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    Clinical Trial Results:
    Efficacy and safety study of F373280 for maintenance of sinus rhythm after electrical cardioversion in patients with persistent atrial fibrillation and chronic heart failure.

    Summary
    EudraCT number
    2012-003487-48
    Trial protocol
    ES   HU   CZ   IT   FR  
    Global end of trial date
    03 Apr 2017

    Results information
    Results version number
    v1(current)
    This version publication date
    11 Apr 2018
    First version publication date
    11 Apr 2018
    Other versions
    Summary report(s)
    Synopsis

    Trial information

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    Trial identification
    Sponsor protocol code
    F373280CA201
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    -
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Institut de Recherche Pierre Fabre
    Sponsor organisation address
    3 Avenue Hubert Curien, Toulouse, France, 31035
    Public contact
    CTI Desk, Clinical Trial Information Desk Pierre Fabre Medicament, contact_essais_cliniques@pierre-fabre.com
    Scientific contact
    Karim KEDDAD, INSTITUT DE RECHERCHE PIERRE FABRE - Centre de R&D Pierre Fabre, 0033 (0)5 34 50 61 69, karim.keddad@pierre-fabre.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
    03 Jul 2017
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    03 Apr 2017
    Global end of trial reached?
    Yes
    Global end of trial date
    03 Apr 2017
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    Primary: Efficacy of F373280 on the maintenance of sinus rhythm after direct electrical cardioversion in patients with persistent atrial fibrillation and chronic heart failure
    Protection of trial subjects
    The study was conducted in compliance with GCP, the current version of the Declaration of Helsinki, and all relevant SOPs in application within Pierre Fabre R&D.
    Background therapy
    F373280 (a mono ester of pantothenic alcohol and DHA) is a novel pro-drug of DHA (molecular formula: C31H49NO5) that exerts antiarrhythmic properties by interacting with electrical and structural remodelling of the atria. According to data obtained in anaesthetised pigs, rats and canine models and the animal studies described in the Investigator’s brochure (IB – F373280, 2013), the non clinical pharmacokinetic profile of F373280 is not associated with specific concerns regarding the proposed clinical phase IIa study. After single administration of different test doses (0.5 g, 1 g, 2 g, 4 g, 8 g and 16 g) of F373280 to six independent cohorts of 8 subjects (6 of whom received F373280 and 2 received placebo), no difference between F373280 and placebo was reported regarding vital signs (heart rate [HR], systolic blood pressure [SBP] and diastolic blood pressure [DBP]), biological parameters (platelets and fibrinogen) and coagulation parameters (bleeding time, prothrombin time/international normalised ratio [INR], activated partial thromboplastin time [aPTT], thrombin clotting time [TCT]). No serious adverse events (SAEs) occurred during the study. After single oral administration (0.5 g to 16 g) of F373280 in 36 young healthy male subjects (six per dose level) no circulating F373280 plasma levels were detected, confirming that F373280 is a prodrug.
    Evidence for comparator
    This is a placebo-controlled study in 2 parallel groups.
    Actual start date of recruitment
    20 May 2013
    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
    Spain: 32
    Country: Number of subjects enrolled
    Czech Republic: 33
    Country: Number of subjects enrolled
    Hungary: 27
    Country: Number of subjects enrolled
    Italy: 39
    Country: Number of subjects enrolled
    Poland: 4
    Worldwide total number of subjects
    135
    EEA total number of subjects
    135
    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)
    54
    From 65 to 84 years
    80
    85 years and over
    1

    Subject disposition

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    Recruitment
    Recruitment details
    157 patients have been screened and signed an informed consent form. After a 1 to 4 week run-in period without study treatment, 135 patients have been randomized to receive either 1g/day of F373280 or placebo per os, for 24 weeks. 1 patient did not receive the study treatment.

    Pre-assignment
    Screening details
    Were included in the study, patients with persistent AF between 7 days and 6 months duration for whom electrical cardioversion is warranted and with history of first documented persistent AF, ischemic or non ischemic heart failure and NYHA class I or II chronic heart failure at selection and at inclusion.

    Pre-assignment period milestones
    Number of subjects started
    135
    Number of subjects completed

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    F373280
    Arm description
    -
    Arm type
    Experimental

    Investigational medicinal product name
    F373280
    Investigational medicinal product code
    F373280
    Other name
    Panthenyl Ester of DHA
    Pharmaceutical forms
    Capsule, soft
    Routes of administration
    Oral use
    Dosage and administration details
    One capsule dosed at 1g each evening with dinner.

    Arm title
    Placebo
    Arm description
    -
    Arm type
    Experimental

    Investigational medicinal product name
    F373280
    Investigational medicinal product code
    F373280
    Other name
    Panthenyl Ester of DHA
    Pharmaceutical forms
    Capsule, soft
    Routes of administration
    Oral use
    Dosage and administration details
    Oral, one capsule of 1g each evening with dinner

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, soft
    Routes of administration
    Oral use
    Dosage and administration details
    Oral, one capsule each evening with dinner

    Number of subjects in period 1
    F373280 Placebo
    Started
    68
    67
    Completed
    34
    30
    Not completed
    34
    37
         Efficacy concerns
    13
    11
         Other reason
    16
    18
         Safety Concerns
    5
    8

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    F373280
    Reporting group description
    -

    Reporting group title
    Placebo
    Reporting group description
    -

    Reporting group values
    F373280 Placebo Total
    Number of subjects
    68 67 135
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        median (full range (min-max))
    67.0 (37 to 85) 67.0 (26 to 84) -
    Gender categorical
    Units: Subjects
        Female
    16 16 32
        Male
    52 51 103
    Subject analysis sets

    Subject analysis set title
    Safety set
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    • Safety Set, composed of all randomised patients who received at least one dose of the study treatment;

    Subject analysis set title
    Full Analysis Set (FAS)
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    Full Analysis Set (FAS), composed of all randomised patients having received at least one dose of the study treatment and with a successful cardioversion observed at Visit 3

    Subject analysis set title
    Per Protocol set
    Subject analysis set type
    Per protocol
    Subject analysis set description
    PP set consisted of all FAS patients without any major protocol deviation or other bias for primery criteria analysis

    Subject analysis sets values
    Safety set Full Analysis Set (FAS) Per Protocol set
    Number of subjects
    134
    101
    95
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        median (full range (min-max))
    67.0 (26 to 85)
    65 (26 to 85)
    65.0 (26 to 85)
    Gender categorical
    Units: Subjects
        Female
    31
    23
    23
        Male
    103
    78
    72

    End points

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    End points reporting groups
    Reporting group title
    F373280
    Reporting group description
    -

    Reporting group title
    Placebo
    Reporting group description
    -

    Subject analysis set title
    Safety set
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    • Safety Set, composed of all randomised patients who received at least one dose of the study treatment;

    Subject analysis set title
    Full Analysis Set (FAS)
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    Full Analysis Set (FAS), composed of all randomised patients having received at least one dose of the study treatment and with a successful cardioversion observed at Visit 3

    Subject analysis set title
    Per Protocol set
    Subject analysis set type
    Per protocol
    Subject analysis set description
    PP set consisted of all FAS patients without any major protocol deviation or other bias for primery criteria analysis

    Primary: Patients with Recurrence of AF or AF emergence (FAS)

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    End point title
    Patients with Recurrence of AF or AF emergence (FAS) [1]
    End point description
    End point type
    Primary
    End point timeframe
    24 weeks
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Due to premature termination of the study only descriptive statistical analysis were performed and this being an abbreviated report, no statistical analysis is detailed.
    End point values
    F373280 Placebo
    Number of subjects analysed
    52
    49
    Units: Number of patients
    36
    31
    Attachments
    Untitled (Filename: F373280 Time to 1st recurrence AF or Atrial flutter - survival curves PP.pdf)
    No statistical analyses for this end point

    Primary: Time to First Recurrence of AF or AF emergence (FAS)

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    End point title
    Time to First Recurrence of AF or AF emergence (FAS) [2]
    End point description
    End point type
    Primary
    End point timeframe
    24 weeks
    Notes
    [2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Due to premature termination of the study only descriptive statistical analysis were performed and this being an abbreviated report, no statistical analysis is detailed.
    End point values
    F373280 Placebo
    Number of subjects analysed
    52
    49
    Units: Days
        median (confidence interval 95%)
    11.0 (6.0 to 45.0)
    16.0 (6.0 to 141.0)
    Attachments
    Time to 1st recurrence of AF/Atrial flutter emerge
    No statistical analyses for this end point

    Primary: Patients with Recurrence of AF or AF emergence (PP)

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    End point title
    Patients with Recurrence of AF or AF emergence (PP) [3]
    End point description
    End point type
    Primary
    End point timeframe
    24 weeks
    Notes
    [3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Due to premature termination of the study only descriptive statistical analysis were performed and this being an abbreviated report, no statistical analysis is detailed.
    End point values
    F373280 Placebo
    Number of subjects analysed
    49
    46
    Units: Number (%) of patients
    34
    30
    No statistical analyses for this end point

    Primary: Time to First Recurrence of AF or AF emergence (PP)

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    End point title
    Time to First Recurrence of AF or AF emergence (PP) [4]
    End point description
    End point type
    Primary
    End point timeframe
    24 weeks
    Notes
    [4] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Due to premature termination of the study only descriptive statistical analysis were performed and this being an abbreviated report, no statistical analysis is detailed.
    End point values
    F373280 Placebo
    Number of subjects analysed
    49
    46
    Units: Days
        median (confidence interval 95%)
    13.0 (6.0 to 45.0)
    15.5 (6.0 to 141.0)
    Attachments
    Time to 1st recurrence of AF/Atrial flutter emerge
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    24 weeks
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    17
    Reporting groups
    Reporting group title
    F373280
    Reporting group description
    -

    Reporting group title
    Placebo
    Reporting group description
    -

    Serious adverse events
    F373280 Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    5 / 67 (7.46%)
    1 / 67 (1.49%)
         number of deaths (all causes)
    1
    0
         number of deaths resulting from adverse events
    Cardiac disorders
    Ventricular tachycardia
         subjects affected / exposed
    0 / 67 (0.00%)
    1 / 67 (1.49%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure
         subjects affected / exposed
    1 / 67 (1.49%)
    0 / 67 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    1 / 67 (1.49%)
    0 / 67 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sick sinus syndrome
         subjects affected / exposed
    1 / 67 (1.49%)
    0 / 67 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pulmonary Edema
         subjects affected / exposed
    1 / 67 (1.49%)
    0 / 67 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Nervous system disorders
    Cerebrovascular accident
         subjects affected / exposed
    1 / 67 (1.49%)
    0 / 67 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Gastric ulcer perforation
         subjects affected / exposed
    1 / 67 (1.49%)
    0 / 67 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Peritonitis
         subjects affected / exposed
    1 / 67 (1.49%)
    0 / 67 (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: 2%
    Non-serious adverse events
    F373280 Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    43 / 67 (64.18%)
    43 / 67 (64.18%)
    Injury, poisoning and procedural complications
    Overdose
         subjects affected / exposed
    2 / 67 (2.99%)
    1 / 67 (1.49%)
         occurrences all number
    2
    1
    Vascular disorders
    Orthostatic hypotension
         subjects affected / exposed
    24 / 67 (35.82%)
    20 / 67 (29.85%)
         occurrences all number
    33
    24
    Cardiac disorders
    Intracardiac thrombus
         subjects affected / exposed
    1 / 67 (1.49%)
    5 / 67 (7.46%)
         occurrences all number
    1
    5
    Cardiac failure
         subjects affected / exposed
    1 / 67 (1.49%)
    4 / 67 (5.97%)
         occurrences all number
    1
    4
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    0 / 67 (0.00%)
    2 / 67 (2.99%)
         occurrences all number
    0
    2
    Nervous system disorders
    Sciatica
         subjects affected / exposed
    0 / 67 (0.00%)
    2 / 67 (2.99%)
         occurrences all number
    0
    2
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    2 / 67 (2.99%)
    0 / 67 (0.00%)
         occurrences all number
    2
    0
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    2 / 67 (2.99%)
    1 / 67 (1.49%)
         occurrences all number
    2
    1

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    01 Mar 2013
    Protocol: contraception method, GP letter (Italy)
    23 Oct 2013
    Adjustment of criteria to improve the feasibility of the study, change of SAEs report recipient
    22 Oct 2014
    Planned end of study postponed to April 2016; • Clarifications regarding the management of VKA treatment; • Precision regarding the primary efficacy criterion; • Deletion of Visit 5 and Visit 8; • Changes in TTEM transmission frequency; • Previous history of a first documented persistent AF without limitation in time instead of no longer than 3 years; • Patients must have a systolic heart failure defined by a reduced ventricular ejection fraction and/or defined also through other echocardiographic parameters mentioned in the ESC guidelines for the diagnosis and treatment of acute and chronic heart failure (2012); • Non-inclusion criteria of the protocol adapted; • Informed consent form updated following the modifications done to version 8 of the protocol
    28 Sep 2016
    • Planned study period: January 2013 – April 2017; • Number of patients: maximum135; • IDMC to review safety data twice during the study (after randomisation of the first 30 patients and after termination of study participation of the first 80 patients)

    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.
    Early termination: small number of patients
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