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    Clinical Trial Results:
    Low-dose Atropine for the Prevention of Childhood Myopia Progression in Danish Children (APP-study)

    Summary
    EudraCT number
    		 2018-001286-16
    Trial protocol
    		 DK  
    Global end of trial date
    30 Apr 2024

    Results information
    Results version number
    		 v1(current)
    This version publication date
    04 May 2025
    First version publication date
    04 May 2025
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    The trial adhered to good APP-study
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03911271
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Rigshospitalet
    Sponsor organisation address
    Valdemar Hansens vej 1, Glostrup, Denmark, 2600
    Public contact
    Department of Ophthalmology, Department of Ophthalmology, +45 38634132, line.kessel.01@regionh.dk
    Scientific contact
    Department of Ophthalmology, Department of Ophthalmology, +45 38634132, line.kessel.01@regionh.dk
    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
    23 Apr 2024
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    23 Apr 2024
    Global end of trial reached?
    Yes
    Global end of trial date
    30 Apr 2024
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Myopia (nearsightedness) is increasing in prevalence throughout the world. It is associated with a risk of potentially blinding complications such as retinal detachment and myopic maculopathy. There is a direct association between the degree of myopia and the risk of complications. Myopia develops in childhood and during adolescence. In order to prevent higher degrees of myopia, we need to halt disease progression in children and teenagers. Low-dose atropine eye drops have been shown to reduce myopia progression by 50% in Asian populations but its effect in non-Asian populations is unknown. The aim of this study is to investigate if low-dose atropine can reduce myopia progression in Danish children and teenagers. The study is an investigator initiated randomized clinical trial conducted as a collaboration between three Danish Eye Departments covering all of Denmark.
    Protection of trial subjects
    The trial adhered to good clinical practice (GCP) guidelines for clinical trials. Serious adverse events were reported to the principal investigator. Low-dose atropine eye drops are widely used outside of Europe with few side effects mainly related to the effect.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    01 Jan 2019
    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
    Denmark: 97
    Worldwide total number of subjects
    97
    EEA total number of subjects
    97
    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)
    66
    Adolescents (12-17 years)
    31
    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
    		 Participants were recruited from private practitioners of Ophthalmology and optometry. Recruitment and follow-up took place between May 2019 and May 2024. Participants were recruited across the geography of Denmark.

    Pre-assignment
    Screening details
    		 Children between 6 and 9 years of age with at least one negative spherical diopter in one eye and children between 9 and 12 years of age with at least two negative spherical diopters in one eye were included. In total 124 children were screened. Of these, 21 did not meet inclusion criteria, 4 declined to participate.

    Period 1
    Period 1 title
    Overall trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst, Carer, Assessor
    Blinding implementation details
    Eye drops were manufactured and given a randomized id by the producer. Participants were allocated randomly to each intervention group and paired with a randomized trial medication id.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Placebo
    Arm description
    		 Participants receiving placebo eye drops for 24 months, then followed by 12-months washout
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo eye drops
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Eye drops
    Routes of administration
    Ocular use
    Dosage and administration details
    One eye drop in each eye before bedtime for two years then one year without treatment (wash-out)

    Arm title
    		 0.01%
    Arm description
    		 Participants who received 0.01% low dose atropine for 24 months, then followed by 12-months washout
    Arm type
    		 Experimental

    Investigational medicinal product name
    0.01% low dose atropine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Eye drops
    Routes of administration
    Ocular use
    Dosage and administration details
    1 eye drop in each eye before bedtime

    Arm title
    		 0.1% loading dose
    Arm description
    		 Children who received 0.1% loading dose for the initial six months followed by 0.01% for 18 months, then followed by 12-months washout
    Arm type
    		 Active comparator

    Investigational medicinal product name
    0.1% low dose atropine and 0.01% low dose atropine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Eye drops
    Routes of administration
    Ocular use
    Dosage and administration details
    0.1% for six months followed by 0.01% for 18 months followed by 12 months washout

    Number of subjects in period 1
    		Placebo 0.01% 0.1% loading dose
    Started
    32
    32
    33
    Completed
    29
    31
    31
    Not completed
    3
    1
    2
         Consent withdrawn by subject
    2
    -
    1
         Lost to follow-up
    1
    1
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Overall trial
    Reporting group description
    		 -

    Reporting group values
    		 Overall trial Total
    Number of subjects
    		 97 97
    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 (full range (min-max))
    		 9.4 (6 to 12) -
    Gender categorical
    Units: Subjects
        Female
    		 55 55
        Male
    		 42 42
    Spherical equivalent refraction
    SER in diopters
    Units: diopters
        arithmetic mean (standard deviation)
    		 -2.99 ( 1.27 ) -
    Axial length
    Axial length in mm
    Units: mm
        arithmetic mean (standard deviation)
    		 24.6 ( 0.84 ) -

    End points

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    End points reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Participants receiving placebo eye drops for 24 months, then followed by 12-months washout

    Reporting group title
    0.01%
    Reporting group description
    		 Participants who received 0.01% low dose atropine for 24 months, then followed by 12-months washout

    Reporting group title
    0.1% loading dose
    Reporting group description
    		 Children who received 0.1% loading dose for the initial six months followed by 0.01% for 18 months, then followed by 12-months washout

    Primary: Axial length

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    End point title
    		 Axial length
    End point description
    End point type
    Primary
    End point timeframe
    0 to 36 months
    End point values
    		 Placebo 0.01% 0.1% loading dose
    Number of subjects analysed
    29
    31
    31
    Units: mm
        arithmetic mean (standard error)
    25.33 ( 0.11 )
    25.25 ( 0.11 )
    25.28 ( 0.11 )
    Statistical analysis title
    		 Linear
    Comparison groups
    Placebo v 0.01% v 0.1% loading dose
    Number of subjects included in analysis
    91
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.05
    Method
    		 Mixed models analysis
    Confidence interval

    Secondary: Spherical equivalent refraction

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    End point title
    		 Spherical equivalent refraction
    End point description
    End point type
    Secondary
    End point timeframe
    0 to 36 months
    End point values
    		 Placebo 0.01% 0.1% loading dose
    Number of subjects analysed
    29
    31
    31
    Units: diopters
        arithmetic mean (standard error)
    -4.43 ( 0.20 )
    4.26 ( 0.20 )
    -4.45 ( 0.20 )
    Statistical analysis title
    		 Linear mixed model
    Comparison groups
    Placebo v 0.01% v 0.1% loading dose
    Number of subjects included in analysis
    91
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.05
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (net)
    Confidence interval

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    0 to 36 months
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    28
    Reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Participants receiving placebo eye drops for 24 months, then followed by 12-months washout

    Reporting group title
    0.01%
    Reporting group description
    		 Participants who received 0.01% low dose atropine for 24 months, then followed by 12-months washout

    Reporting group title
    0.1% loading dose
    Reporting group description
    		 Children who received 0.1% loading dose for the initial six months followed by 0.01% for 18 months, then followed by 12-months washout

    Serious adverse events
    		 Placebo 0.01% 0.1% loading dose
    Total subjects affected by serious adverse events
         subjects affected / exposed
    3 / 32 (9.38%)
    0 / 32 (0.00%)
    0 / 33 (0.00%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    Nervous system disorders
    Suspected meningitis
    Additional description: Suspicion of meningitis which was rejected at hospital stay
         subjects affected / exposed
    3 / 32 (9.38%)
    0 / 32 (0.00%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Immune system disorders
    Lymphadenopathy
         subjects affected / exposed
    1 / 32 (3.13%)
    0 / 32 (0.00%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Appendicitis
         subjects affected / exposed
    1 / 32 (3.13%)
    0 / 32 (0.00%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Placebo 0.01% 0.1% loading dose
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    18 / 32 (56.25%)
    18 / 32 (56.25%)
    33 / 33 (100.00%)
    Eye disorders
    Photophobia
         subjects affected / exposed
    1 / 32 (3.13%)
    4 / 32 (12.50%)
    30 / 33 (90.91%)
         occurrences all number
    1
    4
    30
    Eye redness/irritation
         subjects affected / exposed
    6 / 32 (18.75%)
    6 / 32 (18.75%)
    8 / 33 (24.24%)
         occurrences all number
    6
    6
    8
    Other
         subjects affected / exposed
    11 / 32 (34.38%)
    8 / 32 (25.00%)
    18 / 33 (54.55%)
         occurrences all number
    11
    8
    18

    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.
    Moderate sample size, limited follow-up time (3 years), lack of documentation of other factors influencing myopia progression (parental myopia, myopia progression prior to enrollment)
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    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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