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    Clinical Trial Results:
    An open-label, multicenter phase II study to examine the efficacy and safety of everolimus as second-line therapy in the treatment of patients with metastatic renal cell carcinoma (RECORD-4) Due to EudraCT system limitations, which EMA is aware of, data using 999 as data points in this record are not an accurate representation of the clinical trial results. Please use https://www.novctrd.com/CtrdWeb/home.novfor complete trial results.

    Summary
    EudraCT number
    		 2010-020447-13
    Trial protocol
    		 BG  
    Global end of trial date
    05 May 2015

    Results information
    Results version number
    		 v1(current)
    This version publication date
    06 Jul 2018
    First version publication date
    06 Jul 2018
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    CRAD001L2404
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01491672
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Novartis Pharma AG
    Sponsor organisation address
    CH-4002, Basel, Switzerland,
    Public contact
    Clinical Disclosure Office, Novartis Pharma AG, 41 613241111 x,
    Scientific contact
    Clinical Disclosure Office, Novartis Pharma AG, 41 613241111 x,
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    05 May 2015
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    05 May 2015
    Global end of trial reached?
    Yes
    Global end of trial date
    05 May 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective was to assess the progression-free survival (PFS) in patients who received everolimus as second-line treatment for metastatic renal cell carcinoma.
    Protection of trial subjects
    This study was in compliance with the ethical principles derived from the Declaration of Helsinki and the International Conference on Harmonization (ICH) Good Clinical practices guidelines. All the local regulatory requirements pertinent to safety of trial subjects were also followed during the conduct of the trial.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    30 Nov 2011
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United States: 16
    Country: Number of subjects enrolled
    China: 55
    Country: Number of subjects enrolled
    Bulgaria: 8
    Country: Number of subjects enrolled
    Brazil: 8
    Country: Number of subjects enrolled
    Argentina: 6
    Country: Number of subjects enrolled
    Russian Federation: 41
    Worldwide total number of subjects
    134
    EEA total number of subjects
    8
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    105
    From 65 to 84 years
    29
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 This was an open-label study where all eligible participants were enrolled into one of 3 cohorts based upon prior first-line therapy.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Prior sunitinib
    Arm description
    		 Participants, who received prior sunitinib therapy, received RAD001 10 mg orally once daily.
    Arm type
    		 Experimental

    Investigational medicinal product name
    RAD001
    Investigational medicinal product code
    RAD001
    Other name
    Everolimus
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    10 mg orally once daily

    Arm title
    		 Other prior vascular endothelial growth factor (VEGF)
    Arm description
    		 Participants, who received prior anti-VEGF other than sunitinib, received RAD001 10 mg orally once daily.
    Arm type
    		 Experimental

    Investigational medicinal product name
    RAD001
    Investigational medicinal product code
    RAD001
    Other name
    Everolimus
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    10 mg orally once daily

    Arm title
    		 Prior cytokines
    Arm description
    		 Participants, who received prior cytokine therapy, received RAD001 10 mg orally once daily.
    Arm type
    		 Experimental

    Investigational medicinal product name
    RAD001
    Investigational medicinal product code
    RAD001
    Other name
    Everolimus
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    10 mg orally once daily

    Number of subjects in period 1
    		Prior sunitinib Other prior vascular endothelial growth factor (VEGF) Prior cytokines
    Started
    58
    62
    14
    Safety set
    58
    61
    14
    Completed
    2
    2
    3
    Not completed
    56
    60
    11
         Adverse event, serious fatal
    -
    4
    -
         Consent withdrawn by subject
    6
    7
    -
         Disease progression
    42
    34
    6
         Adverse event, non-fatal
    8
    10
    4
         Protocol deviation
    -
    1
    -
         Lost to follow-up
    -
    4
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Prior sunitinib
    Reporting group description
    		 Participants, who received prior sunitinib therapy, received RAD001 10 mg orally once daily.

    Reporting group title
    Other prior vascular endothelial growth factor (VEGF)
    Reporting group description
    		 Participants, who received prior anti-VEGF other than sunitinib, received RAD001 10 mg orally once daily.

    Reporting group title
    Prior cytokines
    Reporting group description
    		 Participants, who received prior cytokine therapy, received RAD001 10 mg orally once daily.

    Reporting group values
    		 Prior sunitinib Other prior vascular endothelial growth factor (VEGF) Prior cytokines Total
    Number of subjects
    		 58 62 14 134
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0 0
        Newborns (0-27 days)
    		 0 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0 0
        Children (2-11 years)
    		 0 0 0 0
        Adolescents (12-17 years)
    		 0 0 0 0
        Adults (18-64 years)
    		 47 49 9 105
        From 65-84 years
    		 11 13 5 29
        85 years and over
    		 0 0 0 0
    Age Continuous |
    Units: Years
        arithmetic mean (standard deviation)
    		 56 ± 12.06 56.5 ± 11.14 60.3 ± 10.59 -
    Gender, Male/Female
    Units: Participants
        Female
    		 15 22 6 43
        Male
    		 43 40 8 91

    End points

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    End points reporting groups
    Reporting group title
    Prior sunitinib
    Reporting group description
    		 Participants, who received prior sunitinib therapy, received RAD001 10 mg orally once daily.

    Reporting group title
    Other prior vascular endothelial growth factor (VEGF)
    Reporting group description
    		 Participants, who received prior anti-VEGF other than sunitinib, received RAD001 10 mg orally once daily.

    Reporting group title
    Prior cytokines
    Reporting group description
    		 Participants, who received prior cytokine therapy, received RAD001 10 mg orally once daily.

    Subject analysis set title
    All participants
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    All participants received RAD001 10 mg daily.

    Primary: Progression-free survival (PFS) - all participants

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    End point title
    		 Progression-free survival (PFS) - all participants [1]
    End point description
    PFS during second-line treatment was defined as the time from the date of enrollment to the date of the first documented disease progression or death due to any cause. PFS was based on the local radiological data according to the RECIST 1.0 criteria.
    End point type
    Primary
    End point timeframe
    20 months
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analysis was planned for the primary outcome measure.
    End point values
    		 All participants
    Number of subjects analysed
    134
    Units: months
        median (confidence interval 95%)
    7.4 (5.6 to 10.5)
    No statistical analyses for this end point

    Secondary: Duration of PFS for each first-line treatment cohort

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    End point title
    		 Duration of PFS for each first-line treatment cohort
    End point description
    Duration of PFS during second-line treatment was defined as the time from the date of enrollment to the date of the first documented disease progression or death due to any cause. Participants' assessment was based on the local radiological data according to the RECIST 1.0 Criteria.
    End point type
    Secondary
    End point timeframe
    20 months
    End point values
    		 Prior sunitinib Other prior vascular endothelial growth factor (VEGF) Prior cytokines
    Number of subjects analysed
    58
    62
    14
    Units: months
        median (confidence interval 95%)
    5.6 (3.7 to 11.3)
    7.8 (5.7 to 11)
    12.9 (2.6 to 999)
    No statistical analyses for this end point

    Secondary: Overall survival (OS)

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    End point title
    		 Overall survival (OS)
    End point description
    OS was defined as the time from date of enrollment to date of death due to any cause.
    End point type
    Secondary
    End point timeframe
    28 months
    End point values
    		 Prior sunitinib Other prior vascular endothelial growth factor (VEGF) Prior cytokines All participants
    Number of subjects analysed
    58
    62
    14
    134
    Units: months
        median (confidence interval 95%)
    23.8 (13.7 to 999)
    17.2 (11.9 to 999)
    99 (15.9 to 999)
    23.8 (17 to 999)
    No statistical analyses for this end point

    Secondary: Clinical Benefit Rate (CBR)

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    End point title
    		 Clinical Benefit Rate (CBR)
    End point description
    CBR was defined as the proportion of patients with best overall response of complete response (CR) or partial response (PR) or stable disease based on the local radiological data according to the RECIST 1.0 criteria.
    End point type
    Secondary
    End point timeframe
    20 months
    End point values
    		 Prior sunitinib Other prior vascular endothelial growth factor (VEGF) Prior cytokines All participants
    Number of subjects analysed
    58
    62
    14
    134
    Units: Participants
    41
    48
    11
    100
    No statistical analyses for this end point

    Secondary: Objective Response Rate (ORR)

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    End point title
    		 Objective Response Rate (ORR)
    End point description
    ORR was defined as the proportion of participants with best overall response of CR or PR based on the local radiological data according to the RECIST 1.0 Criteria
    End point type
    Secondary
    End point timeframe
    20 months
    End point values
    		 Prior sunitinib Other prior vascular endothelial growth factor (VEGF) Prior cytokines All participants
    Number of subjects analysed
    58
    62
    14
    134
    Units: Participants
    4
    3
    3
    10
    No statistical analyses for this end point

    Secondary: Duration of Response (DoR)

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    End point title
    		 Duration of Response (DoR)
    End point description
    DoR was defined as the time from the first occurrence of PR or CR (as per local radiological review) until the date of the first documented disease progression or death due to underlying cancer.
    End point type
    Secondary
    End point timeframe
    20 months
    End point values
    		 Prior sunitinib Other prior vascular endothelial growth factor (VEGF) Prior cytokines All participants
    Number of subjects analysed
    58
    62
    14
    134
    Units: months
        median (confidence interval 95%)
    10.8 (9.2 to 999)
    7.4 (3.3 to 9.2)
    9.2 (-999 to 999)
    9.2 (3.3 to 999)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events are collected from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV). All adverse events reported in this record are from date of First Patient First Treatment until Last Patient Last Visit.
    Adverse event reporting additional description
    Consistent with EudraCT disclosure specifications, Novartis has reported under the Serious adverse events field “number of deaths resulting from adverse events” all those deaths, resulting from serious adverse events that are deemed to be causally related to treatment by the investigator.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    18.0
    Reporting groups
    Reporting group title
    Prior sunitinib
    Reporting group description
    		 Prior sunitinib

    Reporting group title
    Prior cytokines
    Reporting group description
    		 Prior cytokines

    Reporting group title
    Other prior anti VEGF
    Reporting group description
    		 Other prior anti VEGF

    Serious adverse events
    		 Prior sunitinib Prior cytokines Other prior anti VEGF
    Total subjects affected by serious adverse events
         subjects affected / exposed
    13 / 58 (22.41%)
    3 / 14 (21.43%)
    16 / 61 (26.23%)
         number of deaths (all causes)
    4
    0
    9
         number of deaths resulting from adverse events
    0
    0
    2
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Cancer pain
         subjects affected / exposed
    1 / 58 (1.72%)
    0 / 14 (0.00%)
    0 / 61 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal neoplasm
         subjects affected / exposed
    1 / 58 (1.72%)
    0 / 14 (0.00%)
    0 / 61 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Hypertension
         subjects affected / exposed
    0 / 58 (0.00%)
    0 / 14 (0.00%)
    1 / 61 (1.64%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Thrombosis
         subjects affected / exposed
    0 / 58 (0.00%)
    0 / 14 (0.00%)
    1 / 61 (1.64%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Multi-organ failure
         subjects affected / exposed
    1 / 58 (1.72%)
    0 / 14 (0.00%)
    2 / 61 (3.28%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 2
    Sudden death
         subjects affected / exposed
    0 / 58 (0.00%)
    0 / 14 (0.00%)
    1 / 61 (1.64%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    1 / 58 (1.72%)
    0 / 14 (0.00%)
    1 / 61 (1.64%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hydrothorax
         subjects affected / exposed
    0 / 58 (0.00%)
    0 / 14 (0.00%)
    1 / 61 (1.64%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Interstitial lung disease
         subjects affected / exposed
    1 / 58 (1.72%)
    0 / 14 (0.00%)
    2 / 61 (3.28%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    0 / 58 (0.00%)
    0 / 14 (0.00%)
    1 / 61 (1.64%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pleural fibrosis
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 14 (7.14%)
    0 / 61 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    1 / 58 (1.72%)
    0 / 14 (0.00%)
    0 / 61 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    1 / 58 (1.72%)
    0 / 14 (0.00%)
    3 / 61 (4.92%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    2 / 3
    Psychiatric disorders
    Disorientation
         subjects affected / exposed
    0 / 58 (0.00%)
    0 / 14 (0.00%)
    1 / 61 (1.64%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Investigations
    X-ray with contrast upper gastrointestinal tract abnormal
         subjects affected / exposed
    0 / 58 (0.00%)
    0 / 14 (0.00%)
    1 / 61 (1.64%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Concussion
         subjects affected / exposed
    1 / 58 (1.72%)
    0 / 14 (0.00%)
    0 / 61 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Femur fracture
         subjects affected / exposed
    1 / 58 (1.72%)
    0 / 14 (0.00%)
    0 / 61 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Laceration
         subjects affected / exposed
    1 / 58 (1.72%)
    0 / 14 (0.00%)
    0 / 61 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lower limb fracture
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 14 (7.14%)
    0 / 61 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lumbar vertebral fracture
         subjects affected / exposed
    1 / 58 (1.72%)
    0 / 14 (0.00%)
    0 / 61 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Wound complication
         subjects affected / exposed
    1 / 58 (1.72%)
    0 / 14 (0.00%)
    0 / 61 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Cardiac failure
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 14 (7.14%)
    0 / 61 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac failure congestive
         subjects affected / exposed
    0 / 58 (0.00%)
    0 / 14 (0.00%)
    1 / 61 (1.64%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Cerebral haemorrhage
         subjects affected / exposed
    1 / 58 (1.72%)
    0 / 14 (0.00%)
    0 / 61 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypertensive encephalopathy
         subjects affected / exposed
    0 / 58 (0.00%)
    0 / 14 (0.00%)
    1 / 61 (1.64%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Seizure
         subjects affected / exposed
    1 / 58 (1.72%)
    0 / 14 (0.00%)
    0 / 61 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 58 (0.00%)
    0 / 14 (0.00%)
    2 / 61 (3.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    2 / 58 (3.45%)
    0 / 14 (0.00%)
    0 / 61 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    1 / 58 (1.72%)
    0 / 14 (0.00%)
    0 / 61 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastritis
         subjects affected / exposed
    1 / 58 (1.72%)
    0 / 14 (0.00%)
    0 / 61 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 58 (0.00%)
    0 / 14 (0.00%)
    1 / 61 (1.64%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    1 / 58 (1.72%)
    0 / 14 (0.00%)
    0 / 61 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    1 / 58 (1.72%)
    0 / 14 (0.00%)
    0 / 61 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pathological fracture
         subjects affected / exposed
    1 / 58 (1.72%)
    0 / 14 (0.00%)
    0 / 61 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Anal abscess
         subjects affected / exposed
    0 / 58 (0.00%)
    0 / 14 (0.00%)
    1 / 61 (1.64%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Appendicitis
         subjects affected / exposed
    0 / 58 (0.00%)
    0 / 14 (0.00%)
    1 / 61 (1.64%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    2 / 58 (3.45%)
    0 / 14 (0.00%)
    0 / 61 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lobar pneumonia
         subjects affected / exposed
    0 / 58 (0.00%)
    0 / 14 (0.00%)
    1 / 61 (1.64%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Necrotising fasciitis
         subjects affected / exposed
    1 / 58 (1.72%)
    0 / 14 (0.00%)
    0 / 61 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Perirectal abscess
         subjects affected / exposed
    0 / 58 (0.00%)
    0 / 14 (0.00%)
    1 / 61 (1.64%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    2 / 58 (3.45%)
    0 / 14 (0.00%)
    0 / 61 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    2 / 58 (3.45%)
    0 / 14 (0.00%)
    1 / 61 (1.64%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Hyperglycaemia
         subjects affected / exposed
    1 / 58 (1.72%)
    0 / 14 (0.00%)
    1 / 61 (1.64%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Prior sunitinib Prior cytokines Other prior anti VEGF
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    28 / 58 (48.28%)
    12 / 14 (85.71%)
    33 / 61 (54.10%)
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    2 / 58 (3.45%)
    1 / 14 (7.14%)
    0 / 61 (0.00%)
         occurrences all number
    5
    1
    0
    Blood creatinine increased
         subjects affected / exposed
    1 / 58 (1.72%)
    1 / 14 (7.14%)
    1 / 61 (1.64%)
         occurrences all number
    1
    1
    1
    Blood pressure increased
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 14 (7.14%)
    1 / 61 (1.64%)
         occurrences all number
    0
    1
    1
    Blood uric acid increased
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 14 (7.14%)
    1 / 61 (1.64%)
         occurrences all number
    0
    1
    2
    Hepatitis B DNA increased
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 14 (7.14%)
    0 / 61 (0.00%)
         occurrences all number
    0
    1
    0
    Lymphocyte count decreased
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 14 (7.14%)
    0 / 61 (0.00%)
         occurrences all number
    0
    1
    0
    Weight decreased
         subjects affected / exposed
    2 / 58 (3.45%)
    1 / 14 (7.14%)
    0 / 61 (0.00%)
         occurrences all number
    2
    1
    0
    Vascular disorders
    Hypertension
         subjects affected / exposed
    2 / 58 (3.45%)
    1 / 14 (7.14%)
    1 / 61 (1.64%)
         occurrences all number
    2
    1
    1
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    8 / 58 (13.79%)
    4 / 14 (28.57%)
    8 / 61 (13.11%)
         occurrences all number
    9
    6
    8
    Iron deficiency anaemia
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 14 (7.14%)
    1 / 61 (1.64%)
         occurrences all number
    0
    1
    1
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 14 (7.14%)
    2 / 61 (3.28%)
         occurrences all number
    0
    3
    2
    General physical health deterioration
         subjects affected / exposed
    3 / 58 (5.17%)
    0 / 14 (0.00%)
    1 / 61 (1.64%)
         occurrences all number
    3
    0
    1
    Pyrexia
         subjects affected / exposed
    2 / 58 (3.45%)
    1 / 14 (7.14%)
    5 / 61 (8.20%)
         occurrences all number
    2
    1
    5
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    5 / 58 (8.62%)
    0 / 14 (0.00%)
    1 / 61 (1.64%)
         occurrences all number
    7
    0
    1
    Mouth ulceration
         subjects affected / exposed
    2 / 58 (3.45%)
    1 / 14 (7.14%)
    2 / 61 (3.28%)
         occurrences all number
    2
    1
    2
    Stomatitis
         subjects affected / exposed
    5 / 58 (8.62%)
    5 / 14 (35.71%)
    8 / 61 (13.11%)
         occurrences all number
    6
    5
    9
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    2 / 58 (3.45%)
    0 / 14 (0.00%)
    4 / 61 (6.56%)
         occurrences all number
    2
    0
    4
    Oropharyngeal pain
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 14 (7.14%)
    0 / 61 (0.00%)
         occurrences all number
    0
    1
    0
    Pneumonitis
         subjects affected / exposed
    1 / 58 (1.72%)
    1 / 14 (7.14%)
    4 / 61 (6.56%)
         occurrences all number
    2
    1
    4
    Pneumothorax
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 14 (7.14%)
    0 / 61 (0.00%)
         occurrences all number
    0
    1
    0
    Skin and subcutaneous tissue disorders
    Dry skin
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 14 (7.14%)
    0 / 61 (0.00%)
         occurrences all number
    0
    1
    0
    Renal and urinary disorders
    Proteinuria
         subjects affected / exposed
    4 / 58 (6.90%)
    0 / 14 (0.00%)
    0 / 61 (0.00%)
         occurrences all number
    8
    0
    0
    Infections and infestations
    Localised infection
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 14 (7.14%)
    0 / 61 (0.00%)
         occurrences all number
    0
    1
    0
    Tonsillitis
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 14 (7.14%)
    0 / 61 (0.00%)
         occurrences all number
    0
    1
    0
    Upper respiratory tract infection
         subjects affected / exposed
    3 / 58 (5.17%)
    0 / 14 (0.00%)
    1 / 61 (1.64%)
         occurrences all number
    4
    0
    1
    Metabolism and nutrition disorders
    Diabetes mellitus
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 14 (7.14%)
    0 / 61 (0.00%)
         occurrences all number
    0
    1
    0
    Hypercholesterolaemia
         subjects affected / exposed
    3 / 58 (5.17%)
    2 / 14 (14.29%)
    3 / 61 (4.92%)
         occurrences all number
    3
    2
    3
    Hyperglycaemia
         subjects affected / exposed
    3 / 58 (5.17%)
    1 / 14 (7.14%)
    5 / 61 (8.20%)
         occurrences all number
    3
    1
    6
    Hypertriglyceridaemia
         subjects affected / exposed
    3 / 58 (5.17%)
    2 / 14 (14.29%)
    4 / 61 (6.56%)
         occurrences all number
    3
    4
    5

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    12 Nov 2012
    A change in the sample size of the study. The prior cytokines therapy cohort no longer required a minimum number of patients to be treated with bevacizumab. This change was based upon evidence that there was a decrease in the use of cytokines for advanced mRCC since finalization of the original protocol. An update to hepatitis guidelines to align with current standard Afinitor®/RAD template language which was based upon the update to the everolimus core data sheet. This change provide criteria for identification of patients at risk for hepatitis B and C and also providedguidance to Investigators on prophylactic treatment and monitoring for reactivation of disease; An update to pregnancy language to align with current standard Afinitor®/RAD template language which was based upon the update to the everolimus core data sheet. This extended the duration of use of adequate contraception after the last dose of drug for up to 8 weeks.
    02 Aug 2013
    •A change in the sample size section of the protocol. The other prior anti-VEGF therapy cohorts no longer required a minimum number of patients to be treated with bevacizumab. This change was based upon evidence that there was a decrease in the use of bevacizumab as first-line treatment. An update to pregnancy language to align with the update to the Investigator’s Brochure edition 11 erratum.
    18 May 2014
    A clarification of the end of study and last patient last visit date. The addition of treatment options for patients still benefiting from everolimus treatment at the end of study.

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

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    Due to EudraCT system limitations, which EMA is aware of, data using 999 as data points in this record are not an accurate representation of the clinical trial results. Please use https://www.novctrd.com/CtrdWeb/home.novfor complete trial results.
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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