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    Clinical Trial Results:
    A randomized, double-masked study with intraocular bevacizumab (Avastin®) compared with intraocular triamcinolone (Volon A®) in patients with clinical significant diabetic macular edema

    Summary
    EudraCT number
    		 2007-001553-26
    Trial protocol
    		 AT  
    Global end of trial date
    29 Jul 2014

    Results information
    Results version number
    		 v1(current)
    This version publication date
    12 Jun 2021
    First version publication date
    12 Jun 2021
    Other versions
    Summary report(s)
    		 Intravitreal bevacizumab (Avastin) versus triamcinolone (Volon A) for treatment of diabetic macular edema: one-year results
    Detailed analysis of retinal morphology in patients with diabetic macular edema (DME) randomized to ranibizumab or triamcinolone treatment

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    Protocol 03_10_2007
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT00682539
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Medical University Vienna
    Sponsor organisation address
    Waehringerguertel 18-20, Vienna, Austria, 1090
    Public contact
    Clinical Trial Center, Department of Ophthalmology and Optometry, +43 1 4040048470, eye-studies@meduniwien.ac.at
    Scientific contact
    Clinical Trial Center, Department of Ophthalmology and Optometry, +43 1 4040048470, eye-studies@meduniwien.ac.at
    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
    29 Jul 2014
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    29 Jul 2014
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Primary objectives: Evaluation of efficacy of the treatment with intravitreal administered injections of Bevacizumab (Avastin®) compared with Triamcinolone (Volon A®) in patients with clinical significant diabetic macular edema. The main focus of the assessments of efficacy is: 1. The percent change in macular edema measured with standard optical coherence tomography (OCT). 2. The absolute change in visual acuity analyzed by standardized charts according to the protocol used in the Early Retreatment in Diabetic Retinopathy Study (ETDRS).
    Protection of trial subjects
    The trial followed the tenets of the Helsinki Declaration. Before study inclusion, the interventional study design and examinations for scientific purposes were explained to each patient in a personal interview and informed consent was obtained. Contact information of the study team was provided. Intravitreal injections were administered in local anaesthesia. Lubricant eye drops were used against eye-discomfort after the injection. Patients
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    05 Nov 2007
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Austria: 71
    Worldwide total number of subjects
    71
    EEA total number of subjects
    71
    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)
    44
    From 65 to 84 years
    27
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Study patients were recruited between 2007 and 2014 at the outpatient clinic of the Department of Ophthalmology, Medical University Vienna, Austria.

    Pre-assignment
    Screening details
    		 Only one eye of each patient could be included in the study. Eligibility criteria were patients aged ≥18 years with type 1 or 2 diabetes, a best-corrected visual acuity (BCVA) between 20/25 and 20/400 (Snellen equivalent) and a macula center involving DME with a CRT of more than 300 μm measured with spectral domain (SD) OCT.

    Period 1
    Period 1 title
    Bevacizumab vs Triamcinolone
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Data analyst, Carer
    Blinding implementation details
    There were two teams of study investigators: Investigators examining the patients were masked to treatment arm. Investigators applying the medication were masked to study results. Since Triamcinolone was injected no more than every three months sham injections were given intermittend to maintain patient masking.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Bevacizumab
    Arm description
    		 After a loading dose of three monthly injections of 2.5mg Avastin, PRN treatment based on predefined morphological and functional retreatment criteria, that were reassessed monthly.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Bevacizumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intraocular use
    Dosage and administration details
    Avolume of 0.1 ml containing 2.5mg bevacizumab (Avastin, Roche Pharma AG) was injected at 3.5mm distance from the limbus through the inferotemporal pars plana.

    Arm title
    		 Triamcinolone
    Arm description
    		 15 patients with a clinical significant diabetic macular edema receive an intraocular injection of 8mg triamcinolone at baseline under sterile conditions. 1 and 2 month after the baseline injection, patients receive a sham injection. After three month re-injection of 8mg Triamcinolone is performed as needed following a predefined protocol. In between two injection of 8mg Triamcinolone must be an temporal interval of at least 3 months.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Triamcinolone
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder and solvent for suspension for injection
    Routes of administration
    Intraocular use
    Dosage and administration details
    Avolume of 0.1 ml containing 8mg triamcinolone (Volon A, Dermapharm GmbH) was injected at 3.5mm distance from the limbus through the inferotemporal pars plana.

    Number of subjects in period 1 [1]
    		Bevacizumab Triamcinolone
    Started
    18
    16
    Completed
    15
    15
    Not completed
    3
    1
         Lost to follow-up
    3
    1
    Notes
    [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: The first period was a comparison between bevacizumab and triamcinolone. The second period was a comparison between ranibizumab and triamcinolone. Subjects of the first period did not participate in the second period.
    Period 2
    Period 2 title
    Ranibizumab vs Triamcinolone
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Data analyst, Carer
    Blinding implementation details
    There were two teams of study investigators: Investigators examining the patients were masked to treatment arm. Investigators applying the medication were masked to study results. Since Triamcinolone was injected no more than every three months sham injections were given intermittend to maintain patient masking.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Ranibizumab
    Arm description
    		 After a loading dose of three monthly injections of 0.5mg Lucentis, PRN treatment based on predefined morphological and functional retreatment criteria, that were reassessed monthly.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Ranibizumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection in pre-filled injector
    Routes of administration
    Intraocular use
    Dosage and administration details
    0.5 mg ranibizumab (Lucentis®, Novartis Pharma AG, Vienna, Austria) was injected at 3.5mm distance from the limbus through the inferotemporal pars plana.

    Arm title
    		 Triamcinolone
    Arm description
    		 Patients with a clinical significant diabetic macular edema receive an intraocular injection of 8mg triamcinolone at baseline under sterile conditions. 1 and 2 month after the baseline injection, patients receive a sham injection. After three month re-injection of 8mg Triamcinolone is performed as needed following a predefined protocol. In between two injection of 8mg Triamcinolone must be an temporal interval of at least 3 months.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Triamcinolone
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder and solution for solution for injection
    Routes of administration
    Intraocular use
    Dosage and administration details
    Avolume of 0.1 ml containing 8mg triamcinolone (Volon A, Dermapharm GmbH) was injected at 3.5mm distance from the limbus through the inferotemporal pars plana.

    Number of subjects in period 2
    		Ranibizumab Triamcinolone
    Started
    15
    15
    Completed
    10
    15
    Not completed
    5
    0
         Lost to follow-up
    5
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Bevacizumab
    Reporting group description
    		 After a loading dose of three monthly injections of 2.5mg Avastin, PRN treatment based on predefined morphological and functional retreatment criteria, that were reassessed monthly.

    Reporting group title
    Triamcinolone
    Reporting group description
    		 15 patients with a clinical significant diabetic macular edema receive an intraocular injection of 8mg triamcinolone at baseline under sterile conditions. 1 and 2 month after the baseline injection, patients receive a sham injection. After three month re-injection of 8mg Triamcinolone is performed as needed following a predefined protocol. In between two injection of 8mg Triamcinolone must be an temporal interval of at least 3 months.

    Reporting group values
    		 Bevacizumab Triamcinolone Total
    Number of subjects
    		 18 16 34
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0
        Children (2-11 years)
    		 0 0 0
        Adolescents (12-17 years)
    		 0 0 0
        Adults (18-64 years)
    		 13 11 24
        From 65-84 years
    		 5 5 10
        85 years and over
    		 0 0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 62 ( 7.7 ) 60 ( 14.9 ) -
    Gender categorical
    Units: Subjects
        Female
    		 11 7 18
        Male
    		 7 9 16
    Best corrected visual acuity
    Best correcteed visual acuity (BCVA) was measured on a logarithmic scale ofthe minimum angle ofresolution (logMAR) using ETDRS charts at a distance of 2 m.
    Units: logMAR
        log mean (inter-quartile range (Q1-Q3))
    		 0.3 (0.19 to 0.416) 0.32 (0.197 to 0.432) -
    Central Retinal Subfield Thickness
    Central subfield retinal thickness (CSRT) was measured in the central mm using swept source OCT (optical coherence tomography) technology.
    Units: µm
        arithmetic mean (inter-quartile range (Q1-Q3))
    		 505 (438 to 572) 490 (433 to 546) -
    Subject analysis sets

    Subject analysis set title
    Ranibizumab vs Triamcinolone
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Efficacy of the treatment with intravitreal administered injections of Ranibizumab (Lucentis®) ) compared with triamcinolone (Volon A®) in patients with diabetic macular edema

    Subject analysis sets values
    		 Ranibizumab vs Triamcinolone
    Number of subjects
    25
    Age categorical
    Units: Subjects
        In utero
        Preterm newborn infants (gestational age < 37 wks)
        Newborns (0-27 days)
        Infants and toddlers (28 days-23 months)
        Children (2-11 years)
        Adolescents (12-17 years)
        Adults (18-64 years)
        From 65-84 years
        85 years and over
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    64 ( 13.6 )
    Gender categorical
    Units: Subjects
        Female
    7
        Male
    18
    Best corrected visual acuity
    Best correcteed visual acuity (BCVA) was measured on a logarithmic scale ofthe minimum angle ofresolution (logMAR) using ETDRS charts at a distance of 2 m.
    Units: logMAR
        log mean (inter-quartile range (Q1-Q3))
    Central Retinal Subfield Thickness
    Central subfield retinal thickness (CSRT) was measured in the central mm using swept source OCT (optical coherence tomography) technology.
    Units: µm
        arithmetic mean (inter-quartile range (Q1-Q3))

    End points

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    End points reporting groups
    Reporting group title
    Bevacizumab
    Reporting group description
    		 After a loading dose of three monthly injections of 2.5mg Avastin, PRN treatment based on predefined morphological and functional retreatment criteria, that were reassessed monthly.

    Reporting group title
    Triamcinolone
    Reporting group description
    		 15 patients with a clinical significant diabetic macular edema receive an intraocular injection of 8mg triamcinolone at baseline under sterile conditions. 1 and 2 month after the baseline injection, patients receive a sham injection. After three month re-injection of 8mg Triamcinolone is performed as needed following a predefined protocol. In between two injection of 8mg Triamcinolone must be an temporal interval of at least 3 months.
    Reporting group title
    Ranibizumab
    Reporting group description
    		 After a loading dose of three monthly injections of 0.5mg Lucentis, PRN treatment based on predefined morphological and functional retreatment criteria, that were reassessed monthly.

    Reporting group title
    Triamcinolone
    Reporting group description
    		 Patients with a clinical significant diabetic macular edema receive an intraocular injection of 8mg triamcinolone at baseline under sterile conditions. 1 and 2 month after the baseline injection, patients receive a sham injection. After three month re-injection of 8mg Triamcinolone is performed as needed following a predefined protocol. In between two injection of 8mg Triamcinolone must be an temporal interval of at least 3 months.

    Subject analysis set title
    Ranibizumab vs Triamcinolone
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Efficacy of the treatment with intravitreal administered injections of Ranibizumab (Lucentis®) ) compared with triamcinolone (Volon A®) in patients with diabetic macular edema

    Primary: Visual acuity after 12 months of treatment

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    End point title
    		 Visual acuity after 12 months of treatment
    End point description
    Best correcteed visual acuity (BCVA) was measured monthly on a logarithmic scale of the minimum angle ofresolution (logMAR) using ETDRS charts at a distance of 2 m.
    End point type
    Primary
    End point timeframe
    12 months
    End point values
    		 Bevacizumab Triamcinolone Ranibizumab Triamcinolone
    Number of subjects analysed
    15 [1]
    15 [2]
    10 [3]
    15 [4]
    Units: logMAR
        log mean (inter-quartile range (Q1-Q3))
    0.18 (0.064 to 0.303)
    0.36 (0.194 to 0.523)
    0.18 (0.123 to 0.286)
    0.36 (0.27 to 0.531)
    Notes
    [1] - Results from subjects, who finished the study.
    [2] - Results from subjects, who finished the study.
    [3] - Results from subjects, who finished the study.
    [4] - Results from subjects, who finished the study.
    Statistical analysis title
    		 central retinal thickness analysis
    Statistical analysis description
    Repeated-measures-ANOVA will be used to reveal differences between macular edema measurements before and after treatment and between groups
    Comparison groups
    Bevacizumab v Triamcinolone v Ranibizumab v Triamcinolone
    Number of subjects included in analysis
    55
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 < 0.05
    Method
    		 ANOVA
    Parameter type
    		 Mean difference (final values)
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -
         upper limit
    		 -
    Variability estimate
    Standard deviation

    Primary: Central Retinal Subfield Thickness after 12 months

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    End point title
    		 Central Retinal Subfield Thickness after 12 months
    End point description
    Central subfield retinal thickness (CSRT) was measured in the central mm using swept source OCT (optical coherence tomography) technology.
    End point type
    Primary
    End point timeframe
    12 months.
    End point values
    		 Bevacizumab Triamcinolone Ranibizumab Triamcinolone
    Number of subjects analysed
    15
    15
    10
    15
    Units: µm
        number (not applicable)
    351
    296
    389
    404
    Statistical analysis title
    		 central retinal thickness analysis
    Comparison groups
    Bevacizumab v Triamcinolone v Ranibizumab v Triamcinolone
    Number of subjects included in analysis
    55
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 < 0.05
    Method
    		 ANOVA
    Parameter type
    		 Mean difference (final values)
    Confidence interval

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    12 months
    Adverse event reporting additional description
    Intraocular pressure elevation >25mmHg
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    10.0
    Reporting groups
    Reporting group title
    Bevacizumab
    Reporting group description
    		 -

    Reporting group title
    Triamcinolone
    Reporting group description
    		 -

    Reporting group title
    Ranibizumab
    Reporting group description
    		 -

    Serious adverse events
    		 Bevacizumab Triamcinolone Ranibizumab
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 30 (3.33%)
    0 / 10 (0.00%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    Cardiac disorders
    myocardial infarction
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 30 (3.33%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Bevacizumab Triamcinolone Ranibizumab
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    0 / 15 (0.00%)
    7 / 30 (23.33%)
    1 / 10 (10.00%)
    Eye disorders
    Elevated intraocular pressure
    Additional description: IOP > 25mmHg
         subjects affected / exposed
    0 / 15 (0.00%)
    7 / 30 (23.33%)
    1 / 10 (10.00%)
         occurrences all number
    0
    7
    1

    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.
    None reported

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/24336297
    http://www.ncbi.nlm.nih.gov/pubmed/29063703
    http://www.ncbi.nlm.nih.gov/pubmed/29080915
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