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    Clinical Trial Results:
    Efficacy and Safety of Fixed-Dose Combination atorvastatin/amlodipine/perindopril versus Fixed-Dose Combination of atorvastatin/ amlodipine in Patients with Hypertension and Dyslipidemia.

    Summary
    EudraCT number
    		 2014-005378-12
    Trial protocol
    		 BG   IT  
    Global end of trial date
    08 Sep 2016

    Results information
    Results version number
    		 v1(current)
    This version publication date
    24 Sep 2017
    First version publication date
    24 Sep 2017
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    CL3-05153-006
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 U1111-1166-2705
    Sponsors
    Sponsor organisation name
    Institut de Recherches Internationales Servier
    Sponsor organisation address
    50, rue Carnot, Suresnes, France, 92284
    Public contact
    Clinical study Department, Institut de Recherches Internationales Servier, + 33155724366, clinicaltrials@servier.com
    Scientific contact
    Clinical study Department, Institut de Recherches Internationales Servier, + 33155724366, clinicaltrials@servier.com
    Sponsor organisation name
    Les Laboratoires Servier Representative Office Paveletskaya
    Sponsor organisation address
    Paveletskaya square 2, building 3, Moscow, Russian Federation,
    Public contact
    Les Laboratoires Servier Representative Office Paveletskaya, Les Laboratoires Servier Representative Office Paveletskaya, 7 4959374767,
    Scientific contact
    Les Laboratoires Servier Representative Office Paveletskaya, Les Laboratoires Servier Representative Office Paveletskaya, 7 4959374767,
    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
    08 Sep 2016
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    08 Sep 2016
    Global end of trial reached?
    Yes
    Global end of trial date
    08 Sep 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To demonstrate the superiority of oral fixed-dose combination atorvastatin/amlodipine/perindopril versus the reference drug atorvastatin/amlodipine in lowering office sitting systolic blood pressure (SBP) after 12 weeks of treatment versus baseline (W012-W000).
    Protection of trial subjects
    This study was conducted in accordance with Good Clinical Practice standards, ethical principles stated in the Declaration of Helsinki and applicable regulatory requirements.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    10 Aug 2015
    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
    Ukraine: 138
    Country: Number of subjects enrolled
    Argentina: 91
    Country: Number of subjects enrolled
    Brazil: 21
    Country: Number of subjects enrolled
    Bulgaria: 41
    Country: Number of subjects enrolled
    Italy: 17
    Country: Number of subjects enrolled
    Mexico: 27
    Country: Number of subjects enrolled
    Poland: 148
    Country: Number of subjects enrolled
    Russian Federation: 371
    Worldwide total number of subjects
    854
    EEA total number of subjects
    206
    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)
    633
    From 65 to 84 years
    221
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Five patients (1 in Argentina; 1 in Mexico, 2 in Poland and 1 in Russian Federation) who were randomised were not subsequently included.

    Pre-assignment
    Screening details
    		 M/F, hypertensive and dyslipidaemic patients, aged 40 to 79 years, naive of treatment, or uncontrolled with antihypertensive monotherapy and/or statin, with inclusion criteria 150 ≤ SBP < 180 mmHg and 95 ≤ DBP < 110 mmHg or isolated systolic hypertension and with 130 ≤ LDL-c < 190 mg/dL with risk of 10-year Atherosclerotic CV Disease ≥ 5%.

    Period 1
    Period 1 title
    W000-W012 (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator
    Blinding implementation details
    Treatment allocated by a centralized (Interactive System Response) balanced non-adaptive randomisation process, with stratification on country . S 5153 was supplied as tablets as its matching placebo. Atorvastatin/amlodipine was supplied as capsules as it matching placebo.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 S 5153
    Arm description
    		 Tablets of S 5153 (atorvastatin/amlodipine/perindopril) with doses of 10/5/5 mg, 20/5/5 mg and 20/10/10 mg.
    Arm type
    		 Experimental

    Investigational medicinal product name
    S 5153
    Investigational medicinal product code
    S 5153
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    ­Wash-out period: 2 weeks (3 weeks maximum) without antihypertensive or lipid lowering drugs and without any IMP intake. At inclusion, the patients randomised to the S 5153 group were allocated a kit comprising tablets of S 5153 10/5/5 mg and capsules of placebo. At W4, the dose of statin was titrated to 20 mg, as allowed by the level of 10-year ASCVD risk of the patients. Dose of antihypertensive drugs was titrated according to their BP and maintained for 8 weeks until W12 visit (as specified in Amendment No. 2, the up-titrated drug was to be taken from the day of W4 visit, after BP measurement): -- If BP was not controlled (SBP≥ 140 mmHg or DBP ≥ 90 mmHg), patients were dispensed with a kit of S 5153 20/10/10 mg. -- If BP was controlled (SBP< 140 mmHg and DBP < 90 mmHg), patients were dispensed with a kit of S 5153 20/5/5 mg.

    Arm title
    		 Atorvastatin/amlodipine
    Arm description
    		 Capsules of atorvastatin/amlodipine with doses of 10/5 mg, 20/5 mg and 20/10 mg.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Atorvastatin/amlodipine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Wash-out period: 2 weeks (3 weeks maximum) without antihypertensive or lipid lowering drugs and without any IMP intake. ­At inclusion, the patients randomised to the atorvastatin/amlodipine group were allocated a kit comprising capsules of atorvastatin/amlodipine 10/5 mg and tablets of placebo. At W4, the dose of statin was titrated to 20 mg, as allowed by the level of 10-year ASCVD risk of the patients. Dose of antihypertensive drug was titrated according to their BP and maintained for 8 weeks until W12 visit (as specified in Amendment No. 2, the up-titrated drug was to be taken from the day of W4 visit, after BP measurement): -- If BP was not controlled (SBP≥ 140 mmHg or DBP ≥ 90 mmHg), patients were dispensed with a kit of atorvastatin/amlodipine 20/10 mg. -- If BP was controlled (SBP< 140 mmHg and DBP < 90 mmHg), patients were dispensed with a kit of atorvastatin/amlodipine 20/5 mg.

    Number of subjects in period 1
    		S 5153 Atorvastatin/amlodipine
    Started
    429
    425
    Completed
    402
    401
    Not completed
    27
    24
         Adverse event, serious fatal
    -
    2
         Randomised but not included
    3
    2
         Non medical reason
    8
    7
         Adverse event, non-fatal
    9
    9
         Protocol deviation
    7
    4

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    S 5153
    Reporting group description
    		 Tablets of S 5153 (atorvastatin/amlodipine/perindopril) with doses of 10/5/5 mg, 20/5/5 mg and 20/10/10 mg.

    Reporting group title
    Atorvastatin/amlodipine
    Reporting group description
    		 Capsules of atorvastatin/amlodipine with doses of 10/5 mg, 20/5 mg and 20/10 mg.

    Reporting group values
    		 S 5153 Atorvastatin/amlodipine Total
    Number of subjects
    		 429 425 854
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0
        Children (2-11 years)
    		 0 0 0
        Adolescents (12-17 years)
    		 0 0 0
        Adults (18-64 years)
    		 315 318 633
        From 65-84 years
    		 114 107 221
        85 years and over
    		 0 0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 58.1 ( 8.7 ) 57.7 ( 8.9 ) -
    Gender categorical
    Units: Subjects
        Female
    		 241 234 475
        Male
    		 188 191 379
    Type of dyslipidaemia
    Units: Subjects
        Hypercholesterolaemia
    		 242 235 477
        Mixed dyslipidaemia
    		 187 190 377
    Hypertension duration
    Units: months
        arithmetic mean (standard deviation)
    		 79.2 ( 92.2 ) 73.9 ( 83.2 ) -
    10-year ASCVD risk
    Units: percent
        arithmetic mean (standard deviation)
    		 15.7 ( 8.8 ) 15.7 ( 9.4 ) -
    Dyslipidaemia duration
    Units: months
        arithmetic mean (standard deviation)
    		 32.8 ( 50.1 ) 31 ( 45.8 ) -
    Sitting SBP
    Units: mmHg
        arithmetic mean (standard deviation)
    		 163.1 ( 7.5 ) 163.7 ( 7.1 ) -
    Sitting DBP
    Units: mmHg
        arithmetic mean (standard deviation)
    		 95.2 ( 10.4 ) 95.7 ( 9.5 ) -
    LDL-Cholesterol
    Units: mmol/L
        arithmetic mean (standard deviation)
    		 4.02 ( 0.42 ) 4.03 ( 0.43 ) -

    End points

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    End points reporting groups
    Reporting group title
    S 5153
    Reporting group description
    		 Tablets of S 5153 (atorvastatin/amlodipine/perindopril) with doses of 10/5/5 mg, 20/5/5 mg and 20/10/10 mg.

    Reporting group title
    Atorvastatin/amlodipine
    Reporting group description
    		 Capsules of atorvastatin/amlodipine with doses of 10/5 mg, 20/5 mg and 20/10 mg.

    Subject analysis set title
    Full Analysis Set (FAS)
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    In accordance with the intention-to-treat principle and the Section 5.2.1 of ICH E9 guideline (CPMP/ICH/363/96/step 5, 1998), all patients of the RS having taken at least one dose of IMP and having at least an analysable value at baseline and at least one analysable post-baseline value of mean sitting SBP over W0-W12 period.

    Primary: Change in office sitting SBP from baseline to last post-baseline value

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    End point title
    		 Change in office sitting SBP from baseline to last post-baseline value
    End point description
    End point type
    Primary
    End point timeframe
    Change from baseline to last post-baseline value over W000-W012 period.
    End point values
    		 S 5153 Atorvastatin/amlodipine
    Number of subjects analysed
    423
    420
    Units: mmHg
        arithmetic mean (standard deviation)
    -31.7 ( 13.8 )
    -31.6 ( 13.6 )
    Statistical analysis title
    		 Ancova
    Statistical analysis description
    Between group comparison (S 5153 versus atorvastatin/amlodipine) on the change in office sitting SBP using ANCOVA model, adjusted on fixed, categorical effects of treatment and country, as well as the continuous fixed covariate of baseline.
    Comparison groups
    S 5153 v Atorvastatin/amlodipine
    Number of subjects included in analysis
    843
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.53
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.52
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.14
         upper limit
    		 1.1
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.83

    Secondary: Change in office sitting DBP from baseline to last post-baseline value

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    End point title
    		 Change in office sitting DBP from baseline to last post-baseline value
    End point description
    End point type
    Secondary
    End point timeframe
    Change from baseline to last post-baseline value over W000-W012 period.
    End point values
    		 S 5153 Atorvastatin/amlodipine
    Number of subjects analysed
    423
    420
    Units: mmHg
        arithmetic mean (standard deviation)
    -15.9 ( 12.1 )
    -15.3 ( 11.1 )
    Statistical analysis title
    		 Ancova
    Statistical analysis description
    Between group comparison (S 5153 versus atorvastatin/amlodipine) on the change in DBP using ANCOVA model, adjusted on fixed, categorical effects of treatment and country, as well as the continuous fixed covariate of baseline.
    Comparison groups
    S 5153 v Atorvastatin/amlodipine
    Number of subjects included in analysis
    843
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.106
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.94
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.08
         upper limit
    		 0.2
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.58

    Post-hoc: Change in office sitting SBP from baseline to last post-baseline value in patients with grade 2 systolic-diastolic hypertension at baseline

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    End point title
    		 Change in office sitting SBP from baseline to last post-baseline value in patients with grade 2 systolic-diastolic hypertension at baseline
    End point description
    End point type
    Post-hoc
    End point timeframe
    Change from baseline to last post-baseline value during W000-W012 period.
    End point values
    		 S 5153 Atorvastatin/amlodipine
    Number of subjects analysed
    124
    117
    Units: mmHg
        arithmetic mean (standard deviation)
    -36.5 ( 10.8 )
    -34.5 ( 12.5 )
    Statistical analysis title
    		 Ancova
    Statistical analysis description
    Between group comparison (S 5153 versus atorvastatin/amlodipine) on the change in office sitting SBP using ANCOVA model, adjusted on fixed, categorical effects of treatment and country, as well as the continuous fixed covariate of baseline.
    Comparison groups
    S 5153 v Atorvastatin/amlodipine
    Number of subjects included in analysis
    241
    Analysis specification
    Post-hoc
    Analysis type
    		 superiority
    P-value
    		 = 0.101
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -2.32
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -5.08
         upper limit
    		 0.45
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.4

    Post-hoc: Change in office sitting DBP from baseline to last post-baseline value in patients with grade 2 systolic-diastolic hypertension at baseline

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    End point title
    		 Change in office sitting DBP from baseline to last post-baseline value in patients with grade 2 systolic-diastolic hypertension at baseline
    End point description
    End point type
    Post-hoc
    End point timeframe
    Change from baseline to last post-baseline value during W000-W012 period.
    End point values
    		 S 5153 Atorvastatin/amlodipine
    Number of subjects analysed
    124
    117
    Units: mmHg
        arithmetic mean (standard deviation)
    -24.5 ( 10 )
    -21.7 ( 9.8 )
    Statistical analysis title
    		 Ancova
    Statistical analysis description
    Between group comparison (S 5153 versus atorvastatin/amlodipine) on the change in DBP using ANCOVA model, adjusted on fixed, categorical effects of treatment and country, as well as the continuous fixed covariate of baseline.
    Comparison groups
    S 5153 v Atorvastatin/amlodipine
    Number of subjects included in analysis
    241
    Analysis specification
    Post-hoc
    Analysis type
    		 superiority
    P-value
    		 = 0.016
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -2.97
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -5.38
         upper limit
    		 -0.55
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.23

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    All Adverse Events that occurred, worsened or became serious between the first study drug intake and the last study drug intake + 7 days (both included).
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    19.0
    Reporting groups
    Reporting group title
    S 5153
    Reporting group description
    		 -

    Reporting group title
    Atorvastatin/amlodipine
    Reporting group description
    		 -

    Serious adverse events
    		 S 5153 Atorvastatin/amlodipine
    Total subjects affected by serious adverse events
         subjects affected / exposed
    6 / 425 (1.41%)
    3 / 423 (0.71%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Investigations
    Blood potassium increased
         subjects affected / exposed
    1 / 425 (0.24%)
    0 / 423 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    1 / 425 (0.24%)
    0 / 423 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Congenital, familial and genetic disorders
    Hydrocele
         subjects affected / exposed
    1 / 425 (0.24%)
    0 / 423 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Hypertensive crisis
         subjects affected / exposed
    1 / 425 (0.24%)
    0 / 423 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Acute myocardial infarction
         subjects affected / exposed
    0 / 425 (0.00%)
    1 / 423 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Angina pectoris
         subjects affected / exposed
    0 / 425 (0.00%)
    1 / 423 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Carotid artery stenosis
         subjects affected / exposed
    0 / 425 (0.00%)
    1 / 423 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Thrombocytopenia
         subjects affected / exposed
    1 / 425 (0.24%)
    0 / 423 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Bronchospasm
         subjects affected / exposed
    0 / 425 (0.00%)
    1 / 423 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Lower respiratory tract infection
         subjects affected / exposed
    1 / 425 (0.24%)
    0 / 423 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peritonsillar abscess
         subjects affected / exposed
    1 / 425 (0.24%)
    0 / 423 (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: 0%
    Non-serious adverse events
    		 S 5153 Atorvastatin/amlodipine
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    73 / 425 (17.18%)
    96 / 423 (22.70%)
    Vascular disorders
    Hot flush
         subjects affected / exposed
    1 / 425 (0.24%)
    0 / 423 (0.00%)
         occurrences all number
    1
    0
    Brachiocephalic arteriosclerosis
         subjects affected / exposed
    0 / 425 (0.00%)
    2 / 423 (0.47%)
         occurrences all number
    0
    2
    Haematoma
         subjects affected / exposed
    0 / 425 (0.00%)
    1 / 423 (0.24%)
         occurrences all number
    0
    1
    Hypertension
         subjects affected / exposed
    0 / 425 (0.00%)
    1 / 423 (0.24%)
         occurrences all number
    0
    1
    General disorders and administration site conditions
    Oedema peripheral
         subjects affected / exposed
    11 / 425 (2.59%)
    23 / 423 (5.44%)
         occurrences all number
    13
    23
    Peripheral swelling
         subjects affected / exposed
    2 / 425 (0.47%)
    3 / 423 (0.71%)
         occurrences all number
    2
    3
    Asthenia
         subjects affected / exposed
    1 / 425 (0.24%)
    2 / 423 (0.47%)
         occurrences all number
    1
    2
    Drug intolerance
         subjects affected / exposed
    1 / 425 (0.24%)
    0 / 423 (0.00%)
         occurrences all number
    1
    0
    Soft tissue inflammation
         subjects affected / exposed
    1 / 425 (0.24%)
    0 / 423 (0.00%)
         occurrences all number
    1
    0
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    2 / 425 (0.47%)
    0 / 423 (0.00%)
         occurrences all number
    2
    0
    Epistaxis
         subjects affected / exposed
    0 / 425 (0.00%)
    2 / 423 (0.47%)
         occurrences all number
    0
    2
    Rhinitis allergic
         subjects affected / exposed
    0 / 425 (0.00%)
    1 / 423 (0.24%)
         occurrences all number
    0
    1
    Psychiatric disorders
    Middle insomnia
         subjects affected / exposed
    1 / 425 (0.24%)
    0 / 423 (0.00%)
         occurrences all number
    1
    0
    Investigations
    Blood creatine phosphokinase increased
         subjects affected / exposed
    9 / 425 (2.12%)
    8 / 423 (1.89%)
         occurrences all number
    9
    8
    Alanine aminotransferase increased
         subjects affected / exposed
    8 / 425 (1.88%)
    4 / 423 (0.95%)
         occurrences all number
    8
    4
    Aspartate aminotransferase increased
         subjects affected / exposed
    4 / 425 (0.94%)
    3 / 423 (0.71%)
         occurrences all number
    4
    3
    Creatinine renal clearance decreased
         subjects affected / exposed
    3 / 425 (0.71%)
    1 / 423 (0.24%)
         occurrences all number
    3
    1
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    2 / 425 (0.47%)
    2 / 423 (0.47%)
         occurrences all number
    2
    2
    Blood potassium increased
         subjects affected / exposed
    2 / 425 (0.47%)
    1 / 423 (0.24%)
         occurrences all number
    2
    1
    Blood creatinine increased
         subjects affected / exposed
    1 / 425 (0.24%)
    1 / 423 (0.24%)
         occurrences all number
    1
    1
    Blood alkaline phosphatase increased
         subjects affected / exposed
    1 / 425 (0.24%)
    0 / 423 (0.00%)
         occurrences all number
    1
    0
    Blood triglycerides increased
         subjects affected / exposed
    1 / 425 (0.24%)
    0 / 423 (0.00%)
         occurrences all number
    1
    0
    Blood pressure decreased
         subjects affected / exposed
    0 / 425 (0.00%)
    2 / 423 (0.47%)
         occurrences all number
    0
    2
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    1 / 425 (0.24%)
    1 / 423 (0.24%)
         occurrences all number
    1
    1
    Ankle fracture
         subjects affected / exposed
    1 / 425 (0.24%)
    0 / 423 (0.00%)
         occurrences all number
    1
    0
    Radius fracture
         subjects affected / exposed
    1 / 425 (0.24%)
    0 / 423 (0.00%)
         occurrences all number
    1
    0
    Accidental overdose
         subjects affected / exposed
    0 / 425 (0.00%)
    1 / 423 (0.24%)
         occurrences all number
    0
    1
    Overdose
         subjects affected / exposed
    0 / 425 (0.00%)
    1 / 423 (0.24%)
         occurrences all number
    0
    2
    Rib fracture
         subjects affected / exposed
    0 / 425 (0.00%)
    1 / 423 (0.24%)
         occurrences all number
    0
    1
    Thermal burn
         subjects affected / exposed
    0 / 425 (0.00%)
    1 / 423 (0.24%)
         occurrences all number
    0
    1
    Cardiac disorders
    Supraventricular extrasystoles
         subjects affected / exposed
    1 / 425 (0.24%)
    1 / 423 (0.24%)
         occurrences all number
    1
    1
    Sinus tachycardia
         subjects affected / exposed
    1 / 425 (0.24%)
    0 / 423 (0.00%)
         occurrences all number
    1
    0
    Supraventricular tachycardia
         subjects affected / exposed
    1 / 425 (0.24%)
    0 / 423 (0.00%)
         occurrences all number
    1
    0
    Sinus bradycardia
         subjects affected / exposed
    0 / 425 (0.00%)
    1 / 423 (0.24%)
         occurrences all number
    0
    1
    Nervous system disorders
    Headache
         subjects affected / exposed
    2 / 425 (0.47%)
    6 / 423 (1.42%)
         occurrences all number
    2
    6
    Dizziness
         subjects affected / exposed
    2 / 425 (0.47%)
    1 / 423 (0.24%)
         occurrences all number
    2
    1
    Cervicobrachial syndrome
         subjects affected / exposed
    0 / 425 (0.00%)
    1 / 423 (0.24%)
         occurrences all number
    0
    1
    Tremor
         subjects affected / exposed
    0 / 425 (0.00%)
    1 / 423 (0.24%)
         occurrences all number
    0
    1
    Blood and lymphatic system disorders
    Haemorrhagic diathesis
         subjects affected / exposed
    1 / 425 (0.24%)
    0 / 423 (0.00%)
         occurrences all number
    1
    0
    Eye disorders
    Lacrimation increased
         subjects affected / exposed
    0 / 425 (0.00%)
    1 / 423 (0.24%)
         occurrences all number
    0
    1
    Gastrointestinal disorders
    Dyspepsia
         subjects affected / exposed
    2 / 425 (0.47%)
    3 / 423 (0.71%)
         occurrences all number
    2
    3
    Food poisoning
         subjects affected / exposed
    1 / 425 (0.24%)
    1 / 423 (0.24%)
         occurrences all number
    1
    1
    Gastrooesophageal reflux disease
         subjects affected / exposed
    1 / 425 (0.24%)
    1 / 423 (0.24%)
         occurrences all number
    1
    1
    Abdominal pain upper
         subjects affected / exposed
    1 / 425 (0.24%)
    0 / 423 (0.00%)
         occurrences all number
    1
    0
    Dental caries
         subjects affected / exposed
    1 / 425 (0.24%)
    0 / 423 (0.00%)
         occurrences all number
    1
    0
    Faeces soft
         subjects affected / exposed
    1 / 425 (0.24%)
    0 / 423 (0.00%)
         occurrences all number
    1
    0
    Nausea
         subjects affected / exposed
    1 / 425 (0.24%)
    0 / 423 (0.00%)
         occurrences all number
    1
    0
    Dry mouth
         subjects affected / exposed
    0 / 425 (0.00%)
    1 / 423 (0.24%)
         occurrences all number
    0
    1
    Toothache
         subjects affected / exposed
    0 / 425 (0.00%)
    1 / 423 (0.24%)
         occurrences all number
    0
    1
    Skin and subcutaneous tissue disorders
    Urticaria
         subjects affected / exposed
    2 / 425 (0.47%)
    0 / 423 (0.00%)
         occurrences all number
    2
    0
    Pruritus
         subjects affected / exposed
    1 / 425 (0.24%)
    1 / 423 (0.24%)
         occurrences all number
    1
    1
    Swelling face
         subjects affected / exposed
    1 / 425 (0.24%)
    0 / 423 (0.00%)
         occurrences all number
    1
    0
    Musculoskeletal and connective tissue disorders
    Muscle spasms
         subjects affected / exposed
    1 / 425 (0.24%)
    2 / 423 (0.47%)
         occurrences all number
    1
    4
    Back disorder
         subjects affected / exposed
    1 / 425 (0.24%)
    0 / 423 (0.00%)
         occurrences all number
    1
    0
    Pain in extremity
         subjects affected / exposed
    1 / 425 (0.24%)
    0 / 423 (0.00%)
         occurrences all number
    1
    0
    Periostitis
         subjects affected / exposed
    1 / 425 (0.24%)
    0 / 423 (0.00%)
         occurrences all number
    1
    0
    Arthralgia
         subjects affected / exposed
    0 / 425 (0.00%)
    2 / 423 (0.47%)
         occurrences all number
    0
    2
    Back pain
         subjects affected / exposed
    0 / 425 (0.00%)
    1 / 423 (0.24%)
         occurrences all number
    0
    1
    Joint stiffness
         subjects affected / exposed
    0 / 425 (0.00%)
    1 / 423 (0.24%)
         occurrences all number
    0
    1
    Myalgia
         subjects affected / exposed
    0 / 425 (0.00%)
    1 / 423 (0.24%)
         occurrences all number
    0
    1
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    8 / 425 (1.88%)
    13 / 423 (3.07%)
         occurrences all number
    8
    13
    Respiratory tract infection
         subjects affected / exposed
    3 / 425 (0.71%)
    0 / 423 (0.00%)
         occurrences all number
    3
    0
    Respiratory tract infection viral
         subjects affected / exposed
    2 / 425 (0.47%)
    1 / 423 (0.24%)
         occurrences all number
    2
    1
    Bronchitis
         subjects affected / exposed
    1 / 425 (0.24%)
    1 / 423 (0.24%)
         occurrences all number
    1
    1
    Rhinitis
         subjects affected / exposed
    1 / 425 (0.24%)
    0 / 423 (0.00%)
         occurrences all number
    1
    0
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 425 (0.24%)
    0 / 423 (0.00%)
         occurrences all number
    1
    0
    Conjunctivitis
         subjects affected / exposed
    0 / 425 (0.00%)
    2 / 423 (0.47%)
         occurrences all number
    0
    2
    Influenza
         subjects affected / exposed
    0 / 425 (0.00%)
    2 / 423 (0.47%)
         occurrences all number
    0
    2
    Pulpitis dental
         subjects affected / exposed
    0 / 425 (0.00%)
    1 / 423 (0.24%)
         occurrences all number
    0
    1
    Viral pharyngitis
         subjects affected / exposed
    0 / 425 (0.00%)
    1 / 423 (0.24%)
         occurrences all number
    0
    1
    Metabolism and nutrition disorders
    Hyperkalaemia
         subjects affected / exposed
    2 / 425 (0.47%)
    7 / 423 (1.65%)
         occurrences all number
    2
    7
    Hypercholesterolaemia
         subjects affected / exposed
    1 / 425 (0.24%)
    0 / 423 (0.00%)
         occurrences all number
    1
    0
    Hypokalaemia
         subjects affected / exposed
    1 / 425 (0.24%)
    0 / 423 (0.00%)
         occurrences all number
    1
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    07 Sep 2015
    ­Amendment No. 1 was applicable in all countries. It mainly concerned: - Precisions on the upper limits of biological parameters of triglycerides and kaliaemia, above which the patient was not to be selected or included. - Precisions on the measurements of the blood pressure - Notification of approval of Triveram® (S 5153) in Europe. - Precisions on ERIN notifications. - Precisions on e-CRF completion.
    10 Feb 2016
    Amendment No. 2 was applicable in all countries. It mainly concerned: - Precisions on the limits of blood pressure values for selection. - Notification of approved SmPC of Triveram. - Precision that the first study drug intake should be the day after randomisation, at home, before breakfast. - Blood pressure measurement: if the difference between 2 consecutive SBP measurements was larger than or equal to 15 mmHg, then the set of 3 measurements should not be considered as valid and all 3 measurements were to be repeated after an additional 5 minutes of rest.
    15 Apr 2016
    Amendment No. 3 was applicable in all countries. It modified the estimated standard deviation (from 11.9 mmHg to 13.0 mmHg) and consequently re evaluated the number of patients to be included in the study (from 700 to 830).

    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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    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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