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    Clinical Trial Results:
    A Phase I/IIA Dose Escalation Safety Study of Subretinally Injected SAR422459, Administered to Patients With Stargardt's Macular Degeneration

    Summary
    EudraCT number
    2010-023111-34
    Trial protocol
    FR   NL   IT   Outside EU/EEA  
    Global end of trial date
    16 Aug 2019

    Results information
    Results version number
    v1(current)
    This version publication date
    29 Feb 2020
    First version publication date
    29 Feb 2020
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    TDU13583
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01367444
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Sanofi aventis recherche & Développement
    Sponsor organisation address
    1 avenue Pierre Brossolette, Chilly-Mazarin, France, 91380
    Public contact
    Trial Transparency Team, Sanofi aventis recherche & développement, Contact-US@sanofi.com
    Scientific contact
    Trial Transparency Team, Sanofi aventis recherche & développement, Contact-US@sanofi.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    Yes
    EMA paediatric investigation plan number(s)
    EMEA-002407-PIP01-18
    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?
    Yes
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    27 Sep 2019
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    16 Aug 2019
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    To assess the safety and tolerability of ascending doses of SAR422459 in subjects with Stargardt Macular Degeneration (SMD).
    Protection of trial subjects
    The study was conducted by investigators experienced in the treatment of adult and paediatric subjects with SMD. In case of pediatric subjects recruited: the parent(s) or guardian(s) as well as the children were fully informed of all pertinent aspects of the clinical trial as well as the possibility to discontinue at any time. In addition to the consent form for the parent(s)/guardian(s), an assent form in child-appropriate language was provided and explained to the child. Repeated invasive procedures were minimised. The number of blood samples as well as the amount of blood drawn were adjusted according to age and weight. Anesthesia had been used to minimise distress and discomfort. Adult subjects were fully informed of all pertinent aspects of the clinical trial as well as the possibility to discontinue at any time in language and terms appropriate for the subject and considering the local culture. During the course of the trial, subjects were provided with individual subject cards indicating the nature of the trial the subject is participating, contact details and any information needed in the event of a medical emergency. Collected personal data and human biological samples were processed in compliance with the sponsors personal data protection charter ensuring that the Sponsor abides by the laws governing personal data protection in force in all countries in which it operates.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    08 Jun 2011
    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
    France: 14
    Country: Number of subjects enrolled
    United States: 13
    Worldwide total number of subjects
    27
    EEA total number of subjects
    14
    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)
    1
    Adults (18-64 years)
    25
    From 65 to 84 years
    1
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    The Study was conducted in France and the United States between 08-June-2011 and 02-July-2019. The trial ended prematurely, end of trial date declaration to health authorities was 16-August-2019.

    Pre-assignment
    Screening details
    A total of 35 subjects who had SMD were screened, out of which 27 subjects were enrolled in 7 cohorts (Cohorts 1 to 7).

    Period 1
    Period 1 title
    Overall (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Not applicable
    Blinding used
    Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Cohort 1
    Arm description
    Subjects (aged greater than or equal to [>=] 18 years) with advanced SMD, and visual acuity (VA) less than or equal to (<=) 20/200 in the worst eye and severe cone-rod dysfunction with no detectable or severely abnormal full-field electroretinography (ERG) responses, received SAR422459 at lowest target dose level 1.8*10^5 transducing units (TU)/eye.
    Arm type
    Experimental

    Investigational medicinal product name
    SAR422459
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Subretinal use
    Dosage and administration details
    Subjects received 300 microlitres (μL) of subretinal injection with vector total target dose of 1.8*10^5 TU per eye.

    Arm title
    Cohort 2
    Arm description
    Subjects (aged >=18 years) with SMD, and VA <=20/200 in the worst eye with abnormal full-field ERG responses, received SAR422459 at lowest target dose level 1.8*10^5 TU/eye.
    Arm type
    Experimental

    Investigational medicinal product name
    SAR422459
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Subretinal use
    Dosage and administration details
    Subjects received 300 μL of subretinal injection with vector total target dose of 1.8*10^5 TU per eye.

    Arm title
    Cohort 3
    Arm description
    Subjects (aged >=18 years) with SMD, and VA <=20/200 in the worst eye with abnormal full-field ERG responses, received SAR422459 at escalated target dose level 6*10^5 TU/eye.
    Arm type
    Experimental

    Investigational medicinal product name
    SAR422459
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Subretinal use
    Dosage and administration details
    Subjects received 300 μL of subretinal injection with vector total target dose of 6*10^5 TU per eye.

    Arm title
    Cohort 4
    Arm description
    Subjects (aged >=18 years) with SMD, and VA <=20/200 in the worst eye with abnormal full-field ERG responses, received SAR422459 at target dose level 1.8*10^6 TU/eye.
    Arm type
    Experimental

    Investigational medicinal product name
    SAR422459
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Subretinal use
    Dosage and administration details
    Subjects received 300 μL of subretinal injection with vector total target dose of 1.8*10^6 TU per eye.

    Arm title
    Cohort 5
    Arm description
    Subjects (aged >=18 years) with SMD, and VA <=20/100 in the worst eye with abnormal full-field ERG responses, received SAR422459 at highest target dose level 1.8*10^6 TU/eye.
    Arm type
    Experimental

    Investigational medicinal product name
    SAR422459
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Subretinal use
    Dosage and administration details
    Subjects received 300 μL of subretinal injection with vector total target dose of 1.8*10^6 TU per eye.

    Arm title
    Cohort 6
    Arm description
    Subjects (aged 6 to 26 years) with symptomatic early or childhood-onset SMD, and VA >=20/200 in both eyes at the time of the screening visit and anticipated to experience rapid deterioration in visual function and/or retinal structure, received SAR422459 at highest target dose level 1.8*10^6 TU/eye.
    Arm type
    Experimental

    Investigational medicinal product name
    SAR422459
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Subretinal use
    Dosage and administration details
    Subjects received 300 μL of subretinal injection with vector total target dose of 1.8*10^6 TU per eye.

    Arm title
    Cohort 7
    Arm description
    Paediatric subjects (aged 6 to 17 years) with symptomatic SMD, and VA >=20/100 in both eyes at the time of the screening visit and anticipated to experience rapid deterioration in visual function and/or retinal structure, received SAR422459 at highest target dose level 1.8*10^6 TU/eye.
    Arm type
    Experimental

    Investigational medicinal product name
    SAR422459
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Subretinal use
    Dosage and administration details
    Paediatric subjects received 300 μL of subretinal injection with vector total target dose of 1.8*10^6 TU per eye.

    Number of subjects in period 1
    Cohort 1 Cohort 2 Cohort 3 Cohort 4 Cohort 5 Cohort 6 Cohort 7
    Started
    4
    4
    4
    4
    6
    4
    1
    Completed
    4
    4
    4
    4
    6
    4
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Cohort 1
    Reporting group description
    Subjects (aged greater than or equal to [>=] 18 years) with advanced SMD, and visual acuity (VA) less than or equal to (<=) 20/200 in the worst eye and severe cone-rod dysfunction with no detectable or severely abnormal full-field electroretinography (ERG) responses, received SAR422459 at lowest target dose level 1.8*10^5 transducing units (TU)/eye.

    Reporting group title
    Cohort 2
    Reporting group description
    Subjects (aged >=18 years) with SMD, and VA <=20/200 in the worst eye with abnormal full-field ERG responses, received SAR422459 at lowest target dose level 1.8*10^5 TU/eye.

    Reporting group title
    Cohort 3
    Reporting group description
    Subjects (aged >=18 years) with SMD, and VA <=20/200 in the worst eye with abnormal full-field ERG responses, received SAR422459 at escalated target dose level 6*10^5 TU/eye.

    Reporting group title
    Cohort 4
    Reporting group description
    Subjects (aged >=18 years) with SMD, and VA <=20/200 in the worst eye with abnormal full-field ERG responses, received SAR422459 at target dose level 1.8*10^6 TU/eye.

    Reporting group title
    Cohort 5
    Reporting group description
    Subjects (aged >=18 years) with SMD, and VA <=20/100 in the worst eye with abnormal full-field ERG responses, received SAR422459 at highest target dose level 1.8*10^6 TU/eye.

    Reporting group title
    Cohort 6
    Reporting group description
    Subjects (aged 6 to 26 years) with symptomatic early or childhood-onset SMD, and VA >=20/200 in both eyes at the time of the screening visit and anticipated to experience rapid deterioration in visual function and/or retinal structure, received SAR422459 at highest target dose level 1.8*10^6 TU/eye.

    Reporting group title
    Cohort 7
    Reporting group description
    Paediatric subjects (aged 6 to 17 years) with symptomatic SMD, and VA >=20/100 in both eyes at the time of the screening visit and anticipated to experience rapid deterioration in visual function and/or retinal structure, received SAR422459 at highest target dose level 1.8*10^6 TU/eye.

    Reporting group values
    Cohort 1 Cohort 2 Cohort 3 Cohort 4 Cohort 5 Cohort 6 Cohort 7 Total
    Number of subjects
    4 4 4 4 6 4 1 27
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        median (full range (min-max))
    55.5 (32 to 66) 40 (30 to 63) 44.5 (35 to 60) 40 (28 to 56) 28 (24 to 41) 23 (21 to 37) 16 (16 to 16) -
    Gender categorical
    Units: Subjects
        Female
    1 3 4 0 2 2 1 13
        Male
    3 1 0 4 4 2 0 14
    Race
    Units: Subjects
        Asian
    0 0 1 0 0 0 0 1
        Black or African American
    0 0 0 1 0 0 0 1
        White
    4 4 3 3 6 4 1 25

    End points

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    End points reporting groups
    Reporting group title
    Cohort 1
    Reporting group description
    Subjects (aged greater than or equal to [>=] 18 years) with advanced SMD, and visual acuity (VA) less than or equal to (<=) 20/200 in the worst eye and severe cone-rod dysfunction with no detectable or severely abnormal full-field electroretinography (ERG) responses, received SAR422459 at lowest target dose level 1.8*10^5 transducing units (TU)/eye.

    Reporting group title
    Cohort 2
    Reporting group description
    Subjects (aged >=18 years) with SMD, and VA <=20/200 in the worst eye with abnormal full-field ERG responses, received SAR422459 at lowest target dose level 1.8*10^5 TU/eye.

    Reporting group title
    Cohort 3
    Reporting group description
    Subjects (aged >=18 years) with SMD, and VA <=20/200 in the worst eye with abnormal full-field ERG responses, received SAR422459 at escalated target dose level 6*10^5 TU/eye.

    Reporting group title
    Cohort 4
    Reporting group description
    Subjects (aged >=18 years) with SMD, and VA <=20/200 in the worst eye with abnormal full-field ERG responses, received SAR422459 at target dose level 1.8*10^6 TU/eye.

    Reporting group title
    Cohort 5
    Reporting group description
    Subjects (aged >=18 years) with SMD, and VA <=20/100 in the worst eye with abnormal full-field ERG responses, received SAR422459 at highest target dose level 1.8*10^6 TU/eye.

    Reporting group title
    Cohort 6
    Reporting group description
    Subjects (aged 6 to 26 years) with symptomatic early or childhood-onset SMD, and VA >=20/200 in both eyes at the time of the screening visit and anticipated to experience rapid deterioration in visual function and/or retinal structure, received SAR422459 at highest target dose level 1.8*10^6 TU/eye.

    Reporting group title
    Cohort 7
    Reporting group description
    Paediatric subjects (aged 6 to 17 years) with symptomatic SMD, and VA >=20/100 in both eyes at the time of the screening visit and anticipated to experience rapid deterioration in visual function and/or retinal structure, received SAR422459 at highest target dose level 1.8*10^6 TU/eye.

    Primary: Percentage of Subjects With Treatment-emergent Adverse Events (TEAEs)

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    End point title
    Percentage of Subjects With Treatment-emergent Adverse Events (TEAEs) [1]
    End point description
    An adverse event (AE) was any unfavorable and unintended physical sign, symptom, or laboratory parameter that developed or worsened in severity during the course of the study, whether or not considered related to the investigational product. The TEAEs were defined as any event that started or increased in severity after the subject received IMP, including abnormal laboratory results, electrocardiogram, etc. Analysis was performed on all subjects with SMD who were included in the study.
    End point type
    Primary
    End point timeframe
    From Baseline to Week 48
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Incidence of TEAEs were computed statistically, though they were descriptive. No p-values of cohort comparisons were derived for the early-terminated study.
    End point values
    Cohort 1 Cohort 2 Cohort 3 Cohort 4 Cohort 5 Cohort 6 Cohort 7
    Number of subjects analysed
    4
    4
    4
    4
    6
    4
    1
    Units: percentage of subjects
        number (not applicable)
    100
    100
    100
    100
    100
    100
    100
    No statistical analyses for this end point

    Primary: Percentage of Subjects With TEAEs by Severity

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    End point title
    Percentage of Subjects With TEAEs by Severity [2]
    End point description
    An AE was any unfavorable and unintended physical sign, symptom, or laboratory parameter that developed or worsened in severity during the course of the study, whether or not considered related to the investigational product. For each AE, the severity was categorised as either mild, moderate or severe where 'mild' was defined as discomfort noticed but did not interfere with the subject’s daily routines (an annoyance), 'moderate' was defined as some impairment of function, not hazardous to health (uncomfortable or embarrassing), and 'severe' was defined as significant impairment of function, hazardous to health (incapacitating). Analysis was performed on all subjects with SMD who were included in the study.
    End point type
    Primary
    End point timeframe
    From Baseline to Week 48
    Notes
    [2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Incidence of TEAEs were computed statistically, though they were descriptive. No p-values of cohort comparisons were derived for the early-terminated study.
    End point values
    Cohort 1 Cohort 2 Cohort 3 Cohort 4 Cohort 5 Cohort 6 Cohort 7
    Number of subjects analysed
    4
    4
    4
    4
    6
    4
    1
    Units: percentage of subjects
    number (not applicable)
        Mild
    100
    100
    100
    100
    100
    100
    100
        Moderate
    0
    50
    25
    25
    33
    75
    100
        Severe
    0
    0
    0
    25
    17
    25
    0
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    All Adverse Events (AEs) were collected from time of first dose of study drug up to end of study (Week 48) regardless of seriousness or relationship (causality) to investigational product.
    Adverse event reporting additional description
    Reported AEs were TEAEs that developed/worsened during the ‘on treatment period’ (from Day 0 to Week 48). Analysis was performed on all subjects with SMD who were included in the study.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    22.1
    Reporting groups
    Reporting group title
    Cohort 1
    Reporting group description
    Subjects (aged >=18 years) with advanced SMD, and VA <=20/200 in the worst eye and severe cone-rod dysfunction with no detectable or severely abnormal full-field ERG responses, received SAR422459 at lowest target dose level 1.8*10^5 TU/eye.

    Reporting group title
    Cohort 2
    Reporting group description
    Subjects (aged >=18 years) with SMD, and VA <=20/200 in the worst eye with abnormal full-field ERG responses, received SAR422459 at lowest target target dose level 1.8*10^5 TU/eye.

    Reporting group title
    Cohort 3
    Reporting group description
    Subjects (aged >=18 years) with SMD, and VA <=20/200 in the worst eye with abnormal full-field ERG responses, received SAR422459 at escalated target dose level 6*10^5 TU/eye.

    Reporting group title
    Cohort 4
    Reporting group description
    Subjects (aged >=18 years) with SMD, and VA <=20/200 in the worst eye with abnormal full-field ERG responses, received SAR422459 at target dose level 1.8*10^6 TU/eye.

    Reporting group title
    Cohort 5
    Reporting group description
    Subjects (aged >=18 years) with SMD, and VA <=20/100 in the worst eye with abnormal full-field ERG responses, received SAR422459 at highest target dose level 1.8*10^6 TU/eye.

    Reporting group title
    Cohort 6
    Reporting group description
    Subjects (aged 6 to 26 years) with symptomatic early or childhood-onset SMD, and VA >=20/200 in both eyes at the time of the screening visit and anticipated to experience rapid deterioration in visual function and/or retinal structure, received SAR422459 at highest target dose level 1.8*10^6 TU/eye.

    Reporting group title
    Cohort 7
    Reporting group description
    Paediatric subjects (aged 6 to 17 years) with symptomatic SMD, and VA >=20/100 in both eyes at the time of the screening visit and anticipated to experience rapid deterioration in visual function and/or retinal structure, received SAR422459 at highest target dose level 1.8*10^6 TU/eye.

    Serious adverse events
    Cohort 1 Cohort 2 Cohort 3 Cohort 4 Cohort 5 Cohort 6 Cohort 7
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    1 / 4 (25.00%)
    1 / 1 (100.00%)
         number of deaths (all causes)
    0
    0
    0
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    0
    0
    0
    Investigations
    Intraocular Pressure Increased
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Eye disorders
    Chorioretinopathy
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    1 / 1 (100.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Uveitis
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    1 / 4 (25.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    Cohort 1 Cohort 2 Cohort 3 Cohort 4 Cohort 5 Cohort 6 Cohort 7
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    4 / 4 (100.00%)
    4 / 4 (100.00%)
    4 / 4 (100.00%)
    4 / 4 (100.00%)
    6 / 6 (100.00%)
    4 / 4 (100.00%)
    1 / 1 (100.00%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    Influenza Like Illness
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 6 (16.67%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    Pain
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 6 (16.67%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    Psychiatric disorders
    Depression
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    Insomnia
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    1 / 1 (100.00%)
         occurrences all number
    0
    2
    0
    0
    0
    0
    1
    Injury, poisoning and procedural complications
    Cartilage Injury
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    1 / 1 (100.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    Corneal Abrasion
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    Tongue Injury
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    Investigations
    Colour Vision Tests Abnormal
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    1 / 1 (100.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    Fundoscopy Abnormal
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 6 (16.67%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    Intraocular Pressure Decreased
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    2 / 6 (33.33%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    0
    1
    2
    0
    0
    Intraocular Pressure Increased
         subjects affected / exposed
    2 / 4 (50.00%)
    3 / 4 (75.00%)
    2 / 4 (50.00%)
    1 / 4 (25.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    1 / 1 (100.00%)
         occurrences all number
    3
    3
    2
    1
    0
    0
    1
    Monoclonal Immunoglobulin Present
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    Visual Field Tests Abnormal
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    1 / 4 (25.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    Cardiac disorders
    Ventricular Extrasystoles
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    1 / 4 (25.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    1 / 1 (100.00%)
         occurrences all number
    0
    1
    0
    1
    0
    0
    1
    Oropharyngeal Pain
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    1 / 1 (100.00%)
         occurrences all number
    0
    1
    1
    0
    0
    0
    2
    Rhinorrhoea
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 6 (16.67%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    Blood and lymphatic system disorders
    Lymphopenia
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    1 / 1 (100.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    2
    Headache
         subjects affected / exposed
    1 / 4 (25.00%)
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    1 / 6 (16.67%)
    2 / 4 (50.00%)
    1 / 1 (100.00%)
         occurrences all number
    1
    1
    0
    1
    1
    2
    1
    Tremor
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    1 / 1 (100.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    2
    Visual Field Defect
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 6 (16.67%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    Eye disorders
    Anterior Chamber Cell
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    0
    1
    0
    0
    0
    Anterior Chamber Inflammation
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    Cataract
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    1 / 1 (100.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    1
    Chalazion
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    1 / 4 (25.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    Choroidal Effusion
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 6 (16.67%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    Conjunctival Haemorrhage
         subjects affected / exposed
    3 / 4 (75.00%)
    2 / 4 (50.00%)
    2 / 4 (50.00%)
    1 / 4 (25.00%)
    3 / 6 (50.00%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    3
    2
    2
    1
    3
    0
    0
    Corneal Disorder
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    Diplopia
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 6 (16.67%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    Dyschromatopsia
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 6 (16.67%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    Eye Discharge
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    Eye Disorder
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    1 / 4 (25.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    Eye Inflammation
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 6 (16.67%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    Eye Irritation
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    2 / 6 (33.33%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    1
    2
    0
    0
    Eye Pain
         subjects affected / exposed
    2 / 4 (50.00%)
    2 / 4 (50.00%)
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    1 / 6 (16.67%)
    0 / 4 (0.00%)
    1 / 1 (100.00%)
         occurrences all number
    2
    2
    1
    0
    1
    0
    1
    Eye Pruritus
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    2 / 4 (50.00%)
    0 / 4 (0.00%)
    2 / 6 (33.33%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    2
    0
    2
    0
    0
    Eyelid Irritation
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 6 (16.67%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    Hypotony Of Eye
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    2 / 4 (50.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    2
    0
    Keratic Precipitates
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    Macular Fibrosis
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 6 (16.67%)
    1 / 4 (25.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    1
    0
    Macular Oedema
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    2 / 6 (33.33%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    0
    2
    0
    0
    Necrotising Retinitis
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    1 / 4 (25.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    Ocular Hyperaemia
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    Ocular Hypertension
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    1 / 1 (100.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    Photopsia
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    1 / 4 (25.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    1
    0
    Retinal Disorder
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 6 (16.67%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    Retinal Haemorrhage
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    1 / 6 (16.67%)
    2 / 4 (50.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    0
    1
    1
    3
    0
    Retinal Tear
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    1 / 4 (25.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    Serous Retinal Detachment
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    Subretinal Fibrosis
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    1 / 4 (25.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    Subretinal Fluid
         subjects affected / exposed
    1 / 4 (25.00%)
    1 / 4 (25.00%)
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    2 / 6 (33.33%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    1
    1
    0
    2
    0
    0
    Trichiasis
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    Uveitis
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    1 / 4 (25.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    Vision Blurred
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    1 / 1 (100.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    Visual Impairment
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 6 (16.67%)
    0 / 4 (0.00%)
    1 / 1 (100.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    2
    Vitreous Detachment
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    Vitreous Floaters
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    2 / 6 (33.33%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    1
    0
    2
    0
    0
    Vitreous Haemorrhage
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    Xanthopsia
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 6 (16.67%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    Gastrointestinal disorders
    Dental Caries
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 6 (16.67%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    Irritable Bowel Syndrome
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    Nausea
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 6 (16.67%)
    1 / 4 (25.00%)
    1 / 1 (100.00%)
         occurrences all number
    0
    1
    0
    0
    1
    1
    2
    Vomiting
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    1 / 4 (25.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    1
    0
    Renal and urinary disorders
    Glycosuria
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 6 (16.67%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    Leukocyturia
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 6 (16.67%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    Skin and subcutaneous tissue disorders
    Dermal Cyst
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    Rash
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    1 / 4 (25.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    Rash Erythematous
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    1 / 4 (25.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    Arthritis
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    Back Pain
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    1 / 1 (100.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    Muscle Spasms
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    Neck Pain
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 6 (16.67%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    Osteoarthritis
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 6 (16.67%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    Pain In Extremity
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    1 / 1 (100.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    2
    Synovial Cyst
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 6 (16.67%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    Metabolism and nutrition disorders
    Decreased Appetite
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    1 / 1 (100.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    Infections and infestations
    Conjunctivitis
         subjects affected / exposed
    1 / 4 (25.00%)
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    1
    0
    0
    0
    0
    0
    Conjunctivitis Viral
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    Diarrhoea Infectious
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    Ear Infection
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    Nasopharyngitis
         subjects affected / exposed
    2 / 4 (50.00%)
    2 / 4 (50.00%)
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    1 / 6 (16.67%)
    0 / 4 (0.00%)
    1 / 1 (100.00%)
         occurrences all number
    2
    2
    1
    0
    1
    0
    1
    Sinusitis
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    1 / 4 (25.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    1
    0

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    14 Dec 2010
    1) Amendment of exclusion criteria to include any known allergy to topical, injected or systemic corticosteroids. 2) Addition of guidance on the management of ocular inflammation.
    31 Mar 2011
    1) Inclusion of rationale for clinical dose. 2) Addition of blood samples for immunology and polymerase chain reaction and urine samples for biodistribution assessment at multiple time points. 3) Addition of study stopping criteria relating to inflammation after study drug injection. 4) Inclusion of further details regarding the intraocular injection. 5) Inclusion of text to state the site of subretinal injection would be selected in all subjects based on baseline clinical evaluation and ophthalmology assessments.
    16 Jun 2011
    1) Clarification of the defined subject cohorts. 2) Addition of text to describe the long-term follow-up safety study submitted as a separate protocol.
    24 Jan 2012
    1) Modifications were made to ophthalmology assessments and time points. 2) Addition of Section ‘Adverse Events of Special Interest’ (AESI) and Section ‘Reporting a Serious Adverse Event’ to the protocol.
    14 Apr 2014
    1) Study sponsorship was transferred from Oxford BioMedica Ltd. to Sanofi; administrative updates and alignment with Sanofi protocol standards regarding the AESI and SAE process were made.
    12 Nov 2014
    1) Extension of the safety evaluation to an additional group of subjects (Cohort 6) with a much less advanced stage of the disease that could be observed in adults and children (6 years and older). 2) To decrease the Cohort 5 sample size from up to 12 to up to 6. 3) To allow review of safety and biological data from Cohorts 1 to 5 by the Data Safety Monitoring Board and for an interim report to be submitted to regulatory authorities and institutional review board/ethics committee. 4) Addition of video-recording of surgery and/or intra-operative optical coherence tomography, where available. 5) Addition of new centres in the United States and European Union. 6) Addition of a centralised review committee for Cohort 6 to preoperatively review baseline study assessments. 7) Removal or addition of assessment time points. 8) Addition of secondary endpoints to evaluate safety and biological activity at bleb level. 9) Definition of the study eye.
    10 Mar 2015
    1) To provide clarification regarding the criteria used by Investigators to identify subjects anticipated to experience rapid deterioration.
    16 Dec 2015
    1) Replacement of each occurrence of StarGen™ to SAR422459.
    25 Feb 2016
    1) Changes to inclusion criteria for Cohort 6 to make enrollment for paediatric subjects more homogenous. 2) Addition of 28-day observation period imposed between first and second paediatric subjects enrolled in Cohort 6. 3) Addition of requirement to administer high dose, tapering course of oral systemic steroids early to subjects in particular clinical circumstances following vitreoretinal procedure.
    28 Jul 2016
    1) Inclusion of treatment with systemic corticosteroids following subretinal injection to protocol-defined anti-inflammatory regimen. 2) Addition of inclusion criteria relating to donation of blood, organs, tissues, or cells.
    26 Sep 2017
    1) Addition of Cohort 7. 2) Amendment to definition of baseline for treatment-emergent safety and efficacy signal assessments. 3) Update of inclusion criteria relating to rapid deterioration to better define period of reference assessments.
    29 Nov 2018
    1) Addition of Cohorts 8 and 9 to be treated with a 3-fold lower measured dose. 2) Addition of Diluent to be used with the IMP. 3) Added information of the administered dose by measured strength. 4) Reduction of subject number in Cohorts 6 and 7. 5) Prophylactic intravenous methylprednisolone injection would be administered 2 hours before surgery instead of after surgery. 6) Subretinal recommendation shortening to allow better adaptation of retinotomy and IMP injection to individual subject and surgery practices. 7) Correction of inconsistencies. This amended protocol was approved by Health Authorities, but not by institutional review boards (IRBs)/Ethics committee (EC) and not implemented at site level.

    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 planned analysis was adjusted and carried out on the available safety data collected before the Sponsor’s decision to stop SAR422459 development prematurely.
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