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    Clinical Trial Results:
    Modulating the Vaginal Microbiome after Implantation Failure - A randomized placebo controlled study of lactobacilli supplements

    Summary
    EudraCT number
    		 2018-002376-41
    Trial protocol
    		 DK  
    Global end of trial date
    27 Feb 2021

    Results information
    Results version number
    		 v1(current)
    This version publication date
    08 Mar 2022
    First version publication date
    08 Mar 2022
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    ¨noMICINT
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    The Fertility Clinic, Zealand Region
    Sponsor organisation address
    Lykkebaekvej 14, Koege, Denmark,
    Public contact
    Fertilitetsklinikken, University Hospital Zealand, 0045 59484270,
    Scientific contact
    Fertilitetsklinikken, University Hospital Zealand, 0045 59484270,
    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
    01 Sep 2021
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    27 Feb 2021
    Global end of trial reached?
    Yes
    Global end of trial date
    27 Feb 2021
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Investigate change of microbiome in population after treatment with Vivag Plus or placebo over the course of two months.
    Protection of trial subjects
    We used an intervention with a known side-effect profile and known harmless side-effects.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    15 Apr 2019
    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
    Denmark: 77
    Worldwide total number of subjects
    77
    EEA total number of subjects
    77
    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)
    77
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Patient with an unfavourable vaginal microbiome were offered to participate in the study.

    Pre-assignment
    Screening details
    		 Study population Women aged 18–40 years referred to the Fertility Clinic who prior to fertility treatment had been diagnosed with an unfavorable vaginal microbiome were invited to participate in the study

    Pre-assignment period milestones
    Number of subjects started
    		 77
    Number of subjects completed
    		 74

    Pre-assignment subject non-completion reasons
    Reason: Number of subjects
    		 Pregnancy: 1
    Reason: Number of subjects
    		 COVID-19: 1
    Reason: Number of subjects
    		 Consent withdrawn by subject: 1
    Period 1
    Period 1 title
    Overall trial period (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst, Carer
    Blinding implementation details
    The pharmacy of the Capital Region of Denmark conducted the randomization using a computer-based randomization program (www.randomization.com) and labeled all drug packages to ensure blinding of both clinicians and participants to the content of the packages. Unblinding was not carried out until after completion of the study when all data had been entered and the statistical analysis plan c

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 lactobacillus treatment
    Arm description
    		 The intervention consisted of gelatin capsules containing more than 108 CFU of Lactobacillus gasseri EB01 DSM14869 and more than 108 CFU Lactobacillus rhamnosus PB01 DSM14870.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Vivag
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Vaginal use
    Dosage and administration details
    1 vaginal capsule pr day (before nighttime) for 10 days

    Arm title
    		 placebo group
    Arm description
    		 The placebo formulation was identical in appearance and texture to the study intervention but devoid of bacterial strains.
    Arm type
    		 Placebo

    Investigational medicinal product name
    placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Vaginal use
    Dosage and administration details
    1 vaginal capsule pr day (before nighttime) for 10 days.

    Number of subjects in period 1 [1]
    		lactobacillus treatment placebo group
    Started
    38
    36
    Completed
    38
    36
    Notes
    [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: 77 patients were included in the study but three patient dropped out before the intervention. Therefor did they neither received the intervention og had the first and second sample (primary- and secondary outcome), and they were not included in the analyses. This according to the prespecified protocol.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Overall trial period
    Reporting group description
    		 -

    Reporting group values
    		 Overall trial period Total
    Number of subjects
    		 74 74
    Age categorical
    Units: Subjects
        adults (19-39)
    		 74 74
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 31 ( 4.2 ) -
    Gender categorical
    Units: Subjects
        Female
    		 74 74
    Baseline vaginal microbiome profile
    Units: Subjects
        low
    		 56 56
        medium
    		 18 18
    Partner status
    Units: Subjects
        Male partner
    		 59 59
        Female partner
    		 2 2
        No partner
    		 13 13
    Etnicity
    Units: Subjects
        Caucasian
    		 72 72
        Mediterranean
    		 2 2
    Cause of infertility
    Units: Subjects
        Ideopathic
    		 23 23
        Male factor
    		 27 27
        Cycle disorder
    		 2 2
        Combination
    		 3 3
        Other
    		 2 2
        No partner/female partner
    		 14 14
        Missing
    		 3 3
    Penile-vaginal intercourse
    Units: Subjects
        None
    		 11 11
        Yes, 1-4 per month
    		 25 25
        Yes, 5-12 per month
    		 28 28
        Yes, >12 per month
    		 9 9
        Yes, frequency n.a.
    		 1 1
    Self-assessed vaginal discharge
    Units: Subjects
        Normal
    		 57 57
        Increase
    		 16 16
        Missing
    		 1 1
    Vaginal odour complaints
    Units: Subjects
        Yes
    		 56 56
        No
    		 17 17
        missing
    		 1 1
    BMI
    (kg/m2)
    Units: units
        arithmetic mean (standard deviation)
    		 26.4 ( 5.6 ) -

    End points

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    End points reporting groups
    Reporting group title
    lactobacillus treatment
    Reporting group description
    		 The intervention consisted of gelatin capsules containing more than 108 CFU of Lactobacillus gasseri EB01 DSM14869 and more than 108 CFU Lactobacillus rhamnosus PB01 DSM14870.

    Reporting group title
    placebo group
    Reporting group description
    		 The placebo formulation was identical in appearance and texture to the study intervention but devoid of bacterial strains.

    Primary: Improvement in the vaginal microbiome after intervention

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    End point title
    		 Improvement in the vaginal microbiome after intervention
    End point description
    The primary outcome measure was dichotomous: improvement or no improvement in vaginal microbiome profile occurring in the period between the baseline sample and the first sample after the intervention. An improvement was defined as a shift in profile from low to medium, medium to high, or low to high, whereas no improvement was defined as no change, high to medium, or medium to low
    End point type
    Primary
    End point timeframe
    For each patient the timeframe was from 1-3 month: From baseline sample to the first sample after intervention. This covering the 15th of April 2019 to the 27th of February 2021.
    End point values
    		 lactobacillus treatment placebo group
    Number of subjects analysed
    38
    35 [1]
    Units: 38
        Improvement of vaginal microbiome profil
    11
    14
        No improvement of vaginal microbiome profil
    27
    21
    Notes
    [1] - One sample could not be analysed.
    Statistical analysis title
    		 Chi-square
    Comparison groups
    lactobacillus treatment v placebo group
    Number of subjects included in analysis
    73
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 < 0.05
    Method
    		 Chi-squared
    Parameter type
    		 Risk ratio (RR)
    Point estimate
    0.72
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.38
         upper limit
    		 1.38
    Variability estimate
    Standard deviation

    Secondary: Improvement in the vaginal microbiome after intervention one menstrual cycle after intervention

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    End point title
    		 Improvement in the vaginal microbiome after intervention one menstrual cycle after intervention
    End point description
    Improvement in the vaginal microbiome was defined as a change in the microbiome profile from low to medium, low to high, or medium to high from the baseline sample to the second sample (secondary outcome) or from the baseline sample to the second sample (secondary outcome), whereas no improvement was defined as no change or deterioration.
    End point type
    Secondary
    End point timeframe
    For each patient the timeline was from baseline sample to the second sample (the menstrual cycle after the intervention). This covering from the 15th of April 2019 to the 27th of February 2021.
    End point values
    		 lactobacillus treatment placebo group
    Number of subjects analysed
    36 [2]
    36
    Units: 2
        Improvement in the vaginal microbiome
    11
    12
        No improvement in the vaginal microbiome
    25
    24
    Notes
    [2] - One sample could not be analysed and one sample could not be collected due to COVID-19.
    Statistical analysis title
    		 Chi-square
    Comparison groups
    lactobacillus treatment v placebo group
    Number of subjects included in analysis
    72
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 < 0.05
    Method
    		 Chi-squared
    Parameter type
    		 Risk ratio (RR)
    Point estimate
    0.92
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.47
         upper limit
    		 1.8
    Variability estimate
    Standard deviation

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From the inclusion of the first patient to the last patients last visit (=finished with the study), which was the second sample visit (secondary outcome): 15th of april 2019 to 27th of February 2021.
    Adverse event reporting additional description
    Throughout the study participants will be questioned about adverse events (AE=an unexpected medical event) and adverse reactions (AR= an unexpected/unintended response to a medical product) at every visit to the clinic. AE and AR will be registered in the trial clinical case reports and reported to the Sponsor within 24 hours.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 The Danish Medicines
    Dictionary version
    89,stk 2.
    Reporting groups
    Reporting group title
    Lactobacillus group
    Reporting group description
    		 The lactobacillus treatment will consist of Vivag Plus vaginal supplements. The vaginal capsules consist of cultures of Lactobacillus gasseri and Lactobacillus rhamnosus.

    Reporting group title
    Placebo group
    Reporting group description
    		 The placebo formulation was identical in appearance and texture to the study intervention but devoid of bacterial strains.

    Serious adverse events
    		 Lactobacillus group Placebo group
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 36 (2.78%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Reproductive system and breast disorders
    Tubo-ovarian abscess
    Additional description: Patient developed tubo-ovarian abscess after a hysterosalpingography which was not related to the study.
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 36 (2.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0.8%
    Non-serious adverse events
    		 Lactobacillus group Placebo group
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    1 / 38 (2.63%)
    0 / 36 (0.00%)
    Gastrointestinal disorders
    perianal abscess
    Additional description: Patient developed perianal abscess during the study period, not related to the study.
         subjects affected / exposed
    1 / 38 (2.63%)
    0 / 36 (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? No

    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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    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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