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    Clinical Trial Results:
    A non-randomised, open-label, multicenter phase 4 pilot study on the effect and safety of Iluvien® in chronic diabetic macular edema patients considered insufficiently responsive to available therapies with or without intravitreal corticosteroid therapy. (RESPOND)

    Summary
    EudraCT number
    		 2014-003491-23
    Trial protocol
    		 PT  
    Global end of trial date
    09 Mar 2016

    Results information
    Results version number
    		 v1(current)
    This version publication date
    15 Nov 2020
    First version publication date
    15 Nov 2020
    Other versions
    Summary report(s)
    		 Clinical Study Report

    Trial information

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    Trial identification
    Sponsor protocol code
    4C-2014-06
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02359526
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    AIBILI
    Sponsor organisation address
    Azinhaga Santa Comba, Coimbra, Portugal, 3000
    Public contact
    Sandrina Nunes, AIBILI – Association for Innovation and Biomedical Research on Light and Image, 00351 239480112, sandrina@aibili.pt
    Scientific contact
    Sandrina Nunes, AIBILI – Association for Innovation and Biomedical Research on Light and Image, 00351 239480112, sandrina@aibili.pt
    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 2016
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    09 Mar 2016
    Global end of trial reached?
    Yes
    Global end of trial date
    09 Mar 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To assess the effect and safety of ILUVIEN in patients with chronic DME insufficiently responsive to prior available therapies with or without prior history of intraocular corticosteroid therapy.
    Protection of trial subjects
    This study was designed, implemented and reported in accordance with the ICH Harmonized Tripartite Guidelines for Good Clinical Practice, with applicable local regulations (including European Directive 2001/20/EC, US Code of Federal Regulations Title 21, and Japanese Ministry of Health, Labor, and Welfare), and with the ethical principles laid down in the Declaration of Helsinki. The final study protocol, including the substantial amendments and the final version of the subject information and consent form, were reviewed and approved by an Independent Ethics Committee (IEC) prior to inclusion of subjects. The Investigator ensured that each patient was fully informed about the nature and objective of the study and possible risks associated with participation. Eligible patients only participated in the study after providing written (witnessed, where required by law or regulation), approved informed consent, or, if incapable of doing so, after such consent has been provided by a legally acceptable representative of the patient. In cases where the patient’s representative gives consent, the patient was informed about the study to the extent possible given his/her understanding. If the patient was capable of doing so, he/she indicated assent by personally signing and dating the written informed consent document or a separate assent form. Informed consent was obtained before conducting any study-specific procedures (i.e. all of the procedures described in the protocol). The process of obtaining informed consent is documented in the patient source documents. The Sponsor provided to investigators in a separate document a proposed informed consent form that complies with the ICH GCP guideline and regulatory requirements and considered appropriate for this study.
    Background therapy
    		 The pathogenesis of DME involves several contributing factors including an over-expression of vascular endothelial growth factor (VEGF) and multi-factorial inflammatory processes that lead to the breakdown of the blood-retina barrier and retinal ischemia. Owing to the over expression of VEGF, anti-VEGF therapies are currently used as treatment options in DME. The standard of care and reference therapy for DME (HAS Transparency Commission opinion on Lucentis, 2011) involves the use of laser. In the case that the DME patient still remains insufficiently responsive to laser therapy, subsequent therapy involves on-label treatments such as anti-VEGF therapy and off-label treatment with intravitreal corticosteroids (i.e., referred to herein as current clinical practice). To date, ILUVIEN has not formed part of DME clinical practice and so there is, naturally, limited experience of using ILUVIEN in Portugal. Recently, however, the Portuguese Competent Authority (INFARMED) has conceded marketing authorization and has approved reimbursement for ILUVIEN. Therefore, ILUVIEN will form one of the therapies that can be used by treating physicians in Portugal.
    Evidence for comparator
    		 -
    Actual start date of recruitment
    29 Oct 2014
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety, Efficacy
    Long term follow-up duration
    		 12 Months
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Portugal: 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)
    8
    From 65 to 84 years
    4
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Chronic DME patients considered insufficiently responsive to available therapies (laser, anti-VEGF) with or without intravitreal corticosteroid therapy.

    Pre-assignment
    Screening details
    		 Chronic DME patients and considered as insufficiently responsive as defined as having underwent other previous treatments.

    Period 1
    Period 1 title
    Baseline (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Non-randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 DME Cohort
    Arm description
    		 Cohort of DM patients
    Arm type
    		 Experimental

    Investigational medicinal product name
    Iluvien
    Investigational medicinal product code
    Other name
    fluocinolone acetonide
    Pharmaceutical forms
    Implant in pre-filled syringe
    Routes of administration
    Intravitreal use
    Dosage and administration details
    The implant is an injectable intraocular sustained-release drug delivery system for FAc preloaded into a one-time use sterile applicator. Each implant contains 0.19 mg of FAc as the active ingredient within a cylindrical polyimide tube 3.5 mm long with an internal diameter of 0.34 mm. Inactive ingredients are polyimide, polyvinyl alcohol (PVA) and silicone adhesive. The polyimide tube and silicone adhesive are impermeable to FAc, while the cured PVA coated end of the tube act as a diffusion port allowing the drug to be released. The implant is to be injected through the pars plana into the vitreous using the applicator.

    Investigational medicinal product name
    Iluvien
    Investigational medicinal product code
    Other name
    fluocinolone acetonide
    Pharmaceutical forms
    Implant in pre-filled syringe
    Routes of administration
    Intravitreal use
    Dosage and administration details
    The implant is an injectable intraocular sustained-release drug delivery system for FAc preloaded into a one-time use sterile applicator. Each implant contains 0.19 mg of FAc as the active ingredient within a cylindrical polyimide tube 3.5 mm long with an internal diameter of 0.34 mm. Inactive ingredients are polyimide, polyvinyl alcohol (PVA) and silicone adhesive. The polyimide tube and silicone adhesive are impermeable to FAc, while the cured PVA coated end of the tube act as a diffusion port allowing the drug to be released. The implant is to be injected through the pars plana into the vitreous using the applicator.

    Number of subjects in period 1
    		DME Cohort
    Started
    12
    Baseline
    12
    Completed
    12

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Baseline
    Reporting group description
    		 DME cohort

    Reporting group values
    		 Baseline Total
    Number of subjects
    		 12 12
    Age categorical
    Units: Subjects
        Over 18 years
    		 12 12
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 69.6 ± 9.3 -
    Gender categorical
    Units: Subjects
        Female
    		 4 4
        Male
    		 8 8
    BCVA
    Baseline BCVA
    Units: Letters
        arithmetic mean (standard deviation)
    		 48.7 ± 10.9 -
    CST
    Central subfield thickness
    Units: micrometer
        arithmetic mean (standard deviation)
    		 650.5 ± 140.9 -
    MV
    Macular volume
    Units: milimeters^3
        arithmetic mean (standard deviation)
    		 11.61 ± 2.01 -
    Subject analysis sets

    Subject analysis set title
    Study Population
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Al included patients will be analyzed

    Subject analysis sets values
    		 Study Population
    Number of subjects
    12
    Age categorical
    Units: Subjects
        Over 18 years
    12
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    69.6 ± 9.3
    Gender categorical
    Units: Subjects
        Female
    4
        Male
    8
    BCVA
    Baseline BCVA
    Units: Letters
        arithmetic mean (standard deviation)
    48.7 ± 10.9
    CST
    Central subfield thickness
    Units: micrometer
        arithmetic mean (standard deviation)
    650.5 ± 140.9
    MV
    Macular volume
    Units: milimeters^3
        arithmetic mean (standard deviation)
    11.6 ± 2.01

    End points

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    End points reporting groups
    Reporting group title
    DME Cohort
    Reporting group description
    		 Cohort of DM patients

    Subject analysis set title
    Study Population
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Al included patients will be analyzed

    Primary: BCVA

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    End point title
    		 BCVA
    End point description
    Changes from baseline to month-12
    End point type
    Primary
    End point timeframe
    month-12
    End point values
    		 DME Cohort Study Population
    Number of subjects analysed
    12
    12
    Units: Letters
        arithmetic mean (standard deviation)
    52.4 ± 15.1
    52.4 ± 15.1
    Statistical analysis title
    		 Primary outcomes
    Statistical analysis description
    The efficacy hypotheses • H0: there is no change in BCVA from baseline to Month-12 • H1: there is a change in BCVA from baseline to Month-12 and • H0: there is no change in central retinal thickness assessed using SD-OCT from baseline to Month-12 • H1: there is a change in central retinal thickness assessed using SD-OCT from baseline to Month-12 were tested using Wilcoxon Signed-Rank test, due the small sample size. An alpha of 0.05 was considered in all analyses.
    Comparison groups
    DME Cohort v Study Population
    Number of subjects included in analysis
    24
    Analysis specification
    Pre-specified
    Analysis type
    		 other [1]
    P-value
    		 = 0.255
    Method
    		 Wilcoxon (Mann-Whitney)
    Parameter type
    		 Mean difference (net)
    Point estimate
    0
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 -1
         upper limit
    		 1
    Variability estimate
    Standard deviation
    Dispersion value
    10
    Notes
    [1] - Pilot study. Exploratory analyses.

    Primary: CST

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    End point title
    		 CST
    End point description
    Change of the Central subfield Thickness form baseline
    End point type
    Primary
    End point timeframe
    month-12
    End point values
    		 DME Cohort Study Population
    Number of subjects analysed
    12
    12
    Units: micrometers
        arithmetic mean (standard deviation)
    357.7 ± 169.5
    357.7 ± 169.5
    Statistical analysis title
    		 CST analysis
    Statistical analysis description
    Changes in CST form baseline to month-12
    Comparison groups
    DME Cohort v Study Population
    Number of subjects included in analysis
    24
    Analysis specification
    Pre-specified
    Analysis type
    		 other [2]
    P-value
    		 = 0.003
    Method
    		 Wilcoxon (Mann-Whitney)
    Parameter type
    		 Mean difference (net)
    Point estimate
    0
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 -1
         upper limit
    		 1
    Variability estimate
    Standard deviation
    Dispersion value
    100
    Notes
    [2] - Pilot study. Exploratory analysis

    Primary: MV

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    End point title
    		 MV
    End point description
    Changes of the Macular Volume from baseline to month-12
    End point type
    Primary
    End point timeframe
    Month-12
    End point values
    		 DME Cohort Study Population
    Number of subjects analysed
    12
    12
    Units: milimeters^3
        arithmetic mean (standard deviation)
    9.8 ± 1.9
    9.8 ± 1.9
    Statistical analysis title
    		 MV analysis
    Statistical analysis description
    Changes from baseline
    Comparison groups
    DME Cohort v Study Population
    Number of subjects included in analysis
    24
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [3]
    P-value
    		 = 0.005
    Method
    		 Wilcoxon (Mann-Whitney)
    Parameter type
    		 Median difference (net)
    Point estimate
    0
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 -1
         upper limit
    		 1
    Variability estimate
    Standard deviation
    Dispersion value
    2
    Notes
    [3] - Pilot. Exploratory analysis.

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    24 months (12 months of study plus 12 months of post study)
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    18.1
    Reporting groups
    Reporting group title
    DME Cohort
    Reporting group description
    		 All patients are considered. All received the study IMP.

    Serious adverse events
    		 DME Cohort
    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
    Myocardial infarction
         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: 3%
    Non-serious adverse events
    		 DME Cohort
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    11 / 12 (91.67%)
    Injury, poisoning and procedural complications
    Facial bones fracture
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences all number
    1
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences all number
    1
    Eye disorders
    Cataract
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences all number
    1
    Keratitis
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences all number
    1
    Ocular hypertension
         subjects affected / exposed
    5 / 12 (41.67%)
         occurrences all number
    5
    Vitreous haemorrhage
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences all number
    1
    Infections and infestations
    Conjunctivitis
         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.
    The reduced number of patients included in this exploratory study limited the conclusions, namely the statistical significance of results.

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/28178701
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