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    Clinical Trial Results:
    Safety and efficacy of fixed dose combination of Indapamide SR 1.5 mg / Amlodipine versus Valsartan / Amlodipine over 12-week of treatment with conditional titration based on the blood pressure control, in patients with uncontrolled essential hypertension after 1 month of Amlodipine 5 mg run-in treatment. An international, randomized, double-blind, multicenter controlled study.

    Due to the EudraCT – Results system being out of service between 31 July 2015 and 12 January 2016, these results have been published in compliance with revised timelines.
    Summary
    EudraCT number
    		 2012-001690-84
    Trial protocol
    		 GB   HU   LT   LV   BG   PL  
    Global end of trial date
    27 Feb 2015

    Results information
    Results version number
    		 v1(current)
    This version publication date
    15 Jul 2016
    First version publication date
    15 Jul 2016
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    CL3-05520-006
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 U1111-1139-9138
    Sponsors
    Sponsor organisation name
    Institut de Recherche Internationale Servier
    Sponsor organisation address
    50 rue Carnot, Suresnes, France,
    Public contact
    Clinical Studies Department, Institut de Recherches Internationales Servier, +33 155724366, clinicaltrials@servier.com
    Scientific contact
    Clinical Studies Department, Institut de Recherches Internationales Servier, +33 155724366, clinicaltrials@servier.com
    Sponsor organisation name
    Les Laboratoires Servier Representative Office Paveletskaya
    Sponsor organisation address
    Paveletskaya square 2, builiding 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,
    Sponsor organisation name
    Servier United Kingdom
    Sponsor organisation address
    Framewood road, Slough, United Kingdom,
    Public contact
    Servier United Kingdom, Servier United Kingdom, 44 1753663456,
    Scientific contact
    Servier United Kingdom, Servier United Kingdom, 44 1753663456,
    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
    27 Feb 2015
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    27 Feb 2015
    Global end of trial reached?
    Yes
    Global end of trial date
    27 Feb 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    ­To demonstrate better efficacy of fixed-dose combination strategy Indapamide SR 1.5 mg/Amlodipine versus Valsartan/Amlodipine fixed-dose in lowering office systolic blood pressure at W12.
    Protection of trial subjects
    Controlled hypertension was defined according to the hypertension management guidelines (WHO/ISH, 2003; ESC, 2009) and was in accordance with the recent guideline of The task force for the management of arterial hypertension of the ESH and of the ESC (2013), as the blood pressure values were under the following targets: SBP < 140 mmHg and DBP < 90 mmHg.A run-in period of 4 weeks was dedicated to confirm the essential uncontrolled hypertension under patient’s amlodipine 5 mg treatment. Study treatment should be prematurely and definitively discontinued for a participant for one of the following reasons: - Patients who at the W6 visit had the SBP >= 180 mmHg or DBP >= 110 mmHg (mean of the last 2 out of 3 measurements). - Onset of adverse event, which presented a risk for the patient according to the investigator or requires prescription of a treatment incompatible with the protocol. - Onset of an adverse event which, according to the investigator, made it unsafe for the patient to continue with the study treatment. This included clinically significant abnormal biochemical and haematological parameters, or clinically significant ECG abnormality (except LVH). - ALAT or ASAT>= 1.5 times the upper limit of normal laboratory range. - Pregnancy. - Major protocol deviation preventing the analysis of the main endpoint, or which, in the opinion of the investigator, made it unsafe for the patient to continue to take the study medication and to stay in the study. - Non- medical reason (patient’s personal decision to stop treatment).
    Background therapy
    		 -
    Evidence for comparator
    		 Among a wide number of fixed dual combination marketed worldwide for the treatment of hypertension, valsartan/amlodipine already registered since 2007 in Europe is one of the most commonly prescribed.
    Actual start date of recruitment
    04 Jul 2013
    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
    Poland: 60
    Country: Number of subjects enrolled
    Bulgaria: 67
    Country: Number of subjects enrolled
    Hungary: 7
    Country: Number of subjects enrolled
    Latvia: 34
    Country: Number of subjects enrolled
    Lithuania: 31
    Country: Number of subjects enrolled
    Romania: 41
    Country: Number of subjects enrolled
    Argentina: 51
    Country: Number of subjects enrolled
    Mexico: 14
    Country: Number of subjects enrolled
    Russian Federation: 56
    Country: Number of subjects enrolled
    South Africa: 13
    Country: Number of subjects enrolled
    Thailand: 3
    Country: Number of subjects enrolled
    Ukraine: 66
    Country: Number of subjects enrolled
    Vietnam: 30
    Worldwide total number of subjects
    473
    EEA total number of subjects
    240
    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)
    355
    From 65 to 84 years
    114
    85 years and over
    4

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 An Open label run-in period (4 weeks) was dedicated to confirm the essential uncontrolled hypertension under treatment with amlodipine 5 mg over 4 weeks, in order to check the baseline evaluations. Only eligible patients having still an uncontrolled hypertension under amlodipine 5 mg were randomised to Investigational Medicine Products (IMP).

    Period 1
    Period 1 title
    Double-blind treatment period (12 weeks) (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Indapamide/Amlodipine
    Arm description
    		 Indapamide slow release 1.5mg / Amlodipine 5 mg single pill fixe dose combination as starting dose, possibly up-titrated to the next dose of the treatment strategy to Indapamide slow release 1.5mg / Amlodipine 10 mg, at visit W6, for all non-controlled patients (SBP ≥ 140 and < 180 mmHg and /or DBP ≥ 90 and < 110 mmHg, based on the office blood pressure measurement).
    Arm type
    		 Experimental

    Investigational medicinal product name
    Indapamide/Amlodipine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Indapamide SR 1.5 mg/amlodipine 5 mg single pill fixe dose combination administered orally as one tablet daily, and possibly from W6 in case of up-titration for non-controlled patients: Indapamide SR 1.5 mg/amlodipine 10 mg single pill fixe dose combination administered orally as one tablet daily

    Arm title
    		 Valsartan/Amlodipine
    Arm description
    		 Valsartan 80 mg/Amlodipine 5 mg single pill fixe dose combination as starting dose, possibly up-titrated to the next dose of the treatment strategy to Valsartan 160 mg/Amlodipine 5 mg, at visit W6, for all non-controlled patients (SBP ≥ 140 and < 180 mmHg and /or DBP ≥ 90 and < 110 mmHg, based on the office blood pressure measurement).
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Valsartan/Amlodipine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Valsartan 80 mg/amlodipine 5 mg single pill fixe dose combination administered orally as one capsule daily, and possibly from W6 in case of up-titration for non-controlled patients: Valsartan 160 mg/amlodipine 5 mg single pill fixe dose combination administered orally as one capsule daily.

    Number of subjects in period 1
    		Indapamide/Amlodipine Valsartan/Amlodipine
    Started
    237
    236
    Completed
    220
    223
    Not completed
    17
    13
         Adverse event, non-fatal
    3
    -
         non-medical reasons
    7
    5
         Protocol deviation
    7
    7
         Lack of efficacy
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Indapamide/Amlodipine
    Reporting group description
    		 Indapamide slow release 1.5mg / Amlodipine 5 mg single pill fixe dose combination as starting dose, possibly up-titrated to the next dose of the treatment strategy to Indapamide slow release 1.5mg / Amlodipine 10 mg, at visit W6, for all non-controlled patients (SBP ≥ 140 and < 180 mmHg and /or DBP ≥ 90 and < 110 mmHg, based on the office blood pressure measurement).

    Reporting group title
    Valsartan/Amlodipine
    Reporting group description
    		 Valsartan 80 mg/Amlodipine 5 mg single pill fixe dose combination as starting dose, possibly up-titrated to the next dose of the treatment strategy to Valsartan 160 mg/Amlodipine 5 mg, at visit W6, for all non-controlled patients (SBP ≥ 140 and < 180 mmHg and /or DBP ≥ 90 and < 110 mmHg, based on the office blood pressure measurement).

    Reporting group values
    		 Indapamide/Amlodipine Valsartan/Amlodipine Total
    Number of subjects
    		 237 236 473
    Age categorical
    Results of demographic data are provided in the Full Analysis Set.
    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)
    		 182 173 355
        From 65-84 years
    		 53 61 114
        85 years and over
    		 2 2 4
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 57.4 ( 10.7 ) 57.3 ( 11.9 ) -
    Gender categorical
    Results of demographic data are provided in the Full Analysis Set.
    Units: Subjects
        Female
    		 116 116 232
        Male
    		 121 120 241
    Subject analysis sets

    Subject analysis set title
    Full Analysis Set
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Based on the intention-to-treat principle and ICH E9 guideline, this set corresponded to all patients of the RS who received at least one dose of study treatment and who had at least one baseline analysable value and one post-baseline analysable value for Supine Systolic Blood Pressure.

    Subject analysis sets values
    		 Full Analysis Set
    Number of subjects
    465
    Age categorical
    Results of demographic data are provided in the Full Analysis Set.
    Units: Subjects
        In utero
    0
        Preterm newborn infants (gestational age < 37 wks)
    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)
    348
        From 65-84 years
    113
        85 years and over
    4
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    57.3 ( 11.3 )
    Gender categorical
    Results of demographic data are provided in the Full Analysis Set.
    Units: Subjects
        Female
    228
        Male
    237

    End points

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    End points reporting groups
    Reporting group title
    Indapamide/Amlodipine
    Reporting group description
    		 Indapamide slow release 1.5mg / Amlodipine 5 mg single pill fixe dose combination as starting dose, possibly up-titrated to the next dose of the treatment strategy to Indapamide slow release 1.5mg / Amlodipine 10 mg, at visit W6, for all non-controlled patients (SBP ≥ 140 and < 180 mmHg and /or DBP ≥ 90 and < 110 mmHg, based on the office blood pressure measurement).

    Reporting group title
    Valsartan/Amlodipine
    Reporting group description
    		 Valsartan 80 mg/Amlodipine 5 mg single pill fixe dose combination as starting dose, possibly up-titrated to the next dose of the treatment strategy to Valsartan 160 mg/Amlodipine 5 mg, at visit W6, for all non-controlled patients (SBP ≥ 140 and < 180 mmHg and /or DBP ≥ 90 and < 110 mmHg, based on the office blood pressure measurement).

    Subject analysis set title
    Full Analysis Set
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Based on the intention-to-treat principle and ICH E9 guideline, this set corresponded to all patients of the RS who received at least one dose of study treatment and who had at least one baseline analysable value and one post-baseline analysable value for Supine Systolic Blood Pressure.

    Primary: Office supine systolic blood pressure over 12 weeks (W0-W12)

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    End point title
    		 Office supine systolic blood pressure over 12 weeks (W0-W12)
    End point description
    The change in the office supine systolic blood pressure (SBP) over 12 weeks (W0-W12) was measured. The between group comparison was performed in the Full Analysis Set on the change from Baseline (W0) to last post baseline value at W12 of SBP using an analysis of covariance (ANCOVA) model performed. Analysis included the fixed, categorical effect of treatment with modality Indapamide/A mlodipine and Valsartan/Amlodipine, and categorical fixed effects of country, as well as the continuous fixed covariate of baseline.
    End point type
    Primary
    End point timeframe
    Office supine systolic blood pressure was measured over 12 weeks (W0-W12)
    End point values
    		 Indapamide/Amlodipine Valsartan/Amlodipine
    Number of subjects analysed
    233
    232
    Units: mmHg
        arithmetic mean (standard deviation)
    -20.84 ( 14.85 )
    -19.72 ( 16.13 )
    Statistical analysis title
    		 Office supine systolic blood pressure
    Statistical analysis description
    Analysis of the between-group difference in the change of the office supine blood pressure over 12 weeks (W0-W12), using an analysis of covariance (ANCOVA) model performed. Analysis included the fixed, categorical effect of treatment with modality Indapamide/Amlodipine and Valsartan/Amlodipine, and categorical fixed effects of country, as well as the continuous fixed covariate of baseline.
    Comparison groups
    Indapamide/Amlodipine v Valsartan/Amlodipine
    Number of subjects included in analysis
    465
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.428
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -1.06
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.67
         upper limit
    		 1.56
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.33
    Statistical analysis title
    		 Office supine systolic blood pressure
    Statistical analysis description
    The non-inferiority analysis using a margin of 3 mmHg, of Ind/Aml as compared to Val/Aml strategy was performed on the change from baseline to the last-post baseline value over the W0-W12 period for office SBP and DBP (ISH and SDH gathered) in the FAS.
    Comparison groups
    Indapamide/Amlodipine v Valsartan/Amlodipine
    Number of subjects included in analysis
    465
    Analysis specification
    Post-hoc
    Analysis type
    		 non-inferiority [1]
    P-value
    		 = 0.001
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -1.06
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.67
         upper limit
    		 1.56
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.33
    Notes
    [1] - The objective of superiority was not reached in this study. However, as both strategies (Ind/Aml and Val/Aml) provided a clinically relevant antihypertensive effect, there was a scientific interest of assessing the extent of difference between treatments, exploring the non-inferiority of Ind/Aml against Val/Aml stategy (registered since January 2007 in Europe and worldwide), for which the well-known anti-hypertensive effect was obtained in the present study.

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Double-blind 12 weeks period
    Adverse event reporting additional description
    Emergent aderse events are presented. They were defined as all adverse events which occurred between the first study drug intake date (included) and the last study drug intake date + 7 days (included), or which occurred strictly before the first study drug intake date and which worsened (in terms of intensity) or became serious.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    17.0
    Reporting groups
    Reporting group title
    Ind/Amlo
    Reporting group description
    		 Indapamide slow release 1.5mg / Amlodipine 5 mg single pill fixe dose combination as starting dose, possibly up-titrated to the next dose of the treatment strategy to Indapamide slow release 1.5 mg / Amlodipine 10 mg, at visit W6, for all non-controlled patients (SBP ≥ 140 and < 180 mmHg and /or DBP ≥ 90 and < 110 mmHg, based on the office blood pressure measurement).

    Reporting group title
    Val/Amlo
    Reporting group description
    		 Valsartan 80 mg / Amlodipine 5 mg single pill fixe dose combination as starting dose, possibly up-titrated to the next dose of the treatment strategy to Valsartan 160 mg / Amlodipine 5 mg , at visit W6, for all non-controlled patients (SBP ≥ 140 and < 180 mmHg and /or DBP ≥ 90 and < 110 mmHg, based on the office blood pressure measurement).

    Serious adverse events
    		 Ind/Amlo Val/Amlo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    2 / 236 (0.85%)
    2 / 236 (0.85%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Colon adenoma
         subjects affected / exposed
    0 / 236 (0.00%)
    1 / 236 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal cancer
         subjects affected / exposed
    1 / 236 (0.42%)
    0 / 236 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Myocardial ischaemia
         subjects affected / exposed
    0 / 236 (0.00%)
    1 / 236 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Hypokalaemia
         subjects affected / exposed
    1 / 236 (0.42%)
    0 / 236 (0.00%)
         occurrences causally related to treatment / all
    1 / 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
    		 Ind/Amlo Val/Amlo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    46 / 236 (19.49%)
    27 / 236 (11.44%)
    Vascular disorders
    Orthostatic hypotension
         subjects affected / exposed
    1 / 236 (0.42%)
    0 / 236 (0.00%)
         occurrences all number
    1
    0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    1 / 236 (0.42%)
    0 / 236 (0.00%)
         occurrences all number
    1
    0
    Oedema peripheral
         subjects affected / exposed
    3 / 236 (1.27%)
    1 / 236 (0.42%)
         occurrences all number
    3
    1
    Chest pain
         subjects affected / exposed
    1 / 236 (0.42%)
    0 / 236 (0.00%)
         occurrences all number
    1
    0
    Puncture site oedema
         subjects affected / exposed
    0 / 236 (0.00%)
    1 / 236 (0.42%)
         occurrences all number
    0
    1
    Reproductive system and breast disorders
    Benign prostatic hyperplasia
         subjects affected / exposed
    1 / 236 (0.42%)
    0 / 236 (0.00%)
         occurrences all number
    1
    0
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    0 / 236 (0.00%)
    2 / 236 (0.85%)
         occurrences all number
    0
    2
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    1 / 236 (0.42%)
    1 / 236 (0.42%)
         occurrences all number
    1
    1
    Alcohol abuse
         subjects affected / exposed
    1 / 236 (0.42%)
    0 / 236 (0.00%)
         occurrences all number
    1
    0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    1 / 236 (0.42%)
    2 / 236 (0.85%)
         occurrences all number
    1
    2
    Aspartate aminotransferase increased
         subjects affected / exposed
    1 / 236 (0.42%)
    2 / 236 (0.85%)
         occurrences all number
    1
    2
    Blood bilirubin increased
         subjects affected / exposed
    1 / 236 (0.42%)
    0 / 236 (0.00%)
         occurrences all number
    1
    0
    Blood cholesterol increased
         subjects affected / exposed
    1 / 236 (0.42%)
    0 / 236 (0.00%)
         occurrences all number
    1
    0
    Blood potassium increased
         subjects affected / exposed
    0 / 236 (0.00%)
    1 / 236 (0.42%)
         occurrences all number
    0
    1
    Blood glucose increased
         subjects affected / exposed
    1 / 236 (0.42%)
    1 / 236 (0.42%)
         occurrences all number
    1
    1
    Blood pressure increased
         subjects affected / exposed
    0 / 236 (0.00%)
    1 / 236 (0.42%)
         occurrences all number
    0
    1
    Blood triglycerides increased
         subjects affected / exposed
    1 / 236 (0.42%)
    0 / 236 (0.00%)
         occurrences all number
    1
    0
    Blood uric acid increased
         subjects affected / exposed
    1 / 236 (0.42%)
    1 / 236 (0.42%)
         occurrences all number
    1
    1
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    1 / 236 (0.42%)
    1 / 236 (0.42%)
         occurrences all number
    1
    1
    Injury, poisoning and procedural complications
    Accidental overdose
         subjects affected / exposed
    4 / 236 (1.69%)
    0 / 236 (0.00%)
         occurrences all number
    4
    0
    Excoriation
         subjects affected / exposed
    0 / 236 (0.00%)
    1 / 236 (0.42%)
         occurrences all number
    0
    1
    Fall
         subjects affected / exposed
    1 / 236 (0.42%)
    0 / 236 (0.00%)
         occurrences all number
    1
    0
    Intentional overdose
         subjects affected / exposed
    0 / 236 (0.00%)
    1 / 236 (0.42%)
         occurrences all number
    0
    1
    Limb injury
         subjects affected / exposed
    1 / 236 (0.42%)
    0 / 236 (0.00%)
         occurrences all number
    1
    0
    Spinal column injury
         subjects affected / exposed
    1 / 236 (0.42%)
    0 / 236 (0.00%)
         occurrences all number
    1
    0
    Cardiac disorders
    Atrioventricular block first degree
         subjects affected / exposed
    0 / 236 (0.00%)
    1 / 236 (0.42%)
         occurrences all number
    0
    1
    Bundle branch block right
         subjects affected / exposed
    1 / 236 (0.42%)
    0 / 236 (0.00%)
         occurrences all number
    1
    0
    Palpitations
         subjects affected / exposed
    1 / 236 (0.42%)
    0 / 236 (0.00%)
         occurrences all number
    1
    0
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    5 / 236 (2.12%)
    0 / 236 (0.00%)
         occurrences all number
    5
    0
    Headache
         subjects affected / exposed
    1 / 236 (0.42%)
    0 / 236 (0.00%)
         occurrences all number
    1
    0
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    0 / 236 (0.00%)
    2 / 236 (0.85%)
         occurrences all number
    0
    2
    Abdominal pain upper
         subjects affected / exposed
    0 / 236 (0.00%)
    1 / 236 (0.42%)
         occurrences all number
    0
    1
    Dyspepsia
         subjects affected / exposed
    0 / 236 (0.00%)
    1 / 236 (0.42%)
         occurrences all number
    0
    1
    Nausea
         subjects affected / exposed
    1 / 236 (0.42%)
    0 / 236 (0.00%)
         occurrences all number
    1
    0
    Gastritis
         subjects affected / exposed
    3 / 236 (1.27%)
    0 / 236 (0.00%)
         occurrences all number
    3
    0
    Vomiting
         subjects affected / exposed
    1 / 236 (0.42%)
    0 / 236 (0.00%)
         occurrences all number
    1
    0
    Toothache
         subjects affected / exposed
    1 / 236 (0.42%)
    2 / 236 (0.85%)
         occurrences all number
    1
    2
    Hepatobiliary disorders
    Cholecystitis
         subjects affected / exposed
    0 / 236 (0.00%)
    1 / 236 (0.42%)
         occurrences all number
    0
    1
    Hepatocellular injury
         subjects affected / exposed
    0 / 236 (0.00%)
    1 / 236 (0.42%)
         occurrences all number
    0
    1
    Skin and subcutaneous tissue disorders
    Pruritus
         subjects affected / exposed
    0 / 236 (0.00%)
    1 / 236 (0.42%)
         occurrences all number
    0
    1
    Skin exfoliation
         subjects affected / exposed
    1 / 236 (0.42%)
    0 / 236 (0.00%)
         occurrences all number
    1
    0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    0 / 236 (0.00%)
    1 / 236 (0.42%)
         occurrences all number
    0
    1
    Back pain
         subjects affected / exposed
    1 / 236 (0.42%)
    1 / 236 (0.42%)
         occurrences all number
    1
    1
    Joint swelling
         subjects affected / exposed
    1 / 236 (0.42%)
    0 / 236 (0.00%)
         occurrences all number
    1
    0
    Costochondritis
         subjects affected / exposed
    1 / 236 (0.42%)
    0 / 236 (0.00%)
         occurrences all number
    1
    0
    Pain in extremity
         subjects affected / exposed
    0 / 236 (0.00%)
    1 / 236 (0.42%)
         occurrences all number
    0
    1
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    1 / 236 (0.42%)
    1 / 236 (0.42%)
         occurrences all number
    1
    1
    Influenza
         subjects affected / exposed
    3 / 236 (1.27%)
    1 / 236 (0.42%)
         occurrences all number
    3
    1
    Nasopharyngitis
         subjects affected / exposed
    1 / 236 (0.42%)
    2 / 236 (0.85%)
         occurrences all number
    1
    2
    Rhinitis
         subjects affected / exposed
    1 / 236 (0.42%)
    0 / 236 (0.00%)
         occurrences all number
    1
    0
    Sinusitis
         subjects affected / exposed
    1 / 236 (0.42%)
    0 / 236 (0.00%)
         occurrences all number
    1
    0
    Metabolism and nutrition disorders
    Hypercholesterolaemia
         subjects affected / exposed
    4 / 236 (1.69%)
    3 / 236 (1.27%)
         occurrences all number
    4
    3
    Hyperglycaemia
         subjects affected / exposed
    2 / 236 (0.85%)
    0 / 236 (0.00%)
         occurrences all number
    2
    0
    Hypertriglyceridaemia
         subjects affected / exposed
    0 / 236 (0.00%)
    2 / 236 (0.85%)
         occurrences all number
    0
    2
    Hyperuricaemia
         subjects affected / exposed
    3 / 236 (1.27%)
    0 / 236 (0.00%)
         occurrences all number
    3
    0
    Hypokalaemia
         subjects affected / exposed
    12 / 236 (5.08%)
    2 / 236 (0.85%)
         occurrences all number
    14
    2
    Hypochloraemia
         subjects affected / exposed
    1 / 236 (0.42%)
    0 / 236 (0.00%)
         occurrences all number
    1
    0
    Impaired fasting glucose
         subjects affected / exposed
    1 / 236 (0.42%)
    1 / 236 (0.42%)
         occurrences all number
    1
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    21 Mar 2013
    This amendment to be applied in Argentina was implemented in order to comply with local regulation in Argentina. It concerned the addition of an urinary pregnancy test at W0, W6, and W12 visits, for all women except those who were menopausal or who had a hysterectomy or surgical sterilisation. The result should be verified as being negative and result had to be known before any treatment dispensation at W0, W6 and W12 visits.
    18 Nov 2013
    This substantial amendment was set up in all counries on request of country coordinators. The objective was to provide an adequate version, which was better adapted to each country’s conditions, to respect the regular patient’s follow up recommendations for each country and ensure the maximal safety of the patients. The secondary objective and secondary efficacy criteria were completed. It was specified that during the study the e-GFR should be calculated by the investigator using the e-CRF calculator. Of the methods already authorised by the current version of the protocol and approved in all countries, in reality 3 of them were used in the clinical practice and were chosen to be followed in this protocol. The additional formula for e-GRF was described. As the information about the method of creatinine measurement was frequently missing, if the investigator decided to use the MDRD the MDRD 186 formula and conversion factor 0.95 was applied to all patients. This version took into account the recently published ESH/ESC 2013 guidelines for the management of arterial hypertension, as they confirmed all data previously described in the initial version of the protocol background information.

    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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