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    Clinical Trial Results:
    A Multicentre Prospective Open-label Randomised Clinical Trial Comparing the Efficacy of Fixed versus PRN dosing of 700 μg Dexamethasone Posterior Segment Drug Delivery System (DEX PS DDS) in patients with refractory diabetic macular oedema

    Summary
    EudraCT number
    		 2012-003661-17
    Trial protocol
    		 GB  
    Global end of trial date
    10 Nov 2014

    Results information
    Results version number
    		 v1(current)
    This version publication date
    23 Aug 2018
    First version publication date
    23 Aug 2018
    Other versions
    Summary report(s)
    		 Study Summary
    Trial Results

    Trial information

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    Trial identification
    Sponsor protocol code
    Protocol SS01 Version 7.0 dated 07-
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01892163
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Moorfields Eye Hospital
    Sponsor organisation address
    162 City Road, London, United Kingdom, EC1V 2PD
    Public contact
    Prof. Sobha Sivaprasad, Moorfields Eye Hospital, sobha.sivaprasad@moorfields.nhs.uk
    Scientific contact
    Prof. Sobha Sivaprasad, Moorfields Eye Hospital, sobha.sivaprasad@moorfields.nhs.uk
    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
    06 Nov 2015
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    10 Nov 2014
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To compare the clinical effectiveness and safety of 5-monthly fixed dosing versus pro-re-nata (PRN) Ozurdex treatment in patients with refractory diabetic macular oedema (DMO).
    Protection of trial subjects
    AE and SAE were reported at any point in the study. All AEs and SAEs were discussed at the DMC. The DMC reviewed the accruing trial data and on-going safety issues. There were no safety issues, but if there were any issues that needed further action, these would have been escalated to the Trial Steering Committee who would have then decided whether the study continues, terminates or if any substantial changes to the protocol were required. There was a one week and 8 weeks visit after the baseline and all subsequent Ozurdex injections in both treatment arms. If there was any safety concern in the opinion of the investigator, patients were assessed at an optional post-injection assessment visit. If new safety information results in significant changes in the risk/benefit assessment, the consent form should be reviewed and updated if necessary. All subjects, including those already being treated, should be informed of the new information, given a copy of the revised form and give their consent to continue in the study. If any urgent safety measures are taken the PI/Sponsor shall immediately and in any event no later than 3 days from the date the measures are taken, give written notice to the MHRA and the relevant REC of the measures taken and the circumstances giving rise to those measures
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    05 Feb 2013
    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
    United Kingdom: 100
    Worldwide total number of subjects
    100
    EEA total number of subjects
    100
    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)
    45
    From 65 to 84 years
    53
    85 years and over
    2

    Subject disposition

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    Recruitment
    Recruitment details
    		 A total of 100 patients were enrolled from February 2013 to November 2014 and randomized to study treatment across 5 sites. All recruited patients received the baseline Ozurdex injection and 49/50 (98%) in the fixed arm and 48/50 (96%) in the PRN arm completed the study providing primary outcome data (ITT).

    Pre-assignment
    Screening details
    		 Eligible patients were at least 18 years old with diabetes, BCVA letter score 73 to 34, OCT >300 μm in the central subfield (CST) despite treatment. Exclusion was macular ischemia, previous treatment for DME with steroids in the last 6 months; anti-VEGF therapy in the last one month or macular laser in 3 months, active PDR and substantial cataract

    Pre-assignment period milestones
    Number of subjects started
    		 138 [1]
    Number of subjects completed
    		 100

    Pre-assignment subject non-completion reasons
    Reason: Number of subjects
    		 not meeting inclusion criteria: 29
    Reason: Number of subjects
    		 declined to participate: 6
    Reason: Number of subjects
    		 not known: 3
    Notes
    [1] - The number of subjects reported to have started the pre-assignment period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: 138 patients were screened, 100 patients were enrolled and completed, 38 patients were not enrolled.
    Period 1
    Period 1 title
    Overall Trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Single blind
    Roles blinded
    		 Assessor [2]
    Blinding implementation details
    Primary outcome assessors (optometrists and OCT technicians) were masked to treatment allocation. The patients and clinicians who administered the study treatment and those who performed the safety evaluations were not masked to the treatment arms. The subjects were advised at enrolment that they must not discuss the study arm they were in with the OCT or Visual Acuity examiner.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Fixed
    Arm description
    		 In the intervention arm (fixed dosing), mandated intravitreal Ozurdex was given at baseline, 5 and 10 months if the criteria for deferred treatment were not met at those time-points Ozurdex treatment was deferred if the BCVA was better than 83 letters or the IOP was 30 mmHg or more while on Ozurdex therapy or there was evidence of intraocular infection or severe inflammation
    Arm type
    		 intervention arm

    Investigational medicinal product name
    700 μg Dexamethasone Posterior Segment Drug Delivery System (DEX PS DDS)
    Investigational medicinal product code
    Other name
    OZURDEX
    Pharmaceutical forms
    Intravitreal implant in applicator
    Routes of administration
    Intravitreal use
    Dosage and administration details
    The Ozurdex (Allergan Inc.) drug delivery system is a sustained-release formulation for posterior-segment delivery of dexamethasone, made of a polylacticglycolic acid (PLGA) matrix. It received its market authorisation (EU/1/10/638/001) on 27th July 2010 as Ozurdex 700 micrograms intravitreal implant in applicator. All patients received baseline Ozurdex injection. Intravitreal Ozurdex injections were performed under local anaesthesia and post-injection topical antibiotics were used. Further Ozurdex injections in each arm were performed according to protocol-defined retreatment criteria. In the intervention arm (fixed dosing), mandated intravitreal Ozurdex was given at baseline, 5 and 10 months if the criteria for deferred treatment were not met at those time-points. In addition, safety visits were done at 1 and 8 weeks after any Ozurdex injection in either treatment arms.

    Arm title
    		 PRN dosing arm
    Arm description
    		 In the standard arm (PRN), participants were seen at baseline, 4 months and then monthly to assess the need for re-treatment. If the participants in standard arm were re-treated at any point, the next visit was after 4 months. Re-treatment with Ozurdex was indicated if the CST on OCT exceeded 300 μm and the intraocular pressure (IOP) was ≤ 25 mmHg. If the IOP was between 26 and 30mmHg, topical anti-glaucoma eye drops were given before treatment with Ozurdex at the same sitting. If the IOP recorded was 30 mmHg or more, anti-glaucoma eye drops were given and the patient was reviewed a week later and Ozurdex was injected only if the IOP had reduced to less than 30mmHg. Ozurdex treatment was deferred if the BCVA was better than 83 letters or the IOP was 30 mmHg or more while on Ozurdex therapy or there was evidence of intraocular infection or severe inflammation.
    Arm type
    		 standard

    Investigational medicinal product name
    700 μg Dexamethasone Posterior Segment Drug Delivery System (DEX PS DDS)
    Investigational medicinal product code
    Other name
    OZURDEX
    Pharmaceutical forms
    Intravitreal implant in applicator
    Routes of administration
    Intravitreal use
    Dosage and administration details
    The Ozurdex (Allergan Inc.) drug delivery system is a sustained-release formulation for posterior-segment delivery of dexamethasone, made of a polylacticglycolic acid (PLGA) matrix. It received its market authorisation (EU/1/10/638/001) on 27th July 2010 as Ozurdex 700 micrograms intravitreal implant in applicator. All patients received baseline Ozurdex injection. Intravitreal Ozurdex injections were performed under local anaesthesia and post-injection topical antibiotics were used. Further Ozurdex injections in each arm were performed according to protocol-defined retreatment criteria. In the intervention arm (fixed dosing), mandated intravitreal Ozurdex was given at baseline, 5 and 10 months if the criteria for deferred treatment were not met at those time-points. In addition, safety visits were done at 1 and 8 weeks after any Ozurdex injection in either treatment arms.

    Investigational medicinal product name
    700 μg Dexamethasone Posterior Segment Drug Delivery System (DEX PS DDS)
    Investigational medicinal product code
    Other name
    Ozurdex
    Pharmaceutical forms
    Intravitreal implant in applicator
    Routes of administration
    Intravitreal use
    Dosage and administration details
    In the intervention arm (fixed dosing) mandated dose of intravitreal Ozurdex is given at baseline, 5 and 10 months. In the standard (PRN dosing), re-treatment with Ozurdex is given after the baseline injection if retreatment criteria are met provided the interval between two consecutive injections should exceed 16 weeks. Re-treatment with Ozurdex is indicated in this arm if the following criteria are met:

    Investigational medicinal product name
    Dexamethasone Posterior Segment Drug Delivery System (DEX PS DDS)
    Investigational medicinal product code
    Other name
    Ozurdex
    Pharmaceutical forms
    Intravitreal implant in applicator
    Routes of administration
    Intravitreal use
    Dosage and administration details
    Both treatment arms will receive intravitreal Ozurdex 700μg at all treatment time-points In the intervention arm (fixed dosing) mandated dose of intravitreal Ozurdex is given at baseline, 5 and 10 months. In the standard (PRN dosing), re-treatment with Ozurdex is given after the baseline injection if retreatment criteria are met provided the interval between two consecutive injections should exceed 16 weeks. Re-treatment with Ozurdex is indicated in this arm if the following criteria are met:

    Notes
    [2] - The roles blinded appear inconsistent with a simple blinded trial.
    Justification: The trial was single blinded (the optometrists and OCT technicians were blinded to treatment allocation. The patients and clinicians who administered the study treatment and those who performed the safety evaluations were not blinded to the treatment arms).
    Number of subjects in period 1
    		Fixed PRN dosing arm
    Started
    50
    50
    Completed
    49
    48
    Not completed
    1
    2
         death
    1
    1
         non compliant
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Fixed
    Reporting group description
    		 In the intervention arm (fixed dosing), mandated intravitreal Ozurdex was given at baseline, 5 and 10 months if the criteria for deferred treatment were not met at those time-points Ozurdex treatment was deferred if the BCVA was better than 83 letters or the IOP was 30 mmHg or more while on Ozurdex therapy or there was evidence of intraocular infection or severe inflammation

    Reporting group title
    PRN dosing arm
    Reporting group description
    		 In the standard arm (PRN), participants were seen at baseline, 4 months and then monthly to assess the need for re-treatment. If the participants in standard arm were re-treated at any point, the next visit was after 4 months. Re-treatment with Ozurdex was indicated if the CST on OCT exceeded 300 μm and the intraocular pressure (IOP) was ≤ 25 mmHg. If the IOP was between 26 and 30mmHg, topical anti-glaucoma eye drops were given before treatment with Ozurdex at the same sitting. If the IOP recorded was 30 mmHg or more, anti-glaucoma eye drops were given and the patient was reviewed a week later and Ozurdex was injected only if the IOP had reduced to less than 30mmHg. Ozurdex treatment was deferred if the BCVA was better than 83 letters or the IOP was 30 mmHg or more while on Ozurdex therapy or there was evidence of intraocular infection or severe inflammation.

    Reporting group values
    		 Fixed PRN dosing arm Total
    Number of subjects
    		 50 50 100
    Age categorical
    Units: Subjects
        In utero
    		 0
        Preterm newborn infants (gestational age < 37 wks)
    		 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)
    		 0
        From 65-84 years
    		 0
        85 years and over
    		 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 63.8 ( 11.1 ) 65.4 ( 9.8 ) -
    Gender categorical
    Units: Subjects
        Female
    		 10 16 26
        Male
    		 40 34 74
    Best Corrected Visual Acuity
    Units: ETDRS letters
        arithmetic mean (standard deviation)
    		 57.5 ( 9.5 ) 61.2 ( 8.6 ) -
    OCT Central subfield thickness
    Units: microns
        arithmetic mean (standard deviation)
    		 472.4 ( 113.5 ) 467.9 ( 126.4 ) -

    End points

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    End points reporting groups
    Reporting group title
    Fixed
    Reporting group description
    		 In the intervention arm (fixed dosing), mandated intravitreal Ozurdex was given at baseline, 5 and 10 months if the criteria for deferred treatment were not met at those time-points Ozurdex treatment was deferred if the BCVA was better than 83 letters or the IOP was 30 mmHg or more while on Ozurdex therapy or there was evidence of intraocular infection or severe inflammation

    Reporting group title
    PRN dosing arm
    Reporting group description
    		 In the standard arm (PRN), participants were seen at baseline, 4 months and then monthly to assess the need for re-treatment. If the participants in standard arm were re-treated at any point, the next visit was after 4 months. Re-treatment with Ozurdex was indicated if the CST on OCT exceeded 300 μm and the intraocular pressure (IOP) was ≤ 25 mmHg. If the IOP was between 26 and 30mmHg, topical anti-glaucoma eye drops were given before treatment with Ozurdex at the same sitting. If the IOP recorded was 30 mmHg or more, anti-glaucoma eye drops were given and the patient was reviewed a week later and Ozurdex was injected only if the IOP had reduced to less than 30mmHg. Ozurdex treatment was deferred if the BCVA was better than 83 letters or the IOP was 30 mmHg or more while on Ozurdex therapy or there was evidence of intraocular infection or severe inflammation.

    Primary: BCVA at 12 months ITT analysis

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    End point title
    		 BCVA at 12 months ITT analysis
    End point description
    End point type
    Primary
    End point timeframe
    12 months
    End point values
    		 Fixed PRN dosing arm
    Number of subjects analysed
    49
    48
    Units: ETDRS letters
        arithmetic mean (standard deviation)
    57.8 ( 18.5 )
    61.4 ( 14 )
    Statistical analysis title
    		 Primary endpoint analysis
    Statistical analysis description
    The primary outcome is the difference in mean change in baseline best corrected ETDRS visual acuity (BCVA) letter score at 12 months between the two study arms, after adjusting for baseline BCVA and study site.
    Comparison groups
    Fixed v PRN dosing arm
    Number of subjects included in analysis
    97
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 < 0.05
    Method
    		 descriptive
    Parameter type
    		 Mean difference (final values)
    Confidence interval
         level
    		 95%
         sides
    1-sided
         lower limit
    		 -
         upper limit
    		 -
    Variability estimate
    Standard deviation

    Secondary: Change in central retinal thickness on OCT at 12 months

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    End point title
    		 Change in central retinal thickness on OCT at 12 months
    End point description
    End point type
    Secondary
    End point timeframe
    12 months
    End point values
    		 Fixed PRN dosing arm
    Number of subjects analysed
    47
    47
    Units: microns
        arithmetic mean (standard deviation)
    -179.9 ( 172.4 )
    -90.1 ( 96.2 )
    No statistical analyses for this end point

    Secondary: No of injections per patient

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    End point title
    		 No of injections per patient
    End point description
    End point type
    Secondary
    End point timeframe
    12 months
    End point values
    		 Fixed PRN dosing arm
    Number of subjects analysed
    50
    50
    Units: number
        arithmetic mean (standard deviation)
    2.86 ( 0.45 )
    2.6 ( 0.7 )
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    February 2013 to November 2014
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 not used dictionary
    Dictionary version
    0
    Reporting groups
    Reporting group title
    Fixed dose arm
    Reporting group description
    		 -

    Reporting group title
    PRN dose arm
    Reporting group description
    		 -

    Serious adverse events
    		 Fixed dose arm PRN dose arm
    Total subjects affected by serious adverse events
         subjects affected / exposed
    9 / 50 (18.00%)
    10 / 50 (20.00%)
         number of deaths (all causes)
    1
    1
         number of deaths resulting from adverse events
    0
    0
    General disorders and administration site conditions
    Death
         subjects affected / exposed
    1 / 50 (2.00%)
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Others general
         subjects affected / exposed
    5 / 50 (10.00%)
    3 / 50 (6.00%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Retinal detachment
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cataract surgery in study eye
         subjects affected / exposed
    1 / 50 (2.00%)
    4 / 50 (8.00%)
         occurrences causally related to treatment / all
    1 / 1
    4 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endophthalmitis
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Other ocular
         subjects affected / exposed
    1 / 50 (2.00%)
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Fixed dose arm PRN dose arm
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    50 / 50 (100.00%)
    50 / 50 (100.00%)
    General disorders and administration site conditions
    All Ocular
         subjects affected / exposed
    50 / 50 (100.00%)
    50 / 50 (100.00%)
         occurrences all number
    136
    123

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? No

    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.
    12 month cut off of the study favouring Fixed dose patients, as they had injections at 10 months - so better 12 month results, than PRN Non-inferiority margin of 5 letters might be considered large by some The sample size is a limitation
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    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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