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    Clinical Trial Results:
    A Phase II trial comparing Brivudin 0.1% ophthalmic solution with Aciclovir 3 % ophthalmic ointment in the treatment of patients with herpetic dendritic keratitis

    Summary
    EudraCT number
    		 2009-010971-26
    Trial protocol
    		 DE   ES   IT  
    Global end of trial date
    26 Oct 2010

    Results information
    Results version number
    		 v1(current)
    This version publication date
    15 Nov 2018
    First version publication date
    15 Nov 2018
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    2-BOPH
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Menarini Ricerche S.p.A.
    Sponsor organisation address
    Via Sette Santi, 1, Florence, Italy, 50131
    Public contact
    Corporate Clinical Sciences, Menarini Ricerche S.p.A., +39 05556809990, acapriati@menarini-ricerche.it
    Scientific contact
    Corporate Clinical Sciences, Menarini Ricerche S.p.A., +39 05556809990, acapriati@menarini-ricerche.it
    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
    26 Oct 2010
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    26 Oct 2010
    Global end of trial reached?
    Yes
    Global end of trial date
    26 Oct 2010
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    to compare the efficacy of brivudin 0.1% ophthalmic solution with aciclovir 3.0 % ophthalmic ointment in the healing (corneal re-epithelialisation) of herpetic dendritic keratitis.
    Protection of trial subjects
    If any event(s) related to the conduct of the study or the development of the IMP would have affected the safety of the study participants, the Sponsor and the Investigator would have taken appropriate urgent safety measures to protect the patients against any immediate hazard. The CAs and IRB/ECs would be informed forthwith about these new events and the measures taken. For patients participating in the study, Menarini Ricerche S.p.A. had stipulated an insurance policy in accordance with local regulatory requirements. Details on the insurance company, the insurance number and conditions were made available to patients in the ICF and/or provided as a separate document, in accordance with national requirements.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    27 Jan 2010
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety
    Long term follow-up duration
    		 1 Months
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Spain: 8
    Country: Number of subjects enrolled
    Germany: 4
    Country: Number of subjects enrolled
    Italy: 13
    Worldwide total number of subjects
    25
    EEA total number of subjects
    25
    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)
    17
    From 65 to 84 years
    8
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 After Screeening on Day 1 patients were randomized the same day to either the Brivudin or the Aciclovir arm of the study.

    Period 1
    Period 1 title
    Overall (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded
    Blinding implementation details
    Due to the obvious different appearance of the investigational product and the reference product (ophthalmic solution versus ophthalmic ointment), double-blind conditions could not be ascertained and, consequently, the study was conducted in an open-label fashion. However, a blinded assessment by Independent expert was performed.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Brivudin
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    Brivudin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Eye drops, solution
    Routes of administration
    Ophthalmic use
    Dosage and administration details
    Study medication (Brivudin 0.1% ophthalmic solution) had to be applied 5 times daily until healing of the corneal lesion was assessed by the Investigator. Thereafter, the study treatment had to be continued with the same posology for additional 7 days until the treatment termination visit.

    Arm title
    		 Aciclovir
    Arm description
    		 -
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Aciclovir
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Eye ointment
    Routes of administration
    Ophthalmic use
    Dosage and administration details
    Study medication (Aciclovir 3.0% ophthalmic ointment) had to be applied 5 times daily healing of the corneal lesion was assessed by the Investigator. Thereafter, the study treatment had to be continued with the same posology for additional 7 days until the treatment termination visit.

    Number of subjects in period 1 [1]
    		Brivudin Aciclovir
    Started
    13
    11
    Completed
    12
    11
    Not completed
    1
    0
         Adverse event, non-fatal
    1
    -
    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: Reported data are from ITT population. One patient withdraw consent shortly after randomization and is not considered in the baseline number.

    Baseline characteristics

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

    Reporting group title
    Aciclovir
    Reporting group description
    		 -

    Reporting group values
    		 Brivudin Aciclovir Total
    Number of subjects
    		 13 11 24
    Age categorical
    Units: Subjects
        age 18 to 80 years
    		 13 11 24
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 49.3 ± 16.5 56.6 ± 16.9 -
    Gender categorical
    Units: Subjects
        Female
    		 6 6 12
        Male
    		 7 5 12
    Ophthalmoscopy unaffected eye
    Units: Subjects
        Normal
    		 13 11 24
        Abnormal
    		 0 0 0
    Ophthalmology affected eye
    Units: Subjects
        Normal
    		 12 10 22
        Abnormal
    		 1 1 2
    Visual Acuity Assessment unaffected eye
    Units: Subjects
        High/very high (20/10-20/16)
    		 8 8 16
        Normal/medium (>20/16 - >20/40)
    		 5 3 8
        Reduced (>20/40 - 20/63)
    		 0 0 0
        Severely reduced (>20/63)
    		 0 0 0
    Visual Aciuty Assessment affected eye
    Units: Subjects
        High/very high (20/10 - 20/16)
    		 6 6 12
        Normal/medium (>20/16 - >20/40)
    		 7 4 11
        Reduced (>20/40 - 20/63)
    		 0 1 1
        Severely reduced (>20/63)
    		 0 0 0
    Assessment of IOP affected eye - VALUE
    Units: Subjects
        Value <= 30 mmHg
    		 13 11 24
        Value > 30 mmHg
    		 0 0 0
    Assessment of IOP affected eye - METHOD used
    Units: Subjects
        Pneumatonometry
    		 6 2 8
        Rebound Tonometry
    		 2 0 2
        Palpation
    		 5 9 14
    IOP unaffected eye
    Goldman tonometry
    Units: mmHg
        arithmetic mean (standard deviation)
    		 15.2 ± 2.7 14.3 ± 1.9 -

    End points

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

    Reporting group title
    Aciclovir
    Reporting group description
    		 -

    Primary: Time to healing

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    End point title
    		 Time to healing [1]
    End point description
    The primary efficacy variable was the time to healing of the herpetic corneal lesion (as assessed by the Independent Expert) in the ITT population. Healing was defined as re-epithelialisation of the cornea evidenced by the absence of fluorescein uptake in the area of the corneal lesion.
    End point type
    Primary
    End point timeframe
    Evaluation period was approximately 14 days.
    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 the reduced sample size it was not possible to apply –as originally planned – a Cox Proportional Hazard Model for the calculation of the Hazard Ratio and the corresponding p-value. Results are therefore based on descriptive statistics.
    End point values
    		 Brivudin Aciclovir
    Number of subjects analysed
    13 [2]
    11
    Units: day
        arithmetic mean (standard deviation)
    7.5 ± 2.7
    7.2 ± 3.5
    Notes
    [2] - One patient randomised to Brivudin 0.1% did not provide any post-baseline efficacy assessment.
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events were collected from first study treatment to one month after first study treatment.
    Adverse event reporting additional description
    The safety population includes all patients screened receiving at least one study drug application.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    13.1
    Reporting groups
    Reporting group title
    Brivudin
    Reporting group description
    		 Brivudin 0.1% five times daily for 7 days

    Reporting group title
    Aciclovir
    Reporting group description
    		 Aciclovir 3.0% five times daily for 7 days

    Serious adverse events
    		 Brivudin Aciclovir
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 11 (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
    		 Brivudin Aciclovir
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    5 / 14 (35.71%)
    2 / 11 (18.18%)
    Nervous system disorders
    Headache
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 11 (0.00%)
         occurrences all number
    1
    0
    Eye disorders
    Eye irritation
         subjects affected / exposed
    1 / 14 (7.14%)
    1 / 11 (9.09%)
         occurrences all number
    1
    1
    foreign body sensation in eyes
         subjects affected / exposed
    2 / 14 (14.29%)
    0 / 11 (0.00%)
         occurrences all number
    2
    0
    Vision blurred
         subjects affected / exposed
    2 / 14 (14.29%)
    0 / 11 (0.00%)
         occurrences all number
    2
    0
    Eye pruritus
         subjects affected / exposed
    1 / 14 (7.14%)
    1 / 11 (9.09%)
         occurrences all number
    1
    1
    Photophobia
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 11 (0.00%)
         occurrences all number
    1
    0
    Keratitis
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    1
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 11 (0.00%)
         occurrences all number
    1
    0
    Infections and infestations
    keratitis herpetic
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 11 (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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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    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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