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    Clinical Trial Results:
    A Phase 2b/3, Prospective, Randomized, Double-masked, Active Comparator-controlled, Multi-center Study to Investigate the Efficacy and Safety of Repeated Intravitreal Administration of KSI-301 in Subjects With Neovascular (Wet) Age-related Macular Degeneration

    Summary
    EudraCT number
    		 2018-003428-35
    Trial protocol
    		 LV   GB   DE   CZ   SK   PL   ES   IT  
    Global end of trial date
    26 Apr 2022

    Results information
    Results version number
    		 v1(current)
    This version publication date
    13 Jul 2024
    First version publication date
    13 Jul 2024
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    KSI-CL-102
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT04049266
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Kodiak Sciences Inc.
    Sponsor organisation address
    1200 Page Mill Road, Palo Alto, CA, United States, 94304
    Public contact
    KSI-CL-102 Trial Information, Kodiak Sciences Inc, KSI-CL-102@kodiak.com
    Scientific contact
    KSI-CL-102 Trial Information, Kodiak Sciences Inc, KSI-CL-102@kodiak.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
    27 May 2022
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    17 Nov 2021
    Global end of trial reached?
    Yes
    Global end of trial date
    26 Apr 2022
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    To demonstrate that KSI-301 5 mg is non-inferior to aflibercept 2 mg with respect to mean change in BCVA from Day 1 to Year 1. Year 1 is defined as the mean of the Week 48 and 52 measurements.
    Protection of trial subjects
    The study followed the ethical principles derived from the Declaration of Helsinki and the International Conference on Harmonization (ICH) Good Clinical Practice (GCP) guidelines. All local regulatory requirements pertinent to safety of trial subjects were followed during the conduct of the trial. At the Investigator's discretion, rescue therapy (standard of care) was available. to participants with loss of ≥ 15 BCVA ETDRS letters compared to Day 1.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    08 Oct 2019
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Poland: 16
    Country: Number of subjects enrolled
    Slovakia: 21
    Country: Number of subjects enrolled
    Spain: 9
    Country: Number of subjects enrolled
    Czechia: 29
    Country: Number of subjects enrolled
    Germany: 3
    Country: Number of subjects enrolled
    Latvia: 15
    Country: Number of subjects enrolled
    United States: 464
    Worldwide total number of subjects
    557
    EEA total number of subjects
    93
    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)
    41
    From 65 to 84 years
    427
    85 years and over
    89

    Subject disposition

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    Recruitment
    Recruitment details
    		 Participants were recruited based on physician referral at 72 medical centers between September 2019 and November 2020. The first participant was enrolled on 08 October 2019 and the last on 24 November 2020.

    Pre-assignment
    Screening details
    		 Of 785 participants screened, 559 were randomized to treatment. Two randomized subjects (one subject in KSI-301 arm and one subject in aflibercept arm) never received treatment, so do not have reason for not completing treatment.

    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
    		 Subject, Investigator, Assessor
    Blinding implementation details
    A masked evaluating investigator will be responsible for subject care except the injections and the safety assessment following the injections. An unmasked treating investigator will perform the injections and assess patient safety following the injections.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 KSI-301 5 mg
    Arm description
    		 Drug: KSI-301 5 mg. KSI-301 5 mg will be administered by intravitreal injection into the study eye at 12, 16, and 20 weeks intervals as specified in the study protocol. Drug: Sham Procedure. The sham is a procedure that mimics an intravitreal injection. It involves pressing the blunt end of an empty syringe (without a needle) against the anesthetized eye. It will be administered to participants in both treatments arms at applicable visits to maintain masking.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Tarcocimab tedromer
    Investigational medicinal product code
    KSI-301
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravitreal use
    Dosage and administration details
    5 mg via intravitreal injection

    Arm title
    		 Aflibercept 2 mg
    Arm description
    		 Drug: Aflibercept 2 mg. Aflibercept 2 mg will be administered by intravitreal injection into the study eye once every 4 weeks for 3 consecutive months, followed by once every 8 weeks. Drug: Sham Procedure. The sham is a procedure that mimics an intravitreal injection. It involves pressing the blunt end of an empty syringe (without a needle) against the anesthetized eye. It will be administered to participants in both treatments arms at applicable visits to maintain masking.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Aflibercept
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravitreal use
    Dosage and administration details
    2 mg via intravitreal injection

    Number of subjects in period 1
    		KSI-301 5 mg Aflibercept 2 mg
    Started
    277
    280
    Completed
    240
    254
    Not completed
    37
    26
         Adverse event, serious fatal
    3
    8
         Consent withdrawn by subject
    6
    10
         Physician decision
    1
    -
         Adverse event, non-fatal
    13
    1
         Other
    1
    -
         Non-compliance with study drug
    -
    3
         Lost to follow-up
    2
    2
         Progressive disease
    11
    2

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    KSI-301 5 mg
    Reporting group description
    		 Drug: KSI-301 5 mg. KSI-301 5 mg will be administered by intravitreal injection into the study eye at 12, 16, and 20 weeks intervals as specified in the study protocol. Drug: Sham Procedure. The sham is a procedure that mimics an intravitreal injection. It involves pressing the blunt end of an empty syringe (without a needle) against the anesthetized eye. It will be administered to participants in both treatments arms at applicable visits to maintain masking.

    Reporting group title
    Aflibercept 2 mg
    Reporting group description
    		 Drug: Aflibercept 2 mg. Aflibercept 2 mg will be administered by intravitreal injection into the study eye once every 4 weeks for 3 consecutive months, followed by once every 8 weeks. Drug: Sham Procedure. The sham is a procedure that mimics an intravitreal injection. It involves pressing the blunt end of an empty syringe (without a needle) against the anesthetized eye. It will be administered to participants in both treatments arms at applicable visits to maintain masking.

    Reporting group values
    		 KSI-301 5 mg Aflibercept 2 mg Total
    Number of subjects
    		 277 280 557
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 18 23 41
        From 65-84 years
    		 215 212 427
        85 years and over
    		 44 45 89
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 76.6 ( 7.35 ) 76.2 ( 8.27 ) -
    Gender categorical
    Units: Subjects
        Female
    		 178 168 346
        Male
    		 99 112 211
    Ethnicity
    Units: Subjects
        Hispanic or Latino
    		 17 9 26
        Not Hispanic or Latino
    		 260 271 531
        Unknown or Not Reported
    		 0 0 0
    Race
    Units: Subjects
        American Indian or Alaska Native
    		 1 1 2
        Asian
    		 4 5 9
        Native Hawaiian or Other Pacific Islander
    		 0 0 0
        Black or African American
    		 1 1 2
        White
    		 271 272 543
        More than one race
    		 0 0 0
        Unknown or Not Reported
    		 0 1 1

    End points

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    End points reporting groups
    Reporting group title
    KSI-301 5 mg
    Reporting group description
    		 Drug: KSI-301 5 mg. KSI-301 5 mg will be administered by intravitreal injection into the study eye at 12, 16, and 20 weeks intervals as specified in the study protocol. Drug: Sham Procedure. The sham is a procedure that mimics an intravitreal injection. It involves pressing the blunt end of an empty syringe (without a needle) against the anesthetized eye. It will be administered to participants in both treatments arms at applicable visits to maintain masking.

    Reporting group title
    Aflibercept 2 mg
    Reporting group description
    		 Drug: Aflibercept 2 mg. Aflibercept 2 mg will be administered by intravitreal injection into the study eye once every 4 weeks for 3 consecutive months, followed by once every 8 weeks. Drug: Sham Procedure. The sham is a procedure that mimics an intravitreal injection. It involves pressing the blunt end of an empty syringe (without a needle) against the anesthetized eye. It will be administered to participants in both treatments arms at applicable visits to maintain masking.

    Primary: Change From Baseline in BCVA in the Study Eye Averaged Over Weeks 48 and 52, Full Analysis Set Year 1

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    End point title
    		 Change From Baseline in BCVA in the Study Eye Averaged Over Weeks 48 and 52, Full Analysis Set Year 1
    End point description
    Best Corrected Visual Acuity (BCVA) was measured on the Early Treatment Diabetic Retinopathy Study (ETDRS) chart at a starting distance of 4 meters. The BCVA letter score ranges from 0 to 100 (best score), and a gain in BCVA letter score from baseline indicates an improvement in visual acuity.
    End point type
    Primary
    End point timeframe
    Year 1
    End point values
    		 KSI-301 5 mg Aflibercept 2 mg
    Number of subjects analysed
    277
    280
    Units: ETDRS Letters
        least squares mean (standard error)
    1 ( 0.78 )
    7 ( 0.77 )
    Statistical analysis title
    		 KSI-301 5 mg Q12W-Q20W, Aflibercept 2 mg Q8W
    Comparison groups
    KSI-301 5 mg v Aflibercept 2 mg
    Number of subjects included in analysis
    557
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [1]
    P-value
    		 > 0.9999 [2]
    Method
    		 Mixed models analysis
    Parameter type
    		 Adjusted mean difference
    Point estimate
    -6
    Confidence interval
         level
    		 95.03%
         sides
    2-sided
         lower limit
    		 -8
         upper limit
    		 -4
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.01
    Notes
    [1] - The maximum clinically acceptable true difference between KSI-301 and aflibercept participants to be considered non-inferior is 4 ETDRS letters, i.e. the non-inferiority margin (NI) is 4 letters.
    [2] - MMRM model with treatment, visit, treatment by visit interaction, categories for baseline BCVA, BCVA-low luminance VA baseline, geographical location.

    Secondary: Proportion of Subjects on KSI-301 Arm With a Once Every 12-Weeks, 16-Weeks or 20-Weeks Treatment Interval

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    End point title
    		 Proportion of Subjects on KSI-301 Arm With a Once Every 12-Weeks, 16-Weeks or 20-Weeks Treatment Interval [3]
    End point description
    Number of subjects on KSI-301 arm achieving a Once Every 12-Weeks, 16-Weeks or 20-Weeks Treatment Interval based on individualized treatment response
    End point type
    Secondary
    End point timeframe
    Year 1
    Notes
    [3] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: For the study design for Study KSI-CL-102 (DAZZLE), only the KSI-301 arm had once every 12-weeks, 16-weeks or 20-weeks treatment interval. All patients in Aflibercept arm received treatment at fixed interval of once every 8-weeks. Therefore, this endpoint applies to the KSI-301 arm only and the statistics are meant to be descriptive only.
    End point values
    		 KSI-301 5 mg
    Number of subjects analysed
    234
    Units: Subjects
        Number of participants on the KSI-301 Q12W
    71
        Number of participants on the KSI-301 Q16W
    24
        Number of participants on the KSI-301 Q20W
    139
    No statistical analyses for this end point

    Secondary: Proportion of Subjects Gaining ≥ 5, ≥10 and ≥15 Letters in BCVA From Baseline in the Study Eye, Full Analysis Set Year 1

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    End point title
    		 Proportion of Subjects Gaining ≥ 5, ≥10 and ≥15 Letters in BCVA From Baseline in the Study Eye, Full Analysis Set Year 1
    End point description
    Categorical improvements in Best Corrected Visual Acuity (BCVA) of clinically relevant BCVA measurements corresponding to 1, 2 and 3 lines of the ETDRS vision testing chart
    End point type
    Secondary
    End point timeframe
    Year 1
    End point values
    		 KSI-301 5 mg Aflibercept 2 mg
    Number of subjects analysed
    238
    254
    Units: Subjects
        Gain >=5 ETDRS Letters at Year 1
    103
    148
        Gain >=10 ETDRS Letters at Year 1
    66
    87
        Gain >=15 ETDRS Letters at Year 1
    31
    46
    No statistical analyses for this end point

    Secondary: Proportion of Subjects Who Achieving BCVA Snellen Equivalent of 20/40 or Better in the Study Eye at Year 1

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    End point title
    		 Proportion of Subjects Who Achieving BCVA Snellen Equivalent of 20/40 or Better in the Study Eye at Year 1
    End point description
    Best Corrected Visual Acuity (BCVA) was measured on the Early Treatment Diabetic Retinopathy Study (ETDRS) chart at a starting distance of 4 meters. The BCVA letter score ranges from 0 to 100 (best score), and a gain in BCVA letter score from baseline indicates an improvement in visual acuity. BCVA Snellen equivalent of 20/40 was defined as ≥69 ETDRS letters
    End point type
    Secondary
    End point timeframe
    Year 1
    End point values
    		 KSI-301 5 mg Aflibercept 2 mg
    Number of subjects analysed
    238
    254
    Units: Subjects
    119
    165
    No statistical analyses for this end point

    Secondary: Proportion of Subjects With BCVA Snellen Equivalent of 20/200 or Worse in the Study Eye at Year 1

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    End point title
    		 Proportion of Subjects With BCVA Snellen Equivalent of 20/200 or Worse in the Study Eye at Year 1
    End point description
    Best Corrected Visual Acuity (BCVA) was measured on the Early Treatment Diabetic Retinopathy Study (ETDRS) chart at a starting distance of 4 meters. The BCVA letter score ranges from 0 to 100 (best score), and a gain in BCVA letter score from baseline indicates an improvement in visual acuity. BCVA Snellen equivalent of 20/200 or Worse was defined as BCVA ≤ 38 ETDRS Letters.
    End point type
    Secondary
    End point timeframe
    Year 1
    End point values
    		 KSI-301 5 mg Aflibercept 2 mg
    Number of subjects analysed
    238
    254
    Units: Subjects
    13
    8
    No statistical analyses for this end point

    Secondary: Mean Change in OCT Central Subfield Retinal Thickness (CST) From Day 1

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    End point title
    		 Mean Change in OCT Central Subfield Retinal Thickness (CST) From Day 1
    End point description
    Central subfield thickness (CST) was defined as the distance between the internal limiting membrane (ILM) and the retinal pigment epithelium (RPE) as assessed by a central reading center.
    End point type
    Secondary
    End point timeframe
    Year 1
    End point values
    		 KSI-301 5 mg Aflibercept 2 mg
    Number of subjects analysed
    277
    280
    Units: Microns
        arithmetic mean (standard deviation)
    -96.1 ( 123.39 )
    -134.1 ( 111.17 )
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse Events (AEs) reported through Week 52 or Early Termination (ET) if occurred before Week 52.
    Adverse event reporting additional description
    Safety results for the KSI-301 5mg arm are presented together as patients treated with Q12W dosing received 6 total doses in Year 1 and the patients treated with Q20W dosing received 5 total doses in Year 1. Therefore, presenting all treatment intervals together provides a more robust dataset to evaluate the safety profile of KSI-301.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    23.1
    Reporting groups
    Reporting group title
    KSI-301 5 mg
    Reporting group description
    		 Drug: KSI-301 5 mg. KSI-301 5 mg will be administered by intravitreal injection into the study eye at 12, 16, and 20 weeks intervals as specified in the study protocol. Drug: Sham Procedure. The sham is a procedure that mimics an intravitreal injection. It involves pressing the blunt end of an empty syringe (without a needle) against the anesthetized eye. It will be administered to participants in both treatments arms at applicable visits to maintain masking.

    Reporting group title
    Aflibercept 2 mg
    Reporting group description
    		 Drug: Aflibercept 2 mg. Aflibercept 2 mg will be administered by intravitreal injection into the study eye once every 4 weeks for 3 consecutive months, followed by once every 8 weeks. Drug: Sham Procedure. The sham is a procedure that mimics an intravitreal injection. It involves pressing the blunt end of an empty syringe (without a needle) against the anesthetized eye. It will be administered to participants in both treatments arms at applicable visits to maintain masking.

    Serious adverse events
    		 KSI-301 5 mg Aflibercept 2 mg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    35 / 277 (12.64%)
    33 / 280 (11.79%)
         number of deaths (all causes)
    4
    8
         number of deaths resulting from adverse events
    1
    3
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Benign gastric neoplasm
         subjects affected / exposed
    1 / 277 (0.36%)
    0 / 280 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Invasive ductal breast carcinoma
         subjects affected / exposed
    1 / 277 (0.36%)
    0 / 280 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Basal cell carcinoma
         subjects affected / exposed
    0 / 277 (0.00%)
    1 / 280 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colon cancer recurrent
         subjects affected / exposed
    0 / 277 (0.00%)
    1 / 280 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Prostate cancer
         subjects affected / exposed
    0 / 277 (0.00%)
    1 / 280 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Hypotension
         subjects affected / exposed
    1 / 277 (0.36%)
    0 / 280 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Jugular vein thrombosis
         subjects affected / exposed
    1 / 277 (0.36%)
    0 / 280 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypertension
         subjects affected / exposed
    0 / 277 (0.00%)
    1 / 280 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral ischaemia
         subjects affected / exposed
    0 / 277 (0.00%)
    1 / 280 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Chest discomfort
         subjects affected / exposed
    1 / 277 (0.36%)
    0 / 280 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Death
         subjects affected / exposed
    1 / 277 (0.36%)
    0 / 280 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Perforated ulcer
         subjects affected / exposed
    1 / 277 (0.36%)
    0 / 280 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chest pain
         subjects affected / exposed
    0 / 277 (0.00%)
    1 / 280 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Prostatic varices
         subjects affected / exposed
    1 / 277 (0.36%)
    0 / 280 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pulmonary embolism
         subjects affected / exposed
    1 / 277 (0.36%)
    1 / 280 (0.36%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchiectasis
         subjects affected / exposed
    1 / 277 (0.36%)
    0 / 280 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    0 / 277 (0.00%)
    1 / 280 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hiccups
         subjects affected / exposed
    0 / 277 (0.00%)
    1 / 280 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary hypertension
         subjects affected / exposed
    0 / 277 (0.00%)
    1 / 280 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    0 / 277 (0.00%)
    1 / 280 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Product issues
    Device occlusion
         subjects affected / exposed
    1 / 277 (0.36%)
    0 / 280 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Hip fracture
         subjects affected / exposed
    1 / 277 (0.36%)
    1 / 280 (0.36%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ilium fracture
         subjects affected / exposed
    1 / 277 (0.36%)
    0 / 280 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Radius fracture
         subjects affected / exposed
    1 / 277 (0.36%)
    0 / 280 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal compression fracture
         subjects affected / exposed
    1 / 277 (0.36%)
    0 / 280 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Contusion
         subjects affected / exposed
    0 / 277 (0.00%)
    1 / 280 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Femoral neck fracture
         subjects affected / exposed
    0 / 277 (0.00%)
    1 / 280 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Femur fracture
         subjects affected / exposed
    0 / 277 (0.00%)
    1 / 280 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rib fracture
         subjects affected / exposed
    0 / 277 (0.00%)
    1 / 280 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sternal fracture
         subjects affected / exposed
    0 / 277 (0.00%)
    1 / 280 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Acute myocardial infarction
         subjects affected / exposed
    2 / 277 (0.72%)
    0 / 280 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    1 / 277 (0.36%)
    1 / 280 (0.36%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    1 / 277 (0.36%)
    0 / 280 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pericarditis
         subjects affected / exposed
    1 / 277 (0.36%)
    0 / 280 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Stress cardiomyopathy
         subjects affected / exposed
    1 / 277 (0.36%)
    0 / 280 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Supraventricular extrasystoles
         subjects affected / exposed
    1 / 277 (0.36%)
    0 / 280 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Coronary artery disease
         subjects affected / exposed
    0 / 277 (0.00%)
    2 / 280 (0.71%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocardial ischaemia
         subjects affected / exposed
    0 / 277 (0.00%)
    1 / 280 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Ischaemic stroke
         subjects affected / exposed
    2 / 277 (0.72%)
    0 / 280 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    1 / 277 (0.36%)
    3 / 280 (1.07%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Carotid artery occlusion
         subjects affected / exposed
    1 / 277 (0.36%)
    0 / 280 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebral infarction
         subjects affected / exposed
    0 / 277 (0.00%)
    1 / 280 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    0 / 277 (0.00%)
    1 / 280 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemorrhagic stroke
         subjects affected / exposed
    0 / 277 (0.00%)
    1 / 280 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Toxic encephalopathy
         subjects affected / exposed
    0 / 277 (0.00%)
    1 / 280 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transient aphasia
         subjects affected / exposed
    0 / 277 (0.00%)
    1 / 280 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    1 / 277 (0.36%)
    0 / 280 (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 haemorrhage - Study Eye
         subjects affected / exposed
    2 / 277 (0.72%)
    0 / 280 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neovascular age-related macular degeneration - Study Eye
         subjects affected / exposed
    1 / 277 (0.36%)
    0 / 280 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rhegmatogenous retinal detachment - Study Eye
         subjects affected / exposed
    1 / 277 (0.36%)
    0 / 280 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Gastrointestinal haemorrhage
         subjects affected / exposed
    1 / 277 (0.36%)
    1 / 280 (0.36%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal dilatation
         subjects affected / exposed
    1 / 277 (0.36%)
    0 / 280 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peptic ulcer
         subjects affected / exposed
    1 / 277 (0.36%)
    0 / 280 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspepsia
         subjects affected / exposed
    0 / 277 (0.00%)
    1 / 280 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Bile duct stone
         subjects affected / exposed
    1 / 277 (0.36%)
    0 / 280 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Renal failure
         subjects affected / exposed
    2 / 277 (0.72%)
    0 / 280 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nephrolithiasis
         subjects affected / exposed
    1 / 277 (0.36%)
    2 / 280 (0.71%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute kidney injury
         subjects affected / exposed
    1 / 277 (0.36%)
    0 / 280 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Bursitis
         subjects affected / exposed
    0 / 277 (0.00%)
    1 / 280 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    1 / 277 (0.36%)
    3 / 280 (1.07%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Clostridium difficile colitis
         subjects affected / exposed
    1 / 277 (0.36%)
    0 / 280 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endophthalmitis - Study Eye
         subjects affected / exposed
    1 / 277 (0.36%)
    0 / 280 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyelonephritis
         subjects affected / exposed
    1 / 277 (0.36%)
    0 / 280 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    1 / 277 (0.36%)
    0 / 280 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Staphylococcal infection
         subjects affected / exposed
    1 / 277 (0.36%)
    0 / 280 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    COVID-19
         subjects affected / exposed
    0 / 277 (0.00%)
    2 / 280 (0.71%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    COVID-19 pneumonia
         subjects affected / exposed
    0 / 277 (0.00%)
    2 / 280 (0.71%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Coronavirus infection
         subjects affected / exposed
    0 / 277 (0.00%)
    1 / 280 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Cystitis
         subjects affected / exposed
    0 / 277 (0.00%)
    1 / 280 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    0 / 277 (0.00%)
    1 / 280 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    0 / 277 (0.00%)
    1 / 280 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urosepsis
         subjects affected / exposed
    0 / 277 (0.00%)
    1 / 280 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Hyponatraemia
         subjects affected / exposed
    1 / 277 (0.36%)
    1 / 280 (0.36%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dehydration
         subjects affected / exposed
    1 / 277 (0.36%)
    0 / 280 (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: 5%
    Non-serious adverse events
    		 KSI-301 5 mg Aflibercept 2 mg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    82 / 277 (29.60%)
    84 / 280 (30.00%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    15 / 277 (5.42%)
    16 / 280 (5.71%)
         occurrences all number
    15
    16
    Eye disorders
    Neovascular age-related macular degeneration - Fellow Eye
         subjects affected / exposed
    19 / 277 (6.86%)
    26 / 280 (9.29%)
         occurrences all number
    19
    26
    Retinal haemorrhage - Study Eye
         subjects affected / exposed
    17 / 277 (6.14%)
    4 / 280 (1.43%)
         occurrences all number
    18
    5
    Cataract - Study Eye
         subjects affected / exposed
    15 / 277 (5.42%)
    10 / 280 (3.57%)
         occurrences all number
    15
    10
    Conjunctival haemorrhage - Study Eye
         subjects affected / exposed
    13 / 277 (4.69%)
    24 / 280 (8.57%)
         occurrences all number
    14
    30
    Infections and infestations
    Urinary tract infection
         subjects affected / exposed
    15 / 277 (5.42%)
    16 / 280 (5.71%)
         occurrences all number
    18
    18

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    03 Aug 2020
    Protocol Version 2.0 Major change from Version 1.0 (original protocol) was increased sample size.

    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.
    This study was terminated early by the Sponsor because the study did not meet the primary endpoint. Thus, not all participants in this study completed the full duration of treatment.
    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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