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    Clinical Trial Results:
    A Randomised, Open Label, Outcomes-Assessor Masked, Prospective, Parallel Controlled Group, Phase 3 Clinical Trial of Retinal Gene Therapy for Choroideremia Using an Adeno-Associated Viral Vector (AAV2) Encoding Rab Escort Protein 1 (REP1) [STAR]

    Summary
    EudraCT number
    		 2015-003958-41
    Trial protocol
    		 DE   FI   DK   NL  
    Global end of trial date
    01 Dec 2020

    Results information
    Results version number
    		 v1(current)
    This version publication date
    16 Dec 2021
    First version publication date
    16 Dec 2021
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    273CH301 (NSR-REP-01)
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03496012
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Biogen
    Sponsor organisation address
    225 Binney Street, Cambridge, United States, 02142
    Public contact
    Biogen Study Medical Director, Biogen, clinicaltrials@biogen.com
    Scientific contact
    Biogen Study Medical Director, Biogen, clinicaltrials@biogen.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
    01 Dec 2020
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    01 Dec 2020
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The objective of the study is to evaluate the efficacy and safety of a single sub-retinal injection of BIIB111 in subjects with choroideremia (CHM).
    Protection of trial subjects
    Written informed consent was obtained from each subject or subject’s legally authorized representative, as applicable, prior to evaluations performed for eligibility. Subjects or the subject’s legally authorized representative were given adequate time to review the information in the informed consent/assent and were allowed to ask, and have answered, questions concerning all portions of the conduct of the study.
    Background therapy
    		 Subjects who received BIIB111 (timrepigene emparvovec) were given a 21-day course of oral corticosteroid (e.g., prednisolone/prednisone). The schedule was as follows: 1 milligram per kilogram/day (mg/kg/day) prednisolone/prednisone for a total of 10 days, (beginning 2 days before the vector injection, on the day of injection, and then for 7 days), followed by 0.5 mg/kg/day for 7 days, then 0.25 mg/kg/day for 2 days and 0.125 mg/kg/day for 2 days (21 days in total). Weight captured at Visit 1 (Screening/Baseline) was used to calculate the required dose during the 21-day course, and all doses were rounded to the nearest 1 mg.
    Evidence for comparator
    		 -
    Actual start date of recruitment
    11 Dec 2017
    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
    Germany: 32
    Country: Number of subjects enrolled
    United States: 74
    Country: Number of subjects enrolled
    Finland: 18
    Country: Number of subjects enrolled
    France: 17
    Country: Number of subjects enrolled
    United Kingdom: 13
    Country: Number of subjects enrolled
    Canada: 8
    Country: Number of subjects enrolled
    Netherlands: 5
    Country: Number of subjects enrolled
    Denmark: 2
    Worldwide total number of subjects
    169
    EEA total number of subjects
    74
    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)
    148
    From 65 to 84 years
    21
    85 years and over
    0

    Subject disposition

    		 Close Top of page
    Recruitment
    Recruitment details
    		 Subjects were enrolled at the investigative sites in the United States, Germany, Finland, France, the United Kingdom, Canada, Netherlands, and Denmark from 11 December 2017 to 01 December 2020.

    Pre-assignment
    Screening details
    		 A total of 169 subjects with Choroideremia were randomized in the study (66 subjects in Untreated Control Group; 34 subjects in BIIB111 Low Dose group and 69 subjects in BIIB111 High Dose group). Of which, 161 subjects completed the study.

    Period 1
    Period 1 title
    Overall Study
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded
    Blinding implementation details
    Subjects were dose blinded.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Untreated Control Group
    Arm description
    		 Subjects received no sham surgery or study medication to allow for a controlled comparison.
    Arm type
    		 No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Arm title
    		 BIIB111 Low Dose
    Arm description
    		 Followed by vitrectomy and retinal detachment in the study eye, subjects received a single administration of low dose (1.0 × 10^10 genome particle [gp]) BIIB111 (timrepigene emparvovec) by sub-retinal injection on Day 0 (surgery day).
    Arm type
    		 Experimental

    Investigational medicinal product name
    Timrepigene Emparvovec
    Investigational medicinal product code
    Other name
    AAV2-REP1
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Intraocular use
    Dosage and administration details
    Administered as specified in the treatment arm.

    Arm title
    		 BIIB111 High Dose
    Arm description
    		 Followed by vitrectomy and retinal detachment in the study eye, subjects received a single administration of high dose (1.0 × 10^11 gp) BIIB111 (timrepigene emparvovec) by sub-retinal injection on Day 0 (surgery day).
    Arm type
    		 Experimental

    Investigational medicinal product name
    Timrepigene Emparvovec
    Investigational medicinal product code
    Other name
    AAV2-REP1
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Intraocular use
    Dosage and administration details
    Administered as specified in the treatment arm.

    Number of subjects in period 1
    		Untreated Control Group BIIB111 Low Dose BIIB111 High Dose
    Started
    66
    34
    69
    Completed
    62
    34
    65
    Not completed
    4
    0
    4
         Reason Not Specified
    2
    -
    1
         Serious adverse event
    -
    -
    1
         Withdrawal by subject
    2
    -
    2
    Period 2
    Period 2 title
    Intent to Treat (ITT) Period
    Is this the baseline period?
    		 Yes [1]
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded
    Blinding implementation details
    Subjects were dose blinded.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Untreated Control Group
    Arm description
    		 Subjects received no sham surgery or study medication to allow for a controlled comparison.
    Arm type
    		 No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Arm title
    		 BIIB111 Low Dose
    Arm description
    		 Followed by vitrectomy and retinal detachment in the study eye, subjects received a single administration of low dose (1.0 × 10^10 genome particle [gp]) BIIB111 (timrepigene emparvovec) by sub-retinal injection on Day 0 (surgery day).
    Arm type
    		 Experimental

    Investigational medicinal product name
    Timrepigene Emparvovec
    Investigational medicinal product code
    Other name
    AAV2-REP1
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Intraocular use
    Dosage and administration details
    Administered as specified in the treatment arm.

    Arm title
    		 BIIB111 High Dose
    Arm description
    		 Followed by vitrectomy and retinal detachment in the study eye, subjects received a single administration of high dose (1.0 × 10^11 gp) BIIB111 (timrepigene emparvovec) by sub-retinal injection on Day 0 (surgery day).
    Arm type
    		 Experimental

    Investigational medicinal product name
    Timrepigene Emparvovec
    Investigational medicinal product code
    Other name
    AAV2-REP1
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Intraocular use
    Dosage and administration details
    Administered as specified in the treatment arm.

    Notes
    [1] - Period 1 is not the baseline period. It is expected that period 1 will be the baseline period.
    Justification: Baseline data is reported for ITT population so ITT period is selected as baseline period.
    Number of subjects in period 2 [2]
    		Untreated Control Group BIIB111 Low Dose BIIB111 High Dose
    Started
    62
    34
    65
    Completed
    62
    34
    65
    Notes
    [2] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: Baseline data is reported for ITT population but not randomized population.

    Baseline characteristics

    		 Close Top of page
    Baseline characteristics reporting groups
    Reporting group title
    Untreated Control Group
    Reporting group description
    		 Subjects received no sham surgery or study medication to allow for a controlled comparison.

    Reporting group title
    BIIB111 Low Dose
    Reporting group description
    		 Followed by vitrectomy and retinal detachment in the study eye, subjects received a single administration of low dose (1.0 × 10^10 genome particle [gp]) BIIB111 (timrepigene emparvovec) by sub-retinal injection on Day 0 (surgery day).

    Reporting group title
    BIIB111 High Dose
    Reporting group description
    		 Followed by vitrectomy and retinal detachment in the study eye, subjects received a single administration of high dose (1.0 × 10^11 gp) BIIB111 (timrepigene emparvovec) by sub-retinal injection on Day 0 (surgery day).

    Reporting group values
    		 Untreated Control Group BIIB111 Low Dose BIIB111 High Dose Total
    Number of subjects
    		 62 34 65 161
    Age Categorical
    Units: subjects
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 49.1 ( 13.54 ) 49.8 ( 12.62 ) 47.5 ( 12.91 ) -
    Gender Categorical
    Units: subjects
        Female
    		 0 0 0 0
        Male
    		 62 34 65 161
    Race
    Units: Subjects
        Asian
    		 0 0 1 1
        American Indian or Alaska Native
    		 1 0 0 1
        Black or African American
    		 1 0 0 1
        White
    		 52 30 59 141
        Other
    		 1 0 0 1
        Not Reported
    		 7 4 5 16
    Ethnicity
    Units: Subjects
        Hispanic or Latino
    		 3 1 4 8
        Not Hispanic or Latino
    		 49 26 54 129
        Not Reported
    		 10 7 7 24

    End points

    		 Close Top of page
    End points reporting groups
    Reporting group title
    Untreated Control Group
    Reporting group description
    		 Subjects received no sham surgery or study medication to allow for a controlled comparison.

    Reporting group title
    BIIB111 Low Dose
    Reporting group description
    		 Followed by vitrectomy and retinal detachment in the study eye, subjects received a single administration of low dose (1.0 × 10^10 genome particle [gp]) BIIB111 (timrepigene emparvovec) by sub-retinal injection on Day 0 (surgery day).

    Reporting group title
    BIIB111 High Dose
    Reporting group description
    		 Followed by vitrectomy and retinal detachment in the study eye, subjects received a single administration of high dose (1.0 × 10^11 gp) BIIB111 (timrepigene emparvovec) by sub-retinal injection on Day 0 (surgery day).
    Reporting group title
    Untreated Control Group
    Reporting group description
    		 Subjects received no sham surgery or study medication to allow for a controlled comparison.

    Reporting group title
    BIIB111 Low Dose
    Reporting group description
    		 Followed by vitrectomy and retinal detachment in the study eye, subjects received a single administration of low dose (1.0 × 10^10 genome particle [gp]) BIIB111 (timrepigene emparvovec) by sub-retinal injection on Day 0 (surgery day).

    Reporting group title
    BIIB111 High Dose
    Reporting group description
    		 Followed by vitrectomy and retinal detachment in the study eye, subjects received a single administration of high dose (1.0 × 10^11 gp) BIIB111 (timrepigene emparvovec) by sub-retinal injection on Day 0 (surgery day).

    Primary: Percentage of Subjects with a ≥15 -Letter Improvement from Baseline in Best Corrected Visual Acuity (BCVA) at Month 12 as Measured by the Early Treatment of Diabetic Retinopathy Study (ETDRS) Chart

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    End point title
    		 Percentage of Subjects with a ≥15 -Letter Improvement from Baseline in Best Corrected Visual Acuity (BCVA) at Month 12 as Measured by the Early Treatment of Diabetic Retinopathy Study (ETDRS) Chart
    End point description
    BCVA was assessed for both eyes using the ETDRS visual acuity (VA) chart. BCVA test should be performed prior to pupil dilation, and distance refraction should be carried out before BCVA is measured. Initially, letters are read at a distance of 4 meters from the chart. If <20 letters are read at 4 meters, testing at 1 meter should be performed. BCVA is to be reported as number of letters read correctly by the subject using the ETDRS Scale (ranging from 0 to 100 letters) in the study and fellow eyes. The lower the number of letters read correctly on the eye chart, the worse the vision (or visual acuity). An increase in the number of letters read correctly means that vision has improved. ITT Population included all randomized subjects who received the study treatment (or the phone call for those in the untreated control group) and have at least one post-treatment BCVA measurement.
    End point type
    Primary
    End point timeframe
    Month 12
    End point values
    		 Untreated Control Group BIIB111 Low Dose BIIB111 High Dose
    Number of subjects analysed
    62
    34
    65
    Units: percentage of subjects
    number (confidence interval 95%)
        Study Eye
    0 (0 to 5.8)
    2.9 (0.1 to 15.3)
    4.6 (1.0 to 12.9)
        Fellow Eye
    0 (0 to 5.8)
    0 (0 to 10.3)
    3.1 (0.4 to 10.7)
    Statistical analysis title
    		 Study Eyes of Control Group vs BIIB111 Low Dose
    Comparison groups
    Untreated Control Group v BIIB111 Low Dose
    Number of subjects included in analysis
    96
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.354
    Method
    		 Fisher exact
    Parameter type
    		 Difference in Proportions
    Point estimate
    2.9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.1
         upper limit
    		 15
    Statistical analysis title
    		 Study Eyes of Control Group vs BIIB111 High Dose
    Comparison groups
    Untreated Control Group v BIIB111 High Dose
    Number of subjects included in analysis
    127
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.245
    Method
    		 Fisher exact
    Parameter type
    		 Difference in proportions
    Point estimate
    4.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.4
         upper limit
    		 12.8

    Secondary: Change from Baseline in BCVA at Month 12 Measured by the ETDRS Chart

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    End point title
    		 Change from Baseline in BCVA at Month 12 Measured by the ETDRS Chart
    End point description
    BCVA was assessed for both eyes using the ETDRS VA chart. BCVA test should be performed prior to pupil dilation, and distance refraction should be carried out before BCVA is measured. Initially, letters are read at a distance of 4 meters from the chart. If <20 letters are read at 4 meters, testing at 1 meter should be performed. BCVA is to be reported as number of letters read correctly by the subject using the ETDRS Scale (ranging from 0 to 100 letters) in the study and fellow eyes. The lower the number of letters read correctly on the eye chart, the worse the vision (or visual acuity). An increase in the number of letters read correctly means that vision has improved. ITT Population included all randomized participants who received the study treatment (or the phone call for those in the untreated control group) and have at least one post-treatment BCVA measurement. 'Number Analyzed’ signifies number of participants analyzed at the specified timepoint in this outcome measure.
    End point type
    Secondary
    End point timeframe
    Baseline, Month 12
    End point values
    		 Untreated Control Group BIIB111 Low Dose BIIB111 High Dose
    Number of subjects analysed
    62
    34
    65
    Units: letters
    least squares mean (confidence interval 95%)
        Change From Baseline at Month 12: Study Eye
    -2.3 (-5.31 to 0.61)
    -1.5 (-5.47 to 2.50)
    -0.3 (-3.18 to 2.64)
    No statistical analyses for this end point

    Secondary: Percentage of Subjects with a ≥10 -Letter Improvement from Baseline in BCVA at Month 12 Measured by the ETDRS Chart

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    End point title
    		 Percentage of Subjects with a ≥10 -Letter Improvement from Baseline in BCVA at Month 12 Measured by the ETDRS Chart
    End point description
    BCVA was assessed for both eyes using the ETDRS VA chart. BCVA test should be performed prior to pupil dilation, and distance refraction should be carried out before BCVA is measured. Initially, letters are read at a distance of 4 meters from the chart. If <20 letters are read at 4 meters, testing at 1 meter should be performed. BCVA is to be reported as number of letters read correctly by the subject using the ETDRS Scale (ranging from 0 to 100 letters) in the study and fellow eyes. The lower the number of letters read correctly on the eye chart, the worse the vision (or visual acuity). An increase in the number of letters read correctly means that vision has improved. ITT Population included all randomized participants who received the study treatment (or the phone call for those in the untreated control group) and have at least one post-treatment BCVA measurement.
    End point type
    Secondary
    End point timeframe
    Month 12
    End point values
    		 Untreated Control Group BIIB111 Low Dose BIIB111 High Dose
    Number of subjects analysed
    62
    34
    65
    Units: percentage of subjects
    number (confidence interval 95%)
        Study Eye
    1.6 (0.0 to 8.7)
    17.6 (6.8 to 34.5)
    13.8 (6.5 to 24.7)
        Fellow Eye
    0 (0.0 to 5.8)
    8.8 (1.9 to 23.7)
    6.2 (1.7 to 15.0)
    Statistical analysis title
    		 Study Eyes of Control Group vs BIIB111 Low Dose
    Comparison groups
    Untreated Control Group v BIIB111 Low Dose
    Number of subjects included in analysis
    96
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Difference in proportions
    Point estimate
    16
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 5.3
         upper limit
    		 32.2
    Statistical analysis title
    		 Study Eyes of Control Group vs BIIB111 High Dose
    Comparison groups
    Untreated Control Group v BIIB111 High Dose
    Number of subjects included in analysis
    127
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Difference in proportions
    Point estimate
    12.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 3.5
         upper limit
    		 23

    Secondary: Percentage of Subjects with No Decrease from Baseline in BCVA or a Decrease from Baseline in BCVA of <5 ETDRS Letters at Month 12 Measured by the EDRS Chart

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    End point title
    		 Percentage of Subjects with No Decrease from Baseline in BCVA or a Decrease from Baseline in BCVA of <5 ETDRS Letters at Month 12 Measured by the EDRS Chart
    End point description
    BCVA was assessed for both eyes using the ETDRS VA chart. BCVA test should be performed prior to pupil dilation, and distance refraction should be carried out before BCVA is measured. Initially, letters are read at a distance of 4 meters from the chart. If <20 letters are read at 4 meters, testing at 1 meter should be performed. BCVA is to be reported as number of letters read correctly by the subject using the ETDRS Scale (ranging from 0 to 100 letters) in the study and fellow eyes. The lower the number of letters read correctly on the eye chart, the worse the vision (or visual acuity). An increase in the number of letters read correctly means that vision has improved. ITT Population included all randomized participants who received the study treatment (or the phone call for those in the untreated control group) and have at least one post-treatment BCVA measurement.
    End point type
    Secondary
    End point timeframe
    Month 12
    End point values
    		 Untreated Control Group BIIB111 Low Dose BIIB111 High Dose
    Number of subjects analysed
    62
    34
    65
    Units: percentage of subjects
    number (confidence interval 95%)
        Study Eye
    67.7 (54.7 to 79.1)
    70.6 (52.5 to 84.9)
    83.1 (71.7 to 91.2)
        Fellow Eye
    75.8 (63.3 to 85.8)
    85.3 (68.9 to 95.0)
    90.8 (81.0 to 96.5)
    Statistical analysis title
    		 Study Eyes of Control Group vs BIIB111 Low Dose
    Comparison groups
    Untreated Control Group v BIIB111 Low Dose
    Number of subjects included in analysis
    96
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Difference in proportions
    Point estimate
    2.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -17.2
         upper limit
    		 21
    Statistical analysis title
    		 Study Eyes of Control Group vs BIIB111 High Dose
    Comparison groups
    Untreated Control Group v BIIB111 High Dose
    Number of subjects included in analysis
    127
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Difference in proportions
    Point estimate
    15.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.3
         upper limit
    		 30.1

    Secondary: Change from Baseline in BCVA at Months 4 and 8 Measured by the ETDRS Chart

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    End point title
    		 Change from Baseline in BCVA at Months 4 and 8 Measured by the ETDRS Chart
    End point description
    BCVA was assessed for both eyes using the ETDRS VA chart. BCVA test should be performed prior to pupil dilation, and distance refraction should be carried out before BCVA is measured. Initially, letters are read at a distance of 4 meters from the chart. If <20 letters are read at 4 meters, testing at 1 meter should be performed. BCVA is to be reported as number of letters read correctly by the subject using the ETDRS Scale (ranging from 0 to 100 letters) in the study and fellow eyes. The lower the number of letters read correctly on the eye chart, the worse the vision (or visual acuity). An increase in the number of letters read correctly means that vision has improved. ITT Population included all randomized subjects who received the study treatment (or the phone call for those in the untreated control group) and have at least one post-treatment BCVA measurement. Here n=number of subjects analyzed at the specified timepoint in this outcome measure.
    End point type
    Secondary
    End point timeframe
    Baseline, Months 4 and 8
    End point values
    		 Untreated Control Group BIIB111 Low Dose BIIB111 High Dose
    Number of subjects analysed
    62
    34
    65
    Units: letters
    arithmetic mean (standard deviation)
        Baseline: Study Eye
    60.4 ( 8.66 )
    61.8 ( 8.10 )
    58.7 ( 8.86 )
        Baseline: Fellow Eye
    59.8 ( 23.34 )
    65.3 ( 20.95 )
    62.5 ( 20.47 )
        Month 4: Study Eye (n=61, 34, 65)
    0.2 ( 4.34 )
    -0.4 ( 14.16 )
    0.6 ( 11.11 )
        Month 4: Fellow Eye (n=61, 34, 64)
    -1.1 ( 8.45 )
    0.9 ( 6.67 )
    2.0 ( 6.63 )
        Month 8: Study Eye (n=61, 34, 65)
    -0.8 ( 4.93 )
    -1.1 ( 13.13 )
    0.1 ( 11.71 )
        Month 8: Fellow Eye (n=61, 34, 64)
    -0.4 ( 8.31 )
    1.9 ( 7.06 )
    1.6 ( 5.91 )
    No statistical analyses for this end point

    Secondary: Change from Baseline in Total Area of Preserved Autofluorescence (AF) at Month 12

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    End point title
    		 Change from Baseline in Total Area of Preserved Autofluorescence (AF) at Month 12
    End point description
    Fundus Autofluoroscence was used to assess change in total area of preserved autofluoroscence. A negative change from baseline indicate decline in total area of preserved autofluoroscence. ITT Population included all randomized subjects who received the study treatment (or the phone call for those in the untreated control group) and have at least one post-treatment BCVA measurement. ‘Number of Subjects Analyzed’ signifies number of subjects analyzed in this outcome measure.
    End point type
    Secondary
    End point timeframe
    Baseline, Month 12
    End point values
    		 Untreated Control Group BIIB111 Low Dose BIIB111 High Dose
    Number of subjects analysed
    57
    34
    63
    Units: square millimetres (mm^2)
        least squares mean (standard error)
    -0.3872 ( 0.0389 )
    -0.5413 ( 0.0501 )
    -0.5136 ( 0.0371 )
    No statistical analyses for this end point

    Secondary: Change from Baseline in Distance from Foveal Center to Nearest Border of Preserved AF at Month 12

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    End point title
    		 Change from Baseline in Distance from Foveal Center to Nearest Border of Preserved AF at Month 12
    End point description
    Fundus Autofluoroscence was used to assess change in distance from foveal center (FC) to nearest border of preserved autofluoroscence. ITT Population included all randomized subjects who received the study treatment (or the phone call for those in the untreated control group) and have at least one post-treatment BCVA measurement. ‘Number of Subjects Analyzed’ signifies number of subjects analyzed in this outcome measure.
    End point type
    Secondary
    End point timeframe
    Baseline, Month 12
    End point values
    		 Untreated Control Group BIIB111 Low Dose BIIB111 High Dose
    Number of subjects analysed
    57
    34
    63
    Units: micrometres (µm)
        least squares mean (standard error)
    21.7796 ( 9.6234 )
    23.6171 ( 12.3765 )
    21.1660 ( 9.1863 )
    No statistical analyses for this end point

    Secondary: Change from Baseline in the Foveal Subfield Thickness Using Spectral Domain Optical Coherence Tomography (SD-OCT) at Month 12

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    End point title
    		 Change from Baseline in the Foveal Subfield Thickness Using Spectral Domain Optical Coherence Tomography (SD-OCT) at Month 12
    End point description
    SD-OCT was used to assess change in foveal subfield thickness. The measurements were taken after dilation of the subject’s pupil. A negative change from baseline indicates decline in foveal subfield thickness. ITT Population included all randomized subjects who received the study treatment (or the phone call for those in the untreated control group) and have at least one post-treatment BCVA measurement. ‘Number of Subjects Analyzed’ signifies number of subjects analyzed in this outcome measure.
    End point type
    Secondary
    End point timeframe
    Baseline, Month 12
    End point values
    		 Untreated Control Group BIIB111 Low Dose BIIB111 High Dose
    Number of subjects analysed
    61
    34
    64
    Units: µm
        least squares mean (standard error)
    -6.3152 ( 2.7779 )
    -19.8654 ( 3.6998 )
    -15.7993 ( 2.7233 )
    No statistical analyses for this end point

    Secondary: Change from Baseline in the Total Macular Volume Using SD-OCT at Month 12

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    End point title
    		 Change from Baseline in the Total Macular Volume Using SD-OCT at Month 12
    End point description
    SD-OCT was used to assess change in total macular volume. The measurements were taken after dilation of the subject’s pupil. A negative change from baseline indicates decline in total macular volume. ITT Population included all randomized subjects who received the study treatment (or the phone call for those in the untreated control group) and have at least one post-treatment BCVA measurement. ‘Number of Subjects Analyzed’ signifies number of subjects analyzed in this outcome measure.
    End point type
    Secondary
    End point timeframe
    Baseline, Month 12
    End point values
    		 Untreated Control Group BIIB111 Low Dose BIIB111 High Dose
    Number of subjects analysed
    61
    34
    64
    Units: cubic millimetres (mm^3)
        least squares mean (standard error)
    -0.0895 ( 0.0485 )
    -0.2876 ( 0.0646 )
    -0.2088 ( 0.0476 )
    No statistical analyses for this end point

    Secondary: Change from Baseline in the Central Horizontal Ellipsoid Width Using SD-OCT at Month 12

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    End point title
    		 Change from Baseline in the Central Horizontal Ellipsoid Width Using SD-OCT at Month 12
    End point description
    SD-OCT was used to assess change in central horizontal ellipsoid width. The measurements were taken after dilation of the subject’s pupil. A negative change from baseline indicates decline in central horizontal ellipsoid width. ITT Population included all randomized subjects who received the study treatment (or the phone call for those in the untreated control group) and have at least one post-treatment BCVA measurement. ‘Number of Subjects Analyzed’ signifies number of subjects analyzed in this outcome measure.
    End point type
    Secondary
    End point timeframe
    Baseline, Month 12
    End point values
    		 Untreated Control Group BIIB111 Low Dose BIIB111 High Dose
    Number of subjects analysed
    59
    32
    60
    Units: µm
        least squares mean (standard error)
    -81.9178 ( 20.6192 )
    -116.3811 ( 27.8213 )
    -170.7214 ( 20.4062 )
    No statistical analyses for this end point

    Secondary: Change from Baseline in the Central Ellipsoid Area Using SD-OCT at Month 12

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    End point title
    		 Change from Baseline in the Central Ellipsoid Area Using SD-OCT at Month 12
    End point description
    SD-OCT was used to assess change in central ellipsoid area. The measurements were taken after dilation of the subject’s pupil. A negative change from baseline indicates decline in central ellipsoid area. ITT Population included all randomized subjects who received the study treatment (or the phone call for those in the untreated control group) and have at least one post-treatment BCVA measurement. ‘Number of Subjects Analyzed’ signifies number of subjects analyzed in this outcome measure.
    End point type
    Secondary
    End point timeframe
    Baseline, Month 12
    End point values
    		 Untreated Control Group BIIB111 Low Dose BIIB111 High Dose
    Number of subjects analysed
    37
    18
    44
    Units: mm^2
        least squares mean (standard error)
    -0.2382 ( 0.0364 )
    -0.4229 ( 0.0527 )
    -0.3440 ( 0.0332 )
    No statistical analyses for this end point

    Secondary: Change from Baseline in the Choroidal Thickness Using SD-OCT at Month 12

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    End point title
    		 Change from Baseline in the Choroidal Thickness Using SD-OCT at Month 12
    End point description
    SD-OCT was used to assess change in choroidal thickness. The measurements were taken after dilation of the subject’s pupil. A negative change from baseline indicates decline in choroidal thickness. ITT Population included all randomized subjects who received the study treatment (or the phone call for those in the untreated control group) and have at least one post-treatment BCVA measurement. ‘Number of Subjects Analyzed’ signifies number of subjects analyzed in this outcome measure.
    End point type
    Secondary
    End point timeframe
    Baseline, Month 12
    End point values
    		 Untreated Control Group BIIB111 Low Dose BIIB111 High Dose
    Number of subjects analysed
    61
    34
    64
    Units: µm
        least squares mean (standard error)
    -5.4897 ( 2.1873 )
    -7.9579 ( 2.9207 )
    -4.6371 ( 2.1446 )
    No statistical analyses for this end point

    Secondary: Change from Baseline in the Mean Retinal Sensitivity Microperimetry Variable at Month 12

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    End point title
    		 Change from Baseline in the Mean Retinal Sensitivity Microperimetry Variable at Month 12
    End point description
    Microperimetry was used to assess change in mean retinal sensitivity. A negative change from baseline indicates decline in retinal sensitivity. ITT Population included all randomized subjects who received the study treatment (or the phone call for those in the untreated control group) and have at least one post-treatment BCVA measurement. ‘Number of Subjects Analyzed’ signifies number of subjects analyzed in this outcome measure.
    End point type
    Secondary
    End point timeframe
    Baseline, Month 12
    End point values
    		 Untreated Control Group BIIB111 Low Dose BIIB111 High Dose
    Number of subjects analysed
    58
    34
    61
    Units: decibels (dB)
        least squares mean (standard error)
    -0.3443 ( 0.1134 )
    -0.2965 ( 0.1478 )
    -0.5015 ( 0.1112 )
    No statistical analyses for this end point

    Secondary: Change from Baseline in the Bivariate Contour Ellipse Area 63% Microperimetry Variable at Month 12

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    End point title
    		 Change from Baseline in the Bivariate Contour Ellipse Area 63% Microperimetry Variable at Month 12
    End point description
    Microperimetry was used to assess change in bivariate contour ellipse area 63%. A negative change from baseline indicates decline in bivariate contour ellipse area 63%. ITT Population included all randomized subjects who received the study treatment (or the phone call for those in the untreated control group) and have at least one post-treatment BCVA measurement. ‘Number of Subjects Analyzed’ signifies number of subjects analyzed in this outcome measure.
    End point type
    Secondary
    End point timeframe
    Baseline, Month 12
    End point values
    		 Untreated Control Group BIIB111 Low Dose BIIB111 High Dose
    Number of subjects analysed
    58
    34
    61
    Units: square degree (deg^2)
        least squares mean (standard error)
    -3.2161 ( 1.2623 )
    -3.3771 ( 1.6405 )
    -2.5555 ( 1.2403 )
    No statistical analyses for this end point

    Secondary: Change from Baseline in the Bivariate Contour Ellipse Area 95% Microperimetry Variable at Month 12

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    End point title
    		 Change from Baseline in the Bivariate Contour Ellipse Area 95% Microperimetry Variable at Month 12
    End point description
    Microperimetry was used to assess change in bivariate contour ellipse area 95%. A negative change from baseline indicates decline in bivariate contour ellipse area 95%. ITT Population included all randomized subjects who received the study treatment (or the phone call for those in the untreated control group) and have at least one post-treatment BCVA measurement. ‘Number of Subjects Analyzed’ signifies number of subjects analyzed in this outcome measure.
    End point type
    Secondary
    End point timeframe
    Baseline, Month 12
    End point values
    		 Untreated Control Group BIIB111 Low Dose BIIB111 High Dose
    Number of subjects analysed
    58
    34
    61
    Units: deg^2
        least squares mean (standard error)
    -10.1986 ( 4.1004 )
    -14.6926 ( 5.3134 )
    -11.6863 ( 4.0207 )
    No statistical analyses for this end point

    Secondary: Change from Baseline in Contrast Sensitivity Score at Month 12

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    End point title
    		 Change from Baseline in Contrast Sensitivity Score at Month 12
    End point description
    Change in contrast sensitivity was assessed by Pelli-Robson chart which uses a single large letter size (20/60 optotype), with contrast varying across groups of letters (6 per line), whose contrast varies from high to low. Subjects read letters, starting with highest contrast, until they are unable to read 2 or 3 letters in a single group. Score is assigned based on contrast of last group in which 2 or 3 letters were correctly read. Score is a measure of subject`s log contrast sensitivity ranging from 0-2.25 ( 0 is no letters read and 2.25 is all letters read). Total CS score=[(total letters correct-3) x 0.05]. A negative change and a positive change from baseline indicates a worsening and an improvement in contrast sensitivity respectively. ITT Population=all randomized subjects who received study treatment (phone call for untreated control group) and have at least 1 post-treatment BCVA measurement. ‘Number of Subjects Analyzed’=number of subjects analyzed in this outcome measure.
    End point type
    Secondary
    End point timeframe
    Baseline, Month 12
    End point values
    		 Untreated Control Group BIIB111 Low Dose BIIB111 High Dose
    Number of subjects analysed
    60
    34
    65
    Units: score on a scale
        least squares mean (standard error)
    -0.0595 ( 0.0315 )
    -0.0130 ( 0.0417 )
    -0.0386 ( 0.0304 )
    No statistical analyses for this end point

    Secondary: Change from Baseline in Colour Vision Total Error Score at Month 12

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    End point title
    		 Change from Baseline in Colour Vision Total Error Score at Month 12
    End point description
    Colour vision total error scores were assessed on the Farnsworth Munsell 100 Hue Sort Test. Farnsworth Munsell 100 Hue Test requires placing 100 colour palettes in the correct order based upon colour hue. Scores are determined by the frequency and severity of any displacement in the correct order. One error equates to one misplaced hue, by one step or position. An error score of 0 indicates no errors in ordering the hues while error score greater than 500 indicates virtually no color discrimination. A Total Error Score of 0 to 128 could be seen in a normal population. ITT Population included all randomized subjects who received the study treatment (or the phone call for those in the untreated control group) and have at least one post-treatment BCVA measurement. ‘Number of Subjects Analyzed’ signifies number of subjects analyzed in this outcome measure.
    End point type
    Secondary
    End point timeframe
    Baseline, Month 12
    End point values
    		 Untreated Control Group BIIB111 Low Dose BIIB111 High Dose
    Number of subjects analysed
    51
    28
    51
    Units: score on a scale
        least squares mean (standard error)
    35.0003 ( 23.5973 )
    43.5915 ( 31.7720 )
    54.3777 ( 24.0358 )
    No statistical analyses for this end point

    Secondary: Change from Baseline in Reading Speed Test at Month 12

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    End point title
    		 Change from Baseline in Reading Speed Test at Month 12
    End point description
    The reading speed was calculated using the following formula: [number of words in the text - number of misread words] / reading time x 60. The number of misread words and reading time is collected. A negative change from baseline indicates decline in reading speed. ITT Population included all randomized subjects who received the study treatment (or the phone call for those in the untreated control group) and have at least one post-treatment BCVA measurement. ‘Number of Subjects Analyzed’ signifies number of subjects analyzed in this outcome measure.
    End point type
    Secondary
    End point timeframe
    Baseline, Month 12
    End point values
    		 Untreated Control Group BIIB111 Low Dose BIIB111 High Dose
    Number of subjects analysed
    23
    12
    27
    Units: words per minute
        least squares mean (standard error)
    -149.5590 ( 10.9857 )
    -122.1333 ( 14.3276 )
    -127.4706 ( 9.9110 )
    No statistical analyses for this end point

    Secondary: Change from Baseline in the 25-Item Visual Function Questionnaire (VFQ-25) Composite Scores at Month 12

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    End point title
    		 Change from Baseline in the 25-Item Visual Function Questionnaire (VFQ-25) Composite Scores at Month 12
    End point description
    VFQ-25 consists of a base set of 25 vision-targeted questions representing 11 vision-related constructs, plus an additional single-item general health rating question. All items are scored so that a high score represents better functioning. Each item is then converted to a 0 to 100 scale so that the lowest and highest possible scores are set at 0 and 100 points, respectively. A score of 0 represents the worst outcome and 100 represents the best outcome. A negative change from baseline indicates decline in VFQ-25 score. ITT Population included all randomized subjects who received the study treatment (or the phone call for those in the untreated control group) and have at least one post-treatment BCVA measurement. ‘Number of Subjects Analyzed’ signifies number of subjects analyzed in this outcome measure.
    End point type
    Secondary
    End point timeframe
    Baseline, Month 12
    End point values
    		 Untreated Control Group BIIB111 Low Dose BIIB111 High Dose
    Number of subjects analysed
    58
    34
    63
    Units: score on a scale
        least squares mean (standard error)
    -2.6971 ( 1.2786 )
    1.7236 ( 1.6624 )
    0.7964 ( 1.2308 )
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From Signing of Informed Consent through End of Study (Up to 12 months)
    Adverse event reporting additional description
    Safety population included all randomized subjects who either received study treatment BIIB111 (timrepigene emparvovec) or a post-randomization study visit (control group). Subjects were analyzed according to their actual treatment received.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    23.1
    Reporting groups
    Reporting group title
    Untreated Control Group
    Reporting group description
    		 Subjects received no sham surgery or study medication to allow for a controlled comparison.

    Reporting group title
    BIIB111 Low Dose
    Reporting group description
    		 Followed by vitrectomy and retinal detachment in the study eye, subjects received a single administration of low dose (1.0 × 10^10 gp) BIIB111 (timrepigene emparvovec) by sub-retinal injection on Day 0 (surgery day).

    Reporting group title
    BIIB111 High Dose
    Reporting group description
    		 Followed by vitrectomy and retinal detachment in the study eye, subjects received a single administration of high dose (1.0 × 10^11 gp) BIIB111 (timrepigene emparvovec) by sub-retinal injection on Day 0 (surgery day).

    Serious adverse events
    		 Untreated Control Group BIIB111 Low Dose BIIB111 High Dose
    Total subjects affected by serious adverse events
         subjects affected / exposed
    10 / 65 (15.38%)
    9 / 34 (26.47%)
    11 / 65 (16.92%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    Cardiac disorders
    Angina pectoris
         subjects affected / exposed
    0 / 65 (0.00%)
    1 / 34 (2.94%)
    0 / 65 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Angina unstable
         subjects affected / exposed
    0 / 65 (0.00%)
    0 / 34 (0.00%)
    1 / 65 (1.54%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Aortic valve stenosis
         subjects affected / exposed
    0 / 65 (0.00%)
    0 / 34 (0.00%)
    1 / 65 (1.54%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    0 / 65 (0.00%)
    0 / 34 (0.00%)
    1 / 65 (1.54%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    0 / 65 (0.00%)
    1 / 34 (2.94%)
    0 / 65 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Eye disorders
    Cataract
         subjects affected / exposed
    0 / 65 (0.00%)
    1 / 34 (2.94%)
    0 / 65 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Heterophoria
         subjects affected / exposed
    0 / 65 (0.00%)
    0 / 34 (0.00%)
    1 / 65 (1.54%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Macular hole
         subjects affected / exposed
    1 / 65 (1.54%)
    0 / 34 (0.00%)
    1 / 65 (1.54%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Noninfective retinitis
         subjects affected / exposed
    0 / 65 (0.00%)
    0 / 34 (0.00%)
    1 / 65 (1.54%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Retinal artery embolism
         subjects affected / exposed
    1 / 65 (1.54%)
    0 / 34 (0.00%)
    0 / 65 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Retinal vascular occlusion
         subjects affected / exposed
    0 / 65 (0.00%)
    1 / 34 (2.94%)
    0 / 65 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Visual acuity reduced
         subjects affected / exposed
    8 / 65 (12.31%)
    5 / 34 (14.71%)
    5 / 65 (7.69%)
         occurrences causally related to treatment / all
    0 / 8
    5 / 6
    5 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Visual impairment
         subjects affected / exposed
    0 / 65 (0.00%)
    0 / 34 (0.00%)
    1 / 65 (1.54%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholelithiasis
         subjects affected / exposed
    0 / 65 (0.00%)
    0 / 34 (0.00%)
    1 / 65 (1.54%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Ureterolithiasis
         subjects affected / exposed
    0 / 65 (0.00%)
    1 / 34 (2.94%)
    0 / 65 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    1 / 65 (1.54%)
    0 / 34 (0.00%)
    0 / 65 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Covid-19 pneumonia
         subjects affected / exposed
    1 / 65 (1.54%)
    0 / 34 (0.00%)
    0 / 65 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diverticulitis
         subjects affected / exposed
    0 / 65 (0.00%)
    1 / 34 (2.94%)
    0 / 65 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    1 / 65 (1.54%)
    0 / 34 (0.00%)
    0 / 65 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pilonidal cyst
         subjects affected / exposed
    0 / 65 (0.00%)
    1 / 34 (2.94%)
    0 / 65 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    0 / 65 (0.00%)
    1 / 34 (2.94%)
    0 / 65 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Untreated Control Group BIIB111 Low Dose BIIB111 High Dose
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    9 / 65 (13.85%)
    30 / 34 (88.24%)
    54 / 65 (83.08%)
    Investigations
    Intraocular pressure increased
         subjects affected / exposed
    0 / 65 (0.00%)
    1 / 34 (2.94%)
    6 / 65 (9.23%)
         occurrences all number
    0
    1
    8
    Injury, poisoning and procedural complications
    Corneal abrasion
         subjects affected / exposed
    0 / 65 (0.00%)
    2 / 34 (5.88%)
    0 / 65 (0.00%)
         occurrences all number
    0
    2
    0
    Ocular procedural complication
         subjects affected / exposed
    0 / 65 (0.00%)
    1 / 34 (2.94%)
    5 / 65 (7.69%)
         occurrences all number
    0
    1
    5
    Nervous system disorders
    Headache
         subjects affected / exposed
    0 / 65 (0.00%)
    3 / 34 (8.82%)
    7 / 65 (10.77%)
         occurrences all number
    0
    4
    8
    Eye disorders
    Anterior chamber cell
         subjects affected / exposed
    0 / 65 (0.00%)
    14 / 34 (41.18%)
    24 / 65 (36.92%)
         occurrences all number
    0
    16
    25
    Anterior chamber flare
         subjects affected / exposed
    0 / 65 (0.00%)
    2 / 34 (5.88%)
    4 / 65 (6.15%)
         occurrences all number
    0
    2
    5
    Blepharitis
         subjects affected / exposed
    0 / 65 (0.00%)
    2 / 34 (5.88%)
    1 / 65 (1.54%)
         occurrences all number
    0
    2
    1
    Cataract
         subjects affected / exposed
    3 / 65 (4.62%)
    3 / 34 (8.82%)
    9 / 65 (13.85%)
         occurrences all number
    3
    3
    12
    Cataract subcapsular
         subjects affected / exposed
    0 / 65 (0.00%)
    4 / 34 (11.76%)
    4 / 65 (6.15%)
         occurrences all number
    0
    5
    4
    Conjunctival haemorrhage
         subjects affected / exposed
    0 / 65 (0.00%)
    13 / 34 (38.24%)
    26 / 65 (40.00%)
         occurrences all number
    0
    14
    26
    Conjunctival hyperaemia
         subjects affected / exposed
    0 / 65 (0.00%)
    4 / 34 (11.76%)
    7 / 65 (10.77%)
         occurrences all number
    0
    5
    8
    Eye irritation
         subjects affected / exposed
    0 / 65 (0.00%)
    5 / 34 (14.71%)
    8 / 65 (12.31%)
         occurrences all number
    0
    6
    8
    Eye pain
         subjects affected / exposed
    0 / 65 (0.00%)
    6 / 34 (17.65%)
    11 / 65 (16.92%)
         occurrences all number
    0
    7
    12
    Foreign body sensation in eyes
         subjects affected / exposed
    0 / 65 (0.00%)
    3 / 34 (8.82%)
    9 / 65 (13.85%)
         occurrences all number
    0
    3
    9
    Glare
         subjects affected / exposed
    0 / 65 (0.00%)
    2 / 34 (5.88%)
    1 / 65 (1.54%)
         occurrences all number
    0
    2
    1
    Low luminance best-corrected visual acuity decreased
         subjects affected / exposed
    0 / 65 (0.00%)
    2 / 34 (5.88%)
    7 / 65 (10.77%)
         occurrences all number
    0
    2
    7
    Ocular discomfort
         subjects affected / exposed
    0 / 65 (0.00%)
    0 / 34 (0.00%)
    6 / 65 (9.23%)
         occurrences all number
    0
    0
    6
    Ocular hyperaemia
         subjects affected / exposed
    0 / 65 (0.00%)
    4 / 34 (11.76%)
    7 / 65 (10.77%)
         occurrences all number
    0
    4
    8
    Retinal haemorrhage
         subjects affected / exposed
    1 / 65 (1.54%)
    3 / 34 (8.82%)
    2 / 65 (3.08%)
         occurrences all number
    1
    3
    2
    Vision blurred
         subjects affected / exposed
    0 / 65 (0.00%)
    3 / 34 (8.82%)
    1 / 65 (1.54%)
         occurrences all number
    0
    3
    1
    Vitreal cells
         subjects affected / exposed
    0 / 65 (0.00%)
    3 / 34 (8.82%)
    4 / 65 (6.15%)
         occurrences all number
    0
    3
    4
    Vitritis
         subjects affected / exposed
    0 / 65 (0.00%)
    10 / 34 (29.41%)
    16 / 65 (24.62%)
         occurrences all number
    0
    10
    19
    Psychiatric disorders
    Initial insomnia
         subjects affected / exposed
    0 / 65 (0.00%)
    2 / 34 (5.88%)
    0 / 65 (0.00%)
         occurrences all number
    0
    2
    0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    1 / 65 (1.54%)
    2 / 34 (5.88%)
    0 / 65 (0.00%)
         occurrences all number
    1
    2
    0
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    0 / 65 (0.00%)
    2 / 34 (5.88%)
    1 / 65 (1.54%)
         occurrences all number
    0
    2
    1
    Impetigo
         subjects affected / exposed
    0 / 65 (0.00%)
    2 / 34 (5.88%)
    0 / 65 (0.00%)
         occurrences all number
    0
    3
    0
    Nasopharyngitis
         subjects affected / exposed
    4 / 65 (6.15%)
    3 / 34 (8.82%)
    6 / 65 (9.23%)
         occurrences all number
    4
    3
    8
    Pneumonia
         subjects affected / exposed
    0 / 65 (0.00%)
    2 / 34 (5.88%)
    2 / 65 (3.08%)
         occurrences all number
    0
    2
    2
    Sinusitis
         subjects affected / exposed
    0 / 65 (0.00%)
    2 / 34 (5.88%)
    1 / 65 (1.54%)
         occurrences all number
    0
    2
    1

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    10 Nov 2015
    Removed treatment of the timrepigene emparvovec fellow eye in 4 to 6 subjects. Removed requirement for conducting the International Speed Reading Test in countries where validated translations were not available.
    26 Feb 2016
    Changed volume of timrepigene emparvovec subretinal injection from 0.05 mL to 0.1 mL (containing 1 x 1011 vg). Changed VA inclusion criterion for the study eye, from BCVA of 34 to 78 letters to a BCVA of 34 to 73. Removed randomization method for selection of the ‘Study eye’, and replaced with a requirement for the investigator to use clinical judgment (in collaboration with the subject) to select the ‘Study eye’, which was generally the worse eye. Clarification of management of Screening Identification and inclusion of Screen Failure data. Removed reference to an Interactive Voice/Web Response System for purposes of treatment randomization. Included prednisone (in addition to prednisolone) as the corticosteroid of choice in the 21-day perioperative period. Added requirement that subjects must have had a genetically confirmed diagnosis of CHM prior to the Screening Visit (Visit 1). Visit windows for Visits 7, 8, and 9 decreased from ± 21 days to ± 14 days.
    01 Aug 2017
    Updated title to reflect changes in study design. Changed choice of study control and randomization to a parallel, untreated control 3-arm study design (high-dose, low-dose, untreated-control). Increased sample size from 100 to 140 subjects. Increased the ETDRS BCVA letter improvement from 10 to 15 for the primary endpoint. Amended the key secondary endpoint to utilize Study NSR-CHM-OS1 (NIGHT study) as an historical control.
    15 Mar 2019
    Changes to statistical aspects of the study: Increased the sample size from 140 to 160 subjects; Changed the secondary endpoint from a historical comparison to prospective within-study assessments. Risk-benefit assessment was added to clarify vision loss as a known possible AE, therefore precluding it from SUSAR reporting; definition of SAEs associated with vision loss was also clarified. Other changes involved defining Day 0 for untreated subjects to assure that the duration of follow-up was equal for both treated and untreated subjects.

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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