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    Clinical Trial Results:
    Clinical non-inferiority study between Micronized purified flavonoid fraction 1000 mg, one chewable tablet per day and Micronized Purified Flavonoid Fraction 500 mg, 2 tablets daily after eight weeks of treatment in patients suffering from symptomatic Chronic Venous Disease (CVD). International, multicenter, double-blind, randomized, parallel group study.

    Summary
    EudraCT number
    		 2017-003633-28
    Trial protocol
    		 HU   AT   RO  
    Global end of trial date
    07 Oct 2019

    Results information
    Results version number
    		 v1(current)
    This version publication date
    25 Sep 2020
    First version publication date
    25 Sep 2020
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    CL3-05682-109
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 U1111-1209-6049
    Sponsors
    Sponsor organisation name
    Institut de Recherches Internationales Servier
    Sponsor organisation address
    50 rue Carnot, Suresnes, France, 92284
    Public contact
    Institut de Recherches Internationales Servier, Cardiovascular and Metabolism Centre of Therapeutic Innovation, +33 155724366, clinicaltrials@servier.com
    Scientific contact
    Institut de Recherches Internationales Servier, Cardiovascular and Metabolism Centre of Therapeutic Innovation, +33 155724366, 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
    07 Oct 2019
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    07 Oct 2019
    Global end of trial reached?
    Yes
    Global end of trial date
    07 Oct 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To demonstrate the clinical non-inferiority of efficacy between micronised purified flavonoid fraction (MPFF) 1000 mg, 1 chewable tablet, and MPFF 500 mg, 2 tablets, in improving lower limb discomfort assessed by a 10 cm electronic visual analogue scale (eVAS) after 8 weeks of treatment in patients suffering from CVD.
    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
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    30 Jul 2018
    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
    Thailand: 55
    Country: Number of subjects enrolled
    Turkey: 14
    Country: Number of subjects enrolled
    Vietnam: 32
    Country: Number of subjects enrolled
    Argentina: 125
    Country: Number of subjects enrolled
    Austria: 4
    Country: Number of subjects enrolled
    Brazil: 78
    Country: Number of subjects enrolled
    Hungary: 43
    Country: Number of subjects enrolled
    Romania: 87
    Country: Number of subjects enrolled
    Russian Federation: 173
    Worldwide total number of subjects
    611
    EEA total number of subjects
    134
    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)
    549
    From 65 to 84 years
    62
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 Male or female outpatients, aged from 20 to 75 years old (inclusive) with 18 kg/m² ≤ body mass index ≤ 35 kg/m², suffering from primary CVD with lower limb discomfort ≥ 4 cm on eVAS and belonging to the Clinical Etiological Anatomic Pathophysiologic (CEAP) class C0s to C4s on the most affected leg.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 MPFF chewable tablet 1000 mg
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    MPFF chewable tablet 1000 mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Chewable tablet
    Routes of administration
    Oral use
    Dosage and administration details
    One chewable tablet of MPFF 1000 mg taken daily (in the morning) per os during the meal.

    Arm title
    		 MPFF tablet 2 x 500 mg
    Arm description
    		 -
    Arm type
    		 Active comparator

    Investigational medicinal product name
    MPFF tablet 500 mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    2 tablets of MPFF 500 mg daily (one at midday and one in the evening) taken per os during meals

    Number of subjects in period 1
    		MPFF chewable tablet 1000 mg MPFF tablet 2 x 500 mg
    Started
    309
    302
    Completed
    291
    293
    Not completed
    18
    9
         Adverse event, serious fatal
    -
    1
         non-medical reason
    7
    5
         Adverse event, non-fatal
    5
    1
         Protocol deviation
    6
    2

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    MPFF chewable tablet 1000 mg
    Reporting group description
    		 -

    Reporting group title
    MPFF tablet 2 x 500 mg
    Reporting group description
    		 -

    Reporting group values
    		 MPFF chewable tablet 1000 mg MPFF tablet 2 x 500 mg Total
    Number of subjects
    		 309 302 611
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 278 271 549
        From 65-84 years
    		 31 31 62
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 47.7 ( 12.3 ) 47.7 ( 12.5 ) -
    Gender categorical
    Units: Subjects
        Female
    		 256 246 502
        Male
    		 53 56 109

    End points

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    End points reporting groups
    Reporting group title
    MPFF chewable tablet 1000 mg
    Reporting group description
    		 -

    Reporting group title
    MPFF tablet 2 x 500 mg
    Reporting group description
    		 -

    Subject analysis set title
    Full analysis set
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    In accordance with the intention-to-treat principle and the Section 5.2.1 of ICH E9 guideline, all patients of the randomised set having taken at least one dose of Investigational Medicinal Product (IMP) and having a value at baseline and at least one post-baseline value for the lower limb discomfort assessed by eVAS.

    Primary: Lower limb discomfort (eVAS): change from baseline to W8

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    End point title
    		 Lower limb discomfort (eVAS): change from baseline to W8
    End point description
    Lower limb discomfort defined by the evaluation of the overall symptoms of lower limbs: lack pain, leg heaviness, tiredness and feeling of swelling. On the eVAS scale: 0 = no discomfort and 10-cm = extreme discomfort.
    End point type
    Primary
    End point timeframe
    Discomfort assessed by the patient on an electronic device (auto-evaluation) at site during selection, then weekly at home at same time and same day in the evening (except week-end) and before visits W000, W004 and W008 (evening) in the same conditions.
    End point values
    		 MPFF chewable tablet 1000 mg MPFF tablet 2 x 500 mg
    Number of subjects analysed
    266
    253
    Units: cm
        arithmetic mean (standard deviation)
    -3.6 ( 2.4 )
    -3.6 ( 2.5 )
    Statistical analysis title
    		 Non-inferiority analysis
    Comparison groups
    MPFF chewable tablet 1000 mg v MPFF tablet 2 x 500 mg
    Number of subjects included in analysis
    519
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [1]
    P-value
    		 < 0.0001
    Method
    		 ANCOVA
    Confidence interval
    Notes
    [1] - Non-inferiority margin was set at 1.0 cm. One-sided type I error rate = 0.025. Missing data was imputed by treatment group, using centre and baseline, using multiple imputation approach based on the regression method (after MCMC monotone-data imputation). The analysis included the fixed, categorical effect of treatment, the random categorical effect of centre, as well as the continuous, fixed covariate of baseline.

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    All adverse events which occurred or worsened or became serious according to investigator opinion, between the first IMP intake date, corresponding to the double-blind treatment period (included) and the last IMP intake date + 3 days (included).
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    22.0
    Reporting groups
    Reporting group title
    MPFF chewable tablet 1000 mg
    Reporting group description
    		 -

    Reporting group title
    MPFF tablet 2 x 500 mg
    Reporting group description
    		 -

    Serious adverse events
    		 MPFF chewable tablet 1000 mg MPFF tablet 2 x 500 mg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 307 (0.00%)
    1 / 301 (0.33%)
         number of deaths (all causes)
    0
    1
         number of deaths resulting from adverse events
    0
    1
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    0 / 307 (0.00%)
    1 / 301 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 MPFF chewable tablet 1000 mg MPFF tablet 2 x 500 mg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    33 / 307 (10.75%)
    31 / 301 (10.30%)
    Pregnancy, puerperium and perinatal conditions
    Pregnancy
         subjects affected / exposed
    1 / 307 (0.33%)
    0 / 301 (0.00%)
         occurrences all number
    1
    0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    1 / 307 (0.33%)
    0 / 301 (0.00%)
         occurrences all number
    1
    0
    Chest discomfort
         subjects affected / exposed
    1 / 307 (0.33%)
    0 / 301 (0.00%)
         occurrences all number
    1
    0
    Oedema peripheral
         subjects affected / exposed
    0 / 307 (0.00%)
    1 / 301 (0.33%)
         occurrences all number
    0
    1
    Immune system disorders
    Hypersensitivity
         subjects affected / exposed
    1 / 307 (0.33%)
    0 / 301 (0.00%)
         occurrences all number
    1
    0
    Reproductive system and breast disorders
    Breast dysplasia
         subjects affected / exposed
    1 / 307 (0.33%)
    0 / 301 (0.00%)
         occurrences all number
    1
    0
    Menstruation delayed
         subjects affected / exposed
    1 / 307 (0.33%)
    0 / 301 (0.00%)
         occurrences all number
    1
    0
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    0 / 307 (0.00%)
    1 / 301 (0.33%)
         occurrences all number
    0
    1
    Investigations
    Blood pressure increased
         subjects affected / exposed
    0 / 307 (0.00%)
    1 / 301 (0.33%)
         occurrences all number
    0
    1
    Weight decreased
         subjects affected / exposed
    0 / 307 (0.00%)
    1 / 301 (0.33%)
         occurrences all number
    0
    1
    Injury, poisoning and procedural complications
    Accidental overdose
         subjects affected / exposed
    3 / 307 (0.98%)
    1 / 301 (0.33%)
         occurrences all number
    5
    1
    Fall
         subjects affected / exposed
    1 / 307 (0.33%)
    0 / 301 (0.00%)
         occurrences all number
    1
    0
    Ligament sprain
         subjects affected / exposed
    1 / 307 (0.33%)
    0 / 301 (0.00%)
         occurrences all number
    1
    0
    Limb injury
         subjects affected / exposed
    1 / 307 (0.33%)
    0 / 301 (0.00%)
         occurrences all number
    1
    0
    Road traffic accident
         subjects affected / exposed
    1 / 307 (0.33%)
    0 / 301 (0.00%)
         occurrences all number
    1
    0
    Skin laceration
         subjects affected / exposed
    1 / 307 (0.33%)
    0 / 301 (0.00%)
         occurrences all number
    1
    0
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    1 / 307 (0.33%)
    0 / 301 (0.00%)
         occurrences all number
    1
    0
    Dizziness postural
         subjects affected / exposed
    0 / 307 (0.00%)
    1 / 301 (0.33%)
         occurrences all number
    0
    1
    Headache
         subjects affected / exposed
    3 / 307 (0.98%)
    7 / 301 (2.33%)
         occurrences all number
    3
    8
    Hypoaesthesia
         subjects affected / exposed
    1 / 307 (0.33%)
    0 / 301 (0.00%)
         occurrences all number
    1
    0
    Migraine
         subjects affected / exposed
    0 / 307 (0.00%)
    1 / 301 (0.33%)
         occurrences all number
    0
    1
    Sciatica
         subjects affected / exposed
    0 / 307 (0.00%)
    1 / 301 (0.33%)
         occurrences all number
    0
    1
    Blood and lymphatic system disorders
    Lymphadenopathy
         subjects affected / exposed
    0 / 307 (0.00%)
    1 / 301 (0.33%)
         occurrences all number
    0
    1
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    0 / 307 (0.00%)
    1 / 301 (0.33%)
         occurrences all number
    0
    1
    Abdominal pain upper
         subjects affected / exposed
    2 / 307 (0.65%)
    0 / 301 (0.00%)
         occurrences all number
    2
    0
    Aphthous ulcer
         subjects affected / exposed
    0 / 307 (0.00%)
    1 / 301 (0.33%)
         occurrences all number
    0
    1
    Constipation
         subjects affected / exposed
    0 / 307 (0.00%)
    1 / 301 (0.33%)
         occurrences all number
    0
    1
    Dental caries
         subjects affected / exposed
    0 / 307 (0.00%)
    1 / 301 (0.33%)
         occurrences all number
    0
    1
    Diarrhoea
         subjects affected / exposed
    3 / 307 (0.98%)
    1 / 301 (0.33%)
         occurrences all number
    3
    1
    Dyspepsia
         subjects affected / exposed
    0 / 307 (0.00%)
    2 / 301 (0.66%)
         occurrences all number
    0
    2
    Faeces soft
         subjects affected / exposed
    0 / 307 (0.00%)
    1 / 301 (0.33%)
         occurrences all number
    0
    1
    Gastrointestinal pain
         subjects affected / exposed
    1 / 307 (0.33%)
    0 / 301 (0.00%)
         occurrences all number
    1
    0
    Nausea
         subjects affected / exposed
    7 / 307 (2.28%)
    3 / 301 (1.00%)
         occurrences all number
    7
    3
    Skin and subcutaneous tissue disorders
    Erythema
         subjects affected / exposed
    1 / 307 (0.33%)
    0 / 301 (0.00%)
         occurrences all number
    1
    0
    Pruritus
         subjects affected / exposed
    1 / 307 (0.33%)
    0 / 301 (0.00%)
         occurrences all number
    1
    0
    Rash maculo-papular
         subjects affected / exposed
    1 / 307 (0.33%)
    0 / 301 (0.00%)
         occurrences all number
    1
    0
    Skin hyperpigmentation
         subjects affected / exposed
    1 / 307 (0.33%)
    1 / 301 (0.33%)
         occurrences all number
    1
    1
    Urticaria
         subjects affected / exposed
    1 / 307 (0.33%)
    0 / 301 (0.00%)
         occurrences all number
    1
    0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    0 / 307 (0.00%)
    1 / 301 (0.33%)
         occurrences all number
    0
    1
    Back pain
         subjects affected / exposed
    1 / 307 (0.33%)
    0 / 301 (0.00%)
         occurrences all number
    1
    0
    Intervertebral disc degeneration
         subjects affected / exposed
    0 / 307 (0.00%)
    1 / 301 (0.33%)
         occurrences all number
    0
    1
    Limb discomfort
         subjects affected / exposed
    1 / 307 (0.33%)
    0 / 301 (0.00%)
         occurrences all number
    1
    0
    Lumbar spinal stenosis
         subjects affected / exposed
    0 / 307 (0.00%)
    1 / 301 (0.33%)
         occurrences all number
    0
    1
    Infections and infestations
    Bacterial vaginosis
         subjects affected / exposed
    1 / 307 (0.33%)
    1 / 301 (0.33%)
         occurrences all number
    1
    1
    Bronchitis
         subjects affected / exposed
    1 / 307 (0.33%)
    0 / 301 (0.00%)
         occurrences all number
    1
    0
    Conjunctivitis
         subjects affected / exposed
    0 / 307 (0.00%)
    1 / 301 (0.33%)
         occurrences all number
    0
    2
    Conjunctivitis viral
         subjects affected / exposed
    0 / 307 (0.00%)
    1 / 301 (0.33%)
         occurrences all number
    0
    1
    Gastroenteritis
         subjects affected / exposed
    2 / 307 (0.65%)
    2 / 301 (0.66%)
         occurrences all number
    2
    2
    Nasopharyngitis
         subjects affected / exposed
    2 / 307 (0.65%)
    1 / 301 (0.33%)
         occurrences all number
    2
    1
    Pharyngitis
         subjects affected / exposed
    0 / 307 (0.00%)
    2 / 301 (0.66%)
         occurrences all number
    0
    2
    Upper respiratory tract infection bacterial
         subjects affected / exposed
    0 / 307 (0.00%)
    1 / 301 (0.33%)
         occurrences all number
    0
    1
    Vulvovaginal mycotic infection
         subjects affected / exposed
    1 / 307 (0.33%)
    0 / 301 (0.00%)
         occurrences all number
    1
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    24 Jan 2019
    One substantial amendment to protocol (applicable in all centres in all countries), was issued to add a precision concerning excipients to non-selection criterion No. 32 and clarifications concerning non authorised pharmacological treatments. Moreover, minor modifications were added: implementation of a new procedure related to the archiving of participants’ e-CRF data at the study file, addition of a short name for the study, modification of archiving time of the information relevant to the study after the end of the study.

    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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