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    Clinical Trial Results:
    Sapphire: A Randomized, Masked, Controlled Trial to Study the Safety and Efficacy Of Suprachoroidal CLS-TA in Conjunction with Intravitreal Aflibercept in Subjects with Retinal Vein Occlusion

    Summary
    EudraCT number
    		 2016-004648-12
    Trial protocol
    		 GB   HU   DE   ES   AT   PT   DK   PL   IT  
    Global end of trial date
    18 Dec 2018

    Results information
    Results version number
    		 v1(current)
    This version publication date
    05 Mar 2021
    First version publication date
    05 Mar 2021
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    CLS1003-301
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02980874
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Clearside Biomedical, Inc
    Sponsor organisation address
    900 North Point Parkway, Suite 200, Alpharetta, Georgia, United States, 30005
    Public contact
    Gina Debrah, Clearside Biomedical, Inc., 001 678254-2345, gina.debrah@clearsidebio.com
    Scientific contact
    Thomas Ciulla, MD, MBA, Clearside Biomedical, Inc., 001 678392-2318, thomas.ciulla@clearsidebio.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
    18 Dec 2018
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    18 Dec 2018
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    This study was to demonstrate that suprachoroidal triamcinolone acetonide injectable suspension (CLS-TA) in conjunction with intravitreal aflibercept is superior to intravitreal aflibercept alone in the proportion of subjects demonstrating greater than or equal to (>=) 15 letter improvement in best corrected visual acuity (BCVA) two months from Baseline.
    Protection of trial subjects
    The study was conducted in accordance with ethical principles that had their origin in the Declaration of Helsinki and were consistent with the International Council for Harmonisation Guideline for Good Clinical Practice, and applicable regulatory requirements.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    01 Feb 2017
    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: 10
    Country: Number of subjects enrolled
    Portugal: 5
    Country: Number of subjects enrolled
    Slovakia: 1
    Country: Number of subjects enrolled
    Spain: 5
    Country: Number of subjects enrolled
    United Kingdom: 6
    Country: Number of subjects enrolled
    Denmark: 3
    Country: Number of subjects enrolled
    Hungary: 7
    Country: Number of subjects enrolled
    Canada: 5
    Country: Number of subjects enrolled
    India: 32
    Country: Number of subjects enrolled
    Philippines: 3
    Country: Number of subjects enrolled
    Taiwan: 3
    Country: Number of subjects enrolled
    United States: 365
    Country: Number of subjects enrolled
    Australia: 15
    Worldwide total number of subjects
    460
    EEA total number of subjects
    37
    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)
    196
    From 65 to 84 years
    238
    85 years and over
    26

    Subject disposition

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    Recruitment
    Recruitment details
    		 A total of 653 subjects were screened, of which 460 subjects were randomised into the study.

    Pre-assignment
    Screening details
    		 This study was conducted in subjects with macular edema and retinal vein occlusion.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Active: CLS-TA + Intravitreal Aflibercept + Intravitreal Sham
    Arm description
    		 All subjects were to receive 3 unilateral suprachoroidal injections of 4 milligrams (mg) of CLS-TA in 100 microlitres (mcL) administered 12 weeks apart on Day 0, Week 12, and Week 24, in conjunction with 4 unilateral injections of intravitreal aflibercept of dose 2 mg in 50 mcL in the study eye on Day 0, Week 4, Week 12 and Week 24. Subjects also received intravitreal sham procedures on Week 8, Week 16, and Week 20.
    Arm type
    		 Experimental

    Investigational medicinal product name
    CLS-TA
    Investigational medicinal product code
    Other name
    Triamcinolone acetonide injectable suspension
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Intraocular use
    Dosage and administration details
    Subjects were to receive 3 unilateral SC injections of CLS-TA administered 12 weeks apart in the study eye.

    Investigational medicinal product name
    Aflibercept
    Investigational medicinal product code
    Other name
    Eylea
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravitreal use
    Dosage and administration details
    Subjects were to receive 4 unilateral injections of intravitreal aflibercept.

    Arm title
    		 Control:Intravitreal Aflibercept+Suprachoroidal Sham Procedure
    Arm description
    		 All subjects were to receive 7 unilateral injections of intravitreal aflibercept of dose 2 mg in 50 mcL administered 4 weeks apart on Day 0, Week 4, Week 8, Week 12, Week 16, Week 20, and Week 24 along with 3 suprachoroidal sham procedures administered 12 weeks apart on Day 0, Week 12, and Week 24.
    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
    Subjects were to receive 7 unilateral injections of intravitreal aflibercept.

    Number of subjects in period 1
    		Active: CLS-TA + Intravitreal Aflibercept + Intravitreal Sham Control:Intravitreal Aflibercept+Suprachoroidal Sham Procedure
    Started
    231
    229
    Completed
    128
    127
    Not completed
    103
    102
         Adverse events (AEs)
    2
    7
         Consent withdrawn by subject
    7
    2
         Unknown study completion status
    1
    -
         Other- Unspecified (included study termination)
    88
    88
         Lost to follow-up
    5
    5

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Active: CLS-TA + Intravitreal Aflibercept + Intravitreal Sham
    Reporting group description
    		 All subjects were to receive 3 unilateral suprachoroidal injections of 4 milligrams (mg) of CLS-TA in 100 microlitres (mcL) administered 12 weeks apart on Day 0, Week 12, and Week 24, in conjunction with 4 unilateral injections of intravitreal aflibercept of dose 2 mg in 50 mcL in the study eye on Day 0, Week 4, Week 12 and Week 24. Subjects also received intravitreal sham procedures on Week 8, Week 16, and Week 20.

    Reporting group title
    Control:Intravitreal Aflibercept+Suprachoroidal Sham Procedure
    Reporting group description
    		 All subjects were to receive 7 unilateral injections of intravitreal aflibercept of dose 2 mg in 50 mcL administered 4 weeks apart on Day 0, Week 4, Week 8, Week 12, Week 16, Week 20, and Week 24 along with 3 suprachoroidal sham procedures administered 12 weeks apart on Day 0, Week 12, and Week 24.

    Reporting group values
    		 Active: CLS-TA + Intravitreal Aflibercept + Intravitreal Sham Control:Intravitreal Aflibercept+Suprachoroidal Sham Procedure Total
    Number of subjects
    		 231 229 460
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 66.4 ± 12.31 64.9 ± 12.42 -
    Gender categorical
    Units: Subjects
        Female
    		 97 105 202
        Male
    		 134 124 258
    Race
    Units: Subjects
        American Indian/Alaska Native
    		 2 0 2
        Asian
    		 33 40 73
        Black/African American
    		 10 12 22
        Native Hawaiian/Other Pacific Islander
    		 1 0 1
        White
    		 181 177 358
        Other
    		 2 0 2
        Unknown/Not reported
    		 2 0 2

    End points

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    End points reporting groups
    Reporting group title
    Active: CLS-TA + Intravitreal Aflibercept + Intravitreal Sham
    Reporting group description
    		 All subjects were to receive 3 unilateral suprachoroidal injections of 4 milligrams (mg) of CLS-TA in 100 microlitres (mcL) administered 12 weeks apart on Day 0, Week 12, and Week 24, in conjunction with 4 unilateral injections of intravitreal aflibercept of dose 2 mg in 50 mcL in the study eye on Day 0, Week 4, Week 12 and Week 24. Subjects also received intravitreal sham procedures on Week 8, Week 16, and Week 20.

    Reporting group title
    Control:Intravitreal Aflibercept+Suprachoroidal Sham Procedure
    Reporting group description
    		 All subjects were to receive 7 unilateral injections of intravitreal aflibercept of dose 2 mg in 50 mcL administered 4 weeks apart on Day 0, Week 4, Week 8, Week 12, Week 16, Week 20, and Week 24 along with 3 suprachoroidal sham procedures administered 12 weeks apart on Day 0, Week 12, and Week 24.

    Primary: Percentage of Subjects Demonstrating >=15 Letter Improvement in Best Corrected Visual Acuity (BCVA) in the Study Eye From Baseline at Week 8

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    End point title
    		 Percentage of Subjects Demonstrating >=15 Letter Improvement in Best Corrected Visual Acuity (BCVA) in the Study Eye From Baseline at Week 8
    End point description
    BCVA was evaluated by Early Treatment of Diabetic Retinopathy Study (ETDRS) using standardized lighting and standardized lanes. The results were reported as the number of letters read. Visual acuity testing should precede any examination requiring contact with the eye. Analysis was performed on intent-to-treat (ITT) population that included all randomised subjects.
    End point type
    Primary
    End point timeframe
    Baseline, Week 8
    End point values
    		 Active: CLS-TA + Intravitreal Aflibercept + Intravitreal Sham Control:Intravitreal Aflibercept+Suprachoroidal Sham Procedure
    Number of subjects analysed
    231
    229
    Units: Percentage of subjects
        number (confidence interval 95%)
    49.4 (42.7 to 56.0)
    55.5 (48.8 to 62.0)
    Statistical analysis title
    		 CLS-TA+Aflibercept+Sham versus Aflibercept+Sham
    Comparison groups
    Active: CLS-TA + Intravitreal Aflibercept + Intravitreal Sham v Control:Intravitreal Aflibercept+Suprachoroidal Sham Procedure
    Number of subjects included in analysis
    460
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.187 [1]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Percentage Difference
    Point estimate
    -6.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -15.2
         upper limit
    		 3
    Notes
    [1] - The p-value was based on a CMH test for general association between treatment and response with stratification by type of retinal vein occlusion (BRVO, CRVO).

    Secondary: Mean Change from Baseline in Best Corrected Visual Acuity

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    End point title
    		 Mean Change from Baseline in Best Corrected Visual Acuity
    End point description
    BCVA was evaluated by ETDRS using standardized lighting and standardized lanes. The results were reported as the number of letters read. Visual acuity testing should precede any examination requiring contact with the eye. Analysis was performed on ITT population. Here 'n' signifies number of subjects with available data for specified category.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 8, and Week 24
    End point values
    		 Active: CLS-TA + Intravitreal Aflibercept + Intravitreal Sham Control:Intravitreal Aflibercept+Suprachoroidal Sham Procedure
    Number of subjects analysed
    231
    229
    Units: Change in letters
    least squares mean (standard error)
        Week 8 (n=225,225)
    14.8 ± 0.84
    17.8 ± 0.84
        Week 24 (n=216,213)
    15.5 ± 0.85
    20.5 ± 0.85
    No statistical analyses for this end point

    Secondary: Mean Change From Baseline in Central Subfield Retinal Thickness (CST)

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    End point title
    		 Mean Change From Baseline in Central Subfield Retinal Thickness (CST)
    End point description
    CST was used to assess retinal thickness and disease characterisation and was measured by spectral domain optical coherence tomography (SD-OCT) at each visit. Analysis was performed on ITT population. Here 'n' signifies number of subjects with available data for specified category.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 8, and Week 24
    End point values
    		 Active: CLS-TA + Intravitreal Aflibercept + Intravitreal Sham Control:Intravitreal Aflibercept+Suprachoroidal Sham Procedure
    Number of subjects analysed
    231
    229
    Units: Change in microns
    least squares mean (standard error)
        Week 8 (n=224,221)
    -405.3 ± 3.96
    -403.4 ± 3.99
        Week 24 (n=212,210)
    -354.3 ± 8.01
    -416.2 ± 8.05
    No statistical analyses for this end point

    Secondary: Number of Subjects with Treatment-Emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (TESAEs)

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    End point title
    		 Number of Subjects with Treatment-Emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (TESAEs)
    End point description
    Adverse event (AE) was defined as the development of an undesirable medical condition or the deterioration of a pre-existing medical condition after or during exposure to a pharmaceutical product, whether or not considered causally related to the product. A serious adverse event (SAE) was an AE occurring during any study phase and at any dose of study treatment fulfilled one or more of the following: death, immediately life-threatening, in-patient hospitalisation or prolongation of existing hospitalisation, persistent or significant disability or incapacity, congenital abnormality or birth defect or important medical event. A TEAE was any AE (or SAE) occurring on or after the date of the first dose of study drug or worsening relative to the pre-treatment state. Analysis was performed on safety population that included all randomly assigned subjects who were administered at least 1 dose of the study treatment.
    End point type
    Secondary
    End point timeframe
    From Baseline up to Week 48
    End point values
    		 Active: CLS-TA + Intravitreal Aflibercept + Intravitreal Sham Control:Intravitreal Aflibercept+Suprachoroidal Sham Procedure
    Number of subjects analysed
    231
    229
    Units: subjects
        TEAEs
    180
    156
        TESAEs
    25
    28
    No statistical analyses for this end point

    Secondary: Mean Change From Baseline in Excess Retinal Thickness (ERT)

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    End point title
    		 Mean Change From Baseline in Excess Retinal Thickness (ERT)
    End point description
    Excess retinal thickness was defined as CST minus 300 microns, set to 1 micron if CST was less than or equal to 300 microns. Analysis was performed on ITT population.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 8
    End point values
    		 Active: CLS-TA + Intravitreal Aflibercept + Intravitreal Sham Control:Intravitreal Aflibercept+Suprachoroidal Sham Procedure
    Number of subjects analysed
    231
    229
    Units: Change in microns
    least squares mean (standard error)
        Week 8
    -356.2 ± 2.65
    -353.6 ± 2.67
    No statistical analyses for this end point

    Secondary: Percentage of Subjects With Additional Intravitreal Aflibercept Injections Administered From Week 8 Through Week 20

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    End point title
    		 Percentage of Subjects With Additional Intravitreal Aflibercept Injections Administered From Week 8 Through Week 20
    End point description
    Analysis was performed on ITT population. Here 'n' signifies number of subjects with available data for specified category.
    End point type
    Secondary
    End point timeframe
    Weeks 8, 16, and 20
    End point values
    		 Active: CLS-TA + Intravitreal Aflibercept + Intravitreal Sham Control:Intravitreal Aflibercept+Suprachoroidal Sham Procedure
    Number of subjects analysed
    231
    229
    Units: percentage of subjects
    number (not applicable)
        Week 8 (n=225,226)
    7.6
    0
        Week 16 (n=220,215)
    7.3
    0
        Week 20 (n=216,219)
    12
    0
    No statistical analyses for this end point

    Secondary: Number of Subjects Gaining >=0, >=5, >=10, and >=15 Best Corrected Visual Acuity

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    End point title
    		 Number of Subjects Gaining >=0, >=5, >=10, and >=15 Best Corrected Visual Acuity
    End point description
    BCVA was evaluated by ETDRS using standardized lighting and standardized lanes. The results were reported as the number of letters read. Visual acuity testing should precede any examination requiring contact with the eye. Analysis was performed on ITT population. Here 'n' signifies number of subjects with available data for specified category.
    End point type
    Secondary
    End point timeframe
    Weeks 4, 8 and 48
    End point values
    		 Active: CLS-TA + Intravitreal Aflibercept + Intravitreal Sham Control:Intravitreal Aflibercept+Suprachoroidal Sham Procedure
    Number of subjects analysed
    231
    229
    Units: subjects
    number (not applicable)
        Week 4- Subjects Gained >=0 (n=227,222)
    210
    213
        Week 4- Subjects Gained >=5 (n=227,222)
    181
    190
        Week 4- Subjects Gained >=10 (n=227,222)
    127
    149
        Week 4- Subjects Gained >=15 (n=227,222)
    78
    94
        Week 8- Subjects Gained >=0 (n=224,225)
    212
    217
        Week 8- Subjects Gained >=5 (n=224,225)
    188
    206
        Week 8- Subjects Gained >=10 (n=224,225)
    153
    172
        Week 8- Subjects Gained >=15 (n=224,225)
    114
    126
        Week 48- Subjects Gained >=0 (n=121,124)
    98
    110
        Week 48- Subjects Gained >=5 (n=121,124)
    86
    103
        Week 48- Subjects Gained >=10 (n=121,124)
    67
    94
        Week 48- Subjects Gained >=15 (n=121,124)
    46
    84
    No statistical analyses for this end point

    Secondary: Number of Subjects With Best Corrected Visual Acuity >70

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    End point title
    		 Number of Subjects With Best Corrected Visual Acuity >70
    End point description
    BCVA was evaluated by ETDRS using standardized lighting and standardized lanes. The results were reported as the number of letters read. Visual acuity testing should precede any examination requiring contact with the eye. Analysis was performed on ITT population in subjects with a baseline BCVA <=70 letters. Here 'n' signifies number of subjects with available data for specified category.
    End point type
    Secondary
    End point timeframe
    Weeks 4 and 8
    End point values
    		 Active: CLS-TA + Intravitreal Aflibercept + Intravitreal Sham Control:Intravitreal Aflibercept+Suprachoroidal Sham Procedure
    Number of subjects analysed
    231
    229
    Units: subjects
    number (not applicable)
        Week 4 (n=227,220)
    79
    89
        Week 8 (n=224,223)
    88
    115
    No statistical analyses for this end point

    Secondary: Percentage of Subjects Who Did Not Lose 15 or More Early Treatment of Diabetic Retinopathy Study Letters From Baseline

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    End point title
    		 Percentage of Subjects Who Did Not Lose 15 or More Early Treatment of Diabetic Retinopathy Study Letters From Baseline
    End point description
    Analysis was performed on ITT population. Here 'n' signifies number of subjects with available data for specified category.
    End point type
    Secondary
    End point timeframe
    Weeks 4, 8, 12, 16, 20, 24, 30, 36, 42 and 48
    End point values
    		 Active: CLS-TA + Intravitreal Aflibercept + Intravitreal Sham Control:Intravitreal Aflibercept+Suprachoroidal Sham Procedure
    Number of subjects analysed
    228
    225
    Units: percentage of subjects
    number (confidence interval 95%)
        Week 4 (n=228,222)
    0.9 (0.1 to 3.1)
    0.9 (0.1 to 3.2)
        Week 8 (n=225,225)
    0.9 (0.1 to 3.2)
    0.4 (0.0 to 2.5)
        Week 12 (n=219,224)
    1.4 (0.3 to 4.0)
    0.9 (0.1 to 3.2)
        Week 16 (n=219,212)
    1.8 (0.5 to 4.6)
    0.9 (0.1 to 3.4)
        Week 20 (n=216,214)
    3.2 (1.3 to 6.6)
    0.0 (0.0 to 1.7)
        Week 24 (n=216,213)
    2.3 (0.8 to 5.3)
    1.9 (0.5 to 4.7)
        Week 30 (n=206,209)
    2.4 (0.8 to 5.6)
    2.4 (0.8 to 5.5)
        Week 36 (n=172,174)
    3.5 (1.3 to 7.4)
    3.4 (1.3 to 7.4)
        Week 42 (n=140,140)
    4.3 (1.6 to 9.1)
    2.1 (0.4 to 6.1)
        Week 48 (n=121,124)
    4.1 (1.4 to 9.4)
    4.8 (1.8 to 10.2)
    No statistical analyses for this end point

    Secondary: Percentage of Subjects with Central Subfield Retinal Thickness <300 Microns at Every Study Visit

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    End point title
    		 Percentage of Subjects with Central Subfield Retinal Thickness <300 Microns at Every Study Visit
    End point description
    CST was used to assess retinal thickness and disease characterisation and was measured by Spectral Domain Optical Coherence Tomography (SD-OCT) at each visit. Analysis was performed on ITT population. Here 'n' signifies number of subjects with available data for specified category.
    End point type
    Secondary
    End point timeframe
    Weeks 4 and 8
    End point values
    		 Active: CLS-TA + Intravitreal Aflibercept + Intravitreal Sham Control:Intravitreal Aflibercept+Suprachoroidal Sham Procedure
    Number of subjects analysed
    231
    229
    Units: Percentage of subjects
    number (not applicable)
        Week 4 (n=214,214)
    84.1
    77.1
        Week 8 (n=217,217)
    89.9
    88.9
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From Baseline to Week 48
    Adverse event reporting additional description
    Analysis was performed on safety population which consisted of all randomized subjects who received at least 1 dose of the study treatment.
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    18.1
    Reporting groups
    Reporting group title
    Active: CLS-TA + Intravitreal Aflibercept + Intravitreal Sham
    Reporting group description
    		 All subjects were to receive 3 unilateral suprachoroidal injections of 4 mg of CLS-TA in 100 mcL administered 12 weeks apart on Day 0, Week 12, and Week 24, in conjunction with 4 unilateral injections of intravitreal aflibercept of dose 2 mg in 50 mcL in the study eye on Day 0, Week 4, Week 12 and Week 24. Subjects also received intravitreal sham procedures on Week 8, Week 16, and Week 20.

    Reporting group title
    Control:Intravitreal Aflibercept+Suprachoroidal Sham Procedure
    Reporting group description
    		 All subjects were to receive 7 unilateral injections of intravitreal aflibercept of dose 2 mg in 50 mcLadministered 4 weeks apart on Day 0, Week 4, Week 8, Week 12, Week 16, Week 20, and Week 24 along with 3 suprachoroidal sham procedures administered 12 weeks apart on Day 0, Week 12, and Week 24.

    Serious adverse events
    		 Active: CLS-TA + Intravitreal Aflibercept + Intravitreal Sham Control:Intravitreal Aflibercept+Suprachoroidal Sham Procedure
    Total subjects affected by serious adverse events
         subjects affected / exposed
    25 / 231 (10.82%)
    28 / 229 (12.23%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Ovarian cancer metastatic
         subjects affected / exposed
    1 / 231 (0.43%)
    0 / 229 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Paraganglion neoplasm malignant
         subjects affected / exposed
    0 / 231 (0.00%)
    1 / 229 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Squamous cell carcinoma
         subjects affected / exposed
    0 / 231 (0.00%)
    1 / 229 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Aortic arteriosclerosis
         subjects affected / exposed
    1 / 231 (0.43%)
    0 / 229 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aortic stenosis
         subjects affected / exposed
    0 / 231 (0.00%)
    1 / 229 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypertension
         subjects affected / exposed
    1 / 231 (0.43%)
    0 / 229 (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
    Abasia
         subjects affected / exposed
    1 / 231 (0.43%)
    0 / 229 (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
    1 / 231 (0.43%)
    2 / 229 (0.87%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    1 / 231 (0.43%)
    0 / 229 (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
    1 / 231 (0.43%)
    0 / 229 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pelvic pain
         subjects affected / exposed
    1 / 231 (0.43%)
    0 / 229 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Prostatomegaly
         subjects affected / exposed
    0 / 231 (0.00%)
    1 / 229 (0.44%)
         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
    Dyspnoea
         subjects affected / exposed
    1 / 231 (0.43%)
    1 / 229 (0.44%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung disorder
         subjects affected / exposed
    1 / 231 (0.43%)
    0 / 229 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary congestion
         subjects affected / exposed
    1 / 231 (0.43%)
    0 / 229 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Major depression
         subjects affected / exposed
    1 / 231 (0.43%)
    0 / 229 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mental status changes
         subjects affected / exposed
    0 / 231 (0.00%)
    1 / 229 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Intraocular pressure increased
         subjects affected / exposed
    3 / 231 (1.30%)
    0 / 229 (0.00%)
         occurrences causally related to treatment / all
    3 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Alcohol poisoning
         subjects affected / exposed
    1 / 231 (0.43%)
    0 / 229 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Facial bones fracture
         subjects affected / exposed
    0 / 231 (0.00%)
    1 / 229 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fall
         subjects affected / exposed
    1 / 231 (0.43%)
    0 / 229 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Head injury
         subjects affected / exposed
    1 / 231 (0.43%)
    0 / 229 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Multiple fractures
         subjects affected / exposed
    1 / 231 (0.43%)
    0 / 229 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pelvic fracture
         subjects affected / exposed
    1 / 231 (0.43%)
    0 / 229 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rib fracture
         subjects affected / exposed
    1 / 231 (0.43%)
    0 / 229 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Road traffic accident
         subjects affected / exposed
    1 / 231 (0.43%)
    0 / 229 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal fracture
         subjects affected / exposed
    1 / 231 (0.43%)
    0 / 229 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sternal fracture
         subjects affected / exposed
    1 / 231 (0.43%)
    0 / 229 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Acute coronary syndrome
         subjects affected / exposed
    1 / 231 (0.43%)
    0 / 229 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    2 / 231 (0.87%)
    1 / 229 (0.44%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Coronary artery disease
         subjects affected / exposed
    0 / 231 (0.00%)
    2 / 229 (0.87%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    0 / 231 (0.00%)
    2 / 229 (0.87%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Balance disorder
         subjects affected / exposed
    0 / 231 (0.00%)
    1 / 229 (0.44%)
         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
    1 / 231 (0.43%)
    1 / 229 (0.44%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Coma
         subjects affected / exposed
    1 / 231 (0.43%)
    0 / 229 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dizziness
         subjects affected / exposed
    1 / 231 (0.43%)
    1 / 229 (0.44%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Facial paralysis
         subjects affected / exposed
    1 / 231 (0.43%)
    0 / 229 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hemiplegia
         subjects affected / exposed
    1 / 231 (0.43%)
    0 / 229 (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
    2 / 231 (0.87%)
    0 / 229 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transient global amnesia
         subjects affected / exposed
    1 / 231 (0.43%)
    0 / 229 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    0 / 231 (0.00%)
    3 / 229 (1.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 231 (0.00%)
    3 / 229 (1.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Cataract
         subjects affected / exposed
    1 / 231 (0.43%)
    0 / 229 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Retinal detachment
         subjects affected / exposed
    0 / 231 (0.00%)
    1 / 229 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ulcerative keratitis
         subjects affected / exposed
    0 / 231 (0.00%)
    1 / 229 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Visual acuity reduced
         subjects affected / exposed
    2 / 231 (0.87%)
    0 / 229 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vitreous haemorrhage
         subjects affected / exposed
    0 / 231 (0.00%)
    1 / 229 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Gastritis
         subjects affected / exposed
    1 / 231 (0.43%)
    0 / 229 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal obstruction
         subjects affected / exposed
    0 / 231 (0.00%)
    1 / 229 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Large intestinal obstruction
         subjects affected / exposed
    0 / 231 (0.00%)
    1 / 229 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis acute
         subjects affected / exposed
    1 / 231 (0.43%)
    0 / 229 (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
    Acute kidney injury
         subjects affected / exposed
    1 / 231 (0.43%)
    1 / 229 (0.44%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haematuria
         subjects affected / exposed
    1 / 231 (0.43%)
    0 / 229 (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
    Rotator cuff syndrome
         subjects affected / exposed
    0 / 231 (0.00%)
    1 / 229 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Appendicitis perforated
         subjects affected / exposed
    0 / 231 (0.00%)
    1 / 229 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    0 / 231 (0.00%)
    1 / 229 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colonic abscess
         subjects affected / exposed
    0 / 231 (0.00%)
    1 / 229 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diverticulitis
         subjects affected / exposed
    0 / 231 (0.00%)
    1 / 229 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Empyema
         subjects affected / exposed
    1 / 231 (0.43%)
    0 / 229 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endophthalmitis
         subjects affected / exposed
    0 / 231 (0.00%)
    1 / 229 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatitis C
         subjects affected / exposed
    0 / 231 (0.00%)
    1 / 229 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Perirectal abscess
         subjects affected / exposed
    0 / 231 (0.00%)
    1 / 229 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    1 / 231 (0.43%)
    0 / 229 (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
    0 / 231 (0.00%)
    1 / 229 (0.44%)
         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
    2 / 231 (0.87%)
    0 / 229 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    1 / 231 (0.43%)
    0 / 229 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    2 / 231 (0.87%)
    0 / 229 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lactic acidosis
         subjects affected / exposed
    1 / 231 (0.43%)
    0 / 229 (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
    		 Active: CLS-TA + Intravitreal Aflibercept + Intravitreal Sham Control:Intravitreal Aflibercept+Suprachoroidal Sham Procedure
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    197 / 231 (85.28%)
    116 / 229 (50.66%)
    Investigations
    Intraocular pressure increased
         subjects affected / exposed
    33 / 231 (14.29%)
    9 / 229 (3.93%)
         occurrences all number
    51
    13
    Vascular disorders
    Hypertension
         subjects affected / exposed
    15 / 231 (6.49%)
    15 / 229 (6.55%)
         occurrences all number
    18
    17
    Eye disorders
    Cataract
         subjects affected / exposed
    21 / 231 (9.09%)
    9 / 229 (3.93%)
         occurrences all number
    29
    12
    Cataract subcapsular
         subjects affected / exposed
    20 / 231 (8.66%)
    3 / 229 (1.31%)
         occurrences all number
    22
    3
    Conjunctival haemorrhage
         subjects affected / exposed
    42 / 231 (18.18%)
    28 / 229 (12.23%)
         occurrences all number
    65
    31
    Eye pain
         subjects affected / exposed
    20 / 231 (8.66%)
    11 / 229 (4.80%)
         occurrences all number
    24
    11
    Macular oedema
         subjects affected / exposed
    8 / 231 (3.46%)
    13 / 229 (5.68%)
         occurrences all number
    11
    16
    Visual acuity reduced
         subjects affected / exposed
    16 / 231 (6.93%)
    6 / 229 (2.62%)
         occurrences all number
    18
    7
    Vitreous detachment
         subjects affected / exposed
    13 / 231 (5.63%)
    9 / 229 (3.93%)
         occurrences all number
    16
    10
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    9 / 231 (3.90%)
    13 / 229 (5.68%)
         occurrences all number
    9
    13

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    31 Mar 2017
    The amendments were as follows: 1. Treatment provided during pro re nata (PRN) period restricted to aflibercept only, reference to the use of CLS-TA in the PRN period removed. 2. Inclusion criteria: updated minimum ETDRS BCVA to >=20 letters read. 3. Ophthalmic exclusion criteria: updated to exclude subjects that had received any intraocular or periocular corticosteroid injection, OZURDEX® implant, a RETISERT® implant, or an ILUVIEN® implant. 4. Ophthalmic exclusion criteria: updated to exclude subjects who had >3 macular laser photocoagulation treatments. 5. Addition of ophthalmic exclusion criteria: history of glaucoma, optic nerve head change consistent with glaucoma damage; or ocular hypertension in the study eye requiring more than one medication. 6. Addition of history of laser trabeculoplasty or MIGS surgery to ophthalmic exclusion criteria. 7. General exclusion criteria: updated to allow treatment of blood pressure prior to Baseline. 8. Addition of general exclusion criteria: history of any inflammatory or other medical condition that the investigator might reasonably anticipate would require treatment with high-dose corticosteroids (>10 mg/day oral prednisone or the equivalent) for >14 days. 9. Addition of instruction to collect IOP data on the fellow eye at all visits for comparison to the study eye IOP. 10. Rescue therapy criteria updated to start from Visit 4 (Week 8), and the criteria for additional treatment updated. 11. High dose systemic corticosteroids (>10 mg/day of prednisone or equivalent) for >14 days and Macular (grid/focal) laser added to prohibited medications/treatments.

    Interruptions (globally)
    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    05 Nov 2018
    The study was terminated as the primary (8-week) efficacy endpoint was not met. No additional benefit was observed for subjects receiving CLS-TA + aflibercept as compared to aflibercept monotherapy.
    -

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    Due to the early termination of the trial by sponsor all planned study visits were not completed by all treated subjects; therefore, all planned data was not collected.
    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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