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    Clinical Trial Results:
    Iluvit – An investigator initiated monocentric pilot study to investigate inflammation parameters and growth factors in the vitreous during a cortisone long-term therapy with Iluvien® in patients with chronic diabetic macular edema

    Summary
    EudraCT number
    		 2016-004488-38
    Trial protocol
    		 DE  
    Global end of trial date
    15 Aug 2019

    Results information
    Results version number
    		 v1(current)
    This version publication date
    11 Jan 2022
    First version publication date
    11 Jan 2022
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    ILV-001
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Johann Wolfgang Goethe University Hospital Frankfurt
    Sponsor organisation address
    Theodor-Stern-Kai 7, Frankfurt am Main, Germany, 60590
    Public contact
    Prof. Dr. Frank Koch, Johann Wolfgang Goethe-University Hospital Frankfurt, Department of Ophthalmology, +49 6963015649, fkoch1@icloud.com
    Scientific contact
    Prof. Dr. Frank Koch, Johann Wolfgang Goethe University Hospital Frankfurt, Department of Ophthalmology, +49 6963015649, fkoch1@icloud.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
    04 Oct 2019
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    15 Aug 2019
    Global end of trial reached?
    Yes
    Global end of trial date
    15 Aug 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary aim of this pilot study was to show whether intravitreal Iluvien® therapy has an influence on the inflammatory factor IL-6, which, in conjunction with growth factors, is significantly involved in the development of diabetic macular edema. In a possible main study based on this, the presumed influence of the Iluvien® therapy on the inflammatory factor IL-6 is then to be more precisely determined and statistically analyzed with a larger sample over a longer period of time.
    Protection of trial subjects
    no specific measures
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    04 Sep 2018
    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
    Germany: 12
    Worldwide total number of subjects
    12
    EEA total number of subjects
    12
    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)
    9
    From 65 to 84 years
    3
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Recruitment took place between September 2018 and February 2019.

    Pre-assignment
    Screening details
    		 13 patients were screened for inclusion and deemed eligible to participate. 1 patient chose not to participate and withdrew declaration of consent after completing the screening visit.

    Pre-assignment period milestones
    Number of subjects started
    		 12
    Number of subjects completed
    		 12

    Period 1
    Period 1 title
    T0
    Is this the baseline period?
    		 Yes
    Allocation method
    Non-randomised - controlled
    Blinding used
    		 Not blinded
    Blinding implementation details
    n/a

    Arms
    Arm title
    		 Overall Trial
    Arm description
    		 Single arm study T0: start of treatment (Iluvien implantation at T0), vitreous probe to measure growth factor concentration T2: vitreous probe to measure growth factor concentration T3: vitreous probe to measure growth factor concentration
    Arm type
    		 Experimental

    Investigational medicinal product name
    Iluvien (Fluocinolone acetonide) 190 μg intravitreal implant in applicator
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Intravitreal implant in applicator
    Routes of administration
    Intravitreal use
    Dosage and administration details
    190 μg, once, intravitreal implant in applicator

    Number of subjects in period 1
    		Overall Trial
    Started
    12
    Completed
    12
    Period 2
    Period 2 title
    T2
    Is this the baseline period?
    		 No
    Allocation method
    Non-randomised - controlled
    Blinding used
    		 Not blinded
    Blinding implementation details
    n/a

    Arms
    Arm title
    		 Overall Trial
    Arm description
    		 Single arm study T0: start of treatment (Iluvien implantation at T0), vitreous probe to measure growth factor concentration T2: vitreous probe to measure growth factor concentration T3: vitreous probe to measure growth factor concentration
    Arm type
    		 Experimental

    Investigational medicinal product name
    Iluvien (Fluocinolone acetonide) 190 μg intravitreal implant in applicator
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Intravitreal implant in applicator
    Routes of administration
    Intravitreal use
    Dosage and administration details
    190 μg, once, intravitreal implant in applicator

    Number of subjects in period 2
    		Overall Trial
    Started
    12
    Completed
    12
    Period 3
    Period 3 title
    T4
    Is this the baseline period?
    		 No
    Allocation method
    Non-randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 Overall Trial
    Arm description
    		 Single arm study T0: start of treatment (Iluvien implantation at T0), vitreous probe to measure growth factor concentration T2: vitreous probe to measure growth factor concentration T3: vitreous probe to measure growth factor concentration
    Arm type
    		 Experimental

    Investigational medicinal product name
    Iluvien (Fluocinolone acetonide) 190 μg intravitreal implant in applicator
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Intravitreal implant in applicator
    Routes of administration
    Intravitreal use
    Dosage and administration details
    190 μg, once, intravitreal implant in applicator

    Number of subjects in period 3
    		Overall Trial
    Started
    12
    Completed
    12

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    T0
    Reporting group description
    		 -

    Reporting group values
    		 T0 Total
    Number of subjects
    		 12 12
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 9 9
        From 65-84 years
    		 3 3
    Gender categorical
    Units: Subjects
        Female
    		 3 3
        Male
    		 9 9

    End points

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    End points reporting groups
    Reporting group title
    Overall Trial
    Reporting group description
    		 Single arm study T0: start of treatment (Iluvien implantation at T0), vitreous probe to measure growth factor concentration T2: vitreous probe to measure growth factor concentration T3: vitreous probe to measure growth factor concentration
    Reporting group title
    Overall Trial
    Reporting group description
    		 Single arm study T0: start of treatment (Iluvien implantation at T0), vitreous probe to measure growth factor concentration T2: vitreous probe to measure growth factor concentration T3: vitreous probe to measure growth factor concentration
    Reporting group title
    Overall Trial
    Reporting group description
    		 Single arm study T0: start of treatment (Iluvien implantation at T0), vitreous probe to measure growth factor concentration T2: vitreous probe to measure growth factor concentration T3: vitreous probe to measure growth factor concentration

    Primary: IL-6

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    End point title
    		 IL-6
    End point description
    The primary endpoint of the study was the determination of the IL-6 concentration in the posterior compartment of the vitreous.
    End point type
    Primary
    End point timeframe
    T0: start of treatment (Iluvien implantation) T2: 1 month after Iluvien implantation T4: 6 months after Iluvien implantation
    End point values
    		 Overall Trial Overall Trial Overall Trial
    Number of subjects analysed
    12
    12
    12
    Units: pg/mL
        arithmetic mean (standard deviation)
    84.30 ± 126.81
    49.33 ± 57.08
    46.93 ± 79.63
    Statistical analysis title
    		 Change in IL-6 between T0 and T4
    Comparison groups
    Overall Trial v Overall Trial v Overall Trial
    Number of subjects included in analysis
    36
    Analysis specification
    Pre-specified
    Analysis type
    		 other [1]
    P-value
    		 ≤ 0.05
    Method
    		 Friedmann Test
    Confidence interval
    Notes
    [1] - Single arm study comparing T0(implantation) to T4 (6 months after implantation). The same 12 subjects were analysed throughout the course of the study.

    Secondary: VEGF

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    End point title
    		 VEGF
    End point description
    A secondary endpoint of the study was the determination of the VEGF concentration in the posterior compartment of the vitreous
    End point type
    Secondary
    End point timeframe
    T0: start of treatment (Iluvien implantation) T2: 1 month after Iluvien implantation T4: 6 months after Iluvien implantation
    End point values
    		 Overall Trial Overall Trial Overall Trial
    Number of subjects analysed
    12
    12
    12
    Units: pg/ml
        arithmetic mean (standard deviation)
    280.30 ± 351.50
    286.42 ± 337.93
    179.59 ± 163.96
    Statistical analysis title
    		 Change in VEGF between T0 and T4
    Comparison groups
    Overall Trial v Overall Trial v Overall Trial
    Number of subjects included in analysis
    36
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 ≤ 0.05 [2]
    Method
    		 Friedmann Test
    Confidence interval
    Notes
    [2] - Single arm study comparing T0(implantation) to T4 (6 months after implantation). The same 12 subjects were analysed throughout the course of the study.

    Secondary: IL-1b

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    End point title
    		 IL-1b
    End point description
    A secondary endpoint of the study was the determination of the IL-1b concentration in the posterior compartment of the vitreous
    End point type
    Secondary
    End point timeframe
    T0: start of treatment (Iluvien implantation) T2: 1 month after Iluvien implantation T4: 6 months after Iluvien implantation
    End point values
    		 Overall Trial Overall Trial Overall Trial
    Number of subjects analysed
    12
    12
    12
    Units: pg/ml
        arithmetic mean (standard deviation)
    0.00 ± 0.00
    0.00 ± 0.00
    0.00 ± 0.00
    Statistical analysis title
    		 Change in IL-1b between T0 and T4
    Comparison groups
    Overall Trial v Overall Trial v Overall Trial
    Number of subjects included in analysis
    36
    Analysis specification
    Pre-specified
    Analysis type
    		 other [3]
    P-value
    		 ≤ 0.05
    Method
    		 Friedmann Test
    Confidence interval
    Notes
    [3] - Single arm study comparing T0 (implantation) to T4 (6 months after implantation). The same 12 subjects were analysed throughout the course of the study.

    Secondary: IL-8

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    End point title
    		 IL-8
    End point description
    A secondary endpoint of the study was the determination of the IL-8 concentration in the posterior compartment of the vitreous
    End point type
    Secondary
    End point timeframe
    T0: start of treatment (Iluvien implantation) T2: 1 month after Iluvien implantation T4: 6 months after Iluvien implantation
    End point values
    		 Overall Trial Overall Trial Overall Trial
    Number of subjects analysed
    12
    12
    12
    Units: pg/ml
        arithmetic mean (standard deviation)
    39.90 ± 35.33
    37.09 ± 26.74
    33.80 ± 24.97
    Statistical analysis title
    		 Change in IL-8 between T0 and T4
    Comparison groups
    Overall Trial v Overall Trial v Overall Trial
    Number of subjects included in analysis
    36
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [4]
    P-value
    		 ≤ 0.05
    Method
    		 Friedmann Test
    Confidence interval
    Notes
    [4] - Single arm study comparing T0 (implantation) to T4 (6 months after implantation). The same 12 subjects were analysed throughout the course of the study.

    Secondary: IP-10

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    End point title
    		 IP-10
    End point description
    A secondary endpoint of the study was the determination of the IP-10 concentration in the posterior compartment of the vitreous
    End point type
    Secondary
    End point timeframe
    T0: start of treatment (Iluvien implantation) T2: 1 month after Iluvien implantation T4: 6 months after Iluvien implantation
    End point values
    		 Overall Trial Overall Trial Overall Trial
    Number of subjects analysed
    12
    12
    12
    Units: pg/ml
        arithmetic mean (standard deviation)
    134.81 ± 241.71
    76.50 ± 125.21
    64.13 ± 88.91
    Statistical analysis title
    		 Change in IP-10 between T0 and T4
    Comparison groups
    Overall Trial v Overall Trial v Overall Trial
    Number of subjects included in analysis
    36
    Analysis specification
    Pre-specified
    Analysis type
    		 other [5]
    P-value
    		 ≤ 0.05
    Method
    		 Friedmann Test
    Confidence interval
    Notes
    [5] - Single arm study comparing T0 (implantation) to T4 (6 months after implantation). The same 12 subjects were analysed throughout the course of the study.

    Secondary: ICAM-1

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    End point title
    		 ICAM-1
    End point description
    A secondary endpoint of the study was the determination of the ICAM-1 concentration in the posterior compartment of the vitreous
    End point type
    Secondary
    End point timeframe
    T0: start of treatment (Iluvien implantation) T2: 1 month after Iluvien implantation T4: 6 months after Iluvien implantation
    End point values
    		 Overall Trial Overall Trial Overall Trial
    Number of subjects analysed
    12
    12
    12
    Units: pg/ml
        arithmetic mean (standard deviation)
    839.38 ± 793.78
    532.29 ± 354.71
    513.82 ± 343.09
    Statistical analysis title
    		 Change in ICAM-1 between T0 and T4
    Comparison groups
    Overall Trial v Overall Trial v Overall Trial
    Number of subjects included in analysis
    36
    Analysis specification
    Pre-specified
    Analysis type
    		 other [6]
    P-value
    		 ≤ 0.05
    Method
    		 Friedmann Test
    Confidence interval
    Notes
    [6] - Single arm study comparing T0 (implantation) to T4 (6 months after implantation). The same 12 subjects were analysed throughout the course of the study.

    Secondary: PDGF

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    End point title
    		 PDGF
    End point description
    A secondary endpoint of the study was the determination of the PDGF concentration in the posterior compartment of the vitreous
    End point type
    Secondary
    End point timeframe
    T0: start of treatment (Iluvien implantation) T2: 1 month after Iluvien implantation T4: 6 months after Iluvien implantation
    End point values
    		 Overall Trial Overall Trial Overall Trial
    Number of subjects analysed
    12
    12
    12
    Units: pg/ml
        arithmetic mean (standard deviation)
    31.29 ± 0.00
    31.30 ± 0.00
    31.29 ± 0.00
    Statistical analysis title
    		 Change in PDGF between T0 and T4
    Comparison groups
    Overall Trial v Overall Trial v Overall Trial
    Number of subjects included in analysis
    36
    Analysis specification
    Pre-specified
    Analysis type
    		 other [7]
    P-value
    		 ≤ 0.05
    Method
    		 Friedmann Test
    Confidence interval
    Notes
    [7] - Single arm study comparing T0 (implantation) to T4 (6 months after implantation). The same 12 subjects were analysed throughout the course of the study.

    Secondary: MCP-1

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    End point title
    		 MCP-1
    End point description
    A secondary endpoint of the study was the determination of the MCP-1 concentration in the posterior compartment of the vitreous
    End point type
    Secondary
    End point timeframe
    T0: start of treatment (Iluvien implantation) T2: 1 month after Iluvien implantation T4: 6 months after Iluvien implantation
    End point values
    		 Overall Trial Overall Trial Overall Trial
    Number of subjects analysed
    12
    12
    12
    Units: pg/ml
        arithmetic mean (standard deviation)
    866.46 ± 400.97
    545.63 ± 235.58
    541.85 ± 241.04
    Statistical analysis title
    		 Change in MCP-1 between T0 and T4
    Comparison groups
    Overall Trial v Overall Trial v Overall Trial
    Number of subjects included in analysis
    36
    Analysis specification
    Pre-specified
    Analysis type
    		 other [8]
    P-value
    		 ≤ 0.05
    Method
    		 Friedmann Test
    Confidence interval
    Notes
    [8] - Single arm study comparing T0 (implantation) to T4 (6 months after implantation). The same 12 subjects were analysed throughout the course of the study.

    Secondary: PGF

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    End point title
    		 PGF
    End point description
    A secondary endpoint of the study was the determination of the PGF concentration in the posterior compartment of the vitreous
    End point type
    Secondary
    End point timeframe
    T0: start of treatment (Iluvien implantation) T2: 1 month after Iluvien implantation T4: 6 months after Iluvien implantation
    End point values
    		 Overall Trial Overall Trial Overall Trial
    Number of subjects analysed
    12
    12
    12
    Units: pg/ml
        arithmetic mean (standard deviation)
    95.83 ± 108.37
    128.48 ± 157.68
    75.77 ± 63.20
    Statistical analysis title
    		 Change in PGF between T0 and T4
    Comparison groups
    Overall Trial v Overall Trial v Overall Trial
    Number of subjects included in analysis
    36
    Analysis specification
    Pre-specified
    Analysis type
    		 other [9]
    P-value
    		 ≤ 0.05
    Method
    		 Friedmann Test
    Confidence interval
    Notes
    [9] - Single arm study comparing T0 (implantation) to T4 (6 months after implantation). The same 12 subjects were analysed throughout the course of the study.

    Secondary: PEDF

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    End point title
    		 PEDF
    End point description
    A secondary endpoint of the study was the determination of the PEDF concentration in the posterior compartment of the vitreous
    End point type
    Secondary
    End point timeframe
    T0: start of treatment (Iluvien implantation) T2: 1 month after Iluvien implantation T4: 6 months after Iluvien implantation
    End point values
    		 Overall Trial Overall Trial Overall Trial
    Number of subjects analysed
    12
    12
    12
    Units: pg/ml
        arithmetic mean (standard deviation)
    4696.15 ± 315.84
    4742.98 ± 270.44
    4711.48 ± 266.64
    Statistical analysis title
    		 Change in PEDF between T0 and T4
    Comparison groups
    Overall Trial v Overall Trial v Overall Trial
    Number of subjects included in analysis
    36
    Analysis specification
    Pre-specified
    Analysis type
    		 other [10]
    P-value
    		 ≤ 0.05
    Method
    		 Friedmann Test
    Confidence interval
    Notes
    [10] - Single arm study comparing T0 (implantation) to T4 (6 months after implantation). The same 12 subjects were analysed throughout the course of the study.

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Recording of new adverse events began at the baseline visit (T0, start of treatment) and ended with the completion of the last examination of the patient (T4). AEs that persisted at the end of the study were followed up for up to 28 days after T4 visit.
    Adverse event reporting additional description
    In addition, if available, AEs that occurred before the start of treatment and AEs after the end of study (date of visit T4), were listed.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    22.1
    Reporting groups
    Reporting group title
    All study patients
    Reporting group description
    		 -

    Serious adverse events
    		 All study patients
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 12 (8.33%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    0
    Vascular disorders
    Hypertensive emergency
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Nervous system disorders
    Hypertensive encephalopathy
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 All study patients
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    8 / 12 (66.67%)
    Vascular disorders
    unstable blood pressure
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences all number
    1
    Cardiac disorders
    cardiac insufficiency
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences all number
    1
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences all number
    1
    peripheral edema
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences all number
    1
    Eye disorders
    Blepharitis
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences all number
    3
    Vitreous haemorrhage
         subjects affected / exposed
    3 / 12 (25.00%)
         occurrences all number
    6
    Iris adhesions
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences all number
    1
    Intraocular pressure increased
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences all number
    1
    Conjunctival haemorrhage
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences all number
    1
    Eczema eyelids
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences all number
    1
    Vitreous detachment
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences all number
    1
    Cataract
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences all number
    1
    Angle closure glaucoma
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences all number
    1
    Gastrointestinal disorders
    Colon polyp
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences all number
    1
    Product issues
    Implant stuck in top of needle
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences all number
    1
    implant extrusion through trocar
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences all number
    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.
    small patient cohort (n=12), monocentric length of study: effect on cytokine levels was analysed for 6 months
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