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    Clinical Trial Results:
    A Phase III Randomized, Double-Masked, Parallel Group, Multicenter Study to Compare the Efficacy, Safety, Tolerability, Pharmacokinetics, and Immunogenicity between SCD411 and Eylea® in Subjects with Neovascular Age-related Macular Degeneration

    Summary
    EudraCT number
    		 2019-004132-37
    Trial protocol
    		 HU   CZ   BG   PL   SK   IT  
    Global end of trial date
    08 Sep 2022

    Results information
    Results version number
    		 v1(current)
    This version publication date
    16 Jul 2023
    First version publication date
    16 Jul 2023
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    SCD411-CP101
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT04480463
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 IND: 144376
    Sponsors
    Sponsor organisation name
    SamChunDang Pharm. Co. Ltd.
    Sponsor organisation address
    351, Hyoryeong-ro, Seocho-gu, Seoul, Korea, Republic of, 06643
    Public contact
    Clinical Development, SamChunDang Pharm. Co. Ltd, +82 31-869-7327, scd411clinical@scd.co.kr
    Scientific contact
    Clinical Development, SamChunDang Pharm. Co. Ltd, +82 31-869-7327, scd411clinical@scd.co.kr
    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
    05 May 2023
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    08 Sep 2022
    Global end of trial reached?
    Yes
    Global end of trial date
    08 Sep 2022
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To prove the equivalence of SCD411 as compared with Eylea (aflibercept) in best corrected visual acuity (BCVA) after 8 weeks of treatment among subjects with wet AMD.
    Protection of trial subjects
    The study was to be performed in accordance with the ethical principles that had their origin in the Declaration of Helsinki, ICH GCP, the protocol, and all applicable regulations. A written informed consent in compliance with regulatory authority regulations (eg, US Title 21 Code of Federal Regulations Part 50) was to be obtained from each subject before entering the study or performing any unusual or nonroutine procedure that involved risk to the subject. If the ICF was revised during the course of the study, all active participating subjects had to sign the revised form. Before recruitment and enrollment, each prospective subject was to be given a full explanation of the study and be allowed to read the approved ICF. The investigator was to address all questions raised by the subject. Once the investigator was assured that the subject understood the implications of participating in the study, the subject was to be asked to give consent to participate in the study by signing the ICF. The investigator or designee was to also sign the ICF.
    Background therapy
    		 A total of 317 subjects (55.3%) received at least one prior medication in the study eye, most commonly (>20.0% subjects) anticholinergics (263 subjects [45.9%]) and local anesthetics (144 subjects [25.1%]). A total of 303 subjects (52.9%) received at least one prior medication in the fellow eye, most commonly (>20.0% subjects) anticholinergics (248 subjects [43.3%]) and local anaesthetics (124 subjects [21.6%]). A total of 476 subjects (83.1%) received at least one concomitant medication in the study eye, most commonly (>20.0% subjects) local anesthetics (416 subjects [72.6%]), anticholinergics (288 subjects [50.3%]), fluoroquinolones (263 subjects [45.9%]), and other anti-infectives (236 subjects [41.2%]). A total of 326 subjects (56.9%) received at least one concomitant medication in the fellow eye, most commonly (>20.0% subjects) anticholinergics (227 subjects [39.6%]) and local anesthetics (124 subjects [21.6%]). A total of 538 subjects (93.9%) received at least one non-ocular prior medication, most commonly (>20.0% subjects) other diagnostic agents (256 subjects [44.7%]), 3-hydroxy-3-methylglutaryl (HMG) coenzyme A (CoA) reductase inhibitors (189 subjects [33.0%]), other viral vaccines (138 subjects [24.1%]), dihydropyridine derivatives (117 subjects [20.4%]), selective beta blocking agents (115 subjects [20.1%]), and platelet aggregation inhibitors excluding heparin (115 subjects [20.1%]). A total of 552 subjects (96.3%) received at least one non-ocular concomitant medication, most commonly (>20.0% subjects) other viral vaccines (328 subjects [57.2%]), other diagnostic agents (252 subjects [44.0%]), HMG CoA reductase inhibitors (203 subjects [35.4%]), proton pump inhibitors (136 subjects [23.7%]), platelet aggregation inhibitors excluding heparin (132 subjects [23.0%]), selective beta blocking agents (128 subjects [22.3%]), and dihydropyridine derivatives (126 subjects [22.0%]).
    Evidence for comparator
    		 Eylea (comparator)
    Actual start date of recruitment
    13 Aug 2020
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety, Efficacy
    Long term follow-up duration
    		 1 Months
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Poland: 87
    Country: Number of subjects enrolled
    Slovakia: 29
    Country: Number of subjects enrolled
    Spain: 44
    Country: Number of subjects enrolled
    Bulgaria: 4
    Country: Number of subjects enrolled
    Czechia: 6
    Country: Number of subjects enrolled
    Hungary: 39
    Country: Number of subjects enrolled
    Latvia: 23
    Country: Number of subjects enrolled
    Australia: 13
    Country: Number of subjects enrolled
    India: 9
    Country: Number of subjects enrolled
    Israel: 84
    Country: Number of subjects enrolled
    Japan: 60
    Country: Number of subjects enrolled
    Korea, Republic of: 118
    Country: Number of subjects enrolled
    Russian Federation: 22
    Country: Number of subjects enrolled
    United States: 35
    Worldwide total number of subjects
    573
    EEA total number of subjects
    232
    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)
    73
    From 65 to 84 years
    250
    85 years and over
    250

    Subject disposition

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    Recruitment
    Recruitment details
    		 A total of 576 subjects were randomly assigned to receive either SCD411 (288 subjects) or Eylea (288 subjects) treatment. Two subjects (Subject 1215002 and Subject 1717008) met the exclusion criteria but were randomized in error. Subject 5003008 also did not receive any study drug injection. These 3 subjects were excluded from all analyses sets.

    Pre-assignment
    Screening details
    		 A total of 914 subjects were assessed for eligibility across 132 sites in 14 countries. Upon entry into the study, subjects were assigned a screening number. Subjects who met all inclusion and none of the exclusion criteria were to return to the clinic on Day 1 for further evaluation.

    Period 1
    Period 1 title
    Treatment period (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Investigator, Monitor, Data analyst, Assessor, Subject
    Blinding implementation details
    This was a double-masked study. To prevent bias in treatment assignment, eligible subjects were randomly assigned using the IRT. Subjects and study site staff involved in subject management and study assessments were masked to study treatment assignment.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 SCD411 group
    Arm description
    		 SCD411 was a proposed biosimilar of Eylea having aflibercept as the active substance. SCD411 was administered as IVT injection of 2 mg (0.05 mL) every 4 weeks (approximately every 28 days, monthly) for 3 consecutive doses, followed by a 2 mg (0.05 mL) injection once every 8 weeks (2 months).
    Arm type
    		 Experimental

    Investigational medicinal product name
    Aflibercept biosimilar
    Investigational medicinal product code
    Other name
    SCD411
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravitreal use
    Dosage and administration details
    SCD411 was administered as IVT injection of 2 mg (0.05 mL) every 4 weeks (approximately every 28 days, monthly) for 3 consecutive doses, followed by a 2 mg (0.05 mL) injection once every 8 weeks (2 months).

    Arm title
    		 Eylea group
    Arm description
    		 Eylea was administered as IVT injection of 2 mg (0.05 ml) every 4 weeks (approximately every 28 days, monthly) for the first 3 months, followed by 2 mg (0.05 ml) injection once every 8 weeks (2 months).
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Aflibercept
    Investigational medicinal product code
    Other name
    Eylea
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravitreal use
    Dosage and administration details
    Eylea has been approved for the treatment of wet AMD when administered as IVT injection of 2 mg (0.05 mL) every 4 weeks (approximately every 28 days, monthly) for 3 consecutive doses, followed by a 2 mg (0.05 mL) injection once every 8 weeks (2 months).

    Number of subjects in period 1
    		SCD411 group Eylea group
    Started
    287
    286
    Completed
    260
    259
    Not completed
    27
    27
         Consent withdrawn by subject
    8
    6
         Subject missed first 2 doses of IP
    -
    1
         Adverse event, non-fatal
    5
    4
         Other
    5
    4
         Death
    -
    1
         Investigator decision
    -
    2
         Lost to follow-up
    4
    3
         Sponsor decision
    2
    5
         BCVA decrease of ≥30 letters
    1
    -
         Protocol deviation
    2
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    SCD411 group
    Reporting group description
    		 SCD411 was a proposed biosimilar of Eylea having aflibercept as the active substance. SCD411 was administered as IVT injection of 2 mg (0.05 mL) every 4 weeks (approximately every 28 days, monthly) for 3 consecutive doses, followed by a 2 mg (0.05 mL) injection once every 8 weeks (2 months).

    Reporting group title
    Eylea group
    Reporting group description
    		 Eylea was administered as IVT injection of 2 mg (0.05 ml) every 4 weeks (approximately every 28 days, monthly) for the first 3 months, followed by 2 mg (0.05 ml) injection once every 8 weeks (2 months).

    Reporting group values
    		 SCD411 group Eylea group Total
    Number of subjects
    		 287 286 573
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 33 40 73
        From 65-84 years
    		 131 119 250
        85 years and over
    		 123 127 250
    Age continuous
    Units: years
        median (full range (min-max))
    		 73.0 (54 to 95) 73.0 (50 to 98) -
    Gender categorical
    Units: Subjects
        Female
    		 149 147 296
        Male
    		 138 139 277
    BCVA score for Study Eye
    Best corrected visual acuity (BCVA) score for Study Eye
    Units: letters
        arithmetic mean (standard deviation)
    		 58.6 ± 10.75 59.9 ± 10.60 -
    Subject analysis sets

    Subject analysis set title
    Full Analysis Set
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Full Analysis Set (FAS): The FAS included all randomized subjects who received at least 1 injection of the study drug. Numbers were based on planned treatment group.

    Subject analysis set title
    Per Protocol Set
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Per Protocol Set (PPS): Included all subjects in the Full Analysis Set, excluding those with significant protocol deviations. Numbers were based on planned treatment group.

    Subject analysis sets values
    		 Full Analysis Set Per Protocol Set
    Number of subjects
    573
    558
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    73
    71
        From 65-84 years
    250
    239
        85 years and over
    250
    248
    Age continuous
    Units: years
        median (full range (min-max))
    73.0 (50 to 98)
    73.0 (50 to 98)
    Gender categorical
    Units: Subjects
        Female
    296
    289
        Male
    277
    269
    BCVA score for Study Eye
    Best corrected visual acuity (BCVA) score for Study Eye
    Units: letters
        arithmetic mean (standard deviation)
    59.3 ± 10.69
    59.3 ± 10.69

    End points

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    End points reporting groups
    Reporting group title
    SCD411 group
    Reporting group description
    		 SCD411 was a proposed biosimilar of Eylea having aflibercept as the active substance. SCD411 was administered as IVT injection of 2 mg (0.05 mL) every 4 weeks (approximately every 28 days, monthly) for 3 consecutive doses, followed by a 2 mg (0.05 mL) injection once every 8 weeks (2 months).

    Reporting group title
    Eylea group
    Reporting group description
    		 Eylea was administered as IVT injection of 2 mg (0.05 ml) every 4 weeks (approximately every 28 days, monthly) for the first 3 months, followed by 2 mg (0.05 ml) injection once every 8 weeks (2 months).

    Subject analysis set title
    Full Analysis Set
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Full Analysis Set (FAS): The FAS included all randomized subjects who received at least 1 injection of the study drug. Numbers were based on planned treatment group.

    Subject analysis set title
    Per Protocol Set
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Per Protocol Set (PPS): Included all subjects in the Full Analysis Set, excluding those with significant protocol deviations. Numbers were based on planned treatment group.

    Primary: Change from Baseline in BCVA Score for Study Eye in FAS at Week 8

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    End point title
    		 Change from Baseline in BCVA Score for Study Eye in FAS at Week 8
    End point description
    The primary endpoint was the change from baseline in BCVA as measured by ETDRS letters score or 2702 charts at Week 8. The BCVA score was comparable at Baseline among the treatment groups in the FAS. At Week 8, both treatment groups showed similar improvement from Baseline in the BCVA scores: a mean of 5.5 and 5.8 letters and an LS mean of 5.5 and 5.9 letters in the SCD411 and Eylea groups, respectively.
    End point type
    Primary
    End point timeframe
    From baseline through 8 weeks
    End point values
    		 SCD411 group Eylea group
    Number of subjects analysed
    287
    286
    Units: letters
    arithmetic mean (standard deviation)
        Baseline
    58.6 ± 10.75
    59.9 ± 10.60
        Unadjusted Week 8
    64.2 ± 13.32
    65.7 ± 13.08
    Statistical analysis title
    		 Statistical analysis - FAS
    Statistical analysis description
    The change from baseline in BCVA score for study eye at Week 8 for the primary estimand was summarized and analyzed using MMRM analysis (Mixed-effects model for repeated measures).
    Comparison groups
    SCD411 group v Eylea group
    Number of subjects included in analysis
    573
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence [1]
    Method
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.8
         upper limit
    		 1.1
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.74
    Notes
    [1] - LS mean difference (SCD411 – Eylea), MMRM. The MMRM analysis included the change from baseline as dependent variable; visit, treatment group, and visit × treatment group as fixed effects, and baseline BCVA score as a covariate. An unstructured covariance matrix was used. Degrees of freedom were approximated using Kenward-Roger approach.

    Primary: Change from Baseline in BCVA Score for Study Eye in PPS at Week 8

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    End point title
    		 Change from Baseline in BCVA Score for Study Eye in PPS at Week 8
    End point description
    The primary endpoint was the change from baseline in BCVA as measured by ETDRS letters score or 2702 charts at Week 8. The BCVA score was comparable at Baseline among the treatment groups in the PPS. At Week 8, the analysis based on the PPS yielded results similar to those of the FAS.
    End point type
    Primary
    End point timeframe
    From baseline through 8 weeks
    End point values
    		 SCD411 group Eylea group
    Number of subjects analysed
    275
    283
    Units: letters
    arithmetic mean (standard deviation)
        Baseline
    58.4 ± 10.85
    59.9 ± 10.65
        Unadjusted Week 8
    63.9 ± 13.38
    65.7 ± 13.12
    Statistical analysis title
    		 Statistical analysis - PPS
    Statistical analysis description
    The change from baseline in BCVA score for study eye at Week 8 for the primary estimand was summarized and analyzed using MMRM analysis (Mixed-effects model for repeated measures).
    Comparison groups
    Eylea group v SCD411 group
    Number of subjects included in analysis
    558
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence [2]
    Method
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.9
         upper limit
    		 1
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.75
    Notes
    [2] - LS mean difference (SCD411 – Eylea), MMRM. The MMRM analysis included the change from baseline as dependent variable; visit, treatment group, and visit × treatment group as fixed effects, and baseline BCVA score as a covariate. An unstructured covariance matrix was used. Degrees of freedom were approximated using Kenward-Roger approach.

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events were assessed beginning at enrollment (date of signed informed consent) and up to 28 days after the last dose of the study drug.
    Adverse event reporting additional description
    Overall, SCD411 was well-tolerated with a favorable safety profile that was comparable with Eylea in the total population. The incidence of ocular and non-ocular TEAEs was similar among the 2 treatment groups. No TEAEs leading to death were reported in the study.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    23.0
    Reporting groups
    Reporting group title
    SCD411 group
    Reporting group description
    		 Subjects who were randomized at baseline /Day 1 to receive SCD411 every 4 weeks (approximately every 28 days, monthly) for the first 3 months, followed by 2 mg (0.05 ml) injection once every 8 weeks (2 months).

    Reporting group title
    Eylea group
    Reporting group description
    		 Subjects who were randomized at baseline /Day 1 to receive Eylea every 4 weeks (approximately every 28 days, monthly) for the first 3 months, followed by 2 mg (0.05 ml) injection once every 8 weeks (2 months).

    Serious adverse events
    		 SCD411 group Eylea group
    Total subjects affected by serious adverse events
         subjects affected / exposed
    32 / 287 (11.15%)
    31 / 286 (10.84%)
         number of deaths (all causes)
    0
    1
         number of deaths resulting from adverse events
    0
    1
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Diffuse large B-cell lymphoma
         subjects affected / exposed
    0 / 287 (0.00%)
    1 / 286 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fibroadenoma of breast
         subjects affected / exposed
    0 / 287 (0.00%)
    1 / 286 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    High-grade B-cell lymphoma
         subjects affected / exposed
    0 / 287 (0.00%)
    1 / 286 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung adenocarcinoma stage 0
         subjects affected / exposed
    1 / 287 (0.35%)
    0 / 286 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Prostate cancer
         subjects affected / exposed
    1 / 287 (0.35%)
    0 / 286 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Squamous cell carcinoma of lung
         subjects affected / exposed
    1 / 287 (0.35%)
    0 / 286 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Hypertension
         subjects affected / exposed
    1 / 287 (0.35%)
    0 / 286 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    0 / 287 (0.00%)
    1 / 286 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    0 / 287 (0.00%)
    1 / 286 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune system disorders
    Anaphylactic shock
         subjects affected / exposed
    1 / 287 (0.35%)
    0 / 286 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Benign prostatic hyperplasia
         subjects affected / exposed
    0 / 287 (0.00%)
    1 / 286 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Sleep apnoea syndrome
         subjects affected / exposed
    2 / 287 (0.70%)
    0 / 286 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchiectasis
         subjects affected / exposed
    0 / 287 (0.00%)
    1 / 286 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    0 / 287 (0.00%)
    1 / 286 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Idiopathic pulmonary fibrosis
         subjects affected / exposed
    0 / 287 (0.00%)
    1 / 286 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary mass
         subjects affected / exposed
    1 / 287 (0.35%)
    0 / 286 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Product issues
    Device dislocation
         subjects affected / exposed
    0 / 287 (0.00%)
    1 / 286 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Femoral neck fracture
         subjects affected / exposed
    1 / 287 (0.35%)
    1 / 286 (0.35%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Foot fracture
         subjects affected / exposed
    0 / 287 (0.00%)
    1 / 286 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Joint dislocation
         subjects affected / exposed
    0 / 287 (0.00%)
    1 / 286 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Limb injury
         subjects affected / exposed
    0 / 287 (0.00%)
    1 / 286 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal compression fracture
         subjects affected / exposed
    0 / 287 (0.00%)
    1 / 286 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Venom poisoning
         subjects affected / exposed
    0 / 287 (0.00%)
    1 / 286 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Angina pectoris
         subjects affected / exposed
    0 / 287 (0.00%)
    2 / 286 (0.70%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute myocardial infarction
         subjects affected / exposed
    0 / 287 (0.00%)
    1 / 286 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arrhythmia supraventricular
         subjects affected / exposed
    0 / 287 (0.00%)
    1 / 286 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure
         subjects affected / exposed
    1 / 287 (0.35%)
    0 / 286 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac ventricular thrombosis
         subjects affected / exposed
    0 / 287 (0.00%)
    1 / 286 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocardial ischaemia
         subjects affected / exposed
    0 / 287 (0.00%)
    1 / 286 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Transient ischaemic attack
         subjects affected / exposed
    1 / 287 (0.35%)
    1 / 286 (0.35%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    0 / 287 (0.00%)
    1 / 286 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Intracranial mass
         subjects affected / exposed
    1 / 287 (0.35%)
    0 / 286 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    1 / 287 (0.35%)
    0 / 286 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Autoimmune haemolytic anaemia
         subjects affected / exposed
    0 / 287 (0.00%)
    1 / 286 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Visual acuity reduced
         subjects affected / exposed
    2 / 287 (0.70%)
    1 / 286 (0.35%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Retinal pigment epithelial tear
         subjects affected / exposed
    2 / 287 (0.70%)
    0 / 286 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Amaurosis fugax
         subjects affected / exposed
    0 / 287 (0.00%)
    1 / 286 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Retinal haemorrhage
         subjects affected / exposed
    0 / 287 (0.00%)
    1 / 286 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal hernia
         subjects affected / exposed
    1 / 287 (0.35%)
    0 / 286 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastritis
         subjects affected / exposed
    1 / 287 (0.35%)
    0 / 286 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Large intestine polyp
         subjects affected / exposed
    1 / 287 (0.35%)
    0 / 286 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Bile duct stone
         subjects affected / exposed
    1 / 287 (0.35%)
    0 / 286 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholelithiasis
         subjects affected / exposed
    1 / 287 (0.35%)
    0 / 286 (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
    Haematuria
         subjects affected / exposed
    0 / 287 (0.00%)
    1 / 286 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    0 / 287 (0.00%)
    1 / 286 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteoarthritis
         subjects affected / exposed
    1 / 287 (0.35%)
    0 / 286 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal stenosis
         subjects affected / exposed
    0 / 287 (0.00%)
    1 / 286 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spondylolisthesis
         subjects affected / exposed
    0 / 287 (0.00%)
    1 / 286 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tenosynovitis
         subjects affected / exposed
    1 / 287 (0.35%)
    0 / 286 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Endophthalmitis
         subjects affected / exposed
    1 / 287 (0.35%)
    0 / 286 (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
    2 / 287 (0.70%)
    1 / 286 (0.35%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    2 / 287 (0.70%)
    0 / 286 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aspergilloma
         subjects affected / exposed
    0 / 287 (0.00%)
    1 / 286 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bone tuberculosis
         subjects affected / exposed
    1 / 287 (0.35%)
    0 / 286 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    1 / 287 (0.35%)
    0 / 286 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    COVID-19 pneumonia
         subjects affected / exposed
    1 / 287 (0.35%)
    0 / 286 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diverticulitis
         subjects affected / exposed
    1 / 287 (0.35%)
    0 / 286 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    1 / 287 (0.35%)
    0 / 286 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyelonephritis acute
         subjects affected / exposed
    0 / 287 (0.00%)
    1 / 286 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Staphylococcal bacteraemia
         subjects affected / exposed
    0 / 287 (0.00%)
    1 / 286 (0.35%)
         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 / 287 (0.00%)
    1 / 286 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Hyperkalaemia
         subjects affected / exposed
    0 / 287 (0.00%)
    1 / 286 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    1 / 287 (0.35%)
    0 / 286 (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
    		 SCD411 group Eylea group
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    59 / 287 (20.56%)
    55 / 286 (19.23%)
    Eye disorders
    Punctate keratitis
         subjects affected / exposed
    2 / 287 (0.70%)
    0 / 286 (0.00%)
         occurrences all number
    2
    0
    Visual acuity reduced
         subjects affected / exposed
    13 / 287 (4.53%)
    13 / 286 (4.55%)
         occurrences all number
    13
    13
    Conjunctivitis allergic
         subjects affected / exposed
    2 / 287 (0.70%)
    0 / 286 (0.00%)
         occurrences all number
    2
    0
    Neovascular age-related macular degeneration
         subjects affected / exposed
    19 / 287 (6.62%)
    13 / 286 (4.55%)
         occurrences all number
    19
    13
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    0 / 287 (0.00%)
    2 / 286 (0.70%)
         occurrences all number
    0
    2
    Vomiting
         subjects affected / exposed
    0 / 287 (0.00%)
    2 / 286 (0.70%)
         occurrences all number
    0
    2
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    2 / 287 (0.70%)
    2 / 286 (0.70%)
         occurrences all number
    2
    2
    Osteoporosis
         subjects affected / exposed
    0 / 287 (0.00%)
    2 / 286 (0.70%)
         occurrences all number
    0
    2
    Infections and infestations
    COVID-19
         subjects affected / exposed
    18 / 287 (6.27%)
    21 / 286 (7.34%)
         occurrences all number
    18
    21
    Nasopharyngitis
         subjects affected / exposed
    3 / 287 (1.05%)
    0 / 286 (0.00%)
         occurrences all number
    3
    0

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    24 Nov 2020
    The following is a summary of the major changes implemented with Protocol Amendment 1, Version 2.0, dated 24 Nov 2020: • Section 2.5 Estimands: This section was revised as per the United States Food and Drug Administration (US FDA) requirement of changing the Full Analysis Set (FAS) and the recommendation of not discontinuing subjects from the study when they discontinue study treatment. • Section 3.1 Study Design • Section 4.1.1 Inclusion Criteria • Section 4.1.2 Exclusion Criteria • A new Section 4.2 Selection of Study Eye was added as per the US FDA requirement to clearly define the study eye in the protocol. • Section 4.3.1 Discontinuation From Study Treatment and Section 4.3.2 Withdrawal From the Study • Section 4.3.3 Handling of Withdrawals • Section 4.3.4 Screen Failures • Section 5.2 Treatments Administered • Section 5.2.1 Treatment of Fellow Eye • Section 5.3 Identity of IP: As per the US FDA request, the source of Eylea was updated. • Section 5.8.1 Rescue Treatment • Section 5.8.2 Prohibited Medications • Section 6.1.3 Early Termination/End-of-Study • Section 6.3.3.6 Suspected Unexpected Serious Adverse Reactions (SUSAR) and Nonserious Adverse Events of Special Interest (AESIs) • Section 6.4 Pharmacokinetic Assessments • Section 6.7 Pregnancy • Section 7.1 Estimands and Intercurrent Events • Section 7.2 Sample Size Determination • Section 7.3 Analysis Sets: The definition of the FAS was updated as per the request from US FDA. The definitions of the Safety Set and the PK Set were updated for clarity. • Section 7.5.1.1 Primary Efficacy Outcome Measures • Section 7.5.1.2 Secondary Efficacy Outcome Measures • Section 11.2.2 Protocol Deviations • Section 12 Reference List: The reference list was updated with the European Medicines Agency’s (EMA) overview of Eylea.
    24 Jan 2022
    The following is a summary of the major changes implemented with Protocol Amendment 2, Version 3.0, dated 24 Jan 2022: • Exclusion criterion 29 (Synopsis; Section 4.1.2): For subjects with a history or evidence of cardiac conditions was reworded for clarity. • Statistical methods (Synopsis; Section 3.1 Study Design; Section 7 Statistical Analytical Plan; Section 7.5.6 Interim Analyses): Interim analysis was added to support regulatory filing to the Pharmaceutical and Medical Devices Agency (PMDA). • Section 6.3.3.1 Definitions of Adverse Events; Section 6.3.3.4 Reporting Adverse Events; Section 6.3.3.8 Assessment of Causality: An assessment of AEs was included for the IVT injection procedure. • Section 6.6 Independent Data Monitoring Committee; Section 11.1.1 External Data Monitoring Committee; Section 11.4 Final Report: Text was modified to reflect the addition of an interim analysis. • Throughout the protocol: Changes were made to achieve consistency between different sections of the protocol and statistical analysis plan (SAP) and to improve the readability and overall quality of the document.

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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