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    Clinical Trial Results:
    Treatment of functional EPIFORA with Botulinum Toxin A (BoNTA) versus lateral tarsal strIp (LTS) surgery.

    Summary
    EudraCT number
    		 2016-000740-34
    Trial protocol
    		 ES  
    Global end of trial date
    05 Feb 2019

    Results information
    Results version number
    		 v1(current)
    This version publication date
    30 Jun 2022
    First version publication date
    30 Jun 2022
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    EPITBA12
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Hospital Universitario de Fuenlabrada
    Sponsor organisation address
    Camino del Molino nº 2, Fuenlabrada, Madrid, Spain, 28942
    Public contact
    Borja Maroto, Dr. Borja Maroto Rodríguez, bormar77@yahoo.es
    Scientific contact
    Borja Maroto, Dr. Borja Maroto Rodríguez, +34 659590117, bormar77@yahoo.es
    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
    25 Feb 2019
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    05 Feb 2019
    Global end of trial reached?
    Yes
    Global end of trial date
    05 Feb 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Compare through the Munk Scale the efficacy of Botulinum Toxin A (IncobotulinuntoxinA) versus lateral tarsal strip, which is the usual surgery technique to treat the functional epifora, after 6 weeks of treatment.
    Protection of trial subjects
    The study was conducted in accordance with the tenets of Declaration of the Helsinki and following the legal regulation on clinical trials in Spain. Ethics approval was obtained from the Fuenlabrada University Hospital (Madrid) Institutional Review Board and the study was registered with the clinical trial registration number EudraCT 2016-000740-34.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    01 May 2017
    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: 30
    Worldwide total number of subjects
    30
    EEA total number of subjects
    30
    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)
    15
    From 65 to 84 years
    15
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 30 patients were recruited between November 2017 and July 2018. 15 were randomized to Botulinum Toxin A (BoNTA) and 15 to lateral tarsal strip (LTS). After randomization, 5 patients withdrew their consent. Therefore, 12 patients were treated with BoNTA and 13 with a LTS. One BoNTA-treated patient dropped out of the study due to a lost to follow-up.

    Pre-assignment
    Screening details
    		 Inclusion criteria - Patients older than 18 years. - Epiphora with patent tear duct with a minimum value of grade 3 on the Munk scale.

    Period 1
    Period 1 title
    Overall trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Botulinum Toxin A (BoNTA)
    Arm description
    		 Patients assigned to the BoNTA treatment group received a transconjunctival injection of BoNTA (XEOMIN®, Merz) into the palpebral lobe of the lacrimal gland of the affected eye. BoNTA was reconstituted with sterile saline at a concentration of 50 U in 0.5 ml. The injections were always performed by the same doctor. BoNTA treatment was not repeated in any patient during the study.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Botulinum toxin A injection (XEOMIN®, Merz)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Conjunctival use
    Dosage and administration details
    Injection of botulinum toxin A (XEOMIN®, Merz) in the palpebral lobe of the lacrimal gland of the affected eye. BoNTA was reconstituted with sterile saline at a concentration of 50 U in 0.5 ml. The injections were always performed by the same doctor after administering topical anesthesia to the patient. To deliver BoNTA treatment, the lateral upper eyelid will be manually everted while the patient looks down and away from the lacrimal gland. This maneuver will expose the palpebral lobe of the lacrimal gland where the BoNTA treatment will be injected. This treatment was not repeated in any patient during the study.

    Arm title
    		 Lateral tarsal strip (LTS)
    Arm description
    		 Lateral tarsal strip (LTS) surgery. It will always be performed by the same surgeon. Steps to follow: - Lateral canthotomy with Westcott scissors. Dissection of the orbicularis over the lateral orbital rim to visualize the periosteum. - Cantholysis: cutting of the lower branch of the lateral canthal tendon, separating it from the orbital rim. - Formation of the strip. - Shortening of the strip. - Reinsertion of the strip to the inner face of the lateral orbital rim.
    Arm type
    		 Surgery

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Number of subjects in period 1 [1]
    		Botulinum Toxin A (BoNTA) Lateral tarsal strip (LTS)
    Started
    12
    13
    Completed
    11
    13
    Not completed
    1
    0
         Lost to follow-up
    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: After randomization, 5 patients withdrew their consent.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Botulinum Toxin A (BoNTA)
    Reporting group description
    		 Patients assigned to the BoNTA treatment group received a transconjunctival injection of BoNTA (XEOMIN®, Merz) into the palpebral lobe of the lacrimal gland of the affected eye. BoNTA was reconstituted with sterile saline at a concentration of 50 U in 0.5 ml. The injections were always performed by the same doctor. BoNTA treatment was not repeated in any patient during the study.

    Reporting group title
    Lateral tarsal strip (LTS)
    Reporting group description
    		 Lateral tarsal strip (LTS) surgery. It will always be performed by the same surgeon. Steps to follow: - Lateral canthotomy with Westcott scissors. Dissection of the orbicularis over the lateral orbital rim to visualize the periosteum. - Cantholysis: cutting of the lower branch of the lateral canthal tendon, separating it from the orbital rim. - Formation of the strip. - Shortening of the strip. - Reinsertion of the strip to the inner face of the lateral orbital rim.

    Reporting group values
    		 Botulinum Toxin A (BoNTA) Lateral tarsal strip (LTS) Total
    Number of subjects
    		 12 13 25
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 7 6 13
        From 65-84 years
    		 5 7 12
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 61.50 ( 9.68 ) 62.23 ( 13.02 ) -
    Gender categorical
    Units: Subjects
        Female
    		 12 10 22
        Male
    		 0 3 3
    Functional epiphora eye
    Units: Subjects
        Right
    		 1 3 4
        Left
    		 2 3 5
        Both
    		 9 7 16
    Munk scale
    Subjective evaluation of epiphora was graded using the Munk scale according to the number of times a day the patient reported dabbing away tears: 0 = no epiphora; 1 = occasional epiphora requiring dabbing less than twice a day; 2 = epiphora requiring dabbing 2-4 times a day; 3 = epiphora requiring dabbing 5-10 times a day; 4 = epiphora requiring dabbing more than 10 times a day.
    Units: point
        arithmetic mean (standard deviation)
    		 3.90 ( 0.30 ) 3.90 ( 0.31 ) -
    Schirmer test
    Test that has the purpose of measuring the amount of tears in the eye by humidifying some strips of filter paper placed in the conjunctival fornix.
    Units: mm
        arithmetic mean (standard deviation)
    		 15.24 ( 6.83 ) 12.40 ( 7.01 ) -
    Visual acuity
    Test to measure the best corrected visual acuity (BCVA) on a decimal scale (0-1).
    Units: scale
        arithmetic mean (standard deviation)
    		 0.77 ( 0.22 ) 0.88 ( 0.14 ) -
    Eyelid traction
    Millimeters of separation between the lower eyelid and the eyeball in the horizontal traction of the lower eyelid.
    Units: milimeter
        arithmetic mean (standard deviation)
    		 7.10 ( 1.34 ) 7.60 ( 0.99 ) -
    Eyelid spring
    Number of blinks for the lower eyelid to return to its normal position after downward traction of the lower eyelid.
    Units: Frequency
        arithmetic mean (standard deviation)
    		 0.48 ( 0.60 ) 0.70 ( 0.57 ) -
    Subjective evaluation of epiphora with the quality questionnaire
    Subjective evaluation of epiphora with the quality questionnaire. This is a quality questionnaire that evaluates how often you have discomfort due to your tearing in various activities of daily living using a scale of 0 to 4: Grade 0: It never bothers you. Grade 1: Sometimes. Grade 2: Frequently. Grade 3: Almost always. Grade 4: Always.
    Units: point
        arithmetic mean (standard deviation)
    		 2.71 ( 0.72 ) 2.90 ( 0.92 ) -

    End points

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    End points reporting groups
    Reporting group title
    Botulinum Toxin A (BoNTA)
    Reporting group description
    		 Patients assigned to the BoNTA treatment group received a transconjunctival injection of BoNTA (XEOMIN®, Merz) into the palpebral lobe of the lacrimal gland of the affected eye. BoNTA was reconstituted with sterile saline at a concentration of 50 U in 0.5 ml. The injections were always performed by the same doctor. BoNTA treatment was not repeated in any patient during the study.

    Reporting group title
    Lateral tarsal strip (LTS)
    Reporting group description
    		 Lateral tarsal strip (LTS) surgery. It will always be performed by the same surgeon. Steps to follow: - Lateral canthotomy with Westcott scissors. Dissection of the orbicularis over the lateral orbital rim to visualize the periosteum. - Cantholysis: cutting of the lower branch of the lateral canthal tendon, separating it from the orbital rim. - Formation of the strip. - Shortening of the strip. - Reinsertion of the strip to the inner face of the lateral orbital rim.

    Primary: Munk scale at 6 weeks of treatment

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    End point title
    		 Munk scale at 6 weeks of treatment
    End point description
    Munk scale is a score according to the number of times a day the patient reported dabbing away tears: 0 = no epiphora; 1 = occasional epiphora requiring dabbing less than twice a day; 2 = epiphora requiring dabbing 2-4 times a day; 3 = epiphora requiring dabbing 5-10 times a day; 4 = epiphora requiring dabbing more than 10 times a day.
    End point type
    Primary
    End point timeframe
    January 2018- January 2019
    End point values
    		 Botulinum Toxin A (BoNTA) Lateral tarsal strip (LTS)
    Number of subjects analysed
    11
    10
    Units: point
        arithmetic mean (confidence interval 95%)
    1.43 (0.90 to 2.00)
    2.35 (1.70 to 3.00)
    Statistical analysis title
    		 Change at 6 weeks in the Munk scale (BoNTA)
    Statistical analysis description
    Change at 6 weeks of treatment in the Munk scale from baseline in the BoNTA treatment group using a paired samples t-student test.
    Comparison groups
    Botulinum Toxin A (BoNTA) v Lateral tarsal strip (LTS)
    Number of subjects included in analysis
    21
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -2.48
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3
         upper limit
    		 -1.9
    Statistical analysis title
    		 Change at 6 weeks in the Munk scale (LTS)
    Statistical analysis description
    Change at 6 weeks of treatment in the Munk scale from baseline in the LTS treatment group using a paired samples t-student test.
    Comparison groups
    Botulinum Toxin A (BoNTA) v Lateral tarsal strip (LTS)
    Number of subjects included in analysis
    21
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -1.55
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.2
         upper limit
    		 -0.9
    Statistical analysis title
    		 Change at 6 weeks in the Munk scale
    Statistical analysis description
    Change at 6 weeks of treatment in the Munk scale from baseline using a paired samples t-student test.
    Comparison groups
    Botulinum Toxin A (BoNTA) v Lateral tarsal strip (LTS)
    Number of subjects included in analysis
    21
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.015
    Method
    		 t-test, 2-sided
    Confidence interval

    Secondary: Test schirmer at 6 week of treatment

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    End point title
    		 Test schirmer at 6 week of treatment
    End point description
    Schirmer strip was placed on the lower conjunctival sac between the lateral area and the external third of the sac for 5 min to measure the production of tears in millimeters from 0 to 15 mm.
    End point type
    Secondary
    End point timeframe
    January 2018-January 2019
    End point values
    		 Botulinum Toxin A (BoNTA) Lateral tarsal strip (LTS)
    Number of subjects analysed
    11
    10
    Units: milimeter
        arithmetic mean (confidence interval 95%)
    13.80 (9.70 to 17.90)
    11.75 (8.80 to 14.70)
    Statistical analysis title
    		 Change at 6 weeks in the Schirmer test (BoNTA)
    Statistical analysis description
    Change at 6 weeks of treatment in the Schirmer test from baseline in the BoNTA treatment group using an paired samples t-student test.
    Comparison groups
    Lateral tarsal strip (LTS) v Botulinum Toxin A (BoNTA)
    Number of subjects included in analysis
    21
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.366
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -1.43
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.7
         upper limit
    		 1.8
    Statistical analysis title
    		 Change at 6 weeks in the Schirmer test (LTS)
    Statistical analysis description
    Change at 6 weeks of treatment in the Munk scale from baseline in the BoNTA treatment group using a paired samples t-student test.
    Comparison groups
    Botulinum Toxin A (BoNTA) v Lateral tarsal strip (LTS)
    Number of subjects included in analysis
    21
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.742
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.65
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.7
         upper limit
    		 3.4
    Statistical analysis title
    		 Change at 6 weeks in the Schirmer test
    Statistical analysis description
    Change at 6 weeks of treatment in the Munk scale from baseline using a paired samples t-student test.
    Comparison groups
    Botulinum Toxin A (BoNTA) v Lateral tarsal strip (LTS)
    Number of subjects included in analysis
    21
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.766
    Method
    		 t-test, 2-sided
    Confidence interval

    Secondary: Visual acuity at 6 week of treatment

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    End point title
    		 Visual acuity at 6 week of treatment
    End point description
    Test to measure the best corrected visual acuity (BCVA) on a decimal scale (0-1).
    End point type
    Secondary
    End point timeframe
    January 2018-January 2019
    End point values
    		 Botulinum Toxin A (BoNTA) Lateral tarsal strip (LTS)
    Number of subjects analysed
    11
    10
    Units: scale
        arithmetic mean (confidence interval 95%)
    0.70 (0.60 to 0.80)
    0.86 (0.80 to 0.90)
    Statistical analysis title
    		 Change at 6 weeks in visual acuity (BoNTA)
    Statistical analysis description
    Change at 6 weeks of treatment in the visual acuity from baseline in the BoNTA treatment group using a paired samples t-student test.
    Comparison groups
    Botulinum Toxin A (BoNTA) v Lateral tarsal strip (LTS)
    Number of subjects included in analysis
    21
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.135
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.06
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.2
         upper limit
    		 0
    Statistical analysis title
    		 Change at 6 weeks in the visual acuity (LTS)
    Statistical analysis description
    Change at 6 weeks of treatment in the visual acuity from baseline in the LTS treatment group using a paired samples t-student test.
    Comparison groups
    Botulinum Toxin A (BoNTA) v Lateral tarsal strip (LTS)
    Number of subjects included in analysis
    21
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.125
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.04
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.1
         upper limit
    		 0
    Statistical analysis title
    		 Change at 6 weeks in the visual acuity
    Statistical analysis description
    Change at 6 weeks of treatment in the Munk scale from baseline using a paired samples t-student test.
    Comparison groups
    Botulinum Toxin A (BoNTA) v Lateral tarsal strip (LTS)
    Number of subjects included in analysis
    21
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.682
    Method
    		 t-test, 2-sided
    Confidence interval

    Secondary: Eyelid traction at 6 week of treatment

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    End point title
    		 Eyelid traction at 6 week of treatment
    End point description
    Millimeters of separation between the lower eyelid and the eyeball in the horizontal traction of the lower eyelid.
    End point type
    Secondary
    End point timeframe
    January 2018-January 2019
    End point values
    		 Botulinum Toxin A (BoNTA) Lateral tarsal strip (LTS)
    Number of subjects analysed
    11
    10
    Units: milimeter
        arithmetic mean (confidence interval 95%)
    6.67 (6.20 to 7.10)
    5.60 (5.00 to 6.20)
    Statistical analysis title
    		 Change at 6 weeks in eyelid traction (BoNTA)
    Statistical analysis description
    Change at 6 weeks of treatment in eyelid traction from baseline in the BoNTA treatment group using a paired samples t-student test.
    Comparison groups
    Botulinum Toxin A (BoNTA) v Lateral tarsal strip (LTS)
    Number of subjects included in analysis
    21
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.107
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.43
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1
         upper limit
    		 0.1
    Statistical analysis title
    		 Change at 6 weeks in eyelid traction (LTS)
    Statistical analysis description
    Change at 6 weeks of treatment in eyelid traction from baseline in the LTS treatment group using a paired samples t-student test.
    Comparison groups
    Botulinum Toxin A (BoNTA) v Lateral tarsal strip (LTS)
    Number of subjects included in analysis
    21
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.6
         upper limit
    		 -1.4
    Statistical analysis title
    		 Change at 6 weeks in eyelid traction
    Statistical analysis description
    Change at 6 weeks of treatment in the Munk scale from baseline using a paired samples t-student test.
    Comparison groups
    Botulinum Toxin A (BoNTA) v Lateral tarsal strip (LTS)
    Number of subjects included in analysis
    21
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0006
    Method
    		 t-test, 2-sided
    Confidence interval

    Secondary: Eyelid spring at 6 week of treatment

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    End point title
    		 Eyelid spring at 6 week of treatment
    End point description
    Number of blinks for the lower eyelid to return to its normal position after downward traction of the lower eyelid.
    End point type
    Secondary
    End point timeframe
    January 2018-Junuary 2019
    End point values
    		 Botulinum Toxin A (BoNTA) Lateral tarsal strip (LTS)
    Number of subjects analysed
    11
    10
    Units: Frequency
        arithmetic mean (confidence interval 95%)
    0.38 (0.10 to 0.60)
    0.05 (-0.10 to 0.20)
    Statistical analysis title
    		 Change at 6 weeks in eyelid spring (BoNTA)
    Statistical analysis description
    Change at 6 weeks of treatment in eyelid spring from baseline in the BoNTA treatment group using a paired samples t-student test.
    Comparison groups
    Botulinum Toxin A (BoNTA) v Lateral tarsal strip (LTS)
    Number of subjects included in analysis
    21
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.625
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.3
         upper limit
    		 0.1
    Statistical analysis title
    		 Change at 6 weeks in eyelid spring (LTS)
    Statistical analysis description
    Change at 6 weeks of treatment in eyelid spring from baseline in the LTS treatment group using a paired samples t-student test.
    Comparison groups
    Botulinum Toxin A (BoNTA) v Lateral tarsal strip (LTS)
    Number of subjects included in analysis
    21
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0005
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.65
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.9
         upper limit
    		 -0.4
    Statistical analysis title
    		 Change at 6 weeks in eyelid spring
    Statistical analysis description
    Change at 6 weeks of treatment in eyelid spring from baseline using a paired samples t-student test.
    Comparison groups
    Botulinum Toxin A (BoNTA) v Lateral tarsal strip (LTS)
    Number of subjects included in analysis
    21
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0026
    Method
    		 t-test, 2-sided
    Confidence interval

    Secondary: Subjective evaluation of epiphora with the quality questionnaire at 6 weeks to treatment

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    End point title
    		 Subjective evaluation of epiphora with the quality questionnaire at 6 weeks to treatment
    End point description
    Subjective evaluation of epiphora with the quality questionnaire. This is a quality questionnaire that evaluates how often you have discomfort due to your tearing in various activities of daily living using a scale of 0 to 4: Grade 0: It never bothers you. Grade 1: Sometimes. Grade 2: Frequently. Grade 3: Almost always. Grade 4: Always.
    End point type
    Secondary
    End point timeframe
    January 2018-January 2019
    End point values
    		 Botulinum Toxin A (BoNTA) Lateral tarsal strip (LTS)
    Number of subjects analysed
    6
    7
    Units: points
        arithmetic mean (confidence interval 95%)
    1.35 (0.60 to 2.10)
    1.34 (0.70 to 2.00)
    Statistical analysis title
    		 Change at 6 weeks in quality questionnaire (BoNTA)
    Statistical analysis description
    Change at 6 weeks of treatment in quality questionnaire from baseline in the BoNTA treatment group using a paired samples t-student test.
    Comparison groups
    Botulinum Toxin A (BoNTA) v Lateral tarsal strip (LTS)
    Number of subjects included in analysis
    13
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.007
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (final values)
    Confidence interval
         level
    		 95%
    Statistical analysis title
    		 Change at 6 weeks in quality questionnaire (LTS)
    Statistical analysis description
    Change at 6 weeks of treatment in quality questionnaire from baseline in the LTS treatment group using a paired samples t-student test.
    Comparison groups
    Botulinum Toxin A (BoNTA) v Lateral tarsal strip (LTS)
    Number of subjects included in analysis
    13
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0003
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -1.56
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.2
         upper limit
    		 -0.9
    Statistical analysis title
    		 Change at 6 weeks in quality questionnaire
    Statistical analysis description
    Change at 6 weeks of treatment in quality questionnaire from baseline using a paired samples t-student test.
    Comparison groups
    Botulinum Toxin A (BoNTA) v Lateral tarsal strip (LTS)
    Number of subjects included in analysis
    13
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.918
    Method
    		 t-test, 2-sided
    Confidence interval

    Secondary: Treatment duration

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    End point title
    		 Treatment duration
    End point description
    End point type
    Secondary
    End point timeframe
    January 2018-January 2019
    End point values
    		 Botulinum Toxin A (BoNTA) Lateral tarsal strip (LTS)
    Number of subjects analysed
    12
    13
    Units: week
        arithmetic mean (standard deviation)
    26.14 ( 9.48 )
    23.61 ( 11.79 )
    Statistical analysis title
    		 Differences between the duration of the treatments
    Comparison groups
    Botulinum Toxin A (BoNTA) v Lateral tarsal strip (LTS)
    Number of subjects included in analysis
    25
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.937
    Method
    		 t-test, 2-sided
    Confidence interval

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    January 2018-January 2019
    Adverse event reporting additional description
    There were 9 adverse events in 9 patients (36.0%), of which 5 occurred in 5 patients treated with BoNTA (41.7%) and 4 in 4 patients treated with LST (30.8%). In patients treated with BoNTA, 3 palpebral ptosis, 1 metamorphopsia and 1 conjunctivitis occurred. In those treated with LST, 3 scar discomfort and 1 wound infection occurred.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    22.0
    Reporting groups
    Reporting group title
    BoNTA
    Reporting group description
    		 In patients treated with Botulinum Toxin A (BoNTA), 3 palpebral ptosis, 1 metamorphopsia and 1 conjunctivitis occurred

    Reporting group title
    Lateral tarsal strip (LTS)
    Reporting group description
    		 In those treated with lateral tarsal strip (LTS), 3 scar discomfort and 1 wound infection occurred.

    Serious adverse events
    		 BoNTA Lateral tarsal strip (LTS)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 13 (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: 0%
    Non-serious adverse events
    		 BoNTA Lateral tarsal strip (LTS)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    5 / 12 (41.67%)
    4 / 13 (30.77%)
    Eye disorders
    Eyelid ptosis
         subjects affected / exposed
    3 / 12 (25.00%)
    0 / 13 (0.00%)
         occurrences all number
    3
    0
    Metamorphopsia
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 13 (0.00%)
         occurrences all number
    1
    0
    Skin and subcutaneous tissue disorders
    Wound infection
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    1
    Scar discomfort
         subjects affected / exposed
    0 / 12 (0.00%)
    3 / 13 (23.08%)
         occurrences all number
    0
    3
    Infections and infestations
    Conjunctivitis
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 13 (0.00%)
         occurrences all number
    0
    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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