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    Clinical Trial Results:
    Efficacy and safety of dexamethasone nanoparticles eye drops in diabetic macular edema.

    Summary
    EudraCT number
    2017-001172-36
    Trial protocol
    SE   DK   FI   HU   LV   EE  
    Global end of trial date
    28 Mar 2019

    Results information
    Results version number
    v1(current)
    This version publication date
    19 Apr 2020
    First version publication date
    19 Apr 2020
    Other versions
    Summary report(s)
    Oculis_EU Clinical Trials Register_DX211

    Trial information

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    Trial identification
    Sponsor protocol code
    DX-211
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    -
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Oculis
    Sponsor organisation address
    Alfheimar 74, Reykjavik, Iceland, 104
    Public contact
    Riad Sherif, Oculis ehf., riad.sherif@oculis.com
    Scientific contact
    Fabio Baschiera, Oculis ehf., fabio.baschiera@oculis.com
    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
    08 Nov 2019
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    28 Mar 2019
    Global end of trial reached?
    Yes
    Global end of trial date
    28 Mar 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    1. Compare the effects of DexNP eye drops with eye drops containing vehicle on visual acuity and central macular thickness (CMT) in subjects with DME over 12 weeks. 2. Mean change in CMT as assessed by Spectral Domain Optical Coherence Tomography (SD-OCT) at Weeks 2, 4, 8, 12, and 16 compared to baseline; 3. Monitor safety of the DexNP eye drop suspension treatment over 12 weeks.
    Protection of trial subjects
    A 12-week treatment with monthly visits in recent-onset DME patients was deemed acceptable. DME rescue treatment criteria were listed in the protocol in case of • IOP rise • BCVA worsening • Upon investigator discretion A 4-week Follow up without study treatment was performed for all patients.
    Background therapy
    No
    Evidence for comparator
    NA
    Actual start date of recruitment
    18 Sep 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
    Sweden: 18
    Country: Number of subjects enrolled
    Denmark: 17
    Country: Number of subjects enrolled
    Estonia: 20
    Country: Number of subjects enrolled
    Finland: 20
    Country: Number of subjects enrolled
    Hungary: 61
    Country: Number of subjects enrolled
    Latvia: 8
    Worldwide total number of subjects
    144
    EEA total number of subjects
    144
    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)
    67
    From 65 to 84 years
    77
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    A total of 184 patients were screened and 144 were treated. The ITT , the Per Protocol and the Safety Set population consist of 144 patients.

    Pre-assignment
    Screening details
    1. Had DME of less than 3 years duration since diagnosis 2. Had an ETDRS BCVA letter score between 73 and 24 in the study eye at baseline

    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, Carer

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Active
    Arm description
    Subject in Active arm received 1 DexNP eye drops in the study eye 3 times a day (every 8 hours) for 12 weeks
    Arm type
    Experimental

    Investigational medicinal product name
    DexNP1.5%
    Investigational medicinal product code
    DexNP
    Other name
    Dexamethasone nanoparticle eye drops
    Pharmaceutical forms
    Eye drops, suspension
    Routes of administration
    Ophthalmic use
    Dosage and administration details
    1 DexNP eye drop in the study eye 3 times a day (every 8 hours) for 12 weeks

    Arm title
    Vehicle
    Arm description
    Subjects received vehicle eye drops in the study eye 3 times a day (every 8 hours) for 12 weeks.
    Arm type
    Placebo

    Investigational medicinal product name
    Vehicle
    Investigational medicinal product code
    NA
    Other name
    NA
    Pharmaceutical forms
    Eye drops, suspension
    Routes of administration
    Ophthalmic use
    Dosage and administration details
    Subjects received vehicle eye drops in the study eye 3 times a day (every 8 hours) for 12 weeks.

    Number of subjects in period 1
    Active Vehicle
    Started
    99
    45
    Completed
    91
    42
    Not completed
    8
    3
         Other
    3
    -
         Adverse event, non-fatal
    3
    1
         Consent withdrawn by subject
    1
    1
         Lost to follow-up
    1
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Active
    Reporting group description
    Subject in Active arm received 1 DexNP eye drops in the study eye 3 times a day (every 8 hours) for 12 weeks

    Reporting group title
    Vehicle
    Reporting group description
    Subjects received vehicle eye drops in the study eye 3 times a day (every 8 hours) for 12 weeks.

    Reporting group values
    Active Vehicle Total
    Number of subjects
    99 45 144
    Age categorical
    Age Category (years), n (%)
    Units: Subjects
        In utero
    0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    0 0 0
        Newborns (0-27 days)
    0 0 0
        Infants and toddlers (28 days-23 months)
    0 0 0
        Children (2-11 years)
    0 0 0
        Adolescents (12-17 years)
    0 0 0
        <50
    9 4 13
        50-70
    60 21 81
        ≥70
    30 20 50
    Age continuous
    Age
    Units: years
        arithmetic mean (full range (min-max))
    63.0 (30 to 77) 65.8 (35 to 76) -
    Gender categorical
    Male/female (n)
    Units: Subjects
        Female
    35 17 52
        Male
    64 28 92
    Subject analysis sets

    Subject analysis set title
    ITT population
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    Consisted of all randomized subjects, analysed subjects under the treatment to which they were randomized (V2).

    Subject analysis set title
    Safety Set
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    Included all randomized subjects who received at least one dose of study medication.

    Subject analysis set title
    Per Protocol Set
    Subject analysis set type
    Per protocol
    Subject analysis set description
    It is a subset of the ITT population and included subjects who did not deviate from the protocol in any way likely to seriously affect the primary outcome of the study, analyzed subjects under the treatment actually received.

    Subject analysis sets values
    ITT population Safety Set Per Protocol Set
    Number of subjects
    144
    144
    144
    Age categorical
    Age Category (years), n (%)
    Units: Subjects
        In utero
    0
    0
    0
        Preterm newborn infants (gestational age < 37 wks)
    0
    0
    0
        Newborns (0-27 days)
    0
    0
    0
        Infants and toddlers (28 days-23 months)
    0
    0
    0
        Children (2-11 years)
    0
    0
    0
        Adolescents (12-17 years)
    0
    0
    0
        <50
    13
    13
    13
        50-70
    81
    81
    81
        ≥70
    50
    50
    50
    Age continuous
    Age
    Units: years
        arithmetic mean (full range (min-max))
    64.4 (33 to 85)
    64.4 (33 to 85)
    64.4 (33 to 85)
    Gender categorical
    Male/female (n)
    Units: Subjects
        Female
        Male

    End points

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    End points reporting groups
    Reporting group title
    Active
    Reporting group description
    Subject in Active arm received 1 DexNP eye drops in the study eye 3 times a day (every 8 hours) for 12 weeks

    Reporting group title
    Vehicle
    Reporting group description
    Subjects received vehicle eye drops in the study eye 3 times a day (every 8 hours) for 12 weeks.

    Subject analysis set title
    ITT population
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    Consisted of all randomized subjects, analysed subjects under the treatment to which they were randomized (V2).

    Subject analysis set title
    Safety Set
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    Included all randomized subjects who received at least one dose of study medication.

    Subject analysis set title
    Per Protocol Set
    Subject analysis set type
    Per protocol
    Subject analysis set description
    It is a subset of the ITT population and included subjects who did not deviate from the protocol in any way likely to seriously affect the primary outcome of the study, analyzed subjects under the treatment actually received.

    Primary: Primary endpoint of the study is mean change in ETDRS Best corrected visual acuity (BCVA) letters at Week 12 compared to baseline.

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    End point title
    Primary endpoint of the study is mean change in ETDRS Best corrected visual acuity (BCVA) letters at Week 12 compared to baseline.
    End point description
    Primary endpoint of the study is mean change in ETDRS Best corrected visual acuity (BCVA) letters at Week 12 compared to baseline.
    End point type
    Primary
    End point timeframe
    12 weeks
    End point values
    Active Vehicle ITT population
    Number of subjects analysed
    99 [1]
    45 [2]
    144 [3]
    Units: ETDRS
        number (not applicable)
    2.62
    1.04
    144
    Notes
    [1] - DexNP
    [2] - Vehicle
    [3] - ITT population
    Statistical analysis title
    Change from Baseline in ETDRS BCVA
    Statistical analysis description
    The statistical hypotheses for the primary endpoint of mean change from baseline in ETDRS BCVA letters in the study eye at Week 12. The study was to be considered a success and DexNP superior to Vehicle if the one-sided p-value was less than 0.15 and the difference in mean change from baseline ETDRS BCVA letters was greater than 0.
    Comparison groups
    Active v Vehicle v ITT population
    Number of subjects included in analysis
    288
    Analysis specification
    Pre-specified
    Analysis type
    superiority [4]
    P-value
    ≤ 0.15 [5]
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    0.15
    Confidence interval
         level
    70%
         sides
    1-sided
         lower limit
    0
         upper limit
    -
    Variability estimate
    Standard error of the mean
    Notes
    [4] - The primary analysis of the primary endpoint employed a linear model with change from baseline ETDRS BCVA letters as the response, baseline ETDRS BCVA letters as a covariate, and treatment as a main effect factor, using the ITT population and with multiple imputation pattern mixture model techniques used to impute missing data. Analysis of covariance (ANCOVA) provided a method for comparing response means among two treatment groups adjusted for baseline values as a covariate only.
    [5] - The study was to be considered a success and DexNP superior to Vehicle if the one-sided p-value was less than 0.15 and the difference in mean change from baseline ETDRS BCVA letters was greater than 0.

    Secondary: Central Macular Thickness

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    End point title
    Central Macular Thickness
    End point description
    The endpoint was analyzed similarly to the primary efficacy analyses using ODO (Observed Data Only) on the ITT population.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 12
    End point values
    Active Vehicle ITT population
    Number of subjects analysed
    99
    45
    144
    Units: Micrometer
        least squares mean (confidence interval 70%)
    -53.68 (-62.980 to -44.380)
    -16.87 (-30.812 to -2.935)
    -36.81 (-53.576 to -20.038)
    Statistical analysis title
    CMT Changes from Baseline
    Statistical analysis description
    Statistical Analysis of Change from Baseline in Study Eye Central Macular Thickness using Multiple Imputation (Intent-to-Treat Population)
    Comparison groups
    Active v Vehicle v ITT population
    Number of subjects included in analysis
    288
    Analysis specification
    Pre-specified
    Analysis type
    other [6]
    P-value
    ≤ 0.15 [7]
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    0.15
    Confidence interval
         level
    70%
         sides
    1-sided
         lower limit
    0.15
         upper limit
    -
    Notes
    [6] - Descriptive
    [7] - The study was to be considered a success and DexNP superior to Vehicle if the one-sided p-value was less than 0.15 and the difference in mean change from baseline ETDRS BCVA letters was greater than 0.

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    18 SEP 2017 to 28 MAR 2019
    Adverse event reporting additional description
    An AE was classified as pre-Treatment AE if it started before the first randomized study medication intake (AE onset date < date of first randomized study medication intake). An AE was classified as a treatment emergent AE (TEAE) if the AE onset date was following the constraint.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    21.0
    Reporting groups
    Reporting group title
    DexNP Eye drops
    Reporting group description
    -

    Reporting group title
    Vehicle Eye drops
    Reporting group description
    Placebo group

    Serious adverse events
    DexNP Eye drops Vehicle Eye drops
    Total subjects affected by serious adverse events
         subjects affected / exposed
    11 / 99 (11.11%)
    1 / 45 (2.22%)
         number of deaths (all causes)
    2
    0
         number of deaths resulting from adverse events
    2
    0
    Vascular disorders
    Peripheral arterial occlusive disease
         subjects affected / exposed
    1 / 99 (1.01%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    2 / 99 (2.02%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure
         subjects affected / exposed
    2 / 99 (2.02%)
    1 / 45 (2.22%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Respiratory distress
         subjects affected / exposed
    1 / 99 (1.01%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Retinal detachment
         subjects affected / exposed
    1 / 99 (1.01%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Death
    Additional description: 1 Death 1 Sudden cardiac death
         subjects affected / exposed
    2 / 99 (2.02%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    Endocrine disorders
    Diabetic ulcer
         subjects affected / exposed
    1 / 99 (1.01%)
    1 / 45 (2.22%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Type 2 diabetes mellitus
         subjects affected / exposed
    1 / 99 (1.01%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Influenza like illnessence
         subjects affected / exposed
    1 / 99 (1.01%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    1 / 99 (1.01%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 2%
    Non-serious adverse events
    DexNP Eye drops Vehicle Eye drops
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    70 / 99 (70.71%)
    24 / 45 (53.33%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    3 / 99 (3.03%)
    2 / 45 (4.44%)
         occurrences all number
    3
    2
    peripheral arterial occlusive disease
         subjects affected / exposed
    2 / 99 (2.02%)
    0 / 45 (0.00%)
         occurrences all number
    2
    0
    Surgical and medical procedures
    Surgical and medical procedures
         subjects affected / exposed
    1 / 99 (1.01%)
    3 / 45 (6.67%)
         occurrences all number
    1
    3
    Psychiatric disorders
    Psychiatric disorders
         subjects affected / exposed
    1 / 99 (1.01%)
    1 / 45 (2.22%)
         occurrences all number
    1
    1
    Reproductive system and breast disorders
    Reproductive system and breast disorders
         subjects affected / exposed
    1 / 99 (1.01%)
    0 / 45 (0.00%)
         occurrences all number
    1
    0
    Injury, poisoning and procedural complications
    Injury, poisoning and procedural complications
         subjects affected / exposed
    1 / 99 (1.01%)
    2 / 45 (4.44%)
         occurrences all number
    1
    2
    Investigations
    Intraocular pressure increased
         subjects affected / exposed
    24 / 99 (24.24%)
    0 / 45 (0.00%)
         occurrences all number
    26
    0
    Blood lactate dehydrogenase increased
         subjects affected / exposed
    2 / 99 (2.02%)
    0 / 45 (0.00%)
         occurrences all number
    2
    0
    Blood pressure increased
         subjects affected / exposed
    2 / 99 (2.02%)
    0 / 45 (0.00%)
         occurrences all number
    2
    0
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    2 / 99 (2.02%)
    0 / 45 (0.00%)
         occurrences all number
    2
    0
    Cardiac failure
         subjects affected / exposed
    2 / 99 (2.02%)
    1 / 45 (2.22%)
         occurrences all number
    2
    1
    Respiratory, thoracic and mediastinal disorders
    Respiratory, thoracic and mediastinal disorders
         subjects affected / exposed
    4 / 99 (4.04%)
    0 / 45 (0.00%)
         occurrences all number
    4
    0
    Blood and lymphatic system disorders
    Blood and Lymphatic system disorders
         subjects affected / exposed
    1 / 99 (1.01%)
    0 / 45 (0.00%)
         occurrences all number
    1
    0
    Nervous system disorders
    Dysgeusia
         subjects affected / exposed
    3 / 99 (3.03%)
    0 / 45 (0.00%)
         occurrences all number
    3
    0
    Eye disorders
    Diabetic retinal oedema
         subjects affected / exposed
    70 / 99 (70.71%)
    24 / 45 (53.33%)
         occurrences all number
    134
    50
    Eye irritation
         subjects affected / exposed
    3 / 99 (3.03%)
    0 / 45 (0.00%)
         occurrences all number
    3
    0
    Ocular hypertension
         subjects affected / exposed
    3 / 99 (3.03%)
    1 / 45 (2.22%)
         occurrences all number
    3
    1
    Visual acuity reduced
         subjects affected / exposed
    3 / 99 (3.03%)
    2 / 45 (4.44%)
         occurrences all number
    3
    2
    Cataract
         subjects affected / exposed
    2 / 99 (2.02%)
    1 / 45 (2.22%)
         occurrences all number
    2
    1
    Diabetic retinopathy
         subjects affected / exposed
    2 / 99 (2.02%)
    0 / 45 (0.00%)
         occurrences all number
    3
    0
    Visual acuity reduced transiently
         subjects affected / exposed
    2 / 99 (2.02%)
    0 / 45 (0.00%)
         occurrences all number
    2
    0
    Vitreous haemorrhage
         subjects affected / exposed
    2 / 99 (2.02%)
    0 / 45 (0.00%)
         occurrences all number
    2
    0
    Conjunctival hyperaemia
         subjects affected / exposed
    0 / 99 (0.00%)
    2 / 45 (4.44%)
         occurrences all number
    0
    2
    Ear and labyrinth disorders
    Ear and labyrinth disorders
         subjects affected / exposed
    1 / 99 (1.01%)
    0 / 45 (0.00%)
         occurrences all number
    1
    0
    Gastrointestinal disorders
    Gastrointestinal disorders
         subjects affected / exposed
    4 / 99 (4.04%)
    0 / 45 (0.00%)
         occurrences all number
    3
    0
    Renal and urinary disorders
    Renal and urinary disorders
         subjects affected / exposed
    1 / 99 (1.01%)
    0 / 45 (0.00%)
         occurrences all number
    2
    0
    Skin and subcutaneous tissue disorders
    Skin and subcutaneous tissue disorders
         subjects affected / exposed
    3 / 99 (3.03%)
    1 / 45 (2.22%)
         occurrences all number
    3
    2
    Musculoskeletal and connective tissue disorders
    muscolo skeletal and connective tissue disorders
         subjects affected / exposed
    4 / 99 (4.04%)
    1 / 45 (2.22%)
         occurrences all number
    4
    1
    Metabolism and nutrition disorders
    Diabetes mellitus
         subjects affected / exposed
    3 / 99 (3.03%)
    1 / 45 (2.22%)
         occurrences all number
    3
    1
    Infections and infestations
    Influenza
         subjects affected / exposed
    4 / 99 (4.04%)
    3 / 45 (6.67%)
         occurrences all number
    4
    3
    Nasopharyngitis
         subjects affected / exposed
    4 / 99 (4.04%)
    3 / 45 (6.67%)
         occurrences all number
    4
    3

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    14 Mar 2018
    Protocol Amendment #1: a) The number of subjects was increased from 96 to 144 subjects. b) The statistical power increased from 80% to c) 90%. d) The number of sites participating in the study e) has been increased from 13 to approximately 27. f) Addition of subgroup analysis of anti-VEGF nonresponders, increased the Sample Size. g) Remove interim analysis. h) Minor changes were done throughout the protocol

    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.
    Exploratory study p value
    The status of studies in GB is no longer updated from 1.1.2021
    For the UK, as from 1.1.2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI
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