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    Clinical Trial Results:
    A prospective, multicentre, uncontrolled study of Geonistin vaginal tablets effectiveness with pharmacokinetic evaluation for unspecific and mixed vulvovaginal infections characterized by vaginal discharge

    Summary
    EudraCT number
    		 2016-000078-39
    Trial protocol
    		 HR  
    Global end of trial date
    13 Dec 2016

    Results information
    Results version number
    		 v1(current)
    This version publication date
    28 Feb 2020
    First version publication date
    28 Feb 2020
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    GEO-2014/01-HR
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    PLIVA Croatia Ltd.
    Sponsor organisation address
    Prilaz baruna Filipovića 25, Zagreb, Croatia, 10000
    Public contact
    Mirjana Matrapazovski Kukuruzović, MD, PLIVA Croatia Ltd., 385 13724962, Mirjana.Matrapazovski-Kukuruzovic@pliva.com
    Scientific contact
    Mirjana Matrapazovski Kukuruzović, MD, PLIVA Croatia Ltd., 385 13724962, Mirjana.Matrapazovski-Kukuruzovic@pliva.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
    31 Mar 2017
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    13 Dec 2016
    Global end of trial reached?
    Yes
    Global end of trial date
    13 Dec 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of the study was to evaluate the clinical effectiveness of Geonistin vaginal tablets administered in empirical treatment of female adult patients with unspecific and mixed vulvovaginal infections characterized by vaginal discharge. The secondary objectives of the study were to evaluate the: (1) systemic exposure to oxytetracycline in local treatment of vulvovaginal infections with Geonistin vaginal tablets; (2) cure rate according to the Nugent score (where applicable); (3) microbiology and microscopy results (outcome); and (4) safety of Geonistin vaginal tablets.
    Protection of trial subjects
    The study was conducted according to Helsinki Declaration, in compliance with local regulations and in accordance with PLIVA Croatia Ltd. standard procedures. This study was conducted in full accordance with the International Conference on Harmonization (ICH) Good Clinical Practice (GCP) Consolidated Guideline (E6) and any applicable national and local laws and regulations, European Union [EU] Directive 2001/20/EC on the approximation of the laws, regulations and administrative provisions of the Member States relating to the implementation of GCP in the conduct of clinical trials on medicinal products for human use).
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    01 Sep 2016
    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
    Croatia: 192
    Worldwide total number of subjects
    192
    EEA total number of subjects
    192
    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)
    192
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Physicians were asked to recruit patients that require Geonistin vaginal tablets treatment from their everyday practice during regular office visit, according to predefined inclusion and exclusion criteria. In total 194 patients were assessed for eligibility, 192 patients were enrolled and 189 completed the study.

    Pre-assignment
    Screening details
    		 2 subjects were assessed for eligibility but they were excluded per exclusion criteria.

    Period 1
    Period 1 title
    Geonistin (Baseline)
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 Period 1
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    Geonistin vaginal tablets
    Investigational medicinal product code
    Other name
    Geonistin
    Pharmaceutical forms
    Tablet
    Routes of administration
    Vaginal use
    Dosage and administration details
    One vaginal tablet containing 100 mg oxytetracycline and 100,000 IU nystatin was self-administered by a patient once daily over 6 consecutive days.

    Number of subjects in period 1
    		Period 1
    Started
    192
    Completed
    189
    Not completed
    3
         Lost to follow-up
    3
    Period 2
    Period 2 title
    Geonistin End of Study
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 Period 1
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    Geonistin vaginal tablets
    Investigational medicinal product code
    Other name
    Geonistin
    Pharmaceutical forms
    Tablet
    Routes of administration
    Vaginal use
    Dosage and administration details
    One vaginal tablet containing 100 mg oxytetracycline and 100,000 IU nystatin was self-administered by a patient once daily over 6 consecutive days.

    Number of subjects in period 2
    		Period 1
    Started
    189
    Completed
    189

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Geonistin (Baseline)
    Reporting group description
    		 Geonistin tablets administered for 6 day open label treatment period. One tablet containing 100 mg oxytetracycline and 100,000 IU nystatin was self-administered once daily.

    Reporting group values
    		 Geonistin (Baseline) Total
    Number of subjects
    		 192 192
    Age Categorical
    Units: Subjects
        In utero
    		 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0
        Newborns (0-27 days)
    		 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0
        Children (2-11 years)
    		 0 0
        Adolescents (12-17 years)
    		 0 0
        Adults (18-64 years)
    		 192 192
        From 65-84 years
    		 0 0
        85 years and over
    		 0 0
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 32.6 ± 8.1 -
    Gender Categorical
    Units: Subjects
        Female
    		 192 192
        Male
    		 0 0

    End points

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    End points reporting groups
    Reporting group title
    Period 1
    Reporting group description
    		 -
    Reporting group title
    Period 1
    Reporting group description
    		 -

    Primary: Clinical cure rate after 6 days of treatment

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    End point title
    		 Clinical cure rate after 6 days of treatment
    End point description
    Clinical effectiveness was evaluated on Day 13 (Visit 2) after 6 days of treatment. Signs and symptoms such as vaginal discharge, odor, itching, were rated as present or absent. Clinical cure was defined as signs or symptoms identified on Day 1 that were absent on Day 13. Signs and symptoms were also rated by severity. Severity was rated as mild, moderate, or severe. Cure rate was defined as absent or improved from severe to mild.
    End point type
    Primary
    End point timeframe
    Day 13
    End point values
    		 Period 1 Period 1
    Number of subjects analysed
    189 [1]
    189 [2]
    Units: Participants
    0
    154
    Notes
    [1] - All participants were assessed at end of the study.
    [2] - Of 189 participants counted, 154 were considered cured.
    Statistical analysis title
    		 Confidence interval of a binomial proportion
    Statistical analysis description
    95% two-sided Clopper-Pearson confidence interval for clinical cure rate
    Comparison groups
    Period 1 v Period 1
    Number of subjects included in analysis
    378
    Analysis specification
    Pre-specified
    Analysis type
    		 other [3]
    P-value
    		 < 0.025 [4]
    Method
    		 Clopper-Pearson
    Parameter type
    		 Percentage
    Point estimate
    81.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 75.2
         upper limit
    		 86.7
    Notes
    [3] - Single arm assessed at end of the study (189 participants, not 378 as shown below). 154 out of 189 participants counted were considered cured (154 out of 189 = 81.5%).
    [4] - Statistically significant clinical effect implied by lower limit of 95% confidence interval for cure rate above 60%

    Secondary: Steady-state serum concentrations of oxytetracycline

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    End point title
    		 Steady-state serum concentrations of oxytetracycline
    End point description
    Steady-state serum concentrations were calculated from pharmacokinetic measurements on Day 7.
    End point type
    Secondary
    End point timeframe
    Day 7
    End point values
    		 Period 1
    Number of subjects analysed
    11 [5]
    Units: ng/ml
    arithmetic mean (standard deviation)
        oxytetracycline level
    20.16 ± 4.99
    Notes
    [5] - Number of subjects analyzed equals number of participants with quantifiable data available
    No statistical analyses for this end point

    Secondary: Number of participants clinically cured based on Nugent score

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    End point title
    		 Number of participants clinically cured based on Nugent score
    End point description
    Effectiveness was assessed based on improvement in Nugent scores from Day 1 to Day 13. Nugent scores of 4-6 (intermediate flora) and greater than or equal to 7 (bacterial vaginosis) were included in the analysis. Cured was defined as a Nugent score of 0-3 on Day 13.
    End point type
    Secondary
    End point timeframe
    Day 13 after 6 days of treatment
    End point values
    		 Period 1
    Number of subjects analysed
    138 [6]
    Units: Number of participants
    67
    Notes
    [6] - 138 participants had countable data. 67 out of 138 were considered cured.
    No statistical analyses for this end point

    Secondary: Number of participants cured according to microbiological results

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    End point title
    		 Number of participants cured according to microbiological results
    End point description
    Microbiological cure rate was assessed for participants with microorganisms identified at Day 1 visit. Cure was defined as a negative culture (no growth) for baseline pathogens or 1+ if the baseline value was greater than 1+.
    End point type
    Secondary
    End point timeframe
    Day 13 after 6 days of treatment
    End point values
    		 Period 1
    Number of subjects analysed
    151 [7]
    Units: Number of participants
    119
    Notes
    [7] - Of 151 participants assessed, 119 were considered cured.
    No statistical analyses for this end point

    Secondary: Number of participants who reported at least one adverse event

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    End point title
    		 Number of participants who reported at least one adverse event
    End point description
    Adverse events were collected from signing the informed consent form through Day 13 (Visit 2) and were self-reported until the end of the follow up period (Day 30).
    End point type
    Secondary
    End point timeframe
    Up to Day 30
    End point values
    		 Period 1
    Number of subjects analysed
    192 [8]
    Units: Number of participants
    13
    Notes
    [8] - 13 participants experienced at least one adverse event.
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events (AEs) were collected from the signature of the informed consent form through Day 13 (Visit 2) and were self-reported until the follow up period, Day 30.
    Adverse event reporting additional description
    Reported adverse events (AEs) are adverse events that are treatment emergent. Treatment emergent adverse events were AEs reported between the first dose of Geonistin up until the follow up period, Day 30.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    19.1
    Reporting groups
    Reporting group title
    Geonistin
    Reporting group description
    		 Received at least one dose of Geonistin

    Serious adverse events
    		 Geonistin
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 192 (0.00%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Geonistin
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    13 / 192 (6.77%)
    Cardiac disorders
    Tachycardia
         subjects affected / exposed
    1 / 192 (0.52%)
         occurrences all number
    1
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    1 / 192 (0.52%)
         occurrences all number
    1
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    1 / 192 (0.52%)
         occurrences all number
    1
    Reproductive system and breast disorders
    Breast pain
         subjects affected / exposed
    1 / 192 (0.52%)
         occurrences all number
    1
    Vulvovaginal discomfort
         subjects affected / exposed
    1 / 192 (0.52%)
         occurrences all number
    1
    Vaginitis gardnerella
         subjects affected / exposed
    1 / 192 (0.52%)
         occurrences all number
    1
    Gastrointestinal disorders
    Anal pruritis
         subjects affected / exposed
    1 / 192 (0.52%)
         occurrences all number
    1
    Renal and urinary disorders
    Cystitis
         subjects affected / exposed
    1 / 192 (0.52%)
         occurrences all number
    1
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    1 / 192 (0.52%)
         occurrences all number
    1
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    1 / 192 (0.52%)
         occurrences all number
    1
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    1 / 192 (0.52%)
         occurrences all number
    1
    Enterovirus
         subjects affected / exposed
    1 / 192 (0.52%)
         occurrences all number
    1
    Urinary tract infection
         subjects affected / exposed
    2 / 192 (1.04%)
         occurrences all number
    2
    Tooth abscess
         subjects affected / exposed
    1 / 192 (0.52%)
         occurrences all number
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    07 Nov 2016
    Protocol amendment 1 was prepared to clarify exclusion criteria 13 (ongoing use of vaginal probiotics)

    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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