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    Clinical Trial Results:
    A Randomized, Double-blind, Placebo-Controlled Parallel Arm Dose Titration Study to Assess the Effects of SAR407899 in Patients With Microvascular Angina (MVA) and/or Persistent Stable Angina Despite Angiographically Successful Percutaneous Coronary Intervention (PCI)

    Summary
    EudraCT number
    2016-000629-38
    Trial protocol
    SE   DK   NL  
    Global end of trial date
    23 Jul 2018

    Results information
    Results version number
    v1(current)
    This version publication date
    03 Aug 2019
    First version publication date
    03 Aug 2019
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    ACT14656
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT03236311
    WHO universal trial number (UTN)
    U1111-1182-1709
    Sponsors
    Sponsor organisation name
    Sanofi aventis recherche & développement
    Sponsor organisation address
    1, Avenue Pierre Brossolette, Chilly Mazarin, France, 91385
    Public contact
    Trial Transparency Team, Sanofi aventis recherche & développement, contact-US@sanofi.com
    Scientific contact
    Trial Transparency Team, Sanofi aventis recherche & développement, contact-US@sanofi.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
    22 Nov 2018
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    23 Jul 2018
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    To assess the effects of SAR407899 on coronary vasomotor function using the coronary flow reserve (CFR) in subjects with microvascular angina (MVA) and/or persistent stable angina despite angiographically successful percutaneous coronary intervention (PCI).
    Protection of trial subjects
    Subjects were fully informed of all pertinent aspects of the clinical trial as well as the possibility to discontinue at any time in language and terms appropriate for the subject and considering the local culture. During the course of the trial, subjects were provided with individual subject cards indicating the nature of the trial the subject is participating, contact details and any information needed in the event of a medical emergency. Collected personal data and human biological samples were processed in compliance with the Sanofi-Aventis Group Personal Data Protection Charter ensuring that the Group abides by the laws governing personal data protection in force in all countries in which it operates.
    Background therapy
    Non-investigational medicinal products (NIMPs): NIMPs were the medications used to assess the primary endpoint of the study, i.e., positron emission tomography (PET) radiopharmaceuticals (13N-ammonia and 82Rubidium) and vasodilator stressors (adenosine and regadenoson). The NIMPs were used according to their approved labeling.
    Evidence for comparator
    -
    Actual start date of recruitment
    12 Oct 2017
    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
    Korea, Republic of: 1
    Country: Number of subjects enrolled
    United States: 3
    Country: Number of subjects enrolled
    Sweden: 2
    Country: Number of subjects enrolled
    Denmark: 4
    Worldwide total number of subjects
    10
    EEA total number of subjects
    6
    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)
    7
    From 65 to 84 years
    3
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    The study was conducted in United States, South Korea, Sweden, Netherlands, and Denmark from 12 October 2017 to 23 July 2018.

    Pre-assignment
    Screening details
    A total of 10 subjects who met all of the inclusion criteria and none of the exclusion criteria were randomised and enrolled in the study.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Placebo
    Arm description
    Matching placebo for 4 weeks.
    Arm type
    Placebo

    Investigational medicinal product name
    SAR407899 matching placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo matched to SAR407899 for 4 weeks.

    Arm title
    SAR407899
    Arm description
    SAR407899 with dose titration over 4 weeks administration (3 week titration phase + 1 week maintenance phase).
    Arm type
    Experimental

    Investigational medicinal product name
    SAR407899
    Investigational medicinal product code
    SAR407899
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    SAR407899 for 4 weeks. Dose was titrated individually.

    Number of subjects in period 1
    Placebo SAR407899
    Started
    5
    5
    Completed
    5
    2
    Not completed
    0
    3
         Study terminated by sponsor
    -
    2
         Adverse event, non-fatal
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo
    Reporting group description
    Matching placebo for 4 weeks.

    Reporting group title
    SAR407899
    Reporting group description
    SAR407899 with dose titration over 4 weeks administration (3 week titration phase + 1 week maintenance phase).

    Reporting group values
    Placebo SAR407899 Total
    Number of subjects
    5 5 10
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    64.8 ± 9.3 57.2 ± 8.5 -
    Gender categorical
    Units: Subjects
        Female
    4 4 8
        Male
    1 1 2
    Race
    Units: Subjects
        American Indian or Alaska Native
    0 0 0
        Asian
    1 0 1
        Native Hawaiian or Other Pacific Islander
    0 0 0
        Black or African American
    0 0 0
        White
    4 5 9
        More than one race
    0 0 0
        Unknown or Not Reported
    0 0 0

    End points

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    End points reporting groups
    Reporting group title
    Placebo
    Reporting group description
    Matching placebo for 4 weeks.

    Reporting group title
    SAR407899
    Reporting group description
    SAR407899 with dose titration over 4 weeks administration (3 week titration phase + 1 week maintenance phase).

    Primary: Change From Baseline in Uncorrected Global Coronary Flow Reserve at Week 4

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    End point title
    Change From Baseline in Uncorrected Global Coronary Flow Reserve at Week 4 [1]
    End point description
    Absolute change from baseline to Week 4 in uncorrected global CFR, as assessed by the central core laboratory. The global CFR is the ratio of absolute myocardial blood flow (MBF) at stress over that at rest. The MBF was assessed by 13N-ammonia or 82Rubidium PET scan. Analysis was performed on modified intent-to-treat (mITT) population that included all randomised subjects analysed according to the treatment group allocated by randomisation; who received at least 1 dose or part of a dose of the investigational medicinal product (IMP) and with an evaluable primary efficacy endpoint.
    End point type
    Primary
    End point timeframe
    Baseline, Week 4
    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: As the number of subject randomised fell well below target (10 vs.78), hence no formal statistical analysis was performed.
    End point values
    Placebo SAR407899
    Number of subjects analysed
    4
    2
    Units: ratio
        arithmetic mean (standard deviation)
    0.5 ± 0.6
    0.2 ± 0.7
    No statistical analyses for this end point

    Secondary: Change From Baseline in Angina-induced Physical Limitation Assessed Using Seattle Angina Questionnaire Physical Limitation Scale (SAQ-PL) at Week 4

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    End point title
    Change From Baseline in Angina-induced Physical Limitation Assessed Using Seattle Angina Questionnaire Physical Limitation Scale (SAQ-PL) at Week 4
    End point description
    The SAQ-PL measures how common daily activities representing low, medium, and high exertional requirements were limited by angina (9 items). It was scored by assigning each response an ordinal value, beginning with 1 for the response that implied the 'lowest level of functioning' to 5 for 'not at all limited', and summing across the 9 items. The score of 9 items was then transformed to 0-100 range by subtracting the lowest possible scale score, dividing by the range of the scale and multiplying by 100. The range of scores was 0 to 100, with higher scores indicates better functioning. A change of 10 points was considered to be clinically important. As the number of subjects randomised fell well below target (10 vs. 78), hence no data was collected and no analysis was performed.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 4
    End point values
    Placebo SAR407899
    Number of subjects analysed
    0 [2]
    0 [3]
    Units: score on a scale
        number (not applicable)
    Notes
    [2] - Due to study termination, data was not collected and analysed.
    [3] - Due to study termination, data was not collected and analysed.
    No statistical analyses for this end point

    Secondary: Pharmacokinetic Parameter: SAR407899 Plasma Concentration

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    End point title
    Pharmacokinetic Parameter: SAR407899 Plasma Concentration
    End point description
    As the number of subjects randomised fell well below target (10 vs. 78), hence no data was collected and no analysis was performed.
    End point type
    Secondary
    End point timeframe
    Day 1, 8, 15, 22, and Day 29
    End point values
    Placebo SAR407899
    Number of subjects analysed
    0 [4]
    0 [5]
    Units: nanograms per milliliter
        number (not applicable)
    Notes
    [4] - Due to study termination, data was not collected and analysed.
    [5] - Due to study termination, data was not collected and analysed.
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events (AE) were collected from signature of the informed consent form up to the end of follow up (up to Week 5 post-treatment follow-up visit)
    Adverse event reporting additional description
    Reported AEs are treatment-emergent adverse events i.e.AEs that developed/worsened during ‘treatment emergent period’(time from first dose of study drug administration up to 7 days after last dose of study drug). Analysis was performed on safety population which included all randomised subjects who received at least one dose or part of dose of IMP.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    21.0
    Reporting groups
    Reporting group title
    Placebo
    Reporting group description
    Matching placebo for 4 weeks.

    Reporting group title
    SAR407899
    Reporting group description
    SAR407899 with dose titration over 4 weeks administration (3 week titration phase + 1 week maintenance phase).

    Serious adverse events
    Placebo SAR407899
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 5 (0.00%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Placebo SAR407899
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    4 / 5 (80.00%)
    5 / 5 (100.00%)
    Injury, poisoning and procedural complications
    Contusion
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 5 (0.00%)
         occurrences all number
    1
    0
    Sports Injury
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 5 (0.00%)
         occurrences all number
    1
    0
    Cardiac disorders
    Angina Pectoris
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 5 (20.00%)
         occurrences all number
    0
    2
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 5 (20.00%)
         occurrences all number
    0
    1
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    2 / 5 (40.00%)
    2 / 5 (40.00%)
         occurrences all number
    2
    5
    Dizziness Postural
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 5 (20.00%)
         occurrences all number
    0
    4
    Headache
         subjects affected / exposed
    1 / 5 (20.00%)
    2 / 5 (40.00%)
         occurrences all number
    1
    2
    Migraine
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 5 (20.00%)
         occurrences all number
    0
    2
    General disorders and administration site conditions
    Non-Cardiac Chest Pain
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 5 (0.00%)
         occurrences all number
    1
    0
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 5 (0.00%)
         occurrences all number
    2
    0
    Gastrointestinal disorders
    Abdominal Pain
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 5 (20.00%)
         occurrences all number
    0
    1
    Abdominal Pain Lower
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 5 (20.00%)
         occurrences all number
    0
    1
    Skin and subcutaneous tissue disorders
    Dermatitis Allergic
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 5 (20.00%)
         occurrences all number
    0
    1
    Infections and infestations
    Hordeolum
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 5 (0.00%)
         occurrences all number
    2
    0
    Nasopharyngitis
         subjects affected / exposed
    1 / 5 (20.00%)
    1 / 5 (20.00%)
         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
    31 Mar 2017
    Following amendment changes were made: The population of the study and its inclusion/exclusion criteria, modified to include both subjects with MVA and subjects with persistent stable angina despite angiographically successful elective PCI; the technique used to assess the primary endpoint, CFR: a non-invasive technique using PET scan replacing the invasive coronary angiogram; the statistical considerations including sample size calculation yielding more subjects to be randomised, stratification according to the sub-type of subject population and planned analyses, including those for the Data Monitoring Committee; the characterisation of female subjects pertaining to the potential for pregnancy that could be included in the study was further defined; biomarkers of endothelial dysfunction were deleted except the assessment of two biomarkers levels; the EQ-5D-5L questionnaire on quality of life was deleted as the study treatment duration was too short to allow detection of meaningful changes; change to the study title, inclusion/exclusion criteria, total expected number of subjects, study treatment, endpoints, statistical considerations, assessment of IMP, change to vital signs, and change to Appendix A.
    05 Dec 2017
    Amendment changes: Clarified inclusion criterion 01C: symptomatic stable angina pectoris (typical or atypical symptoms) with at least once weekly episodes will be required to be an average of at least weekly episodes over the past month; deletion of inclusion criterion 01D (i.e. electrocardiogram[ECG]evidence of ischemia with ST-segment depression during a symptom limited exercise test or non-invasive evidence of ischemia [echo, single photon emission computed tomography, magnetic resonance imaging, PET] within previous 12 months); change to inclusion criterion 01E, whereby the time until previous imaging for evidence of non-obstructive coronary artery disease was changed from 12 to 24months.In subjects with stenting,minimum diameter stenosis of <10% was required.Coronary computed tomography angiography without regional abnormal perfusion defects within 12months in subjects without previous elective PCI). Use of instantaneous wave-free ratio as an alternative to fractional flow reserve was allowed; change to exclusion criterion 03 to allow calcium channel blockers (CCBs) during the study (any use of long-acting nitrates and/or CCBs and/or PDE-5 inhibitors within one week prior to baseline PET scan or anticipated to be used during the study); precisions of exclusion criterion 12 (i.e., regional local flow abnormal perfusion defects at baseline PET scan) were given; deletion of exclusion criterion13 (subjects with any ECG abnormalities preventing the interpretation of ischemia);change to exclusion criterion25 as systolic blood pressure <110 mmHg from <120 mmHg at baseline;addition of exclusion criterion for breast-feeding subjects; expansion of window period up to the Day1 visit for the baseline PET assessment from 3 to 7 days; changes to prohibited medications and authorized concomitant medications;assessment methods and activity parameters; clarified vital signs and ECG methodology; addition of NIMP; changed storage conditions and shelf life; deletion of Appendix A.
    18 Apr 2018
    Following amendment changes were made: Opened the subject recruitment to subjects with MVA and stable symptoms who did not have recent coronary artery imaging with a special focus on those from large sites having access to existing registries of coronary microvascular dysfunction subjects; altered the study protocol so that it fits better with clinical practice at academic sites and previous guidelines on management of acute coronary syndrome; provided guidance on how to handle subjects who undergo premature study drug discontinuation; cancellation of “elective”; change to the inclusion/exclusion criteria; change to duration of study participation; change to safety endpoints; change to sample blood volume; change to pharmacokinetic endpoint; change to screening visit, assessment methods and activity parameters; change to baseline/randomisation/Day 1 visit, visits 2, 3, 4, and 6, change to definition of source data; and handling of subjects after permanent treatment discontinuation.

    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.
    The study was prematurely terminated due to small number of subjects entering randomisation.
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