1/39 (2.6%)
    Excessive bronchial secretion 0/96 (0%) 0/94 (0%) 0/46 (0%) 0/46 (0%) 0/86 (0%) 0/69 (0%) 0/41 (0%) 2/39 (5.1%)
    Skin and subcutaneous tissue disorders
    Acne NOS 0/96 (0%) 11/94 (11.7%) 0/46 (0%) 1/46 (2.2%) 0/86 (0%) 0/69 (0%) 0/41 (0%) 1/39 (2.6%)
    Vascular disorders
    Hypertension NOS 5/96 (5.2%) 4/94 (4.3%) 4/46 (8.7%) 6/46 (13%) 0/86 (0%) 3/69 (4.3%) 2/41 (4.9%) 3/39 (7.7%)
    Hypertension aggravated 0/96 (0%) 5/94 (5.3%) 1/46 (2.2%) 1/46 (2.2%) 3/86 (3.5%) 1/69 (1.4%) 1/41 (2.4%) 1/39 (2.6%)

    Limitations/Caveats

    [Not Specified]

    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 (ie, data from all sites) in the clinical trial.

    Results Point of Contact

    Name/Title Study Director
    Organization Novartis Pharmaceuticals
    Phone 862 778-8300
    Email
    Responsible Party:
    Novartis Pharmaceuticals
    ClinicalTrials.gov Identifier:
    NCT00377962
    Other Study ID Numbers:
    • CRAD001AIC01
    First Posted:
    Sep 19, 2006
    Last Update Posted:
    Jul 30, 2020
    Last Verified:
    Jul 1, 2020