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    Clinical Trial Results:
    Efficacy and safety of topical administration of timolol maleate 0.5% solution in the treatment of Child Proliferative Hemangioma Early Stage Surface. Randomized Controlled Study

    Summary
    EudraCT number
    		 2013-005199-17
    Trial protocol
    		 ES  
    Global end of trial date
    09 Jan 2017

    Results information
    Results version number
    		 v1(current)
    This version publication date
    02 Jul 2021
    First version publication date
    02 Jul 2021
    Other versions
    Summary report(s)
    		 summary

    Trial information

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    Trial identification
    Sponsor protocol code
    IIBSP-TIM-2013-156
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02731287
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Institut de Recerca de l'Hospital de la Santa Creu i Sant Pau - IIB Sant Pau
    Sponsor organisation address
    Sant Quintí 77-79, Barcelona, Spain, 08041
    Public contact
    Enrique Peña, Institut de Recerca HSCSP, 34 935537636, epenag@santpau.cat
    Scientific contact
    Enrique Peña, Institut de Recerca HSCSP, 34 935537636, epenag@santpau.cat
    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 Nov 2017
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    09 Jan 2017
    Global end of trial reached?
    Yes
    Global end of trial date
    09 Jan 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To determine the efficacy of timolol maleate 0.5% solution in the treatment of infantile hemangiomas surface during the early proliferative stage.
    Protection of trial subjects
    This study has been organized in accordance with the Declaration of Helsinki, the Good Clinical Practice guidelines and national regulations. The study protocol has been reviewed by an Ethics Committee, whose task is to verify that the necessary requirements for the protection of the nursing baby and her rights have been met. The Ethics Committee issued a favorable opinion before the start of the study. The study protocol has been sent to the health authorities and they have authorized it. The doctor treating has been informed of the nursing baby's participation in this clinical trial. Likewise, they will be given a patient file with the contact details of the sponsor / researcher, the study drug and the indication. The sponsor of the study has an insurance policy that complies with current legislation and compensation will be granted in the event of deterioration of health or injury that may occur in relation to the infant's participation in the study.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    06 Oct 2014
    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
    Spain: 70
    Worldwide total number of subjects
    70
    EEA total number of subjects
    70
    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)
    70
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    0
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Seventy patients were included in this study. Thirty-three patients were randomly distributed in the treatment group (timolol) and 37 patients were distributed in the same way in the placebo group.In the timolol group, 22 patients completed the 36th week follow-up and in the placebo group just 25 patients.

    Pre-assignment
    Screening details
    		 -Growth / ulceration of the lesion. Change to propranolol (n = 7) -Parents notice lack of effectiveness and want to do off-label treatment (n = 3) -Loss of follow-up / Refusal to finish the study (n = 12) -Fail screening (n=1)

    Pre-assignment period milestones
    Number of subjects started
    		 70
    Number of subjects completed
    		 70

    Period 1
    Period 1 title
    Week 0
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Data analyst
    Blinding implementation details
    The protocol has been designed as a double-blind, placebo-controlled study. The assignment of treatments will be done blindly. The package and label product's look similar. Researchers and parents or legal guardians doesn't know what product patients receive during the study. Participants have been randomized with a 1: 1 ratio. Randomization has been managed by an independent randomization team carried out by the Department of Pharmacy (HSCSP)

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Timolol group
    Arm description
    		 Timolol maleate 0.5% solution (ophthalmic eye drops) Dosage: 2 drops / 12 hours Route of administration: topical Pharmaceutical form: ophthalmic eye drops
    Arm type
    		 Experimental

    Investigational medicinal product name
    Timolol maleate
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Ear/eye drops, solution
    Routes of administration
    Ophthalmic use
    Dosage and administration details
    Dosage: 2 drops / 12 hours

    Arm title
    		 Placebo group
    Arm description
    		 Saline solution (ophthalmic eye drops) Dosage: 2 drops c / 12 hrs Route of administration: topical Pharmaceutical form: ophthalmic eye drops
    Arm type
    		 Placebo

    Investigational medicinal product name
    Saline solution
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Ear/eye drops, solution
    Routes of administration
    Ophthalmic use
    Dosage and administration details
    Dosage: 2 drops / 12 hours

    Number of subjects in period 1
    		Timolol group Placebo group
    Started
    33
    37
    Completed
    33
    37
    Period 2
    Period 2 title
    Week 12
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Investigator, Monitor, Subject, Data analyst

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Timolol group
    Arm description
    		 Timolol maleate 0.5% solution (ophthalmic eye drops) Dosage: 2 drops / 12 hours Route of administration: topical Pharmaceutical form: ophthalmic eye drops
    Arm type
    		 Experimental

    Investigational medicinal product name
    Timolol maleate
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Ear/eye drops, solution
    Routes of administration
    Ophthalmic use
    Dosage and administration details
    Dosage: 2 drops / 12 hours

    Arm title
    		 Placebo group
    Arm description
    		 Saline solution (ophthalmic eye drops) Dosage: 2 drops c / 12 hrs Route of administration: topical Pharmaceutical form: ophthalmic eye drops
    Arm type
    		 Placebo

    Investigational medicinal product name
    Saline solution
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Ear/eye drops, solution
    Routes of administration
    Ophthalmic use
    Dosage and administration details
    Dosage: 2 drops / 12 hours

    Number of subjects in period 2
    		Timolol group Placebo group
    Started
    33
    37
    Completed
    29
    31
    Not completed
    4
    6
         Lack of efficacy
    4
    6
    Period 3
    Period 3 title
    Week 24
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Timolol group
    Arm description
    		 Timolol maleate 0.5% solution (ophthalmic eye drops) Dosage: 2 drops / 12 hours Route of administration: topical Pharmaceutical form: ophthalmic eye drops
    Arm type
    		 Experimental

    Investigational medicinal product name
    Timolol maleate
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Ear/eye drops, solution
    Routes of administration
    Ophthalmic use
    Dosage and administration details
    Dosage: 2 drops / 12 hours

    Arm title
    		 Placebo group
    Arm description
    		 Saline solution (ophthalmic eye drops) Dosage: 2 drops c / 12 hrs Route of administration: topical Pharmaceutical form: ophthalmic eye drops
    Arm type
    		 Placebo

    Investigational medicinal product name
    Saline solution
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Ear/eye drops, solution
    Routes of administration
    Ophthalmic use
    Dosage and administration details
    Dosage: 2 drops / 12 hours

    Number of subjects in period 3
    		Timolol group Placebo group
    Started
    29
    31
    Completed
    29
    31
    Period 4
    Period 4 title
    Week 36
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Timolol group
    Arm description
    		 Timolol maleate 0.5% solution (ophthalmic eye drops) Dosage: 2 drops / 12 hours Route of administration: topical Pharmaceutical form: ophthalmic eye drops
    Arm type
    		 Experimental

    Investigational medicinal product name
    Timolol maleate
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Ear/eye drops, solution
    Routes of administration
    Ophthalmic use
    Dosage and administration details
    Dosage: 2 drops / 12 hours

    Arm title
    		 Placebo group
    Arm description
    		 Saline solution (ophthalmic eye drops) Dosage: 2 drops c / 12 hrs Route of administration: topical Pharmaceutical form: ophthalmic eye drops
    Arm type
    		 Placebo

    Investigational medicinal product name
    Saline solution
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Ear/eye drops, solution
    Routes of administration
    Ophthalmic use
    Dosage and administration details
    Dosage: 2 drops / 12 hours

    Number of subjects in period 4
    		Timolol group Placebo group
    Started
    29
    31
    Completed
    22
    25
    Not completed
    7
    6
         Consent withdrawn by subject
    2
    -
         Error inclusion
    -
    1
         Lost to follow-up
    5
    5

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Timolol group
    Reporting group description
    		 Timolol maleate 0.5% solution (ophthalmic eye drops) Dosage: 2 drops / 12 hours Route of administration: topical Pharmaceutical form: ophthalmic eye drops

    Reporting group title
    Placebo group
    Reporting group description
    		 Saline solution (ophthalmic eye drops) Dosage: 2 drops c / 12 hrs Route of administration: topical Pharmaceutical form: ophthalmic eye drops

    Reporting group values
    		 Timolol group Placebo group Total
    Number of subjects
    		 33 37 70
    Age categorical
    Units: Subjects
        Newborns (0-27 days)
    		 0 4 4
        Infants and toddlers (28 days-23 months)
    		 33 33 66
    Gender categorical
    Units: Subjects
        Female
    		 29 27 56
        Male
    		 4 10 14

    End points

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    End points reporting groups
    Reporting group title
    Timolol group
    Reporting group description
    		 Timolol maleate 0.5% solution (ophthalmic eye drops) Dosage: 2 drops / 12 hours Route of administration: topical Pharmaceutical form: ophthalmic eye drops

    Reporting group title
    Placebo group
    Reporting group description
    		 Saline solution (ophthalmic eye drops) Dosage: 2 drops c / 12 hrs Route of administration: topical Pharmaceutical form: ophthalmic eye drops
    Reporting group title
    Timolol group
    Reporting group description
    		 Timolol maleate 0.5% solution (ophthalmic eye drops) Dosage: 2 drops / 12 hours Route of administration: topical Pharmaceutical form: ophthalmic eye drops

    Reporting group title
    Placebo group
    Reporting group description
    		 Saline solution (ophthalmic eye drops) Dosage: 2 drops c / 12 hrs Route of administration: topical Pharmaceutical form: ophthalmic eye drops
    Reporting group title
    Timolol group
    Reporting group description
    		 Timolol maleate 0.5% solution (ophthalmic eye drops) Dosage: 2 drops / 12 hours Route of administration: topical Pharmaceutical form: ophthalmic eye drops

    Reporting group title
    Placebo group
    Reporting group description
    		 Saline solution (ophthalmic eye drops) Dosage: 2 drops c / 12 hrs Route of administration: topical Pharmaceutical form: ophthalmic eye drops
    Reporting group title
    Timolol group
    Reporting group description
    		 Timolol maleate 0.5% solution (ophthalmic eye drops) Dosage: 2 drops / 12 hours Route of administration: topical Pharmaceutical form: ophthalmic eye drops

    Reporting group title
    Placebo group
    Reporting group description
    		 Saline solution (ophthalmic eye drops) Dosage: 2 drops c / 12 hrs Route of administration: topical Pharmaceutical form: ophthalmic eye drops

    Subject analysis set title
    Eficacy evaluation
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Cualitative evaluation of Childish Hemangioma (CH): -Color intensity -Surface component -Hemangioma resolution compared to baseline -Evolution of the resolution of the hemangioma compared to the previous visit -Evaluation of the hemangioma compared to the baseline

    Primary: Resolution of Childish Hemangioma (CH)

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    End point title
    		 Resolution of Childish Hemangioma (CH)
    End point description
    The primary endpoint (complete /almost complete or not) will be evaluated comparing the cualitative characteristics of the CH pictures took between the 24 week and the basal visit. Success rates will be based on centralized independent qualitative assessments, that will be described in the complete set of analyzes by treatment group and time of evaluation (W12 and W24).
    End point type
    Primary
    End point timeframe
    the 24th week
    End point values
    		 Timolol group Placebo group Timolol group Placebo group
    Number of subjects analysed
    33
    37
    29
    31
    Units: percent
    number (not applicable)
        complete/almost complete
    33
    37
    29
    31
        not complete
    0
    0
    29
    31
    Statistical analysis title
    		 Resolution comparative
    Statistical analysis description
    This analysis will allow to know if there is a stadistic difference between Timolol and Placebo group.
    Comparison groups
    Placebo group v Timolol group
    Number of subjects included in analysis
    60
    Analysis specification
    Post-hoc
    Analysis type
    		 equivalence
    P-value
    		 < 0.05
    Method
    		 Fisher exact
    Parameter type
    		 Odds ratio (OR)
    Confidence interval
         level
    		 95%
         sides
    1-sided
         lower limit
    		 -
         upper limit
    		 -

    Secondary: Size of CH

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    End point title
    		 Size of CH
    End point description
    Evaluations will be made regarding the volume and thickness of HI in weeks 2, 4, 8, 12, 24 and 36. The data obtained will be expressed in percentages (%). The average of both measurements will be taken into account to determine the evolution of the HI with respect to the treatment and the evaluation time, using the Wilcoxon test. Any value of P <0.05 will be considered significant.
    End point type
    Secondary
    End point timeframe
    Weeks: 12,24
    End point values
    		 Timolol group Placebo group Timolol group Placebo group
    Number of subjects analysed
    23
    24
    22
    35
    Units: Subjects
        flat
    15
    10
    15
    14
        slight elevation
    4
    10
    3
    8
        Moderate elevation
    2
    3
    2
    2
        Marked elevation
    2
    1
    2
    1
    Attachments
    		 Size of CH
    Statistical analysis title
    		 Evolution of CH between treatment and time of eval
    Comparison groups
    Timolol group v Placebo group
    Number of subjects included in analysis
    47
    Analysis specification
    Post-hoc
    Analysis type
    		 equivalence
    P-value
    		 < 0.05
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    After drug administration and durig the 36 weeks of follow-up.
    Adverse event reporting additional description
    treatment group, patient code, sex and age, term notified by the investigator, preferred term, starting day based on the date of the first administration of the study treatment, duration, measure taken in relation to the administration of the treatment of the study, use of a corrective treatment, outcome and relationship with the treatment
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    21.1
    Reporting groups
    Reporting group title
    Timolol group
    Reporting group description
    		 Timolol maleate 0.5% solution (ophthalmic eye drops) Dosage: 2 drops / 12 hours Route of administration: topical Pharmaceutical form: ophthalmic eye drops

    Reporting group title
    Placebo group
    Reporting group description
    		 Saline solution (ophthalmic eye drops) Dosage: 2 drops c / 12 hrs Route of administration: topical Pharmaceutical form: ophthalmic eye drops

    Serious adverse events
    		 Timolol group Placebo group
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 33 (0.00%)
    0 / 37 (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
    		 Timolol group Placebo group
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    5 / 33 (15.15%)
    8 / 37 (21.62%)
    Respiratory, thoracic and mediastinal disorders
    Bronchiolitis
         subjects affected / exposed
    1 / 33 (3.03%)
    4 / 37 (10.81%)
         occurrences all number
    1
    4
    Skin and subcutaneous tissue disorders
    Xerosis
         subjects affected / exposed
    1 / 33 (3.03%)
    1 / 37 (2.70%)
         occurrences all number
    1
    1
    Ulcerated haemangioma
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 37 (2.70%)
         occurrences all number
    0
    1
    Infected dermal cyst
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 37 (2.70%)
         occurrences all number
    0
    1
    Dermatitis atopic
         subjects affected / exposed
    1 / 33 (3.03%)
    1 / 37 (2.70%)
         occurrences all number
    1
    1
    Dermatitis
         subjects affected / exposed
    2 / 33 (6.06%)
    0 / 37 (0.00%)
         occurrences all number
    2
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    17 Mar 2015
    The amentment was done for including a new investigative site (Hospital Virgen de la Macarena- Virgen del Rocío en Sevilla) changing the protocol bversion ( V5.0) and the ICF (V3.0)

    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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