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    Clinical Trial Results:
    A phase III, two-armed, randomised, double blind, parallel study to compare the efficacy and safety in high CHD-risk patients with mixed dyslipidaemia of a 12-week administration of a fixed dose combination of Fenofibrate 160 mg and Pravastatin 40 mg (PRAVAFENIX®) versus Atorvastatin 20 mg.

    Summary
    EudraCT number
    		 2012-000575-17
    Trial protocol
    		 BG   LV   HR  
    Global end of trial date
    16 Mar 2015

    Results information
    Results version number
    		 v1(current)
    This version publication date
    26 Mar 2016
    First version publication date
    26 Mar 2016
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    FENOPRA-III-12-1
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Laboratoires SMB S.A.
    Sponsor organisation address
    Rue de la Pastorale, 26-28, Brussels, Belgium, 1080
    Public contact
    CLINICAL DEPARTMENT, LABORATOIRES SMB S.A., 32 2 412 09 93, clinique@smb.be
    Scientific contact
    CLINICAL DEPARTMENT, LABORATOIRES SMB S.A., 32 2 412 09 93, clinique@smb.be
    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
    07 Sep 2015
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    16 Mar 2015
    Global end of trial reached?
    Yes
    Global end of trial date
    16 Mar 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The objective of the present study is to demonstrate the non-inferiority of the efficacy of Fenofibrate 160 mg/Pravastatin 40 mg fixed combination (PRAVAFENIX®) versus Atorvastatin 20 mg, in high CHD-risk patients with mixed dyslipidaemia not at goals on Atorvastatin 10 mg regarding TG (between 150 mg/dl and 600 mg/dl) and HDL-C (< 40 mg/dl for male and < 50 mg/dl for female).
    Protection of trial subjects
    This study was conducted in accordance with Good Clinical Practices (GCPs), including International Conference on Harmonization (ICH) Guidelines, Directive 2001/20/EC of the European Parliament and the most recent version of the declaration of Helsinki (64th WMA General Assembly, Fortaleza, October 2013).
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    16 Oct 2012
    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
    Romania: 100
    Country: Number of subjects enrolled
    Georgia: 14
    Country: Number of subjects enrolled
    Macedonia, the former Yugoslav Republic of: 241
    Country: Number of subjects enrolled
    Bosnia and Herzegovina: 1
    Country: Number of subjects enrolled
    Croatia: 16
    Country: Number of subjects enrolled
    Bulgaria: 24
    Country: Number of subjects enrolled
    Latvia: 34
    Worldwide total number of subjects
    430
    EEA total number of subjects
    174
    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)
    319
    From 65 to 84 years
    111
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 The study was conducted in 7 countries between October 2012 and March 2015. 82 sites were activated and 75 sites were active and screened at least one patient. The patients were randomized (Fenofibrate 160 mg/Pravastatin 40 mg fixed dose combination or Atorvastatin 20 mg) after a run-in period of 8 weeks under atorvastatin 10 mg.

    Pre-assignment
    Screening details
    		 • Obtain signed ICF • Confirmation of mixed dislipidaemia • Demographic data, Medical history, Physical Examination, Vital signs • Review Diet compliance • Contraceptive method • Laboratory test • Prior & Concomitant medication review • Review of inclusion/exclusion criteria

    Period 1
    Period 1 title
    Efficacy Phase (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Atorvastatin 20 mg
    Arm description
    		 -
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Atorvastatin 20 mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    Atorvastatin 20 mg (ATORSTATINEG® or TOTALIP®), one blinded capsule, taken once a day orally.

    Arm title
    		 Pravafenix 160/40 mg
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    Fenofibrate 160 mg / Pravastatin 40 mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    Fenofibrate 160 mg/Pravastatin 40 mg fixed dose combination (PRAVAFENIX®), one capsule, taken once a day orally.

    Number of subjects in period 1
    		Atorvastatin 20 mg Pravafenix 160/40 mg
    Started
    215
    215
    Completed
    209
    207
    Not completed
    6
    8
         Consent withdrawn by subject
    3
    1
         Adverse event, non-fatal
    -
    4
         Other
    1
    -
         Protocol deviation
    2
    3

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Efficacy Phase
    Reporting group description
    		 -

    Reporting group values
    		 Efficacy Phase Total
    Number of subjects
    		 430 430
    Age categorical
    Units: Subjects
        In utero
    		 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0
        Newborns (0-27 days)
    		 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0
        Children (2-11 years)
    		 0 0
        Adolescents (12-17 years)
    		 0 0
        Adults (18-64 years)
    		 319 319
        From 65-84 years
    		 111 111
        85 years and over
    		 0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 58.62 ( 10.22 ) -
    Gender categorical
    Units: Subjects
        Female
    		 215 215
        Male
    		 215 215

    End points

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    End points reporting groups
    Reporting group title
    Atorvastatin 20 mg
    Reporting group description
    		 -

    Reporting group title
    Pravafenix 160/40 mg
    Reporting group description
    		 -

    Primary: Mean percent change in plasma non-HDL cholesterol at week 12 compared to the baseline

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    End point title
    		 Mean percent change in plasma non-HDL cholesterol at week 12 compared to the baseline
    End point description
    End point type
    Primary
    End point timeframe
    Week 12 compared to the baseline value.
    End point values
    		 Atorvastatin 20 mg Pravafenix 160/40 mg
    Number of subjects analysed
    183
    173
    Units: percent
        arithmetic mean (standard deviation)
    -2.79 ( 25.42 )
    7.83 ( 30.29 )
    Statistical analysis title
    		 A student t-test
    Comparison groups
    Pravafenix 160/40 mg v Atorvastatin 20 mg
    Number of subjects included in analysis
    356
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 < 0.05
    Method
    		 t-test, 1-sided
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.94
    Confidence interval
         level
    		 95%
         sides
    1-sided
         lower limit
    		 0.94
         upper limit
    		 -
    Variability estimate
    Standard deviation

    Secondary: Mean percent change in HDL-C at W12 compared to baseline

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    End point title
    		 Mean percent change in HDL-C at W12 compared to baseline
    End point description
    End point type
    Secondary
    End point timeframe
    Week 12 compared to baseline in HDL-C.
    End point values
    		 Atorvastatin 20 mg Pravafenix 160/40 mg
    Number of subjects analysed
    183
    173
    Units: percent
        arithmetic mean (standard deviation)
    11.86 ( 33.6 )
    18.1 ( 25.78 )
    No statistical analyses for this end point

    Secondary: Mean percent change in LDL at week 12 compared to baseline

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    End point title
    		 Mean percent change in LDL at week 12 compared to baseline
    End point description
    End point type
    Secondary
    End point timeframe
    Week 12 compared to baseline
    End point values
    		 Atorvastatin 20 mg Pravafenix 160/40 mg
    Number of subjects analysed
    183
    173
    Units: percent
        arithmetic mean (standard deviation)
    5.46 ( 35.38 )
    26.88 ( 38.14 )
    No statistical analyses for this end point

    Secondary: Mean percent change in cholesterol at week 12 compared to baseline

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    End point title
    		 Mean percent change in cholesterol at week 12 compared to baseline
    End point description
    End point type
    Secondary
    End point timeframe
    Week 12 compared to baseline
    End point values
    		 Atorvastatin 20 mg Pravafenix 160/40 mg
    Number of subjects analysed
    183
    173
    Units: percent
        arithmetic mean (standard deviation)
    0.15 ( 20.75 )
    9.65 ( 23.32 )
    No statistical analyses for this end point

    Secondary: Mean percent change in TG at week 12 compared to baseline

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    End point title
    		 Mean percent change in TG at week 12 compared to baseline
    End point description
    End point type
    Secondary
    End point timeframe
    Week 12 compared to baseline
    End point values
    		 Atorvastatin 20 mg Pravafenix 160/40 mg
    Number of subjects analysed
    183
    173
    Units: percent
        arithmetic mean (standard deviation)
    -11.62 ( 36.47 )
    -26.4 ( 36.6 )
    No statistical analyses for this end point

    Secondary: Mean percent change in ApoA1 at week 12 compared to baseline

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    End point title
    		 Mean percent change in ApoA1 at week 12 compared to baseline
    End point description
    End point type
    Secondary
    End point timeframe
    Week 12 compared to baseline
    End point values
    		 Atorvastatin 20 mg Pravafenix 160/40 mg
    Number of subjects analysed
    177
    168
    Units: percent
        arithmetic mean (standard deviation)
    1.7 ( 16.83 )
    8.63 ( 16.36 )
    No statistical analyses for this end point

    Secondary: Mean percent change in ApoB at week 12 compared to baseline

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    End point title
    		 Mean percent change in ApoB at week 12 compared to baseline
    End point description
    End point type
    Secondary
    End point timeframe
    Week 12 compared to baseline
    End point values
    		 Atorvastatin 20 mg Pravafenix 160/40 mg
    Number of subjects analysed
    177
    168
    Units: percent
        arithmetic mean (standard deviation)
    -1.75 ( 23.9 )
    8.7 ( 27.19 )
    No statistical analyses for this end point

    Secondary: Mean percent change in ApoB/ApoA1 ratio at week 12 compared to baseline

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    End point title
    		 Mean percent change in ApoB/ApoA1 ratio at week 12 compared to baseline
    End point description
    End point type
    Secondary
    End point timeframe
    Week 12 compared to baseline
    End point values
    		 Atorvastatin 20 mg Pravafenix 160/40 mg
    Number of subjects analysed
    177
    168
    Units: percent
        arithmetic mean (standard deviation)
    -1.96 ( 25.08 )
    1.64 ( 26.48 )
    No statistical analyses for this end point

    Adverse events

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    Adverse events information [1]
    Timeframe for reporting adverse events
    Efficacy period (12 weeks).
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    18
    Reporting groups
    Reporting group title
    Atorvastatin 20 mg (arm 1)
    Reporting group description
    		 -

    Reporting group title
    Pravafenix 160/40 mg (arm 2)
    Reporting group description
    		 -

    Notes
    [1] - There are no non-serious adverse events recorded for these results. It is expected that there will be at least one non-serious adverse event reported.
    Justification: No adverse event reach the incidence of 5% in any of the study groups.
    Serious adverse events
    		 Atorvastatin 20 mg (arm 1) Pravafenix 160/40 mg (arm 2)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 215 (0.47%)
    0 / 215 (0.00%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Cardiac disorders
    ISCHAEMIC CARDIOMYOPATHY
         subjects affected / exposed
    1 / 215 (0.47%)
    0 / 215 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Atorvastatin 20 mg (arm 1) Pravafenix 160/40 mg (arm 2)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    0 / 215 (0.00%)
    0 / 215 (0.00%)

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    18 Sep 2012
    The purpose of the protocol version 2.0 was to notify a change concerning the secondary packaging for the run-in treatment. In fact the run-in treatments were packaged in bottles and not in boxes as mentioned in the protocol version 1.0.
    19 Jun 2013
    Further to the comments from the Latvian authorities, the protocol and the ICF have been adapted to exclude the oral anticoagulants from the permitted therapies. Oral anticoagulants should be titrated down when initiating treatment with the test treatment PRAVAFENIX® due to potential interaction with fenofibrate. The risk of interactions existed with vitamin K antagonists i.e. oral anticoagulants, namely warfarin, acenocoumarol and phenprocoumone. Titration of the anticoagulant was not feasible in the study as the study medication was blinded during the efficacy phase and statin (the other arm) did not require anticoagulant down titration. To avoid the appearance of any safety issue, it was preferred to non include patients taking oral anticoagulants.
    13 Sep 2013
    The sponsor encountered a significant problem to buy the sufficient quantity of AtorstatinEG® (comparator) with an adequate expiry date needed for the replacement of current treatment at sites (scheduled for October 2013). The expiry date of available batches (Mid 2014) did not allow sufficient flexibility in patient recruitment. Therefore the sponsor decided to change the comparator from AtorstatinEG® to Totalip®. The molecule remained the same “Atorvastatin” but the commercial name was different. Totalip® and AtorstatinEG® were generic drugs of the originator Lipitor®. All these tablets were immediate release film-coated tablets with Atorvastatin Calcium salt as Active Ingredient. Posology and route of administration (oral administration, once a day, with or without food) were identical for all the drug formulations. For the run-in phase of the trial the sponsor used tablets of Totalip® 10mg instead of tablets of AtorstatinEG® 10mg but for the efficacy phase of the trial the sponsor used also tablets of Totalip® 10 mg (the blinded capsule will contain 2 tablets of 10mg). Tablet of Totalip® 20 mg cannot be used due to the high size of the tablet. Blinding was not affected by using two 10 mg tablets as the capsules were also filled with microcrystalline cellulose. In-vitro dissolution profiles of blinded capsules (containing either 1 tablet of AtorstatinEG® 20mg or 2 tablets of Totalip® 10 mg) compared to the unblinded tablets were identical.

    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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