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    Clinical Trial Results:
    Corneal cross-linking versus standard care in children with keratoconus, a randomised, multicentre, observer-masked trial of efficacy and safety

    Summary
    EudraCT number
    		 2016-001460-11
    Trial protocol
    		 GB  
    Global end of trial date
    20 Dec 2023

    Results information
    Results version number
    		 v1(current)
    This version publication date
    03 May 2024
    First version publication date
    03 May 2024
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    15/0599
    Additional study identifiers
    ISRCTN number
    		 ISRCTN17303768
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    UCL
    Sponsor organisation address
    90 High Holborn, London, United Kingdom,
    Public contact
    Clinical Project Manager, UCL CCTU, +44 020 3108 3942 , v.mccudden@ucl.ac.uk
    Scientific contact
    Clinical Project Manager, UCL CCTU, +44 020 3108 3942 , v.mccudden@ucl.ac.uk
    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 Jan 2023
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    26 Jan 2023
    Global end of trial reached?
    Yes
    Global end of trial date
    20 Dec 2023
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of the clinical trial is to establish whether cross-linking is efficacious in stabilising the progression of keratoconus, and whether it is safe in patients under 17 years. The main outcome measure will be the change in Kmax overall in the 2 groups in the time from randomisation and completion of 18 months follow-up. Kmax is an indicator derived from corneal topography and changes in this measure indicate whether keratoconus is progressing or not. Safety of CXL will also be monitored carefully at all follow up time points.
    Protection of trial subjects
    The trial was conducted in compliance with the approved protocol, the Declaration of Helsinki (2008), the principles of Good Clinical Practice (GCP) as laid down by the Commission Directive 2005/28/EC with implementation in national legislation in the UK by Statutory Instrument 2004/1031 and subsequent amendments, the Human Tissue (Quality and Safety for Human Application) Regulations 2007, the UK Data Protection Act 2018, and the National Health Service (NHS) Research Governance Framework for Health and Social Care (RGF). Averse Events were collected throughout the trial and treated accordingly. As participation was voluntary, participants were free to discontinue at any given time without giving reason and without it affecting their normal standard of care.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    01 Jul 2016
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety, Efficacy, Scientific research
    Long term follow-up duration
    		 30 Months
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United Kingdom: 60
    Worldwide total number of subjects
    60
    EEA total number of subjects
    0
    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)
    60
    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
    		 -

    Pre-assignment
    Screening details
    		 -

    Pre-assignment period milestones
    Number of subjects started
    		 60
    Number of subjects completed
    		 60

    Period 1
    Period 1 title
    Baseline
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Single blind
    Roles blinded
    		 Assessor [1]
    Blinding implementation details
    Assessors were masked to treatment allocation.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Cross-linking (CXL)
    Arm description
    		 Corneal collagen cross-linking (CXL) in one or both eyes (according to whether progression is confirmed in one eye or both), under general or local anaesthesia as applicable, followed by standard management.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Riboflavin eye drops
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Ear/eye/nasal drops, solution
    Routes of administration
    Ocular use
    Dosage and administration details
    Following removal of corneal epithelium and administration of riboflavin drops, ultraviolet light will be administered according to standardised parameters of 10mW/cm2 for a 5.4J/cm2 total energy dose.

    Arm title
    		 Standard care
    Arm description
    		 Standard management alone, including refraction testing with provision of glasses and/or specialist contact lens fitting. Glasses or contact lenses to be provided for one or both eyes as required for best corrected visual acuity. Those patients who develop advanced disease and poor spectacle- and lens corrected visual acuity during the course of the trial will be offered corneal transplantation.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    No IMP
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Not assigned
    Routes of administration
    Other use
    Dosage and administration details
    No IMP.

    Notes
    [1] - The roles blinded appear inconsistent with a simple blinded trial.
    Justification: We reported the trial as an observer-masked trial. We did not call it a single-blind trial as neither the main investigators nor the patients were masked. However, the only way to add clarification of masking of assessor is by clicking the single-blind option on the form.
    Number of subjects in period 1
    		Cross-linking (CXL) Standard care
    Started
    30
    30
    Completed
    30
    30
    Period 2
    Period 2 title
    ITT
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Single blind
    Roles blinded
    		 Assessor [2]

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Cross-linking (CXL)
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    Riboflavin eye drops
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Ear/eye/nasal drops, solution
    Routes of administration
    Ocular use
    Dosage and administration details
    Following removal of corneal epithelium and administration of riboflavin drops, ultraviolet light will be administered according to standardised parameters of 10mW/cm2 for a 5.4J/cm2 total energy dose.

    Arm title
    		 Standard care
    Arm description
    		 Standard management alone to include provision of glasses and/or contact lenses as required for best corrected visual acuity.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    No IMP
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Not assigned
    Routes of administration
    Other use
    Dosage and administration details
    No IMP

    Notes
    [2] - The roles blinded appear inconsistent with a simple blinded trial.
    Justification: We reported the trial as an observer-masked trial. We did not call it a single-blind trial as neither the main investigators nor the patients were masked. However, the only way to add clarification of masking of assessor is by clicking the single-blind option on the form.
    Number of subjects in period 2
    		Cross-linking (CXL) Standard care
    Started
    30
    30
    Completed
    30
    28
    Not completed
    0
    2
         Consent withdrawn by subject
    -
    2
    Period 3
    Period 3 title
    LTFU
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Cross-linking (CXL)
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    Riboflavin eye drops
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Ear/eye/nasal drops, solution
    Routes of administration
    Ocular use
    Dosage and administration details
    Following removal of corneal epithelium and administration of riboflavin drops, ultraviolet light will be administered according to standardised parameters of 10mW/cm2 for a 5.4J/cm2 total energy dose.

    Arm title
    		 Standard care
    Arm description
    		 -
    Arm type
    		 Active comparator

    Investigational medicinal product name
    No IMP
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Not assigned
    Routes of administration
    Other use
    Dosage and administration details
    Not an IMP - standard management alone to include provision of glasses and/or contact lenses as required for best corrected visual acuity.

    Number of subjects in period 3
    		Cross-linking (CXL) Standard care
    Started
    30
    28
    Completed
    22
    16
    Not completed
    8
    12
         Consent withdrawn by subject
    8
    12

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Cross-linking (CXL)
    Reporting group description
    		 Corneal collagen cross-linking (CXL) in one or both eyes (according to whether progression is confirmed in one eye or both), under general or local anaesthesia as applicable, followed by standard management.

    Reporting group title
    Standard care
    Reporting group description
    		 Standard management alone, including refraction testing with provision of glasses and/or specialist contact lens fitting. Glasses or contact lenses to be provided for one or both eyes as required for best corrected visual acuity. Those patients who develop advanced disease and poor spectacle- and lens corrected visual acuity during the course of the trial will be offered corneal transplantation.

    Reporting group values
    		 Cross-linking (CXL) Standard care Total
    Number of subjects
    		 30 30 60
    Age categorical
    Units: Subjects
        In utero
    		 0
        Preterm newborn infants (gestational age < 37 wks)
    		 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)
    		 0
        From 65-84 years
    		 0
        85 years and over
    		 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 15.2 ( 1.1 ) 15.2 ( 1.6 ) -
    Gender categorical
    Units: Subjects
        Female
    		 5 11 16
        Male
    		 25 19 44
    Number of eyes eligible
    Units: Subjects
        One
    		 27 26 53
        Two
    		 3 4 7
    Ethnicity
    Units: Subjects
        White
    		 12 5 17
        Mixed
    		 4 2 6
        Asian or Asian British
    		 10 17 27
        Black or Black British
    		 3 4 7
        Other
    		 1 2 3
    Use of refractive correction aid
    Units: Subjects
        Yes
    		 21 20 41
        No
    		 9 10 19
    Family history of Keratoconus
    Units: Subjects
        Yes
    		 10 16 26
        No
    		 20 14 34
    K2 in Study eye
    Units: Dioptre
        arithmetic mean (standard deviation)
    		 49.1 ( 3.5 ) 50.2 ( 3.4 ) -
    Apical thickness
    Units: µm
        arithmetic mean (standard deviation)
    		 512 ( 47.9 ) 507 ( 41.2 ) -
    Uncorrected visual acuity in study eye
    Units: logMar
        arithmetic mean (standard deviation)
    		 0.6 ( 0.4 ) 0.7 ( 0.4 ) -
    Best corrected visual acuity in study eye
    Units: logMar
        arithmetic mean (standard deviation)
    		 0.5 ( 0.4 ) 0.5 ( 0.4 ) -

    End points

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    End points reporting groups
    Reporting group title
    Cross-linking (CXL)
    Reporting group description
    		 Corneal collagen cross-linking (CXL) in one or both eyes (according to whether progression is confirmed in one eye or both), under general or local anaesthesia as applicable, followed by standard management.

    Reporting group title
    Standard care
    Reporting group description
    		 Standard management alone, including refraction testing with provision of glasses and/or specialist contact lens fitting. Glasses or contact lenses to be provided for one or both eyes as required for best corrected visual acuity. Those patients who develop advanced disease and poor spectacle- and lens corrected visual acuity during the course of the trial will be offered corneal transplantation.
    Reporting group title
    Cross-linking (CXL)
    Reporting group description
    		 -

    Reporting group title
    Standard care
    Reporting group description
    		 Standard management alone to include provision of glasses and/or contact lenses as required for best corrected visual acuity.
    Reporting group title
    Cross-linking (CXL)
    Reporting group description
    		 -

    Reporting group title
    Standard care
    Reporting group description
    		 -

    Primary: Difference in K2

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    End point title
    		 Difference in K2
    End point description
    End point type
    Primary
    End point timeframe
    At 18months post randomisation.
    End point values
    		 Cross-linking (CXL) Standard care
    Number of subjects analysed
    30
    23
    Units: D
        arithmetic mean (standard deviation)
    49.7 ( 3.8 )
    53.4 ( 5.8 )
    Statistical analysis title
    		 Primary analysis
    Comparison groups
    Standard care v Cross-linking (CXL)
    Number of subjects included in analysis
    53
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.002
    Method
    		 Mixed models analysis
    Parameter type
    		 Median difference (final values)
    Point estimate
    -3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.93
         upper limit
    		 -1.08
    Statistical analysis title
    		 Per protocol analysis
    Comparison groups
    Standard care v Cross-linking (CXL)
    Number of subjects included in analysis
    53
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.001
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -3.23
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -5.21
         upper limit
    		 -1.26

    Secondary: Difference in apical thickness

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    End point title
    		 Difference in apical thickness
    End point description
    End point type
    Secondary
    End point timeframe
    At 18 months from randomisation
    End point values
    		 Cross-linking (CXL) Standard care
    Number of subjects analysed
    28
    22
    Units: µm
        arithmetic mean (standard deviation)
    501.8 ( 38.0 )
    479.9 ( 46.3 )
    Statistical analysis title
    		 Secondary outcome analysis
    Comparison groups
    Standard care v Cross-linking (CXL)
    Number of subjects included in analysis
    50
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.1
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    16.37
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.87
         upper limit
    		 35.61

    Secondary: Difference in uncorrected visual acuity

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    End point title
    		 Difference in uncorrected visual acuity
    End point description
    End point type
    Secondary
    End point timeframe
    At 18months from randomisation
    End point values
    		 Cross-linking (CXL) Standard care
    Number of subjects analysed
    29
    25
    Units: logMar
        arithmetic mean (standard deviation)
    0.5 ( 0.3 )
    0.8 ( 0.6 )
    Statistical analysis title
    		 Secondary outcome analysis
    Comparison groups
    Standard care v Cross-linking (CXL)
    Number of subjects included in analysis
    54
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.002
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.13
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.5
         upper limit
    		 -0.11

    Secondary: Difference in best corrected visual acuity

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    End point title
    		 Difference in best corrected visual acuity
    End point description
    End point type
    Secondary
    End point timeframe
    At 18 months from randomisation.
    End point values
    		 Cross-linking (CXL) Standard care
    Number of subjects analysed
    29
    25
    Units: logMar
        arithmetic mean (standard deviation)
    0.4 ( 0.4 )
    0.6 ( 0.6 )
    Statistical analysis title
    		 Secondary outcome analysis
    Comparison groups
    Standard care v Cross-linking (CXL)
    Number of subjects included in analysis
    54
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.002
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.48
         upper limit
    		 -0.11

    Secondary: Progression free survival

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    End point title
    		 Progression free survival
    End point description
    End point type
    Secondary
    End point timeframe
    From randomisation to 18 months.
    End point values
    		 Cross-linking (CXL) Standard care
    Number of subjects analysed
    30
    28
    Units: Number of progressions
        Progressed
    2
    12
        Did not progress
    28
    16
    Statistical analysis title
    		 Secondary outcome analysis
    Comparison groups
    Cross-linking (CXL) v Standard care
    Number of subjects included in analysis
    58
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.008
    Method
    		 Regression, Cox
    Parameter type
    		 Cox proportional hazard
    Point estimate
    0.13
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.03
         upper limit
    		 0.59

    Other pre-specified: Difference in K2

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    End point title
    		 Difference in K2
    End point description
    End point type
    Other pre-specified
    End point timeframe
    At 48 months from randomisation.
    End point values
    		 Cross-linking (CXL) Standard care
    Number of subjects analysed
    20
    11
    Units: D
        arithmetic mean (standard deviation)
    48.8 ( 3.4 )
    54.0 ( 5.7 )
    Statistical analysis title
    		 LTFU outcome analysis
    Comparison groups
    Standard care v Cross-linking (CXL)
    Number of subjects included in analysis
    31
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.02
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -3.23
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -5.99
         upper limit
    		 -0.46

    Other pre-specified: Difference in apical thickness

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    End point title
    		 Difference in apical thickness
    End point description
    End point type
    Other pre-specified
    End point timeframe
    At 48 months from randomisation
    End point values
    		 Cross-linking (CXL) Standard care
    Number of subjects analysed
    21
    15
    Units: µm
        arithmetic mean (standard deviation)
    475.7 ( 31.3 )
    446.2 ( 42.2 )
    Statistical analysis title
    		 LTFU outcome analysis
    Comparison groups
    Standard care v Cross-linking (CXL)
    Number of subjects included in analysis
    36
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.02
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    25.86
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 3.54
         upper limit
    		 48.18

    Other pre-specified: Difference in uncorrected visual acuity

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    End point title
    		 Difference in uncorrected visual acuity
    End point description
    End point type
    Other pre-specified
    End point timeframe
    At 48 months from randomisation.
    End point values
    		 Cross-linking (CXL) Standard care
    Number of subjects analysed
    21
    15
    Units: logMar
        arithmetic mean (standard deviation)
    0.5 ( 0.4 )
    0.9 ( 0.5 )
    Statistical analysis title
    		 LTFU outcome analysis
    Comparison groups
    Standard care v Cross-linking (CXL)
    Number of subjects included in analysis
    36
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.005
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.36
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.62
         upper limit
    		 -0.11

    Other pre-specified: Difference in best corrected visual acuity

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    End point title
    		 Difference in best corrected visual acuity
    End point description
    End point type
    Other pre-specified
    End point timeframe
    At 48 weeks post randomisation.
    End point values
    		 Cross-linking (CXL) Standard care
    Number of subjects analysed
    21
    16
    Units: logMar
        median (standard deviation)
    0.4 ( 0.4 )
    0.7 ( 0.5 )
    Statistical analysis title
    		 LTFU outcome analysis
    Comparison groups
    Cross-linking (CXL) v Standard care
    Number of subjects included in analysis
    37
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.004
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.32
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.55
         upper limit
    		 -0.11

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From randomisation to 18 months.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 CTCAE
    Dictionary version
    4
    Reporting groups
    Reporting group title
    Cross-linking (CXL)
    Reporting group description
    		 -

    Reporting group title
    Standard care
    Reporting group description
    		 -

    Serious adverse events
    		 Cross-linking (CXL) Standard care
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 30 (0.00%)
    0 / 30 (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
    		 Cross-linking (CXL) Standard care
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    4 / 30 (13.33%)
    2 / 30 (6.67%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Cyst on Right eyebrow
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 30 (0.00%)
         occurrences all number
    1
    0
    Congenital, familial and genetic disorders
    ADHD
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    1
    Autism spectrum disorder
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    1
    General disorders and administration site conditions
    Flu like symptoms
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 30 (0.00%)
         occurrences all number
    1
    0
    Hayfever
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    1
    Tonsilitis
         subjects affected / exposed
    2 / 30 (6.67%)
    0 / 30 (0.00%)
         occurrences all number
    2
    0
    Hypermobility syndrome
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    1
    Loose sutureto graft (non-eye)
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 30 (0.00%)
         occurrences all number
    1
    0
    Eye disorders
    Eye pain
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 30 (0.00%)
         occurrences all number
    1
    0
    Lump on cornea
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 30 (0.00%)
         occurrences all number
    1
    0
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    1
    Musculoskeletal and connective tissue disorders
    Clavicle pain post fracture
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    17 Jun 2016
    • Measurement of corneal thickness was changed from central to apical • To clarify in the protocol that the ophthalmologist will be blinded to the Kmax value which will be measured by optometrist. • To clarify the secondary outcome measure from ‘Time to Keratoconus Progression’ to ‘Time to Keratoconus progression (defined as >1.5 dioptres increase in Kmax)’ • Administrative changes throughout the protocol.
    23 Jan 2017
    1. Clarification of inclusion criterion 1 - Progression for eligibility is defined as an increase of at least 1.5 dioptres in Kmax on Pentacam corneal topography (or equivalent on other topography devices) between two examinations done using the same scanning technique at least 3 months apart. 2. Clarification of exclusion criterion 3 – Addition of another parameter under exclusion criteria and changing the upper limit of Kmax. Steepest corneal meridian (K2) >62 dioptres and maximum corneal curvature (Kmax) >70 dioptres 3. Clarification of primary outcome - Primary outcome measure is the value of the steepest corneal meridian (K2) in the study eye at 18 months post randomisation using standard Pentacam corneal topography 4. Changing the outcome measure from Kmax to K2 – Across the entire protocol 5. Administrative changes throughout the protocol
    08 Nov 2017
    1. Amended the Primary Registry to EudraCT as this was where the study was first registered 2. Udated the number of sites participating in Keralink 3. Re-defined the ‘end of trial’ taking into account the added longer term follow up sub-study 4. Clarified the change in data collection from UCL CCTU receiving copies of paper CRFs and updating the MACRO database to sites team members remotely entering the data in the MACRO database 5. Confirmed that the study data will be published in two stages: following the end of the main study and following completion of the longer term follow up sub-study 6. Confirmed the addition of one optional sub-study (longer term follow up) 7. Appendix 1 – the addition of the longer term follow up sub-study 8. Administrative changes throughout the protocol
    12 Feb 2020
    Appendix 1 / Section 11.1.5 – the addition of remote consent for participants of the main KERALINK study who have previously declined consent to participate in the long term follow up sub-study.

    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

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/31515418
    http://www.ncbi.nlm.nih.gov/pubmed/32532321
    http://www.ncbi.nlm.nih.gov/pubmed/33892046
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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
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