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    Clinical Trial Results:
    TOPAZ: A Randomized, Masked, Controlled Trial to Study the Safety and Efficacy of Suprachoroidal CLS-TA in Combination With an Intravitreal Anti-VEGF Agent in Subjects With Retinal Vein Occlusion

    Summary
    EudraCT number
    		 2017-002089-37
    Trial protocol
    		 GB   HU   EE  
    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

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    Trial identification
    Sponsor protocol code
    CLS1003-302
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03203447
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Clearside Biomedical, Inc.
    Sponsor organisation address
    900 North Point Parkway, Suite 200, Alpharetta, United States, GA 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 in pharmacologic treatment naïve subjects with retinal vein occlusion (RVO), suprachoroidal (SC) triamcinolone acetonide injectable suspension (CLS-TA) administered with an intravitreal (IVT) anti-Vascular endothelial growth factor (anti-VEGF) agent was superior to an IVT anti-VEGF agent alone using a best corrected visual acuity (BCVA) outcome.
    Protection of trial subjects
    The study was conducted in accordance with the ethical principles stated in the Declaration of Helsinki and the International Council on Harmonization (ICH) Guideline for Good Clinical Practice (GCP) and applicable regulatory requirements.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    02 Mar 2018
    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
    Australia: 5
    Country: Number of subjects enrolled
    Hungary: 2
    Country: Number of subjects enrolled
    India: 121
    Country: Number of subjects enrolled
    United States: 197
    Worldwide total number of subjects
    325
    EEA total number of subjects
    2
    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)
    167
    From 65 to 84 years
    146
    85 years and over
    12

    Subject disposition

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    Recruitment
    Recruitment details
    		 325 subjects were randomized in study. 3 subjects were randomized but not received treatment. Therefore, efficacy data, based on intent-to-treat population, included all 325 subjects, while adverse event data, based on safety population, subjects received 1 or more treatments, included 322 subjects. Study was terminated due to sponsor discretion.

    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
    		 CLS-TA + Intravitreal Anti-VEGF agent + Intravitreal Sham
    Arm description
    		 All subjects were to receive 3 unilateral SC 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 an IVT anti-VEGF agent (either ranibizumab 0.5 mg in 0.05 millilitres [mL] or bevacizumab 1.25 mg in 0.05 mL) in the study eye on Day 0, Week 4, Week 12 and Week 24. Subjects also received IVT 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 administer with 3 unilateral SC injections of CLS-TA for 12 weeks apart at Day 0, Week 12 and Week 24 in the study eye.

    Investigational medicinal product name
    Ranibizumab
    Investigational medicinal product code
    Other name
    Lucentis
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravitreal use
    Dosage and administration details
    Subjects were to administer with 4 unilateral injections of IVT ranibizumab at Day 0, Week 4, Week 12 and Week 24.

    Investigational medicinal product name
    Bevacizumab
    Investigational medicinal product code
    Other name
    Avastin
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravitreal use
    Dosage and administration details
    Subjects were to administer with 4 unilateral injections of IVT bevacizumab at Day 0, Week 4, Week 12 and Week 24.

    Arm title
    		 Intravitreal Anti-VEGF agent + Suprachoroidal Sham procedure
    Arm description
    		 All subjects were to receive 7 unilateral injections of IVT anti-VEGF agent (either ranibizumab 0.5 mg in 0.05 mL or bevacizumab 1.25 mg in 0.05 mL) administered 4 weeks apart on Day 0, Week 4, Week 8, Week 12, Week 16, Week 20, and Week 24 along with 3 sham SC procedures administered 12 weeks apart on Day 0, Week 12, and Week 24 in the study eye.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Ranibizumab
    Investigational medicinal product code
    Other name
    Lucentis
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravitreal use
    Dosage and administration details
    Subjects were to administer with 7 unilateral injections of ranibizumab administered 4 weeks apart at Day 0, Week 4, Week 8, Week 12, Week 16, Week 20 and Week 24.

    Investigational medicinal product name
    Bevacizumab
    Investigational medicinal product code
    Other name
    Avastin
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravitreal use
    Dosage and administration details
    Subjects were to administer with 7 unilateral injections of bevacizumab administered 4 weeks apart at Day 0, Week 4, Week 8, Week 12, Week 16, Week 20 and Week 24.

    Number of subjects in period 1
    		CLS-TA + Intravitreal Anti-VEGF agent + Intravitreal Sham Intravitreal Anti-VEGF agent + Suprachoroidal Sham procedure
    Started
    162
    163
    Treated
    160
    162
    Completed
    0
    0
    Not completed
    162
    163
         Consent withdrawn by subject
    2
    1
         Study Termination
    156
    150
         Unknown
    3
    2
         Lost to follow-up
    1
    10

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    CLS-TA + Intravitreal Anti-VEGF agent + Intravitreal Sham
    Reporting group description
    		 All subjects were to receive 3 unilateral SC 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 an IVT anti-VEGF agent (either ranibizumab 0.5 mg in 0.05 millilitres [mL] or bevacizumab 1.25 mg in 0.05 mL) in the study eye on Day 0, Week 4, Week 12 and Week 24. Subjects also received IVT sham procedures on Week 8, Week 16, and Week 20.

    Reporting group title
    Intravitreal Anti-VEGF agent + Suprachoroidal Sham procedure
    Reporting group description
    		 All subjects were to receive 7 unilateral injections of IVT anti-VEGF agent (either ranibizumab 0.5 mg in 0.05 mL or bevacizumab 1.25 mg in 0.05 mL) administered 4 weeks apart on Day 0, Week 4, Week 8, Week 12, Week 16, Week 20, and Week 24 along with 3 sham SC procedures administered 12 weeks apart on Day 0, Week 12, and Week 24 in the study eye.

    Reporting group values
    		 CLS-TA + Intravitreal Anti-VEGF agent + Intravitreal Sham Intravitreal Anti-VEGF agent + Suprachoroidal Sham procedure Total
    Number of subjects
    		 162 163 325
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 63.7 ( 13.03 ) 62.7 ( 12.29 ) -
    Gender categorical
    Units: Subjects
        Female
    		 82 70 152
        Male
    		 80 93 173
    Race
    Units: Subjects
        Asian
    		 73 70 143
        Black or African American
    		 6 3 9
        Native Hawaiian or Other Pacific Islander
    		 1 2 3
        White
    		 78 85 163
        Other
    		 2 1 3
        Unknown/Not reported
    		 1 2 3
        Not applicable
    		 1 0 1

    End points

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    End points reporting groups
    Reporting group title
    CLS-TA + Intravitreal Anti-VEGF agent + Intravitreal Sham
    Reporting group description
    		 All subjects were to receive 3 unilateral SC 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 an IVT anti-VEGF agent (either ranibizumab 0.5 mg in 0.05 millilitres [mL] or bevacizumab 1.25 mg in 0.05 mL) in the study eye on Day 0, Week 4, Week 12 and Week 24. Subjects also received IVT sham procedures on Week 8, Week 16, and Week 20.

    Reporting group title
    Intravitreal Anti-VEGF agent + Suprachoroidal Sham procedure
    Reporting group description
    		 All subjects were to receive 7 unilateral injections of IVT anti-VEGF agent (either ranibizumab 0.5 mg in 0.05 mL or bevacizumab 1.25 mg in 0.05 mL) administered 4 weeks apart on Day 0, Week 4, Week 8, Week 12, Week 16, Week 20, and Week 24 along with 3 sham SC procedures administered 12 weeks apart on Day 0, Week 12, and Week 24 in the study eye.

    Primary: Percentage of Subjects Demonstrating >= 15 Letter Improvement in Best Corrected Visual Acuity (BCVA) in the Study Eye From Baseline to 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 to Week 8
    End point description
    BCVA were measured using an eye chart and reported as the number of letters read correctly (ranging from 0 to 100 letters). The lower the number of letters read correctly on the eye chart, the worse the vision (or visual acuity). An increase in the number of letters read correctly indicated improved vision. Analysis was performed on ITT population.
    End point type
    Primary
    End point timeframe
    Baseline, Week 8
    End point values
    		 CLS-TA + Intravitreal Anti-VEGF agent + Intravitreal Sham Intravitreal Anti-VEGF agent + Suprachoroidal Sham procedure
    Number of subjects analysed
    162
    163
    Units: percentage of subjects
        number (confidence interval 95%)
    39.5 (31.9 to 47.5)
    46.6 (38.8 to 54.6)
    Statistical analysis title
    		 Active versus Control
    Comparison groups
    CLS-TA + Intravitreal Anti-VEGF agent + Intravitreal Sham v Intravitreal Anti-VEGF agent + Suprachoroidal Sham procedure
    Number of subjects included in analysis
    325
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.191 [1]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Percentage Difference
    Point estimate
    -7.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -17.9
         upper limit
    		 3.6
    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 in the Study Eye

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    End point title
    		 Mean Change From Baseline in Best Corrected Visual Acuity in the Study Eye
    End point description
    BCVA is measured using an eye chart and is reported as the number of letters read correctly (ranging from 0 to 100 letters). The lower the number of letters read correctly on the eye chart, the worse the vision (or visual acuity). An increase in the number of letters read correctly means that vision has improved. Analysis was performed on ITT population. Here, ‘n’ = number of subjects analysed for each specified category. In the below table, 99999 represents that data was not collected for the specified endpoint because there was no subject assessed at the particular time point.
    End point type
    Secondary
    End point timeframe
    Baseline, Weeks 4, 8, 12, 16, 20, 24, 30 and 36
    End point values
    		 CLS-TA + Intravitreal Anti-VEGF agent + Intravitreal Sham Intravitreal Anti-VEGF agent + Suprachoroidal Sham procedure
    Number of subjects analysed
    162
    163
    Units: letters
    least squares mean (standard error)
        Week 4 (n = 146, 152)
    11.2 ( 0.85 )
    12.1 ( 0.84 )
        Week 8 (n = 116, 112)
    14.3 ( 0.93 )
    15.5 ( 0.94 )
        Week 12 (n = 77, 74)
    14.1 ( 1.06 )
    17.1 ( 1.08 )
        Week 16 (n = 49, 50)
    16.2 ( 1.25 )
    19.4 ( 1.24 )
        Week 20 (n = 28, 31)
    15.5 ( 1.55 )
    20.9 ( 1.49 )
        Week 24 (n = 16, 17)
    13.8 ( 1.96 )
    20.7 ( 1.91 )
        Week 30 (n = 5, 5)
    14.2 ( 3.32 )
    25.1 ( 3.32 )
        Week 36 (n =2, 0)
    17.0 ( 5.15 )
    99999 ( 99999 )
    No statistical analyses for this end point

    Secondary: Mean Change from Baseline in Central Subfield Retinal Thickness (CST) in the Study Eye

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    End point title
    		 Mean Change from Baseline in Central Subfield Retinal Thickness (CST) in the Study Eye
    End point description
    Mean Change from Baseline in CST in the study eye were assessed. Analysis was performed on ITT population. Here, ‘n’ = number of subjects analysed for each specified category. In the below table, 99999 represents that data was not collected for the specified endpoint because there was no subject assessed at the particular time point.
    End point type
    Secondary
    End point timeframe
    Baseline, Weeks 4, 8, 12, 16, 20, 24, 30, and 36
    End point values
    		 CLS-TA + Intravitreal Anti-VEGF agent + Intravitreal Sham Intravitreal Anti-VEGF agent + Suprachoroidal Sham procedure
    Number of subjects analysed
    162
    159
    Units: microns
    least squares mean (standard error)
        Week 4 (n = 146, 151)
    -368.4 ( 9.07 )
    -319.9 ( 9.00 )
        Week 8 (n = 115, 109)
    -386.4 ( 9.76 )
    -338.9 ( 9.96 )
        Week 12 (n= 75, 74)
    -328.9 ( 11.11 )
    -349.9 ( 11.19 )
        Week 16 (n = 49, 50)
    -403.2 ( 12.76 )
    -356.9 ( 12.72 )
        Week 20 (n = 27, 31)
    -398.8 ( 15.85 )
    -373.3 ( 15.08 )
        Week 24 (n = 16, 17)
    -353.6 ( 19.60 )
    -374.7 ( 19.12 )
        Week 30 (n = 4, 5)
    -417.5 ( 36.59 )
    -356.3 ( 32.76 )
        Week 36 (n = 2, 0)
    -387.2 ( 50.86 )
    99999 ( 99999 )
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From Baseline through Week 48
    Adverse event reporting additional description
    Analysis was performed on the safety population that consisted of all randomised 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
    CLS-TA + Intravitreal Anti-VEGF agent + Intravitreal Sham
    Reporting group description
    		 All subjects were to receive 3 unilateral SC injections of 4 mg of CLS-TA 100 mcL, in conjunction with 4 unilateral injections of an IVT anti-VEGF agent (either ranibizumab 0.5 mg in 0.05 mL or bevacizumab 1.25 mg in 0.05 mL) in the study eye along with the sham IVT procedures.

    Reporting group title
    Intravitreal Anti-VEGF agent + Suprachoroidal Sham procedure
    Reporting group description
    		 All subjects were to receive 7 unilateral injections of IVT anti-VEGF agent (either ranibizumab 0.5 mg in 0.05 mL or bevacizumab 1.25 mg in 0.05 mL) along with 3 sham SC procedures in the study eye.

    Serious adverse events
    		 CLS-TA + Intravitreal Anti-VEGF agent + Intravitreal Sham Intravitreal Anti-VEGF agent + Suprachoroidal Sham procedure
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 160 (0.63%)
    3 / 162 (1.85%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    0 / 160 (0.00%)
    1 / 162 (0.62%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Cardiac failure congestive
         subjects affected / exposed
    1 / 160 (0.63%)
    0 / 162 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain upper
         subjects affected / exposed
    0 / 160 (0.00%)
    1 / 162 (0.62%)
         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
    Pulmonary embolism
         subjects affected / exposed
    0 / 160 (0.00%)
    1 / 162 (0.62%)
         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
    1 / 160 (0.63%)
    0 / 162 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Mental status changes
         subjects affected / exposed
    0 / 160 (0.00%)
    1 / 162 (0.62%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Urinary tract infection
         subjects affected / exposed
    0 / 160 (0.00%)
    1 / 162 (0.62%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Hyperglycaemia
         subjects affected / exposed
    0 / 160 (0.00%)
    1 / 162 (0.62%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 CLS-TA + Intravitreal Anti-VEGF agent + Intravitreal Sham Intravitreal Anti-VEGF agent + Suprachoroidal Sham procedure
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    11 / 160 (6.88%)
    1 / 162 (0.62%)
    Investigations
    Intraocular pressure increased
         subjects affected / exposed
    11 / 160 (6.88%)
    1 / 162 (0.62%)
         occurrences all number
    14
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    14 Dec 2017
    Following changes were made: Various formatting changes done throughout the protocol; ‘aflibercept’ replaced with ‘intravitreal anti-VEGF agent’ or ‘IVT anti-VEGF agent’ including of Lucentis and Avastin. Removed the post injection slit lamp ophthalmoscopy assessment from Appendix A to reflect common clinical procedures.
    25 Jan 2018
    Following changes were made: Clarified the distinction between serious and severe adverse events.

    Interruptions (globally)
    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    18 Dec 2018
    The Sponsor terminated the study prior to completion of enrollment due to the failure of companion phase 3 study (CLS1003-301).
    -

    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, 325 of the planned 460 were enrolled. 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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