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    Clinical Trial Results:
    Evaluation of the pharmacodynamics, pharmacokinetics and safety of repeated escalating oral doses of S 38844 versus placebo in patients with chronic heart failure and left ventricular systolic dysfunction. A phase II, randomised, double-blind, parallel-group, placebo controlled, international multicentre study.

    Summary
    EudraCT number
    		 2013-003000-39
    Trial protocol
    		 HU   BE   SK   EE   LT   LV  
    Global end of trial date
    08 Jun 2015

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

    Trial information

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    Trial identification
    Sponsor protocol code
    CL2-38844-010
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Institut de Recherches Internationales Servier
    Sponsor organisation address
    50 rue Carnot, Suresnes, France,
    Public contact
    ITP (Innovative Therapeutic Pole), Institut de Recherches Internationales Servier, +33 155 72 43 66, clinicaltrials@servier.com
    Scientific contact
    ITP (Innovative Therapeutic Pole), Institut de Recherches Internationales Servier, +33 155 72 43 66, clinicaltrials@servier.com
    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 Jun 2015
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    08 Jun 2015
    Global end of trial reached?
    Yes
    Global end of trial date
    08 Jun 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the pharmacodynamics in relation to resting heart rate (HR) of two different schemes of starting doses and two step titration doses of S 38844 versus placebo in patients with moderate to severe chronic heart failure (CHF) and left ventricular systolic dysfunction treated with optimal background therapy.
    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. After the subject has ended his/her participation in the trial, the investigator provided appropriate medication and/or arranged access to appropriate care for the patient.
    Background therapy
    		 Optimal cardiovascular background therapy of the chronic heart failure according to the investigator’s judgement based on based on the last recommendations (ESC guidelines 2012).
    Evidence for comparator
    		 -
    Actual start date of recruitment
    01 Aug 2014
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Russian Federation: 13
    Country: Number of subjects enrolled
    Ukraine: 35
    Country: Number of subjects enrolled
    Singapore: 4
    Country: Number of subjects enrolled
    Slovakia: 15
    Country: Number of subjects enrolled
    Belgium: 2
    Country: Number of subjects enrolled
    Bulgaria: 19
    Country: Number of subjects enrolled
    Estonia: 8
    Country: Number of subjects enrolled
    Hungary: 13
    Country: Number of subjects enrolled
    Latvia: 10
    Country: Number of subjects enrolled
    Lithuania: 11
    Worldwide total number of subjects
    130
    EEA total number of subjects
    78
    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)
    90
    From 65 to 84 years
    40
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 Study population were men or women aged 18 years or more with moderate to severe CHF and left ventricular ejection fraction ≤ 35%, with HR ≥ 75 bpm and treated with optimal background therapy.

    Period 1
    Period 1 title
    Double blind treatment period (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator
    Blinding implementation details
    Treatment randomisation and allocation centralized (interactive response system). Study products of identical appearance, taste and packaging.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 S38844 25mg
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    S38844 25mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    3 successive periods of 3 weeks with dose escalation: a starting dose of 25 mg once daily was dispensed at W0 (baseline) , then optionally up-titrated to 50 mg once daily at W3 then to 100 mg once daily (highest possible dose) at W6.

    Arm title
    		 S38844 50mg
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    S38844 50 mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    3 successive periods of 3 weeks with dose escalation: a starting dose of 50 mg once daily was dispensed at W0 (baseline), then optionally up-titrated to 100 mg once daily (highest possible dose) at W3 or at W6.

    Arm title
    		 Placebo
    Arm description
    		 -
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    3 successive periods of 3 weeks with dose escalation matching placebo tablet once daily.

    Number of subjects in period 1
    		S38844 25mg S38844 50mg Placebo
    Started
    52
    52
    26
    Completed
    47
    44
    23
    Not completed
    5
    8
    3
         Adverse event, serious fatal
    -
    -
    1
         Consent withdrawn by subject
    2
    2
    2
         Adverse event, non-fatal
    1
    5
    -
         Protocol deviation
    2
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    S38844 25mg
    Reporting group description
    		 -

    Reporting group title
    S38844 50mg
    Reporting group description
    		 -

    Reporting group title
    Placebo
    Reporting group description
    		 -

    Reporting group values
    		 S38844 25mg S38844 50mg Placebo Total
    Number of subjects
    		 52 52 26 130
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 40 33 17 90
        From 65-84 years
    		 12 19 9 40
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 57.3 ± 9.4 59.8 ± 10.7 61.1 ± 9.5 -
    Gender categorical
    Units: Subjects
        Female
    		 13 8 4 25
        Male
    		 39 44 22 105

    End points

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    End points reporting groups
    Reporting group title
    S38844 25mg
    Reporting group description
    		 -

    Reporting group title
    S38844 50mg
    Reporting group description
    		 -

    Reporting group title
    Placebo
    Reporting group description
    		 -

    Subject analysis set title
    Per Protocol Set
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    All patients of Randomised Set having taken at least 1 dose of IMP and having completed the 9-week double blind treatment period (titration period) in accordance with the protocol, i.e. having an analysable HR value (i.e. primary endpoint) at baseline and at W9 under treatment without relevant deviation which could affect the HR evaluation.

    Primary: Change in resting heart rate

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    End point title
    		 Change in resting heart rate
    End point description
    End point type
    Primary
    End point timeframe
    9-week treatment period
    End point values
    		 S38844 25mg S38844 50mg Placebo
    Number of subjects analysed
    44
    40
    20
    Units: beats per minute
        arithmetic mean (standard error)
    -16.58 ± 10.31
    -19.05 ± 11.86
    -9.5 ± 6.27
    Statistical analysis title
    		 Primary analysis
    Statistical analysis description
    Between-group difference was estimated using an ANCOVA adjusted on heart rate at baseline and treatment group.
    Comparison groups
    S38844 25mg v Placebo
    Number of subjects included in analysis
    64
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Mean difference (net)
    Point estimate
    -5.76
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -10.67
         upper limit
    		 -0.86
    Variability estimate
    Standard error of the mean
    Dispersion value
    2.47
    Statistical analysis title
    		 Primary analysis
    Statistical analysis description
    Between-group difference was estimated using an ANCOVA adjusted on heart rate at baseline and treatment group.
    Comparison groups
    S38844 50mg v Placebo
    Number of subjects included in analysis
    60
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Median difference (net)
    Point estimate
    -8.03
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -13.02
         upper limit
    		 -3.05
    Variability estimate
    Standard error of the mean
    Dispersion value
    2.51

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events were reported all over the study. Adverse events reported over the 9-week double-blind treatment period are presented here as it was the only period of the study when patients received active treatment (S38844).
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    17.0
    Reporting groups
    Reporting group title
    S38844 25mg
    Reporting group description
    		 -

    Reporting group title
    S38844 50mg
    Reporting group description
    		 -

    Reporting group title
    Placebo
    Reporting group description
    		 -

    Serious adverse events
    		 S38844 25mg S38844 50mg Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    4 / 52 (7.69%)
    4 / 52 (7.69%)
    1 / 26 (3.85%)
         number of deaths (all causes)
    0
    0
    1
         number of deaths resulting from adverse events
    0
    0
    0
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    1 / 52 (1.92%)
    1 / 52 (1.92%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bradycardia
         subjects affected / exposed
    1 / 52 (1.92%)
    1 / 52 (1.92%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Atrial flutter
         subjects affected / exposed
    0 / 52 (0.00%)
    1 / 52 (1.92%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac failure acute
         subjects affected / exposed
    0 / 52 (0.00%)
    0 / 52 (0.00%)
    1 / 26 (3.85%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Myocardial ischaemia
         subjects affected / exposed
    0 / 52 (0.00%)
    0 / 52 (0.00%)
    1 / 26 (3.85%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ventricular arrhythmia
         subjects affected / exposed
    0 / 52 (0.00%)
    0 / 52 (0.00%)
    1 / 26 (3.85%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Nervous system disorders
    Ischaemic stroke
         subjects affected / exposed
    0 / 52 (0.00%)
    1 / 52 (1.92%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Partial seizures
         subjects affected / exposed
    0 / 52 (0.00%)
    1 / 52 (1.92%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Eye disorders
    Photopsia
         subjects affected / exposed
    1 / 52 (1.92%)
    0 / 52 (0.00%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    renal failure chronic
         subjects affected / exposed
    1 / 52 (1.92%)
    0 / 52 (0.00%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 3%
    Non-serious adverse events
    		 S38844 25mg S38844 50mg Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    22 / 52 (42.31%)
    22 / 52 (42.31%)
    5 / 26 (19.23%)
    Investigations
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    1 / 52 (1.92%)
    0 / 52 (0.00%)
    1 / 26 (3.85%)
         occurrences all number
    1
    0
    1
    Blood alkaline phosphatase increased
         subjects affected / exposed
    0 / 52 (0.00%)
    0 / 52 (0.00%)
    1 / 26 (3.85%)
         occurrences all number
    0
    0
    1
    White blood cell count decreased
         subjects affected / exposed
    0 / 52 (0.00%)
    0 / 52 (0.00%)
    1 / 26 (3.85%)
         occurrences all number
    0
    0
    1
    Injury, poisoning and procedural complications
    Thermal burn
         subjects affected / exposed
    0 / 52 (0.00%)
    0 / 52 (0.00%)
    1 / 26 (3.85%)
         occurrences all number
    0
    0
    1
    Cardiac disorders
    Bradycardia
         subjects affected / exposed
    2 / 52 (3.85%)
    6 / 52 (11.54%)
    0 / 26 (0.00%)
         occurrences all number
    2
    7
    0
    Ventricular extrasystoles
         subjects affected / exposed
    1 / 52 (1.92%)
    1 / 52 (1.92%)
    1 / 26 (3.85%)
         occurrences all number
    1
    1
    1
    Atrial fibrillation
         subjects affected / exposed
    0 / 52 (0.00%)
    2 / 52 (3.85%)
    0 / 26 (0.00%)
         occurrences all number
    0
    2
    0
    Coronary artery stenosis
         subjects affected / exposed
    0 / 52 (0.00%)
    0 / 52 (0.00%)
    1 / 26 (3.85%)
         occurrences all number
    0
    0
    1
    Ischaemic cardiomyopathy
         subjects affected / exposed
    0 / 52 (0.00%)
    0 / 52 (0.00%)
    1 / 26 (3.85%)
         occurrences all number
    0
    0
    1
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    1 / 52 (1.92%)
    2 / 52 (3.85%)
    0 / 26 (0.00%)
         occurrences all number
    1
    2
    0
    Eye disorders
    Photopsia
         subjects affected / exposed
    9 / 52 (17.31%)
    7 / 52 (13.46%)
    0 / 26 (0.00%)
         occurrences all number
    9
    7
    0
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    0 / 52 (0.00%)
    0 / 52 (0.00%)
    1 / 26 (3.85%)
         occurrences all number
    0
    0
    1
    Musculoskeletal and connective tissue disorders
    Musculoskeletal stiffness
         subjects affected / exposed
    0 / 52 (0.00%)
    0 / 52 (0.00%)
    1 / 26 (3.85%)
         occurrences all number
    0
    0
    1
    Infections and infestations
    Influenza
         subjects affected / exposed
    0 / 52 (0.00%)
    1 / 52 (1.92%)
    1 / 26 (3.85%)
         occurrences all number
    0
    1
    1
    Conjunctivitis
         subjects affected / exposed
    0 / 52 (0.00%)
    0 / 52 (0.00%)
    1 / 26 (3.85%)
         occurrences all number
    0
    0
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    28 Apr 2014
    Pregnancy testing was added at entry and during the study. The list of adverse events to be documented with specific information was updated.
    22 Jul 2014
    To implement the recommendations of Data Monitoring Committee, mainly to cancel the IMP dose of 150 mg which was planned in the study protocol. Consequently, highest possible S38844 dose administered to patients during the study was 100 mg once daily.
    21 Jan 2015
    Main change: the sample size was reconsidered as a total of 125 patients to be included.

    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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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
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