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    Clinical Trial Results:
    A randomized, active controlled, patient and investigator masked, multiple dose proof-of-concept study of intravitreal LKA651 in patients with diabetic macular edema

    Summary
    EudraCT number
    		 2018-000031-28
    Trial protocol
    		 DE   ES  
    Global end of trial date
    31 Aug 2022

    Results information
    Results version number
    		 v2(current)
    This version publication date
    07 Oct 2023
    First version publication date
    31 Aug 2023
    Other versions
    		 v1
    Version creation reason
    • Correction of full data set
    changed title for OM 1 and 2 Description changed for OM 1 changed unit of measure from µm to ratio OM 11 AE timeframe and description changed

    Trial information

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    Trial identification
    Sponsor protocol code
    CLKA651X2202
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03927690
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Novartis Pharma AG
    Sponsor organisation address
    Novartis Campus, Basel, Switzerland,
    Public contact
    Clinical Disclosure Office, Novartis Pharma AG, 41 613241111, Novartis.email@Novartis.com
    Scientific contact
    Clinical Disclosure Office, Novartis Pharma AG, 41 613241111, Novartis.email@Novartis.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
    31 Aug 2022
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    17 Jun 2022
    Global end of trial reached?
    Yes
    Global end of trial date
    31 Aug 2022
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objectives of this study were to evaluate the safety/tolerability of three q4w Intravitreal (IVT) doses of LKA651 alone or in combination with Lucentis in patients with diabetic macular edema (DME) and to evaluate the efficacy, in reference to Lucentis monotherapy, of three q4w IVT doses of LKA651 in treating DME when administered as monotherapy or in combination with Lucentis. For this, the endpoints were ocular and systemic adverse events (AEs), vital signs (blood pressure, heart rate) and Electrocardiogram (ECG) intervals, safety laboratory measures (including reticulocyte count) and complete ophthalmic exam. Due to EudraCT system limitations, which EMA is aware of, data using 999 as data points in this record are not an accurate representation of the clinical trial results. Please use https://www.novctrd.com for complete trial results.
    Protection of trial subjects
    The study was in compliance with the ethical principles derived from the Declaration of Helsinki and the International Conference on Harmonization (ICH) Good Clinical Practice (GCP) guidelines. All the local regulatory requirements pertinent to safety of trial subjects were also followed during the conduct of the trial.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    24 May 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
    United States: 52
    Country: Number of subjects enrolled
    Germany: 6
    Country: Number of subjects enrolled
    Spain: 18
    Country: Number of subjects enrolled
    Turkey: 15
    Worldwide total number of subjects
    91
    EEA total number of subjects
    24
    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)
    55
    From 65 to 84 years
    36
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 The study population consisted of male and female patients with DME, who were 18 to 85 years of age at screening, and who were either treatment naive or experienced i.e. had been treated with anti VEGF therapy > 90 days before baseline.

    Pre-assignment period milestones
    Number of subjects started
    		 91
    Number of subjects completed
    		 91

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Investigator, Monitor, Subject, Carer, Data analyst, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 LKA651
    Arm description
    		 LKA651 5 mg Intravitreal injection, every 4 weeks for a total of 3 doses in the treatment phase
    Arm type
    		 Experimental

    Investigational medicinal product name
    LKA651
    Investigational medicinal product code
    LKA651
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravitreal use
    Dosage and administration details
    5 mg intravitreal injection, every 4 weeks for a total of 3 doses in the treatment phase

    Arm title
    		 LKA651 + Lucentis
    Arm description
    		 LKA651 1 mg + Lucentis 0.3 mg (U.S. sites) or 0.5 mg (ex U.S. sites) Intravitreal injection, every 4 weeks for a total of 3 doses in the treatment phase
    Arm type
    		 Experimental

    Investigational medicinal product name
    LKA651
    Investigational medicinal product code
    LKA651
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravitreal use
    Dosage and administration details
    LKA651 1 mg intravitreal injection, every 4 weeks for a total of 3 doses in the treatment phase

    Investigational medicinal product name
    50242-080-01
    Investigational medicinal product code
    50242-080-01
    Other name
    Ranibizumab
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravitreal use
    Dosage and administration details
    Lucentis 0.3 mg (U.S. sites) or 0.5 mg (ex U.S. sites) intravitreal injection, every 4 weeks for a total of 3 doses in the treatment phase

    Arm title
    		 Lucentis
    Arm description
    		 Lucentis 0.3 mg (U.S. sites) or 0.5 mg (ex U.S. sites) Intravitreal injection, every 4 weeks for a total of 3 doses in the treatment phase
    Arm type
    		 Active comparator

    Investigational medicinal product name
    50242-080-01
    Investigational medicinal product code
    50242-080-01
    Other name
    Ranibizumab
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravitreal use
    Dosage and administration details
    0.3 mg (U.S. sites) or 0.5 mg (ex U.S. sites) intravitreal injection, every 4 weeks for a total of 3 doses in the treatment phase

    Number of subjects in period 1
    		LKA651 LKA651 + Lucentis Lucentis
    Started
    28
    30
    33
    Completed
    21
    27
    31
    Not completed
    7
    3
    2
         Adverse event, serious fatal
    1
    -
    -
         Consent withdrawn by subject
    3
    1
    1
         Adverse event, non-fatal
    1
    -
    -
         Lost to follow-up
    2
    2
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    LKA651
    Reporting group description
    		 LKA651 5 mg Intravitreal injection, every 4 weeks for a total of 3 doses in the treatment phase

    Reporting group title
    LKA651 + Lucentis
    Reporting group description
    		 LKA651 1 mg + Lucentis 0.3 mg (U.S. sites) or 0.5 mg (ex U.S. sites) Intravitreal injection, every 4 weeks for a total of 3 doses in the treatment phase

    Reporting group title
    Lucentis
    Reporting group description
    		 Lucentis 0.3 mg (U.S. sites) or 0.5 mg (ex U.S. sites) Intravitreal injection, every 4 weeks for a total of 3 doses in the treatment phase

    Reporting group values
    		 LKA651 LKA651 + Lucentis Lucentis Total
    Number of subjects
    		 28 30 33 91
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0 0
        Newborns (0-27 days)
    		 0 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0 0
        Children (2-11 years)
    		 0 0 0 0
        Adolescents (12-17 years)
    		 0 0 0 0
        Adults (18-64 years)
    		 17 18 20 55
        From 65-84 years
    		 11 12 13 36
        85 years and over
    		 0 0 0 0
    Age Continuous
    Units: Years
        arithmetic mean (standard deviation)
    		 61.6 ± 8.58 63.8 ± 8.18 61.2 ± 9.02 -
    Sex: Female, Male
    Units: Participants
        Female
    		 9 13 10 32
        Male
    		 19 17 23 59
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    		 0 1 1 2
        Asian
    		 2 1 0 3
        Native Hawaiian or Other Pacific Islander
    		 0 1 0 1
        Black or African American
    		 3 0 0 3
        White
    		 23 27 32 82
        More than one race
    		 0 0 0 0
        Unknown or Not Reported
    		 0 0 0 0

    End points

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    End points reporting groups
    Reporting group title
    LKA651
    Reporting group description
    		 LKA651 5 mg Intravitreal injection, every 4 weeks for a total of 3 doses in the treatment phase

    Reporting group title
    LKA651 + Lucentis
    Reporting group description
    		 LKA651 1 mg + Lucentis 0.3 mg (U.S. sites) or 0.5 mg (ex U.S. sites) Intravitreal injection, every 4 weeks for a total of 3 doses in the treatment phase

    Reporting group title
    Lucentis
    Reporting group description
    		 Lucentis 0.3 mg (U.S. sites) or 0.5 mg (ex U.S. sites) Intravitreal injection, every 4 weeks for a total of 3 doses in the treatment phase

    Primary: Overall incidence of Adverse Events

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    End point title
    		 Overall incidence of Adverse Events [1]
    End point description
    Incidence of adverse events (AEs) is defined as number of participants with AEs, including changes from baseline in vital signs, electrocardiograms and laboratory results qualifying and reported as AEs. The severity of the AEs (mild, moderate, severe) was based on the Common Terminology Criteria for Adverse Events (CTCAE). Number of participants in each category is reported in the table. A participants who falls multiple times in one category is counted only once. Disc = discontinuation Trt = study treatment
    End point type
    Primary
    End point timeframe
    Adverse events are reported from first dose of study treatment until end of study treatment plus 12 weeks post treatment, up to a maximum timeframe of approximately 24 weeks (approximately 168 days).
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: not applicable for AE data
    End point values
    		 LKA651 LKA651 + Lucentis Lucentis
    Number of subjects analysed
    28
    30
    33
    Units: Participants
        AEs, Patients with AEs
    20
    16
    19
        AEs of mild intensity
    16
    15
    19
        AEs of moderate intensity
    8
    6
    3
        AEs of severe intensity
    4
    2
    1
        Study drug-related AEs
    2
    1
    2
        Serious AEs
    3
    4
    1
        AEs leading to disc. of study treatment
    1
    0
    0
        Study-drug related AEs leading to disc. of trt
    1
    0
    0
        Non-serious AEs
    20
    16
    19
    No statistical analyses for this end point

    Primary: Incidence of ocular Adverse Events by preferred term in study eye

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    End point title
    		 Incidence of ocular Adverse Events by preferred term in study eye [2]
    End point description
    An AE is any untoward medical occurrence (e.g., any unfavorable and unintended sign [including abnormal laboratory findings], symptom or disease) in a patient or clinical investigation patient.
    End point type
    Primary
    End point timeframe
    Adverse events are reported from first dose of study treatment until end of study treatment plus 12 weeks post treatment, up to a maximum timeframe of approximately 24 weeks (approximately 168 days).
    Notes
    [2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: not applicable for AE data
    End point values
    		 LKA651 LKA651 + Lucentis Lucentis
    Number of subjects analysed
    28
    30
    33
    Units: Participants
        Patients with at least one ocular AE in study eye
    11
    7
    9
        Conjunctival haemorrhage
    1
    4
    2
        Diabetic retinal oedema
    2
    1
    2
        Diabetic retinopathy
    1
    1
    1
        Visual acuity reduced
    3
    0
    0
        Vitreous haemorrhage
    1
    0
    2
        Dry eye
    0
    1
    1
        Macular oedema
    2
    0
    0
        Ocular hypertension
    2
    0
    0
        Abnormal sensation in eye
    0
    0
    1
        Anterior chamber flare
    0
    1
    0
        Corneal erosion
    1
    0
    0
        Cystoid macular oedema
    1
    0
    0
        Dacryostenosis acquired
    1
    0
    0
        Eye pain
    1
    0
    0
        Eyelids pruritus
    0
    0
    1
        Lenticular opacities
    0
    0
    1
        Punctate keratitis
    0
    1
    0
        Retinal cyst
    1
    0
    0
        Retinal detachment
    1
    0
    0
        Retinal exudates
    1
    0
    0
        Retinal haemorrhage
    1
    0
    0
        Vitreoretinal traction syndrome
    0
    0
    1
    No statistical analyses for this end point

    Primary: Number of participants with non-ocular Adverse Events (>=2%)

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    End point title
    		 Number of participants with non-ocular Adverse Events (>=2%) [3]
    End point description
    An AE is any untoward medical occurrence (e.g., any unfavorable and unintended sign [including abnormal laboratory findings], symptom or disease) in a patient or clinical investigation patient.
    End point type
    Primary
    End point timeframe
    Adverse events are reported from first dose of study treatment until end of study treatment plus 12 weeks post treatment, up to a maximum timeframe of approximately 24 weeks (approximately 168 days).
    Notes
    [3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: not applicable for AE data
    End point values
    		 LKA651 LKA651 + Lucentis Lucentis
    Number of subjects analysed
    28
    30
    33
    Units: Participants
    16
    15
    14
    No statistical analyses for this end point

    Primary: Intraocular pressure (IOP) in study eye

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    End point title
    		 Intraocular pressure (IOP) in study eye [4]
    End point description
    Intraocular pressure was measured per the study site’s regular practice.
    End point type
    Primary
    End point timeframe
    Screening, and Day 85
    Notes
    [4] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: summary statistics provided in lieu of statistical analysis
    End point values
    		 LKA651 LKA651 + Lucentis Lucentis
    Number of subjects analysed
    28
    30
    33
    Units: mmHg
    arithmetic mean (standard deviation)
        Screening
    15.1 ± 3.20
    14.9 ± 3.44
    15.5 ± 2.88
        Day 85 (n=24,28,31)
    15.5 ± 3.56
    15.6 ± 3.67
    15.2 ± 3.79
    No statistical analyses for this end point

    Primary: Best Corrected Visual Acuity (BCVA) by Early Treatment Diabetic Retinopathy Study (ETDRS) visual acuity charts in study eye

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    End point title
    		 Best Corrected Visual Acuity (BCVA) by Early Treatment Diabetic Retinopathy Study (ETDRS) visual acuity charts in study eye
    End point description
    BCVA was assessed using Early Treatment Diabetic Retinopathy Study (ETDRS) visual acuity testing charts. Visual function of the study eye was assessed using the ETDRS protocol. BCVA in study eye was analyzed with a mixed model for repeated measures. The model included treatment, visit, and the treatment by visit interaction as independent variables. An unstructured residual covariance structure was used. Baseline BCVA value and treatment naïve and treatment experienced variable were used as covariates. Min and max possible scores are 0-100 respectively. A higher score represents better visual functioning.
    End point type
    Primary
    End point timeframe
    Days 2, 8, 15, 29, 43, 57, and 85
    End point values
    		 LKA651 LKA651 + Lucentis Lucentis
    Number of subjects analysed
    28
    30
    33
    Units: Scores on a scale
    arithmetic mean (confidence interval 90%)
        Day 2 (n=6,17,10)
    61.5 (58.6 to 64.4)
    64.4 (62.3 to 66.6)
    64.1 (61.8 to 66.5)
        Day 8 (n=6,16,10)
    65.2 (61.7 to 68.7)
    68.6 (66.1 to 71.2)
    66.2 (63.4 to 69.0)
        Day 15 (n=6,16,10)
    65.9 (62.4 to 69.4)
    68.6 (65.8 to 71.4)
    68.4 (65.4 to 71.3)
        Day 29 (n=25,28,32)
    65.5 (62.6 to 68.4)
    68.2 (65.3 to 71.0)
    68.5 (65.9 to 71.1)
        Day 43 (n=5,16,8)
    67.8 (64.4 to 71.1)
    70.4 (67.6 to 73.3)
    69.1 (66.2 to 71.9)
        Day 57 (n=24,27,31)
    67.6 (64.7 to 70.5)
    71.5 (68.6 to 74.4)
    70.0 (67.4 to 72.6)
        Day 85 (n=23,27,31)
    67.8 (64.8 to 70.9)
    72.5 (69.5 to 75.4)
    70.5 (67.8 to 73.2)
    Statistical analysis title
    		 LKA651 v Lucentis
    Statistical analysis description
    Day 2
    Comparison groups
    LKA651 v Lucentis
    Number of subjects included in analysis
    61
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.887
    Method
    		 Mixed model repeated measures analysis
    Parameter type
    		 Difference (Test vs Reference)
    Point estimate
    -2.6
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 -6.2
         upper limit
    		 1
    Statistical analysis title
    		 LKA651 + Lucentis v Lucentis
    Statistical analysis description
    Day 2
    Comparison groups
    LKA651 + Lucentis v Lucentis
    Number of subjects included in analysis
    63
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.431
    Method
    		 Mixed model repeated measures analysis
    Parameter type
    		 Difference (Test vs Reference)
    Point estimate
    0.3
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 -2.6
         upper limit
    		 3.2
    Statistical analysis title
    		 LKA651 v Lucentis
    Statistical analysis description
    Day 8
    Comparison groups
    LKA651 v Lucentis
    Number of subjects included in analysis
    61
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.647
    Method
    		 Mixed model repeated measures analysis
    Parameter type
    		 Difference (Test vs Reference)
    Point estimate
    -1
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 -5.4
         upper limit
    		 3.4
    Statistical analysis title
    		 LKA651 + Lucentis v Lucentis
    Statistical analysis description
    Day 8
    Comparison groups
    LKA651 + Lucentis v Lucentis
    Number of subjects included in analysis
    63
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.13
    Method
    		 Mixed model repeated measures analysis
    Parameter type
    		 Difference (Test vs Reference)
    Point estimate
    2.4
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 -1.1
         upper limit
    		 6
    Statistical analysis title
    		 LKA651 v Lucentis
    Statistical analysis description
    Day 15
    Comparison groups
    LKA651 v Lucentis
    Number of subjects included in analysis
    61
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.818
    Method
    		 Mixed model repeated measures analysis
    Parameter type
    		 Difference (Test vs Reference)
    Point estimate
    -2.5
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 -6.9
         upper limit
    		 2
    Statistical analysis title
    		 LKA651 + Lucentis v Lucentis
    Statistical analysis description
    Day 15
    Comparison groups
    LKA651 + Lucentis v Lucentis
    Number of subjects included in analysis
    63
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.457
    Method
    		 Mixed model repeated measures analysis
    Parameter type
    		 Difference (Test vs Reference)
    Point estimate
    0.3
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 -3.6
         upper limit
    		 4.1
    Statistical analysis title
    		 LKA651 v Lucentis
    Statistical analysis description
    Day 29
    Comparison groups
    LKA651 v Lucentis
    Number of subjects included in analysis
    61
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.906
    Method
    		 Mixed model repeated measures analysis
    Parameter type
    		 Difference (Test vs Reference)
    Point estimate
    -3.1
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 -6.9
         upper limit
    		 0.8
    Statistical analysis title
    		 LKA651 + Lucentis v Lucentis
    Statistical analysis description
    Day 29
    Comparison groups
    LKA651 + Lucentis v Lucentis
    Number of subjects included in analysis
    63
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.566
    Method
    		 Mixed model repeated measures analysis
    Parameter type
    		 Difference (Test vs Reference)
    Point estimate
    -0.4
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 -4.1
         upper limit
    		 3.3
    Statistical analysis title
    		 LKA651 v Lucentis
    Statistical analysis description
    Day 43
    Comparison groups
    LKA651 v Lucentis
    Number of subjects included in analysis
    61
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.686
    Method
    		 Mixed model repeated measures analysis
    Parameter type
    		 Difference (Test vs Reference)
    Point estimate
    -1.3
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 -5.6
         upper limit
    		 3.1
    Statistical analysis title
    		 LKA651 + Lucentis v Lucentis
    Statistical analysis description
    Day 43
    Comparison groups
    LKA651 + Lucentis v Lucentis
    Number of subjects included in analysis
    63
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.28
    Method
    		 Mixed model repeated measures analysis
    Parameter type
    		 Difference (Test vs Reference)
    Point estimate
    1.4
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 -2.5
         upper limit
    		 5.2
    Statistical analysis title
    		 LKA651 v Lucentis
    Statistical analysis description
    Day 57
    Comparison groups
    LKA651 v Lucentis
    Number of subjects included in analysis
    61
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.849
    Method
    		 Mixed model repeated measures analysis
    Parameter type
    		 Difference (Test vs Reference)
    Point estimate
    -2.4
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 -6.3
         upper limit
    		 1.4
    Statistical analysis title
    		 LKA651 + Lucentis v Lucentis
    Statistical analysis description
    Day 57
    Comparison groups
    LKA651 + Lucentis v Lucentis
    Number of subjects included in analysis
    63
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.254
    Method
    		 Mixed model repeated measures analysis
    Parameter type
    		 Difference (Test vs Reference)
    Point estimate
    1.5
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 -2.2
         upper limit
    		 5.2
    Statistical analysis title
    		 LKA651 v Lucentis
    Statistical analysis description
    Day 85
    Comparison groups
    LKA651 v Lucentis
    Number of subjects included in analysis
    61
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.866
    Method
    		 Mixed model repeated measures analysis
    Parameter type
    		 Difference (Test vs Reference)
    Point estimate
    -2.7
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 -6.6
         upper limit
    		 1.3
    Statistical analysis title
    		 LKA651 + Lucentis v Lucentis
    Statistical analysis description
    Day 85
    Comparison groups
    LKA651 + Lucentis v Lucentis
    Number of subjects included in analysis
    63
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.198
    Method
    		 Mixed model repeated measures analysis
    Parameter type
    		 Difference (Test vs Reference)
    Point estimate
    2
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 -1.9
         upper limit
    		 5.8

    Primary: Inner Macular Thickness (inferior)

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    End point title
    		 Inner Macular Thickness (inferior) [5]
    End point description
    Macular thickness was measured by spectral domain optical coherence tomography (SD-OCT).
    End point type
    Primary
    End point timeframe
    Week 12 (Day 85)
    Notes
    [5] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: summary statistics provided in lieu of statistical analysis
    End point values
    		 LKA651 LKA651 + Lucentis Lucentis
    Number of subjects analysed
    24
    28
    31
    Units: micrometer
        arithmetic mean (standard deviation)
    503.06 ± 137.235
    400.82 ± 53.180
    390.48 ± 48.097
    No statistical analyses for this end point

    Primary: Inner Macular Thickness (temporal)

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    End point title
    		 Inner Macular Thickness (temporal) [6]
    End point description
    Macular thickness was measured by spectral domain optical coherence tomography (SD-OCT).
    End point type
    Primary
    End point timeframe
    Week 12 (Day 85)
    Notes
    [6] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: summary statistics provided in lieu of statistical analysis
    End point values
    		 LKA651 LKA651 + Lucentis Lucentis
    Number of subjects analysed
    24
    28
    31
    Units: micrometer
        arithmetic mean (standard deviation)
    505.27 ± 141.410
    414.64 ± 67.032
    404.93 ± 56.099
    No statistical analyses for this end point

    Primary: Outer Macular Thickness (inferior)

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    End point title
    		 Outer Macular Thickness (inferior) [7]
    End point description
    Macular thickness was measured by spectral domain optical coherence tomography (SD-OCT).
    End point type
    Primary
    End point timeframe
    Week 12 (Day 85)
    Notes
    [7] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: summary statistics provided in lieu of statistical analysis
    End point values
    		 LKA651 LKA651 + Lucentis Lucentis
    Number of subjects analysed
    23
    28
    31
    Units: micrometer
        arithmetic mean (standard deviation)
    388.66 ± 88.128
    349.39 ± 44.538
    342.88 ± 50.612
    No statistical analyses for this end point

    Primary: Outer Macular Thickness (temporal)

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    End point title
    		 Outer Macular Thickness (temporal) [8]
    End point description
    Macular thickness was measured by spectral domain optical coherence tomography (SD-OCT).
    End point type
    Primary
    End point timeframe
    Week 12 (Day 85)
    Notes
    [8] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: summary statistics provided in lieu of statistical analysis
    End point values
    		 LKA651 LKA651 + Lucentis Lucentis
    Number of subjects analysed
    23
    28
    31
    Units: micrometer
        arithmetic mean (standard deviation)
    404.60 ± 103.616
    371.83 ± 70.124
    352.24 ± 56.793
    No statistical analyses for this end point

    Primary: Number of participants without changes in foveal avascular zone as measured by Fluorescein angiography (FA) in study eye

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    End point title
    		 Number of participants without changes in foveal avascular zone as measured by Fluorescein angiography (FA) in study eye [9]
    End point description
    Foveal avascular zone was assessed by fluorescein angiography (FA). EoS = End of Study
    End point type
    Primary
    End point timeframe
    Days 29, 57, 85, End of Study (Up to Day 140)
    Notes
    [9] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: summary statistics provided in lieu of statistical analysis
    End point values
    		 LKA651 LKA651 + Lucentis Lucentis
    Number of subjects analysed
    21
    25
    30
    Units: Participants
        Day 29 - NO CHANGE (n=3,16,11)
    3
    16
    11
        Day 57 - NO CHANGE (n=3,16,7)
    3
    16
    7
        Day 85 - NO CHANGE (n=21,25,29)
    21
    25
    29
        EoS (Up to Day 140) NO CHANGE (n=17,23,30)
    17
    22
    30
        EoS (Up to Day 140) CANNOT GRADE (n=0,23,0)
    999
    1
    999
    No statistical analyses for this end point

    Primary: Mixed model repeated measures analysis of ratio to baseline in central subfield retinal thickness (CSFT) in the study eye

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    End point title
    		 Mixed model repeated measures analysis of ratio to baseline in central subfield retinal thickness (CSFT) in the study eye
    End point description
    Central subfield thickness was measured by spectral domain optical coherence tomography (SD-OCT). Central subfield retinal thickness was analyzed with a mixed model for repeated measures. The model included treatment, visit, and the treatment by visit interaction as independent variables. An unstructured residual covariance structure was used. Log-transformed baseline central subfield retinal thickness and treatment naïve and treatment experienced variable were used as covariates. Results were back‑transformed to show results as a ratio to baseline.
    End point type
    Primary
    End point timeframe
    Days 8, 15, 29, 43, 57, 85
    End point values
    		 LKA651 LKA651 + Lucentis Lucentis
    Number of subjects analysed
    25
    28
    32
    Units: µm
    geometric mean (confidence interval 90%)
        Day 8 (n=6,16,10)
    0.99 (0.92 to 1.07)
    0.83 (0.78 to 0.88)
    0.83 (0.78 to 0.88)
        Day 15 (n=6,16,10)
    0.97 (0.90 to 1.05)
    0.83 (0.78 to 0.88)
    0.80 (0.76 to 0.86)
        Day 29 (n=25,28,32)
    1.00 (0.94 to 1.05)
    0.80 (0.76 to 0.85)
    0.82 (0.78 to 0.86)
        Day 43 (n=5,16,8)
    1.04 (0.97 to 1.13)
    0.76 (0.71 to 0.81)
    0.79 (0.74 to 0.84)
        Day 57 (n=24,27,30)
    0.95 (0.89 to 1.00)
    0.75 (0.70 to 0.80)
    0.80 (0.76 to 0.84)
        Day 85 (n=23,27,31)
    0.97 (0.91 to 1.05)
    0.75 (0.70 to 0.80)
    0.78 (0.73 to 0.83)
    Statistical analysis title
    		 LKA651 v Lucentis
    Statistical analysis description
    Day 8
    Comparison groups
    LKA651 v Lucentis
    Number of subjects included in analysis
    57
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.998
    Method
    		 Mixed model repeated measures analysis
    Parameter type
    		 Difference (Test vs Reference)
    Point estimate
    1.2
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 1.08
         upper limit
    		 1.33
    Statistical analysis title
    		 LKA651 + Lucentis v Lucentis
    Statistical analysis description
    Day 8
    Comparison groups
    LKA651 + Lucentis v Lucentis
    Number of subjects included in analysis
    60
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.527
    Method
    		 Mixed model repeated measures analysis
    Parameter type
    		 Difference (Test vs Reference)
    Point estimate
    1
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0.92
         upper limit
    		 1.09
    Statistical analysis title
    		 LKA651 v Lucentis
    Statistical analysis description
    Day 15
    Comparison groups
    LKA651 v Lucentis
    Number of subjects included in analysis
    57
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.999
    Method
    		 Mixed model repeated measures analysis
    Parameter type
    		 Difference (Test vs Reference)
    Point estimate
    1.21
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 1.1
         upper limit
    		 1.33
    Statistical analysis title
    		 LKA651 + Lucentis v Lucentis
    Statistical analysis description
    Day 15
    Comparison groups
    LKA651 + Lucentis v Lucentis
    Number of subjects included in analysis
    60
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.716
    Method
    		 Mixed model repeated measures analysis
    Parameter type
    		 Difference (Test vs Reference)
    Point estimate
    1.03
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0.95
         upper limit
    		 1.12
    Statistical analysis title
    		 LKA651 v Lucentis
    Statistical analysis description
    Day 29
    Comparison groups
    LKA651 v Lucentis
    Number of subjects included in analysis
    57
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 1
    Method
    		 Mixed model repeated measures analysis
    Parameter type
    		 Difference (Test vs Reference)
    Point estimate
    1.21
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 1.13
         upper limit
    		 1.31
    Statistical analysis title
    		 LKA651 + Lucentis v Lucentis
    Statistical analysis description
    Day 29
    Comparison groups
    LKA651 + Lucentis v Lucentis
    Number of subjects included in analysis
    60
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.281
    Method
    		 Mixed model repeated measures analysis
    Parameter type
    		 Difference (Test vs Reference)
    Point estimate
    0.98
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0.91
         upper limit
    		 1.05
    Statistical analysis title
    		 LKA651 + Lucentis v Lucentis
    Statistical analysis description
    Day 43
    Comparison groups
    LKA651 + Lucentis v Lucentis
    Number of subjects included in analysis
    60
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.2
    Method
    		 Mixed model repeated measures analysis
    Parameter type
    		 Difference (Test vs Reference)
    Point estimate
    0.96
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0.88
         upper limit
    		 1.04
    Statistical analysis title
    		 LKA651 v Lucentis
    Statistical analysis description
    Day 43
    Comparison groups
    LKA651 v Lucentis
    Number of subjects included in analysis
    57
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 1
    Method
    		 Mixed model repeated measures analysis
    Parameter type
    		 Difference (Test vs Reference)
    Point estimate
    1.32
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 1.2
         upper limit
    		 1.46
    Statistical analysis title
    		 LKA651 v Lucentis
    Statistical analysis description
    Day 57
    Comparison groups
    LKA651 v Lucentis
    Number of subjects included in analysis
    57
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 1
    Method
    		 Mixed model repeated measures analysis
    Parameter type
    		 Difference (Test vs Reference)
    Point estimate
    1.18
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 1.09
         upper limit
    		 1.28
    Statistical analysis title
    		 LKA651 v Lucentis
    Statistical analysis description
    Day 85
    Comparison groups
    LKA651 v Lucentis
    Number of subjects included in analysis
    57
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 1
    Method
    		 Mixed model repeated measures analysis
    Parameter type
    		 Difference (Test vs Reference)
    Point estimate
    1.26
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 1.14
         upper limit
    		 1.38
    Statistical analysis title
    		 LKA651 + Lucentis v Lucentis
    Statistical analysis description
    Day 57
    Comparison groups
    LKA651 + Lucentis v Lucentis
    Number of subjects included in analysis
    60
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.083
    Method
    		 Mixed model repeated measures analysis
    Parameter type
    		 Difference (Test vs Reference)
    Point estimate
    0.94
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0.87
         upper limit
    		 1.01
    Statistical analysis title
    		 LKA651 + Lucentis v Lucentis
    Statistical analysis description
    Day 85
    Comparison groups
    LKA651 + Lucentis v Lucentis
    Number of subjects included in analysis
    60
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.254
    Method
    		 Mixed model repeated measures analysis
    Parameter type
    		 Difference (Test vs Reference)
    Point estimate
    0.96
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0.88
         upper limit
    		 1.06

    Secondary: Number of participants who needed retreatment with anti-VEGF in study eye after week 12

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    End point title
    		 Number of participants who needed retreatment with anti-VEGF in study eye after week 12
    End point description
    End point type
    Secondary
    End point timeframe
    Week 12 (Day 85) up to Day 140
    End point values
    		 LKA651 LKA651 + Lucentis Lucentis
    Number of subjects analysed
    25
    29
    32
    Units: Participants
    16
    16
    21
    No statistical analyses for this end point

    Secondary: Time to retreatment in study eye with anti-VEGF after week 12

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    End point title
    		 Time to retreatment in study eye with anti-VEGF after week 12
    End point description
    Time to retreatment with anti VEGF (as determined by the investigator) after Week 12 during the additional 12 week extension phase (that was up to 16 weeks after the last dose) was examined with a Kaplan Meier plot.
    End point type
    Secondary
    End point timeframe
    Week 12 (Day 85) up to Day 140
    End point values
    		 LKA651 LKA651 + Lucentis Lucentis
    Number of subjects analysed
    25
    29
    32
    Units: Days after Day 85 (Week 12)
        median (confidence interval 95%)
    55.0 (17.0 to 999)
    34.0 (12.0 to 999)
    31.0 (9.0 to 109.0)
    No statistical analyses for this end point

    Secondary: Summary statistics of Pharmacokinetics - serum concentrations of LKA651

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    End point title
    		 Summary statistics of Pharmacokinetics - serum concentrations of LKA651
    End point description
    PK parameters were determined using non-compartmental methods using the most recent version of WinNonlin Phoenix (Version 8.2). Concentrations below the lower limit of quantification (LLOQ) were treated as 1/2 LLOQ in summary statistics.
    End point type
    Secondary
    End point timeframe
    Day 1 - 4 hrs post dose, Day 2, Day 8, Day 15, Day 29 - 4 hrs post dose, Day 43, Day 57 - 4 hrs post dose, Day 85
    End point values
    		 LKA651 LKA651 + Lucentis Lucentis
    Number of subjects analysed
    19
    23
    0 [10]
    Units: ng/mL
    arithmetic mean (standard deviation)
        Day 1 - 4 hrs post dose (n = 6,15,0)
    114 ± 211
    4.43 ± 17.1
    ±
        Day 2 (n=6,15,0)
    36.3 ± 29.2
    8.13 ± 21.6
    ±
        Day 8 (n=6,15,0)
    16.2 ± 27.5
    2.08 ± 8.06
    ±
        Day 15 (n=5,15,0)
    7.24 ± 16.2
    0.00 ± 0.00
    ±
        Day 29 - 4 hrs post dose (n=0,6,0)
    999 ± 999
    7.60 ± 18.6
    ±
        Day 43 (n=1,6,0)
    0.00 ± 0.00
    0.00 ± 0.00
    ±
        Day 57 - 4 hrs post dose (n=0,6,0)
    999 ± 999
    0.00 ± 0.00
    ±
        Day 85 (n=19,23,0)
    0.00 ± 0.00
    0.00 ± 0.00
    ±
    Notes
    [10] - Serum concentrations of LKA651 do not apply to the Lucentis arm
    No statistical analyses for this end point

    Secondary: Summary statistics of Pharmacokinetics - AUC0-28d of LKA651 (serum)

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    End point title
    		 Summary statistics of Pharmacokinetics - AUC0-28d of LKA651 (serum)
    End point description
    Area under the curve over the dosing interval 0 to 28 days.
    End point type
    Secondary
    End point timeframe
    Day 1 - 4 hrs post dose, Day 2, Day 8, Day 15, Day 29 - 4 hrs post dose, Day 43, Day 57 - 4 hrs post dose, Day 85
    End point values
    		 LKA651 LKA651 + Lucentis Lucentis
    Number of subjects analysed
    0 [11]
    0 [12]
    0 [13]
    Units: h*ng/mL
        arithmetic mean (standard deviation)
    ±
    ±
    ±
    Notes
    [11] - Could not be derived b/c of limited number of LKA651 concentrations above the LLoQ
    [12] - Could not be derived b/c of limited number of LKA651 concentrations above the LLoQ
    [13] - Could not be derived b/c of limited number of LKA651 concentrations above the LLoQ.
    No statistical analyses for this end point

    Secondary: Summary statistics of Pharmacokinetics - serum concentrations of Lucentis

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    End point title
    		 Summary statistics of Pharmacokinetics - serum concentrations of Lucentis
    End point description
    End point type
    Secondary
    End point timeframe
    Day 1 - 4 hrs post dose, Day 2, Day 8, Day 15, Day 29 - 4 hrs post dose, Day 43, Day 57 - 4 hrs post dose, Day 85
    End point values
    		 LKA651 LKA651 + Lucentis Lucentis
    Number of subjects analysed
    0 [14]
    0 [15]
    0 [16]
    Units: ng/mL
        arithmetic mean (standard deviation)
    ±
    ±
    ±
    Notes
    [14] - Could not be derived b/c of limited number of Lucentis concentrations above the LLoQ
    [15] - Could not be derived b/c of limited number of Lucentis concentrations above the LLoQ
    [16] - Could not be derived b/c of limited number of Lucentis concentrations above the LLoQ
    No statistical analyses for this end point

    Secondary: Summary statistics of Pharmacokinetics - AUC0-28d of Lucentis (serum)

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    End point title
    		 Summary statistics of Pharmacokinetics - AUC0-28d of Lucentis (serum)
    End point description
    Area under the curve over the dosing interval 0 to 28 days.
    End point type
    Secondary
    End point timeframe
    Day 1 - 4 hrs post dose, Day 2, Day 8, Day 15, Day 29 - 4 hrs post dose, Day 43, Day 57 - 4 hrs post dose, Day 85
    End point values
    		 LKA651 LKA651 + Lucentis Lucentis
    Number of subjects analysed
    0 [17]
    0 [18]
    0 [19]
    Units: h*ng/mL
        arithmetic mean (standard deviation)
    ±
    ±
    ±
    Notes
    [17] - Could not be derived b/c of limited number of Lucentis concentrations above the LLoQ
    [18] - Could not be derived b/c of limited number of Lucentis concentrations above the LLoQ
    [19] - Could not be derived b/c of limited number of Lucentis concentrations above the LLoQ
    No statistical analyses for this end point

    Post-hoc: All Collected Deaths

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    End point title
    		 All Collected Deaths
    End point description
    On-treatment deaths are reported from first dose of study treatment until end of study treatment plus 12 weeks post treatment, up to a maximum timeframe of approximately 24 weeks (approximately 168 days). Post-treatment deaths are reported for the timeframe of greater than 30 days after last treatment, until study completion, up to Day 169. All deaths refer to the sum of on-treatment and post-treatment deaths.
    End point type
    Post-hoc
    End point timeframe
    On-treatment – up to 12 weeks; Post-treatment - greater than 30 days after last treatment, until study completion, up to Day 169
    End point values
    		 LKA651 LKA651 + Lucentis Lucentis
    Number of subjects analysed
    28
    30
    33
    Units: Participants
        On-Treatment Deaths
    0
    0
    0
        Post-Treatment Deaths
    1
    0
    0
        All Deaths
    1
    0
    0
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events are reported from first dose of study treatment until end of study treatment plus 12 weeks post treatment, up to a maximum timeframe of approximately 24 weeks (approximately 168 days).
    Adverse event reporting additional description
    Consistent with EudraCT disclosure specifications, Novartis has reported under the Serious adverse events field “number of deaths resulting from adverse events” all those deaths, resulting from serious adverse events that are deemed to be causally related to treatment by the investigator.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    25.0
    Reporting groups
    Reporting group title
    LKA651
    Reporting group description
    		 LKA651 5 mg Intravitreal injection, every 4 weeks for a total of 3 doses in the treatment phase

    Reporting group title
    Lucentis
    Reporting group description
    		 Lucentis 0.3 mg (U.S. sites) or 0.5 mg (ex U.S. sites) Intravitreal injection, every 4 weeks for a total of 3 doses in the treatment phase

    Reporting group title
    Total
    Reporting group description
    		 Total

    Reporting group title
    LKA651 + Lucentis Combo
    Reporting group description
    		 LKA651 1 mg + Lucentis 0.3 mg (U.S. sites) or 0.5 mg (ex U.S. sites) Intravitreal injection, every 4 weeks for a total of 3 doses in the treatment phase

    Serious adverse events
    		 LKA651 Lucentis Total LKA651 + Lucentis Combo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    3 / 28 (10.71%)
    1 / 33 (3.03%)
    8 / 91 (8.79%)
    4 / 30 (13.33%)
         number of deaths (all causes)
    1
    0
    1
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Bone cancer metastatic
         subjects affected / exposed
    0 / 28 (0.00%)
    0 / 33 (0.00%)
    1 / 91 (1.10%)
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Prostate cancer metastatic
         subjects affected / exposed
    0 / 28 (0.00%)
    0 / 33 (0.00%)
    1 / 91 (1.10%)
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Angina unstable
         subjects affected / exposed
    0 / 28 (0.00%)
    0 / 33 (0.00%)
    1 / 91 (1.10%)
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Haemorrhagic stroke
         subjects affected / exposed
    1 / 28 (3.57%)
    0 / 33 (0.00%)
    1 / 91 (1.10%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    Eye disorders
    Retinal detachment
         subjects affected / exposed
    1 / 28 (3.57%)
    0 / 33 (0.00%)
    1 / 91 (1.10%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Cyclic vomiting syndrome
         subjects affected / exposed
    0 / 28 (0.00%)
    0 / 33 (0.00%)
    1 / 91 (1.10%)
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Varices oesophageal
         subjects affected / exposed
    0 / 28 (0.00%)
    0 / 33 (0.00%)
    1 / 91 (1.10%)
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Confusional state
         subjects affected / exposed
    0 / 28 (0.00%)
    0 / 33 (0.00%)
    1 / 91 (1.10%)
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    COVID-19
         subjects affected / exposed
    0 / 28 (0.00%)
    1 / 33 (3.03%)
    1 / 91 (1.10%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    0 / 28 (0.00%)
    1 / 33 (3.03%)
    1 / 91 (1.10%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    COVID-19 pneumonia
         subjects affected / exposed
    1 / 28 (3.57%)
    0 / 33 (0.00%)
    1 / 91 (1.10%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    0 / 28 (0.00%)
    0 / 33 (0.00%)
    1 / 91 (1.10%)
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 LKA651 Lucentis Total LKA651 + Lucentis Combo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    20 / 28 (71.43%)
    19 / 33 (57.58%)
    55 / 91 (60.44%)
    16 / 30 (53.33%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    3 / 28 (10.71%)
    3 / 33 (9.09%)
    7 / 91 (7.69%)
    1 / 30 (3.33%)
         occurrences all number
    3
    4
    8
    1
    Essential hypertension
         subjects affected / exposed
    0 / 28 (0.00%)
    1 / 33 (3.03%)
    1 / 91 (1.10%)
    0 / 30 (0.00%)
         occurrences all number
    0
    1
    1
    0
    Reproductive system and breast disorders
    Benign prostatic hyperplasia
         subjects affected / exposed
    0 / 28 (0.00%)
    0 / 33 (0.00%)
    1 / 91 (1.10%)
    1 / 30 (3.33%)
         occurrences all number
    0
    0
    1
    1
    Respiratory, thoracic and mediastinal disorders
    Hypoxia
         subjects affected / exposed
    0 / 28 (0.00%)
    1 / 33 (3.03%)
    1 / 91 (1.10%)
    0 / 30 (0.00%)
         occurrences all number
    0
    1
    1
    0
    Epistaxis
         subjects affected / exposed
    0 / 28 (0.00%)
    1 / 33 (3.03%)
    1 / 91 (1.10%)
    0 / 30 (0.00%)
         occurrences all number
    0
    1
    1
    0
    Acute respiratory failure
         subjects affected / exposed
    1 / 28 (3.57%)
    0 / 33 (0.00%)
    1 / 91 (1.10%)
    0 / 30 (0.00%)
         occurrences all number
    1
    0
    1
    0
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    0 / 28 (0.00%)
    1 / 33 (3.03%)
    1 / 91 (1.10%)
    0 / 30 (0.00%)
         occurrences all number
    0
    1
    1
    0
    Investigations
    Blood creatinine increased
         subjects affected / exposed
    2 / 28 (7.14%)
    0 / 33 (0.00%)
    2 / 91 (2.20%)
    0 / 30 (0.00%)
         occurrences all number
    2
    0
    2
    0
    Blood creatine phosphokinase increased
         subjects affected / exposed
    1 / 28 (3.57%)
    0 / 33 (0.00%)
    1 / 91 (1.10%)
    0 / 30 (0.00%)
         occurrences all number
    1
    0
    1
    0
    Blood cholesterol increased
         subjects affected / exposed
    0 / 28 (0.00%)
    0 / 33 (0.00%)
    1 / 91 (1.10%)
    1 / 30 (3.33%)
         occurrences all number
    0
    0
    1
    1
    Blood triglycerides increased
         subjects affected / exposed
    1 / 28 (3.57%)
    1 / 33 (3.03%)
    2 / 91 (2.20%)
    0 / 30 (0.00%)
         occurrences all number
    1
    1
    2
    0
    Blood urea increased
         subjects affected / exposed
    1 / 28 (3.57%)
    0 / 33 (0.00%)
    1 / 91 (1.10%)
    0 / 30 (0.00%)
         occurrences all number
    1
    0
    1
    0
    Blood glucose increased
         subjects affected / exposed
    1 / 28 (3.57%)
    0 / 33 (0.00%)
    2 / 91 (2.20%)
    1 / 30 (3.33%)
         occurrences all number
    1
    0
    2
    1
    Pancreatic enzymes increased
         subjects affected / exposed
    1 / 28 (3.57%)
    0 / 33 (0.00%)
    1 / 91 (1.10%)
    0 / 30 (0.00%)
         occurrences all number
    1
    0
    1
    0
    Lipase increased
         subjects affected / exposed
    1 / 28 (3.57%)
    0 / 33 (0.00%)
    1 / 91 (1.10%)
    0 / 30 (0.00%)
         occurrences all number
    1
    0
    1
    0
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    0 / 28 (0.00%)
    1 / 33 (3.03%)
    1 / 91 (1.10%)
    0 / 30 (0.00%)
         occurrences all number
    0
    1
    1
    0
    Glycosylated haemoglobin increased
         subjects affected / exposed
    0 / 28 (0.00%)
    0 / 33 (0.00%)
    1 / 91 (1.10%)
    1 / 30 (3.33%)
         occurrences all number
    0
    0
    1
    1
    Intraocular pressure increased
         subjects affected / exposed
    1 / 28 (3.57%)
    0 / 33 (0.00%)
    2 / 91 (2.20%)
    1 / 30 (3.33%)
         occurrences all number
    1
    0
    3
    2
    Lymphocyte count decreased
         subjects affected / exposed
    0 / 28 (0.00%)
    0 / 33 (0.00%)
    1 / 91 (1.10%)
    1 / 30 (3.33%)
         occurrences all number
    0
    0
    1
    1
    Urine ketone body present
         subjects affected / exposed
    1 / 28 (3.57%)
    0 / 33 (0.00%)
    1 / 91 (1.10%)
    0 / 30 (0.00%)
         occurrences all number
    1
    0
    1
    0
    SARS-CoV-2 test positive
         subjects affected / exposed
    1 / 28 (3.57%)
    0 / 33 (0.00%)
    2 / 91 (2.20%)
    1 / 30 (3.33%)
         occurrences all number
    1
    0
    2
    1
    Prostatic specific antigen increased
         subjects affected / exposed
    0 / 28 (0.00%)
    0 / 33 (0.00%)
    1 / 91 (1.10%)
    1 / 30 (3.33%)
         occurrences all number
    0
    0
    1
    1
    Urine leukocyte esterase positive
         subjects affected / exposed
    1 / 28 (3.57%)
    0 / 33 (0.00%)
    1 / 91 (1.10%)
    0 / 30 (0.00%)
         occurrences all number
    1
    0
    1
    0
    Injury, poisoning and procedural complications
    XIIth nerve injury
         subjects affected / exposed
    1 / 28 (3.57%)
    0 / 33 (0.00%)
    1 / 91 (1.10%)
    0 / 30 (0.00%)
         occurrences all number
    1
    0
    1
    0
    Thoracic vertebral fracture
         subjects affected / exposed
    0 / 28 (0.00%)
    0 / 33 (0.00%)
    1 / 91 (1.10%)
    1 / 30 (3.33%)
         occurrences all number
    0
    0
    1
    1
    Skin laceration
         subjects affected / exposed
    0 / 28 (0.00%)
    0 / 33 (0.00%)
    1 / 91 (1.10%)
    1 / 30 (3.33%)
         occurrences all number
    0
    0
    1
    1
    Foot fracture
         subjects affected / exposed
    0 / 28 (0.00%)
    1 / 33 (3.03%)
    1 / 91 (1.10%)
    0 / 30 (0.00%)
         occurrences all number
    0
    1
    1
    0
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    1 / 28 (3.57%)
    0 / 33 (0.00%)
    1 / 91 (1.10%)
    0 / 30 (0.00%)
         occurrences all number
    1
    0
    1
    0
    Coronary artery disease
         subjects affected / exposed
    0 / 28 (0.00%)
    1 / 33 (3.03%)
    1 / 91 (1.10%)
    0 / 30 (0.00%)
         occurrences all number
    0
    1
    1
    0
    Atrioventricular block first degree
         subjects affected / exposed
    0 / 28 (0.00%)
    0 / 33 (0.00%)
    1 / 91 (1.10%)
    1 / 30 (3.33%)
         occurrences all number
    0
    0
    1
    1
    Tachycardia
         subjects affected / exposed
    0 / 28 (0.00%)
    1 / 33 (3.03%)
    1 / 91 (1.10%)
    0 / 30 (0.00%)
         occurrences all number
    0
    1
    1
    0
    Sinus bradycardia
         subjects affected / exposed
    1 / 28 (3.57%)
    0 / 33 (0.00%)
    1 / 91 (1.10%)
    0 / 30 (0.00%)
         occurrences all number
    1
    0
    1
    0
    Nervous system disorders
    VIth nerve paralysis
         subjects affected / exposed
    0 / 28 (0.00%)
    1 / 33 (3.03%)
    1 / 91 (1.10%)
    0 / 30 (0.00%)
         occurrences all number
    0
    1
    1
    0
    Headache
         subjects affected / exposed
    0 / 28 (0.00%)
    1 / 33 (3.03%)
    1 / 91 (1.10%)
    0 / 30 (0.00%)
         occurrences all number
    0
    1
    1
    0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    1 / 28 (3.57%)
    1 / 33 (3.03%)
    4 / 91 (4.40%)
    2 / 30 (6.67%)
         occurrences all number
    1
    1
    4
    2
    Eye disorders
    Abnormal sensation in eye
         subjects affected / exposed
    0 / 28 (0.00%)
    1 / 33 (3.03%)
    1 / 91 (1.10%)
    0 / 30 (0.00%)
         occurrences all number
    0
    1
    1
    0
    Anterior chamber flare
         subjects affected / exposed
    0 / 28 (0.00%)
    0 / 33 (0.00%)
    1 / 91 (1.10%)
    1 / 30 (3.33%)
         occurrences all number
    0
    0
    1
    1
    Dacryostenosis acquired
         subjects affected / exposed
    1 / 28 (3.57%)
    0 / 33 (0.00%)
    1 / 91 (1.10%)
    0 / 30 (0.00%)
         occurrences all number
    1
    0
    1
    0
    Cystoid macular oedema
         subjects affected / exposed
    1 / 28 (3.57%)
    0 / 33 (0.00%)
    1 / 91 (1.10%)
    0 / 30 (0.00%)
         occurrences all number
    1
    0
    1
    0
    Conjunctival haemorrhage
         subjects affected / exposed
    1 / 28 (3.57%)
    2 / 33 (6.06%)
    8 / 91 (8.79%)
    5 / 30 (16.67%)
         occurrences all number
    1
    2
    10
    7
    Corneal erosion
         subjects affected / exposed
    1 / 28 (3.57%)
    0 / 33 (0.00%)
    1 / 91 (1.10%)
    0 / 30 (0.00%)
         occurrences all number
    1
    0
    1
    0
    Diabetic retinal oedema
         subjects affected / exposed
    3 / 28 (10.71%)
    2 / 33 (6.06%)
    6 / 91 (6.59%)
    1 / 30 (3.33%)
         occurrences all number
    4
    3
    8
    1
    Dry eye
         subjects affected / exposed
    0 / 28 (0.00%)
    1 / 33 (3.03%)
    2 / 91 (2.20%)
    1 / 30 (3.33%)
         occurrences all number
    0
    1
    2
    1
    Epiretinal membrane
         subjects affected / exposed
    0 / 28 (0.00%)
    0 / 33 (0.00%)
    1 / 91 (1.10%)
    1 / 30 (3.33%)
         occurrences all number
    0
    0
    1
    1
    Diabetic retinopathy
         subjects affected / exposed
    1 / 28 (3.57%)
    1 / 33 (3.03%)
    3 / 91 (3.30%)
    1 / 30 (3.33%)
         occurrences all number
    1
    1
    4
    2
    Lenticular opacities
         subjects affected / exposed
    0 / 28 (0.00%)
    1 / 33 (3.03%)
    1 / 91 (1.10%)
    0 / 30 (0.00%)
         occurrences all number
    0
    1
    1
    0
    Eyelids pruritus
         subjects affected / exposed
    0 / 28 (0.00%)
    1 / 33 (3.03%)
    1 / 91 (1.10%)
    0 / 30 (0.00%)
         occurrences all number
    0
    1
    1
    0
    Eye pain
         subjects affected / exposed
    1 / 28 (3.57%)
    0 / 33 (0.00%)
    1 / 91 (1.10%)
    0 / 30 (0.00%)
         occurrences all number
    1
    0
    1
    0
    Retinal cyst
         subjects affected / exposed
    1 / 28 (3.57%)
    0 / 33 (0.00%)
    1 / 91 (1.10%)
    0 / 30 (0.00%)
         occurrences all number
    2
    0
    2
    0
    Retinal exudates
         subjects affected / exposed
    1 / 28 (3.57%)
    0 / 33 (0.00%)
    1 / 91 (1.10%)
    0 / 30 (0.00%)
         occurrences all number
    1
    0
    1
    0
    Macular oedema
         subjects affected / exposed
    2 / 28 (7.14%)
    0 / 33 (0.00%)
    2 / 91 (2.20%)
    0 / 30 (0.00%)
         occurrences all number
    2
    0
    2
    0
    Punctate keratitis
         subjects affected / exposed
    0 / 28 (0.00%)
    0 / 33 (0.00%)
    1 / 91 (1.10%)
    1 / 30 (3.33%)
         occurrences all number
    0
    0
    1
    1
    Ocular hypertension
         subjects affected / exposed
    2 / 28 (7.14%)
    0 / 33 (0.00%)
    2 / 91 (2.20%)
    0 / 30 (0.00%)
         occurrences all number
    3
    0
    3
    0
    Visual acuity reduced
         subjects affected / exposed
    3 / 28 (10.71%)
    0 / 33 (0.00%)
    3 / 91 (3.30%)
    0 / 30 (0.00%)
         occurrences all number
    4
    0
    4
    0
    Retinal oedema
         subjects affected / exposed
    0 / 28 (0.00%)
    0 / 33 (0.00%)
    1 / 91 (1.10%)
    1 / 30 (3.33%)
         occurrences all number
    0
    0
    1
    1
    Retinal haemorrhage
         subjects affected / exposed
    1 / 28 (3.57%)
    0 / 33 (0.00%)
    1 / 91 (1.10%)
    0 / 30 (0.00%)
         occurrences all number
    1
    0
    1
    0
    Vitreoretinal traction syndrome
         subjects affected / exposed
    0 / 28 (0.00%)
    1 / 33 (3.03%)
    1 / 91 (1.10%)
    0 / 30 (0.00%)
         occurrences all number
    0
    1
    1
    0
    Vitreous haemorrhage
         subjects affected / exposed
    1 / 28 (3.57%)
    2 / 33 (6.06%)
    3 / 91 (3.30%)
    0 / 30 (0.00%)
         occurrences all number
    1
    2
    3
    0
    Gastrointestinal disorders
    Gastrooesophageal reflux disease
         subjects affected / exposed
    0 / 28 (0.00%)
    0 / 33 (0.00%)
    1 / 91 (1.10%)
    1 / 30 (3.33%)
         occurrences all number
    0
    0
    1
    1
    Hepatobiliary disorders
    Hepatotoxicity
         subjects affected / exposed
    0 / 28 (0.00%)
    0 / 33 (0.00%)
    1 / 91 (1.10%)
    1 / 30 (3.33%)
         occurrences all number
    0
    0
    1
    1
    Hepatic steatosis
         subjects affected / exposed
    1 / 28 (3.57%)
    0 / 33 (0.00%)
    1 / 91 (1.10%)
    0 / 30 (0.00%)
         occurrences all number
    1
    0
    1
    0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    1 / 28 (3.57%)
    0 / 33 (0.00%)
    1 / 91 (1.10%)
    0 / 30 (0.00%)
         occurrences all number
    1
    0
    1
    0
    Chronic kidney disease
         subjects affected / exposed
    1 / 28 (3.57%)
    0 / 33 (0.00%)
    1 / 91 (1.10%)
    0 / 30 (0.00%)
         occurrences all number
    1
    0
    1
    0
    Urinary incontinence
         subjects affected / exposed
    0 / 28 (0.00%)
    0 / 33 (0.00%)
    1 / 91 (1.10%)
    1 / 30 (3.33%)
         occurrences all number
    0
    0
    1
    1
    Nephrolithiasis
         subjects affected / exposed
    1 / 28 (3.57%)
    0 / 33 (0.00%)
    1 / 91 (1.10%)
    0 / 30 (0.00%)
         occurrences all number
    1
    0
    1
    0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    1 / 28 (3.57%)
    0 / 33 (0.00%)
    2 / 91 (2.20%)
    1 / 30 (3.33%)
         occurrences all number
    1
    0
    2
    1
    Sjogren's syndrome
         subjects affected / exposed
    0 / 28 (0.00%)
    0 / 33 (0.00%)
    1 / 91 (1.10%)
    1 / 30 (3.33%)
         occurrences all number
    0
    0
    1
    1
    Myopathy
         subjects affected / exposed
    1 / 28 (3.57%)
    0 / 33 (0.00%)
    1 / 91 (1.10%)
    0 / 30 (0.00%)
         occurrences all number
    1
    0
    1
    0
    Infections and infestations
    Adenoviral conjunctivitis
         subjects affected / exposed
    0 / 28 (0.00%)
    1 / 33 (3.03%)
    2 / 91 (2.20%)
    1 / 30 (3.33%)
         occurrences all number
    0
    1
    2
    1
    COVID-19
         subjects affected / exposed
    2 / 28 (7.14%)
    0 / 33 (0.00%)
    2 / 91 (2.20%)
    0 / 30 (0.00%)
         occurrences all number
    2
    0
    2
    0
    Herpes zoster
         subjects affected / exposed
    1 / 28 (3.57%)
    0 / 33 (0.00%)
    1 / 91 (1.10%)
    0 / 30 (0.00%)
         occurrences all number
    1
    0
    1
    0
    Coronavirus infection
         subjects affected / exposed
    0 / 28 (0.00%)
    1 / 33 (3.03%)
    1 / 91 (1.10%)
    0 / 30 (0.00%)
         occurrences all number
    0
    1
    1
    0
    Conjunctivitis
         subjects affected / exposed
    1 / 28 (3.57%)
    0 / 33 (0.00%)
    1 / 91 (1.10%)
    0 / 30 (0.00%)
         occurrences all number
    1
    0
    1
    0
    Nasopharyngitis
         subjects affected / exposed
    0 / 28 (0.00%)
    0 / 33 (0.00%)
    2 / 91 (2.20%)
    2 / 30 (6.67%)
         occurrences all number
    0
    0
    2
    2
    Sinusitis
         subjects affected / exposed
    0 / 28 (0.00%)
    0 / 33 (0.00%)
    2 / 91 (2.20%)
    2 / 30 (6.67%)
         occurrences all number
    0
    0
    2
    2
    Urinary tract infection
         subjects affected / exposed
    1 / 28 (3.57%)
    1 / 33 (3.03%)
    3 / 91 (3.30%)
    1 / 30 (3.33%)
         occurrences all number
    1
    1
    3
    1
    Metabolism and nutrition disorders
    Diabetes mellitus
         subjects affected / exposed
    0 / 28 (0.00%)
    2 / 33 (6.06%)
    2 / 91 (2.20%)
    0 / 30 (0.00%)
         occurrences all number
    0
    2
    2
    0
    Hypercholesterolaemia
         subjects affected / exposed
    0 / 28 (0.00%)
    1 / 33 (3.03%)
    1 / 91 (1.10%)
    0 / 30 (0.00%)
         occurrences all number
    0
    1
    1
    0
    Hyperglycaemia
         subjects affected / exposed
    2 / 28 (7.14%)
    1 / 33 (3.03%)
    4 / 91 (4.40%)
    1 / 30 (3.33%)
         occurrences all number
    2
    1
    4
    1
    Hyperkalaemia
         subjects affected / exposed
    0 / 28 (0.00%)
    1 / 33 (3.03%)
    1 / 91 (1.10%)
    0 / 30 (0.00%)
         occurrences all number
    0
    1
    1
    0
    Hyperlipasaemia
         subjects affected / exposed
    1 / 28 (3.57%)
    0 / 33 (0.00%)
    1 / 91 (1.10%)
    0 / 30 (0.00%)
         occurrences all number
    1
    0
    1
    0
    Hyperlipidaemia
         subjects affected / exposed
    0 / 28 (0.00%)
    1 / 33 (3.03%)
    1 / 91 (1.10%)
    0 / 30 (0.00%)
         occurrences all number
    0
    1
    1
    0
    Hypertriglyceridaemia
         subjects affected / exposed
    1 / 28 (3.57%)
    0 / 33 (0.00%)
    1 / 91 (1.10%)
    0 / 30 (0.00%)
         occurrences all number
    1
    0
    1
    0
    Hypocalcaemia
         subjects affected / exposed
    0 / 28 (0.00%)
    0 / 33 (0.00%)
    1 / 91 (1.10%)
    1 / 30 (3.33%)
         occurrences all number
    0
    0
    1
    1
    Hypomagnesaemia
         subjects affected / exposed
    0 / 28 (0.00%)
    0 / 33 (0.00%)
    1 / 91 (1.10%)
    1 / 30 (3.33%)
         occurrences all number
    0
    0
    1
    1
    Hyponatraemia
         subjects affected / exposed
    1 / 28 (3.57%)
    0 / 33 (0.00%)
    1 / 91 (1.10%)
    0 / 30 (0.00%)
         occurrences all number
    1
    0
    1
    0
    Type 2 diabetes mellitus
         subjects affected / exposed
    0 / 28 (0.00%)
    1 / 33 (3.03%)
    3 / 91 (3.30%)
    2 / 30 (6.67%)
         occurrences all number
    0
    1
    3
    2
    Vitamin B complex deficiency
         subjects affected / exposed
    0 / 28 (0.00%)
    0 / 33 (0.00%)
    1 / 91 (1.10%)
    1 / 30 (3.33%)
         occurrences all number
    0
    0
    1
    1
    Vitamin D deficiency
         subjects affected / exposed
    0 / 28 (0.00%)
    1 / 33 (3.03%)
    1 / 91 (1.10%)
    0 / 30 (0.00%)
         occurrences all number
    0
    1
    1
    0

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    24 Jan 2019
    The purpose of this amendment was to address recommendations and requests from Health Authorities and the EC CTA review process. In addition, one inclusion criteria was changed to increase the retinal thickness required for entry into the study, which ensured that patients with significant DME were enrolled and increased the potential benefit of treatment. Two exploratory objectives were removed: measurement of systemic serum EPO, since preliminary assessment of serum EPO levels in Study CLKA651X2104 before and after treatment with LKA651 5mg remained unaffected. Also, analysis of serum biomarkers was removed because the relationship between these biomarkers and disease progression was yet to be identified.
    05 Dec 2019
    The purpose of this amendment was to alter some of the eligibility criteria in light of final PK and safety information from Study CLKA651X2104, in addition to favorable preliminary safety information from the first 4 patients recruited in the current study. PK analysis demonstrated that systemic serum exposure of total LKA651 was low in Study CLKA651X2104, with only 6 out of 12 patients in the top 2 doses (2.5 mg and 5 mg) having detectable LKA651 serum concentrations through Day 5 (4 days post dose). Therefore, eligibility criteria based on systemic conditions, including the cut-off for hemoglobin and heart failure classification were relaxed. Furthermore, drawing of blood samples for PK throughout the study was reduced.
    11 Mar 2020
    The purpose of this amendment was to alter the eligibility criteria, allowing previously treated patients to be enrolled in the study and to add an interim analysis: The amendment allowed enrollment of treatment-naive patients while also allowing patients who had been treated with anti-VEGF therapy more than 90 days prior to baseline. The 90-day washout period was used to allow for patients with recurrent macular edema >320 µm (as per inclusion criteria) who could benefit from LKA651 and/or Lucentis therapy. The interim analysis was planned to be conducted when approximately 2/3 of target population enrollment (60 patients) had reached Day 85, was to be used primarily for internal decision-making purposes regarding further development of LKA651.
    01 Dec 2020
    The purpose of this amendment was to reduce the number and duration of in-clinic visits, in light of the favorable safety findings from the sentinel safety cohorts. Visits were reduced to lower patient and site burden. Due to the reduced number of visits, for the remaining patients to enroll into the study, there would be fewer overall blood draws for PK sampling, and language was updated to reflect that PK analysis will be performed in a subset of patients. 1 inclusion and 3 exclusion criteria were also amended
    20 Jan 2021
    The purpose of this amendment was to clarify the exclusion criteria pertaining to history of laser photocoagulation in the study eye. Exclusion criteria #1 was updated to be aligned with the updated Exclusion criteria #3 (updated in Amendment 4).
    06 Jul 2022
    The purpose of this amendment was to amend the secondary endpoint by removing the DRSS. This amendment also added the ICDR for diabetic retinopathy to the exploratory endpoint for evaluating diabetic retinopathy progression.

    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.
    Due to EudraCT system limitations, which EMA is aware of, data using 999 as data points in this record are not an accurate representation of the clinical trial results. Please use https://www.novctrd.com for complete trial results.
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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