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    Clinical Trial Results:
    A randomized, open label, two-way crossover study investigating the relative bioavailability of a single 5 mg dose of everolimus administered as either 5x1 mg everolimus intact tablets or 5x1 mg everolimus tablets suspended in 30 mL of water to healthy subjects.

    Summary
    EudraCT number
    		 2012-000299-40
    Trial protocol
    		 Outside EU/EEA  
    Global end of trial date
    12 Jan 2009

    Results information
    Results version number
    		 v1(current)
    This version publication date
    25 Oct 2018
    First version publication date
    25 Oct 2018
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    CRAD001C2121
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    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 61324 1111,
    Scientific contact
    Clinical Disclosure Office, Novartis Pharma AG, +41 61324 1111,
    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
    12 Jan 2009
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    12 Jan 2009
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The main objective of the trial was to evaluate the bioavailability of 5*1 milligrams (mg) everolimus intact tablets and tablets suspended in 30 millilitres (mL) of water.
    Protection of trial subjects
    The study was in compliance with the ethical principles derived from the Declaration of Helsinki and in compliance with all International Conference on Harmonization (ICH) Good Clinical Practice (GCP) Guidelines. All the local regulatory requirements pertinent to safety of trial subjects were followed.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    19 Nov 2008
    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: 40
    Worldwide total number of subjects
    40
    EEA total number of subjects
    0
    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)
    40
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 The study was conducted at one center in the United States.

    Pre-assignment
    Screening details
    		 A total of 40 subjects were enrolled, of which 37 completed the study.

    Period 1
    Period 1 title
    Overall period
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded
    Blinding implementation details
    The study was open label study, hence no blinding was performed.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Everolimus (Intact then Suspended)
    Arm description
    		 Subjects after (30 minutes) having a light, fat-free breakfast were orally administered with dose of 5 mg everolimus intact tablets (reference product) followed by dose of 5 mg everolimus suspended tablets in 30 mL with additional 30 mL of water after suspension (test product) on Day 1 and 15, respectively. A washout of 14 days was maintained between the treatment period.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Everolimus
    Investigational medicinal product code
    RAD001
    Other name
    Pharmaceutical forms
    Oral suspension, Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects were orally administered with 5 mg everolimus intact tablet (5 tablets- 1 mg each) followed by 5 mg everolimus suspended tablets (5 tablets- 1 mg each) in 30 mL with additional 30 mL of water after suspension on Day 1 and 15, respectively.

    Arm title
    		 Everolimus (Suspended then Intact)
    Arm description
    		 Subjects after (30 minutes) having a light, fat-free breakfast were orally administered with dose of 5 mg everolimus suspended tablets in 30 mL with additional 30 mL of water after suspension (test product) followed by dose of 5 mg everolimus intact tablets (reference product) on Day 1 and 15, respectively. A washout of 14 days was maintained between the treatment period.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Everolimus
    Investigational medicinal product code
    RAD001
    Other name
    Pharmaceutical forms
    Oral suspension, Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects were orally administered with 5 mg everolimus suspended tablets (5 tablets- 1 mg each) in 30 mL with additional 30 mL of water after suspension followed by 5 mg everolimus intact tablet (5 tablets- 1 mg each) on Day 1 and 15, respectively.

    Number of subjects in period 1
    		Everolimus (Intact then Suspended) Everolimus (Suspended then Intact)
    Started
    20
    20
    Completed
    17
    20
    Not completed
    3
    0
         Abnormal laboratory values
    2
    -
         Lost to follow-up
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Everolimus (Intact then Suspended)
    Reporting group description
    		 Subjects after (30 minutes) having a light, fat-free breakfast were orally administered with dose of 5 mg everolimus intact tablets (reference product) followed by dose of 5 mg everolimus suspended tablets in 30 mL with additional 30 mL of water after suspension (test product) on Day 1 and 15, respectively. A washout of 14 days was maintained between the treatment period.

    Reporting group title
    Everolimus (Suspended then Intact)
    Reporting group description
    		 Subjects after (30 minutes) having a light, fat-free breakfast were orally administered with dose of 5 mg everolimus suspended tablets in 30 mL with additional 30 mL of water after suspension (test product) followed by dose of 5 mg everolimus intact tablets (reference product) on Day 1 and 15, respectively. A washout of 14 days was maintained between the treatment period.

    Reporting group values
    		 Everolimus (Intact then Suspended) Everolimus (Suspended then Intact) Total
    Number of subjects
    		 20 20 40
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 20 20 40
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 34.2 ± 9.22 32.1 ± 6.58 -
    Gender categorical
    Units: Subjects
        Female
    		 19 18 37
        Male
    		 1 2 3

    End points

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    End points reporting groups
    Reporting group title
    Everolimus (Intact then Suspended)
    Reporting group description
    		 Subjects after (30 minutes) having a light, fat-free breakfast were orally administered with dose of 5 mg everolimus intact tablets (reference product) followed by dose of 5 mg everolimus suspended tablets in 30 mL with additional 30 mL of water after suspension (test product) on Day 1 and 15, respectively. A washout of 14 days was maintained between the treatment period.

    Reporting group title
    Everolimus (Suspended then Intact)
    Reporting group description
    		 Subjects after (30 minutes) having a light, fat-free breakfast were orally administered with dose of 5 mg everolimus suspended tablets in 30 mL with additional 30 mL of water after suspension (test product) followed by dose of 5 mg everolimus intact tablets (reference product) on Day 1 and 15, respectively. A washout of 14 days was maintained between the treatment period.

    Subject analysis set title
    Everolimus (Intact)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    All subjects who received 5 mg everolimus intact tablets during the study.

    Subject analysis set title
    Everolimus (Suspended)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    All subjects who received 5 mg everolimus suspended tablets in 30 mL of water during the study.

    Primary: Area under the curve (AUC) from time zero to infinity (AUC0-inf) of everolimus

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    End point title
    		 Area under the curve (AUC) from time zero to infinity (AUC0-inf) of everolimus
    End point description
    (AUC0-inf) was defined as the area under the curve from time zero to infinity. AUC0-inf was estimated by non-compartmental method, using WinNonLin version 5.0.1. Everolimus concentrations in blood were determined by Liquid chromatography–mass spectrometry (LC-MS) method following liquid extraction. The method had a lower limit of quantification (LLOQ) of 0.3 ng/mL. The analysis was performed in pharmacokinetic analysis set (PAS) population, defined as all subjects who had completed at least one period with evaluable pharmacokinetic samples.
    End point type
    Primary
    End point timeframe
    Pre dose, 0.5 h, 1 h, 1.5 h, 2 h, 2.5 h, 3 h, 4 h, 5 h, 6 h, 8 h, 12 h, 24 h at Day 1, 12 h and 24 h at Day 2, Day 3, Day 4, Day 5 and Day 6
    End point values
    		 Everolimus (Intact) Everolimus (Suspended)
    Number of subjects analysed
    39
    36
    Units: Nanograms (ng)*hour(h) / Milliliter(mL)
        geometric mean (geometric coefficient of variation)
    192.32 ± 38.89
    169.54 ± 43.87
    Statistical analysis title
    		 AUC0-inf of everolimus
    Statistical analysis description
    Comparison of AUC0-inf for everolimus intact and suspended was evaluated. AUC0-inf was analyzed using a linear mixed model. The number of subjects analyzed for this end point were 39 for everolimus (intact) and 36 for everolimus (suspended), but since this is a cross-over study, the subjects analyzed feature as 75 below, which is the total of the two arms that are being compared [everolimus (intact) (N=39) and everolimus (suspended) (N=36)].
    Comparison groups
    Everolimus (Intact) v Everolimus (Suspended)
    Number of subjects included in analysis
    75
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    Method
    Parameter type
    		 Geometric mean ratio
    Point estimate
    0.88
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0.8
         upper limit
    		 0.96

    Primary: Maximum drug concentration in blood (Cmax) of everolimus

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    End point title
    		 Maximum drug concentration in blood (Cmax) of everolimus
    End point description
    Cmax was defined as the maximum (peak) drug concentration in blood after drug administration. It was estimated by means of non-compartmental method, using WinNonLin v5.0.1. Everolimus concentrations in blood were determined by a LC-MS method following liquid extraction. The method had a LLOQ of 0.3 ng/mL. The analysis was performed in PAS population.
    End point type
    Primary
    End point timeframe
    Pre dose, 0.5 h, 1 h, 1.5 h, 2 h, 2.5 h, 3 h, 4 h, 5 h, 6 h, 8 h, 12 h, 24 h at Day 1, 12 h and 24 h at Day 2, Day 3, Day 4, Day 5 and Day 6
    End point values
    		 Everolimus (Intact) Everolimus (Suspended)
    Number of subjects analysed
    39
    36
    Units: ng/mL
        geometric mean (geometric coefficient of variation)
    26.52 ± 44.34
    19.08 ± 43.58
    Statistical analysis title
    		 Cmax of everolimus
    Statistical analysis description
    Comparison of Cmax for everolimus intact and suspended was evaluated. Cmax was analyzed using a linear mixed model. The number of subjects analyzed for this end point were 39 for everolimus (intact) and 36 for everolimus (suspended), but since this is a cross-over study, the subjects analyzed feature as 75 below, which is the total of the two arms that are being compared [everolimus (intact) (N=39) and everolimus (suspended) (N=36)].
    Comparison groups
    Everolimus (Intact) v Everolimus (Suspended)
    Number of subjects included in analysis
    75
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    Method
    Parameter type
    		 Geometric mean ratio
    Point estimate
    0.72
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0.63
         upper limit
    		 0.82

    Secondary: Area under the curve (AUC) from time zero to time of the last quantifiable concentration in blood AUC(0-t) of everolimus

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    End point title
    		 Area under the curve (AUC) from time zero to time of the last quantifiable concentration in blood AUC(0-t) of everolimus
    End point description
    AUC(0-t) was defined as the AUC from time zero to time of the last quantifiable concentration in blood. AUC(0-t) was estimated by means of non-compartmental method, using WinNonLin v5.0.1. Everolimus concentrations in blood were determined by a LC-MS method following liquid extraction. The method had a LLOQ of 0.3 ng/mL. The analysis was performed in PAS population.
    End point type
    Secondary
    End point timeframe
    Pre dose, 0.5 h, 1 h, 1.5 h, 2 h, 2.5 h, 3 h, 4 h, 5 h, 6 h, 8 h, 12 h, 24 h at Day 1, 12 h and 24 h at Day 2, Day 3, Day 4, Day 5 and Day 6
    End point values
    		 Everolimus (Intact) Everolimus (Suspended)
    Number of subjects analysed
    39
    36
    Units: ng*h/mL
        geometric mean (geometric coefficient of variation)
    170.76 ± 42.76
    146.71 ± 49.21
    No statistical analyses for this end point

    Secondary: Time to reach peak or maximum concentration in blood (Tmax) of everolimus

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    End point title
    		 Time to reach peak or maximum concentration in blood (Tmax) of everolimus
    End point description
    Tmax was defined as the time to reach peak or maximum concentration in blood. Tmax was estimated by means of non-compartmental method, using WinNonLin v5.0.1. Everolimus concentrations in blood were determined by a LC-MS method following liquid extraction. The method had a LLOQ of 0.3 ng/mL. The analysis was performed in PAS population.
    End point type
    Secondary
    End point timeframe
    Pre dose, 0.5 h, 1 h, 1.5 h, 2 h, 2.5 h, 3 h, 4 h, 5 h, 6 h, 8 h, 12 h, 24 h at Day 1, 12 h and 24 h at Day 2, Day 3, Day 4, Day 5 and Day 6
    End point values
    		 Everolimus (Intact) Everolimus (Suspended)
    Number of subjects analysed
    39
    36
    Units: hour
        median (full range (min-max))
    1 (0.5 to 1.5)
    1 (0.5 to 2)
    No statistical analyses for this end point

    Secondary: Slowest disposition (hybrid) rate constant (λZ) of everolimus

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    End point title
    		 Slowest disposition (hybrid) rate constant (λZ) of everolimus
    End point description
    λZ was defined as the slowest disposition (hybrid) rate constant. λZ was estimated by means of non-compartmental method, using WinNonLin v5.0.1. Everolimus concentrations in blood were determined by a LC-MS method following liquid extraction. The method had a LLOQ of 0.3 ng/mL. The analysis was performed in PAS population.
    End point type
    Secondary
    End point timeframe
    Pre dose, 0.5 h, 1 h, 1.5 h, 2 h, 2.5 h, 3 h, 4 h, 5 h, 6 h, 8 h, 12 h, 24 h at Day 1, 12 h and 24 h at Day 2, Day 3, Day 4, Day 5 and Day 6
    End point values
    		 Everolimus (Intact) Everolimus (Suspended)
    Number of subjects analysed
    39
    36
    Units: per hour (1/h)
        geometric mean (geometric coefficient of variation)
    0.02 ± 22.75
    0.02 ± 21.54
    No statistical analyses for this end point

    Secondary: Apparent volume of distribution (Vd/F) of everolimus

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    End point title
    		 Apparent volume of distribution (Vd/F) of everolimus
    End point description
    Vd/F was defined as the apparent volume of distribution. Vd/F was estimated by means of non-compartmental method, using WinNonLin v5.0.1. Everolimus concentrations in blood were determined by a LC-MS method following liquid extraction. The method had a LLOQ of 0.3 ng/mL. The analysis was performed in PAS population.
    End point type
    Secondary
    End point timeframe
    Pre dose, 0.5 h, 1 h, 1.5 h, 2 h, 2.5 h, 3 h, 4 h, 5 h, 6 h, 8 h, 12 h, 24 h at Day 1, 12 h and 24 h at Day 2, Day 3, Day 4, Day 5 and Day 6
    End point values
    		 Everolimus (Intact) Everolimus (Suspended)
    Number of subjects analysed
    39
    36
    Units: litre(s)
        geometric mean (geometric coefficient of variation)
    1317.92 ± 35.23
    1494.39 ± 40.43
    No statistical analyses for this end point

    Secondary: Total body apparent oral clearance of drug (CL/F) from the blood of everolimus

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    End point title
    		 Total body apparent oral clearance of drug (CL/F) from the blood of everolimus
    End point description
    CL/F was defined as the total body apparent oral clearance of drug. CL/F was estimated by means of non-compartmental method, using WinNonLin v5.0.1. Everolimus concentrations in blood were determined by a LC-MS method following liquid extraction. The method had a LLOQ of 0.3 ng/mL. The analysis was performed in PAS population.
    End point type
    Secondary
    End point timeframe
    Pre dose, 0.5 h, 1 h, 1.5 h, 2 h, 2.5 h, 3 h, 4 h, 5 h, 6 h, 8 h, 12 h, 24 h at Day 1, 12 h and 24 h at Day 2, Day 3, Day 4, Day 5 and Day 6
    End point values
    		 Everolimus (Intact) Everolimus (Suspended)
    Number of subjects analysed
    39
    36
    Units: Litre (L)/hour(h)/meter square(m2)
        geometric mean (geometric coefficient of variation)
    12.82 ± 46.65
    14.45 ± 48.86
    No statistical analyses for this end point

    Secondary: Elimination half-life associated with the terminal slope (λz) of a semi logarithmic concentration-time curve (T ½) of everolimus

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    End point title
    		 Elimination half-life associated with the terminal slope (λz) of a semi logarithmic concentration-time curve (T ½) of everolimus
    End point description
    T ½ was defined as the elimination half-life associated with the terminal slope (λz) of a semi logarithmic concentration-time curve. T ½ was estimated by means of non-compartmental method, using WinNonLin v5.0.1. Everolimus concentrations in blood were determined by a LC-MS method following liquid extraction. The method had a LLOQ of 0.3 ng/mL. The analysis was performed in PAS population.
    End point type
    Secondary
    End point timeframe
    Pre dose, 0.5 h, 1 h, 1.5 h, 2 h, 2.5 h, 3 h, 4 h, 5 h, 6 h, 8 h, 12 h, 24 h at Day 1, 12 h and 24 h at Day 2, Day 3, Day 4, Day 5 and Day 6
    End point values
    		 Everolimus (Intact) Everolimus (Suspended)
    Number of subjects analysed
    39
    36
    Units: hour
        median (full range (min-max))
    35.85 (22.5 to 67.5)
    34.934 (20.3 to 64.5)
    No statistical analyses for this end point

    Secondary: Number of subjects with Adverse Events (AEs), Serious Adverse Events (SAEs), AE leading to discontinuation and who died

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    End point title
    		 Number of subjects with Adverse Events (AEs), Serious Adverse Events (SAEs), AE leading to discontinuation and who died
    End point description
    AEs are defined as any unfavorable and unintended diagnosis, symptom, sign (including an abnormal laboratory finding), syndrome or disease which either occurs during study, having been absent at baseline, or, if present at baseline, appears to worsen. Serious adverse events are any untoward medical occurrences that result in death, are life threatening, require (or prolong) hospitalization, cause persistent or significant disability/incapacity, result in congenital anomalies or birth defects, or are other conditions which in judgment of investigators represent significant hazards. The analysis was performed on safety set population defined as all subjects who received at least one of the study treatment.
    End point type
    Secondary
    End point timeframe
    From day 1 to day 29
    End point values
    		 Everolimus (Intact) Everolimus (Suspended)
    Number of subjects analysed
    40
    37
    Units: Subjects
        AEs
    15
    14
        SAEs
    0
    0
        Deaths
    0
    0
        AEs leading to discontinuation
    2
    0
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Serious Adverse Events are monitored from date of First Subject First Visit (FSFV) until Last Subject Last Visit (LSLV). All other adverse events are monitored from First Subject First Treatment until LSLV
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    11.1
    Reporting groups
    Reporting group title
    Everolimus (Intact)
    Reporting group description
    		 All subjects who received 5 mg everolimus intact tablets during the study.

    Reporting group title
    All Subjects
    Reporting group description
    		 All subjects who received 5 mg everolimus intact tablets or suspended tablets in 30 mL of water during the study.

    Reporting group title
    Everolimus (Suspended)
    Reporting group description
    		 All subjects who received 5 mg everolimus suspended tablets in 30 mL of water during the study.

    Serious adverse events
    		 Everolimus (Intact) All Subjects Everolimus (Suspended)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 40 (0.00%)
    0 / 40 (0.00%)
    0 / 37 (0.00%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Everolimus (Intact) All Subjects Everolimus (Suspended)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    13 / 40 (32.50%)
    20 / 40 (50.00%)
    12 / 37 (32.43%)
    Investigations
    ALANINE AMINOTRANSFERASE INCREASED
         subjects affected / exposed
    2 / 40 (5.00%)
    3 / 40 (7.50%)
    2 / 37 (5.41%)
         occurrences all number
    2
    4
    2
    ASPARTATE AMINOTRANSFERASE INCREASED
         subjects affected / exposed
    2 / 40 (5.00%)
    3 / 40 (7.50%)
    2 / 37 (5.41%)
         occurrences all number
    2
    4
    2
    BLOOD TRIGLYCERIDES INCREASED
         subjects affected / exposed
    2 / 40 (5.00%)
    2 / 40 (5.00%)
    0 / 37 (0.00%)
         occurrences all number
    2
    2
    0
    NEUTROPHIL COUNT INCREASED
         subjects affected / exposed
    1 / 40 (2.50%)
    3 / 40 (7.50%)
    2 / 37 (5.41%)
         occurrences all number
    1
    3
    2
    WHITE BLOOD CELL COUNT INCREASED
         subjects affected / exposed
    1 / 40 (2.50%)
    3 / 40 (7.50%)
    2 / 37 (5.41%)
         occurrences all number
    1
    3
    2
    Nervous system disorders
    DIZZINESS
         subjects affected / exposed
    2 / 40 (5.00%)
    2 / 40 (5.00%)
    1 / 37 (2.70%)
         occurrences all number
    2
    3
    1
    HEADACHE
         subjects affected / exposed
    6 / 40 (15.00%)
    8 / 40 (20.00%)
    2 / 37 (5.41%)
         occurrences all number
    7
    9
    2
    SOMNOLENCE
         subjects affected / exposed
    1 / 40 (2.50%)
    2 / 40 (5.00%)
    1 / 37 (2.70%)
         occurrences all number
    1
    2
    1
    Gastrointestinal disorders
    DIARRHOEA
         subjects affected / exposed
    1 / 40 (2.50%)
    4 / 40 (10.00%)
    3 / 37 (8.11%)
         occurrences all number
    1
    4
    3
    FLATULENCE
         subjects affected / exposed
    2 / 40 (5.00%)
    2 / 40 (5.00%)
    1 / 37 (2.70%)
         occurrences all number
    3
    5
    2
    NAUSEA
         subjects affected / exposed
    1 / 40 (2.50%)
    2 / 40 (5.00%)
    1 / 37 (2.70%)
         occurrences all number
    1
    2
    1
    VOMITING
         subjects affected / exposed
    1 / 40 (2.50%)
    2 / 40 (5.00%)
    1 / 37 (2.70%)
         occurrences all number
    1
    2
    1
    Respiratory, thoracic and mediastinal disorders
    NASAL CONGESTION
         subjects affected / exposed
    0 / 40 (0.00%)
    2 / 40 (5.00%)
    2 / 37 (5.41%)
         occurrences all number
    0
    2
    2
    Skin and subcutaneous tissue disorders
    PRURITUS
         subjects affected / exposed
    1 / 40 (2.50%)
    2 / 40 (5.00%)
    1 / 37 (2.70%)
         occurrences all number
    1
    2
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    19 Nov 2008
    The amendment excluded female subjects with child-bearing potential from the clinical study. All female subjects in the clinical study were to be either post-menopausal or surgically sterilized.

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

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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