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    Clinical Trial Results:
    A Randomized, Double-Masked, Sham-Controlled, Pivotal Clinical Trial to Evaluate the Efficacy of a Single Intravitreal Injection of GS010 (rAAV2/2-ND4) in Subjects Affected for 6 Months or Less by Leber Hereditary Optic Neuropathy Due to the G11778A Mutation in the Mitochondrial NADH Dehydrogenase 4 Gene

    Summary
    EudraCT number
    2015-001265-11
    Trial protocol
    DE   GB   IT  
    Global end of trial date
    04 Jul 2019

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

    Trial information

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    Trial identification
    Sponsor protocol code
    GS-LHON-CLIN-03A
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT02652767
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    GenSight Biologics
    Sponsor organisation address
    74 Rue du Faubourg Saint-Antoine, Paris, France, 75012
    Public contact
    Regulatory Affairs Director, GENSIGHT-BIOLOGICS, 0033 176217220, ipengue@gensight-biologics.com
    Scientific contact
    Regulatory Affairs Director, GENSIGHT-BIOLOGICS, 0033 176217220, ipengue@gensight-biologics.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?
    Yes
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    04 Jul 2019
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    07 Aug 2018
    Global end of trial reached?
    Yes
    Global end of trial date
    04 Jul 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the efficacy of GS010 compared with Sham at Week 48 in the change from baseline of the Log of the Minimal Angle of Resolution (LogMAR) in participants affected for 6 months or less by Leber hereditary optical neuropathy (LHON).
    Protection of trial subjects
    In order to ensure the protection of trial participants, a Data and Safety Monitoring Board meeting was convened at least every 6 months to review the safety data. Additionally, to minimize pain, an intraocular pressure (IOP) lowering agent was administered 60-120 minutes prior to investigational medicinal product (IMP) administration. Finally, the following safety assessments were conducted: - IOP of each eye was measured using Goldmann applanation tonometry according to the usual procedure at each site. - A fluorescein angiogram was obtained at post-IMP administration visits at which the investigator documents the initial presence of significant vitreous inflammation that requires treatment.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    23 Feb 2016
    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
    United Kingdom: 5
    Country: Number of subjects enrolled
    United States: 16
    Country: Number of subjects enrolled
    France: 11
    Country: Number of subjects enrolled
    Germany: 4
    Country: Number of subjects enrolled
    Italy: 3
    Worldwide total number of subjects
    39
    EEA total number of subjects
    23
    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)
    4
    Adults (18-64 years)
    34
    From 65 to 84 years
    1
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    A total of 39 participants were enrolled across 7 sites in 4 European countries and the United States.

    Pre-assignment
    Screening details
    A total of 39 participants were enrolled. The right eye of each participant was randomly assigned either GS010 or the sham procedure in a 1:1 ratio. The left eye of each participant recieved the other treatment, which was not allocated to the right eye.

    Period 1
    Period 1 title
    Overall trial (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator, Monitor, Data analyst, Carer, Assessor

    Arms
    Arm title
    Overall trial: All participants
    Arm description
    All participants who were enrolled and received both study treatments, GS010 and sham. All participants received both GS010 and the sham procedure simultaneously. The right eye of each participant was randomly assigned to receive either GS010 or the sham treatment. The left eye received the treatment which was not allocated to the right eye. GS010: Either the right or left eye received one single dose of GS010 (9E10 vg/eye) via an intravitreal (IVT) injection. The volume of the injected formula was 90 µL. The injection was performed in the vitreous humor under local anesthesia. Sham procedure: One single Sham IVT injection was performed by applying pressure to the eye at the location of a typical IVT injection procedure, using the blunt end of a syringe without a needle.
    Arm type
    Experimental

    Investigational medicinal product name
    GS010 (rAAV2/2-ND4)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Intravitreal use
    Dosage and administration details
    9E10 vg/eye (volume of injection of 90 μL) by intravitreal injection.

    Investigational medicinal product name
    Sham
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Route of administration not applicable
    Dosage and administration details
    Sham procedure was performed by applying pressure to the eye at the location of a typical procedure using the blunt end of a syringe without a needle.

    Number of subjects in period 1
    Overall trial: All participants
    Started
    39
    Participants who completed Week 48
    38
    Completed
    35
    Not completed
    4
         Adverse event, serious fatal
    2
         Consent withdrawn by subject
    1
         Lost to follow-up
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Overall trial
    Reporting group description
    -

    Reporting group values
    Overall trial Total
    Number of subjects
    39 39
    Age categorical
    Units: Subjects
        In utero
    0 0
        Preterm newborn infants (gestational age < 37 wks)
    0 0
        Newborns (0-27 days)
    0 0
        Infants and toddlers (28 days-23 months)
    0 0
        Children (2-11 years)
    0 0
        Adolescents (12-17 years)
    4 4
        Adults (18-64 years)
    34 34
        From 65-84 years
    1 1
        85 years and over
    0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    36.3 ± 15.5 -
    Gender categorical
    Units: Subjects
        Female
    7 7
        Male
    32 32
    Weight
    Units: kg
        arithmetic mean (standard deviation)
    73.9 ± 17.8 -
    Height
    Units: cm
        arithmetic mean (standard deviation)
    174.5 ± 7.7 -

    End points

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    End points reporting groups
    Reporting group title
    Overall trial: All participants
    Reporting group description
    All participants who were enrolled and received both study treatments, GS010 and sham. All participants received both GS010 and the sham procedure simultaneously. The right eye of each participant was randomly assigned to receive either GS010 or the sham treatment. The left eye received the treatment which was not allocated to the right eye. GS010: Either the right or left eye received one single dose of GS010 (9E10 vg/eye) via an intravitreal (IVT) injection. The volume of the injected formula was 90 µL. The injection was performed in the vitreous humor under local anesthesia. Sham procedure: One single Sham IVT injection was performed by applying pressure to the eye at the location of a typical IVT injection procedure, using the blunt end of a syringe without a needle.

    Subject analysis set title
    GS010 treatment
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    All participants and eyes that were treated with GS010 in either the right or left eye. The same participants also received sham comparator in the eye (right or left) that did not receive GS010 IVT injection. One participant was excluded from the intent-to-treat population due to receiving a smaller volume of study treatment than specified in the protocol.

    Subject analysis set title
    Sham comparator
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    All participants and eyes that were given the sham comparator in either the right or left eye. The same participants also received GS010 IVT injection in the eye (right or left) that did not receive sham comparator. One participant was excluded from the intent-to-treat population due to receiving a smaller volume of study treatment than specified in the protocol.

    Primary: Change From Baseline in ETDRS Visual Acuity (Quantitative Score) at Week 48

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    End point title
    Change From Baseline in ETDRS Visual Acuity (Quantitative Score) at Week 48
    End point description
    Visual acuity was derived from the Early Treatment Diabetic Retinopathy Study (ETDRS) chart. Visual acuity is measured in "logarithm of the minimal angle of resolution" (LogMAR), which was derived from the number of letters participants could read on the ETDRS chart. 1 ETDRS line = 5 letters 1 ETDRS line = 0.1 LogMAR A lower LogMAR score denotes better visual acuity. A positive change from baseline indicates a worsening in symptoms. Change = (Week 48 score - Baseline score).
    End point type
    Primary
    End point timeframe
    Baseline and Week 48
    End point values
    GS010 treatment Sham comparator
    Number of subjects analysed
    38 [1]
    38 [2]
    Units: LogMAR
        least squares mean (standard error)
    0.380 ± 0.129
    0.392 ± 0.129
    Notes
    [1] - Intent-to-treat (ITT) population.
    [2] - Intent-to-treat (ITT) population.
    Statistical analysis title
    Difference between GS010 Eyes and Sham Eyes
    Statistical analysis description
    The analysis compared GS010 treated eyes to Sham eyes of all 38 intent-to-treat participants.
    Comparison groups
    GS010 treatment v Sham comparator
    Number of subjects included in analysis
    76
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.889
    Method
    ANCOVA
    Parameter type
    Mean difference (net)
    Point estimate
    -0.012
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.182
         upper limit
    0.158

    Secondary: Change From Baseline in ETDRS Visual Acuity (Quantitative Score)

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    End point title
    Change From Baseline in ETDRS Visual Acuity (Quantitative Score)
    End point description
    Visual acuity was derived from the Early Treatment Diabetic Retinopathy Study (ETDRS) chart. Visual acuity is measured in "logarithm of the minimal angle of resolution" (LogMAR), which was derived from the number of letters participants could read on the ETDRS chart. 1 ETDRS line = 5 letters 1 ETDRS line = 0.1 LogMAR A lower LogMAR score denotes better visual acuity. A positive change from baseline indicates a worsening in symptoms. Change = (Week 72 score - Baseline score) or (Week 96 score - Baseline score). Missing data were imputed by the linear interpolation method.
    End point type
    Secondary
    End point timeframe
    Baseline; Week 72 and Week 96
    End point values
    GS010 treatment Sham comparator
    Number of subjects analysed
    38 [3]
    38 [4]
    Units: LogMAR
    least squares mean (standard error)
        Week 72
    0.192 ± 0.104
    0.216 ± 0.104
        Week 96
    0.178 ± 0.120
    0.207 ± 0.120
    Notes
    [3] - Intent-to-treat (ITT) population.
    [4] - Intent-to-treat (ITT) population.
    No statistical analyses for this end point

    Secondary: Number of Eye Responders to Treatment

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    End point title
    Number of Eye Responders to Treatment
    End point description
    An eye was determined as a responder to treatment based on 2 different definitions. Definition 1: An eye responder was defined by an improvement of the Early Treatment Diabetic Retinopathy Study (ETDRS) visual acuity score of at least 15 letters compared to Baseline, or a final visual acuity greater than a Snellen acuity equivalent of 20/200. Definition 2: An eye responder was defined by an improvement of the ETDRS score of at least 20 letters compared to Baseline.
    End point type
    Secondary
    End point timeframe
    Baseline; Week 48; Week 72 and Week 96
    End point values
    GS010 treatment Sham comparator
    Number of subjects analysed
    38 [5]
    38 [6]
    Units: Number of Eyes
        Week 48 Definition 1
    4
    3
        Week 48 Definition 2
    9
    10
        Week 72 Definition 1
    6
    5
        Week 72 Definition 2
    11
    9
        Week 96 Definition 1
    7
    5
        Week 96 Definition 2
    13
    11
    Notes
    [5] - Intent-to-treat (ITT) population.
    [6] - Intent-to-treat (ITT) population.
    No statistical analyses for this end point

    Secondary: Number of Subject Responders to Treatment

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    End point title
    Number of Subject Responders to Treatment
    End point description
    A subject responder was defined as a participant whose Early Treatment Diabetic Retinopathy Study (ETDRS) score of the treated eye (that received GS010), was at least 15 letters better than the sham eye, or whose treated eye had a "logarithm of the minimal angle of resolution" (LogMAR) acuity score of at least 0.3 LogMAR better than the sham eye.
    End point type
    Secondary
    End point timeframe
    Week 48; Week 72 and Week 96
    End point values
    Overall trial: All participants
    Number of subjects analysed
    38 [7]
    Units: Number of Participants
        Week 48
    4
        Week 72
    2
        Week 96
    5
    Notes
    [7] - Intent-to-treat (ITT) population. Full sample size analysis population was used at Week 96.
    No statistical analyses for this end point

    Secondary: Change From Baseline in GCL Macular Volume

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    End point title
    Change From Baseline in GCL Macular Volume
    End point description
    Ganglion cell layer (GCL) macular volume was measured as a parameter of spectral domain-optical coherence tomography (SD-OCT). SD-OCT was obtained with the Spectralis® OCT (Heidelberg Engineering).
    End point type
    Secondary
    End point timeframe
    Baseline; Week 48; Week 72 and Week 96
    End point values
    GS010 treatment Sham comparator
    Number of subjects analysed
    36 [8]
    37 [9]
    Units: mm^3
    least squares mean (standard error)
        Week 48
    -0.184 ± 0.014
    -0.207 ± 0.014
        Week 72
    -0.204 ± 0.015
    -0.226 ± 0.015
        Week 96
    -0.208 ± 0.015
    -0.221 ± 0.015
    Notes
    [8] - ITT population. Week 48 N 36 Week 72 N 33 Week 96 N 33 Data at Baseline and the post-dose visit.
    [9] - ITT population. Week 48 N 37 Week 72 N 34 Week 96 N 33 Data at Baseline and the post-dose visit.
    No statistical analyses for this end point

    Secondary: Change From Baseline in RNFL Temporal Quadrant Thickness

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    End point title
    Change From Baseline in RNFL Temporal Quadrant Thickness
    End point description
    Retinal nerve fiber layer (RNFL) temporal quadrant thickness was measured as a parameter of spectral domain-optical coherence tomography (SD-OCT). SD-OCT was obtained with the Spectralis® OCT (Heidelberg Engineering).
    End point type
    Secondary
    End point timeframe
    Baseline; Week 48; Week 72 and Week 96
    End point values
    GS010 treatment Sham comparator
    Number of subjects analysed
    37 [10]
    37 [11]
    Units: µm
    least squares mean (standard error)
        Week 48
    -22.8 ± 1.0
    -24.7 ± 1.0
        Week 72
    -25.5 ± 0.9
    -26.0 ± 0.9
        Week 96
    -24.2 ± 0.8
    -26.1 ± 0.8
    Notes
    [10] - ITT population. Week 48 N 37 Week 72 N 34 Week 96 N 32 Data at Baseline and the post-dose visit.
    [11] - ITT population. Week 48 N 37 Week 72 N 34 Week 96 N 33 Data at Baseline and the post-dose visit.
    No statistical analyses for this end point

    Secondary: Change From Baseline in RNFL Papillomacular Bundle Thickness

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    End point title
    Change From Baseline in RNFL Papillomacular Bundle Thickness
    End point description
    Papillomacular bundle thickness was measured as a parameter of spectral domain-optical coherence tomography (SD-OCT). SD-OCT was obtained with the Spectralis® OCT (Heidelberg Engineering).
    End point type
    Secondary
    End point timeframe
    Baseline; Week 48; Week 72 and Week 96
    End point values
    GS010 treatment Sham comparator
    Number of subjects analysed
    37 [12]
    37 [13]
    Units: µm
    least squares mean (standard error)
        Week 48
    -10.4 ± 1.0
    -12.4 ± 1.0
        Week 72
    -12.8 ± 1.0
    -13.1 ± 1.0
        Week 96
    -11.2 ± 1.0
    -13.3 ± 1.0
    Notes
    [12] - ITT population. Week 48 N 37 Week 72 N 34 Week 96 N 32 Data at Baseline and the post-dose visit.
    [13] - ITT population. Week 48 N 37 Week 72 N 34 Week 96 N 33 Data at Baseline and the post-dose visit.
    No statistical analyses for this end point

    Secondary: Change From Baseline in ETDRS Total Macular Volume

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    End point title
    Change From Baseline in ETDRS Total Macular Volume
    End point description
    Early Treatment Diabetic Retinopathy Study (ETDRS) total macular volume was measured as a parameter of spectral domain-optical coherence tomography (SD-OCT). SD-OCT was obtained with the Spectralis® OCT (Heidelberg Engineering).
    End point type
    Secondary
    End point timeframe
    Baseline; Week 48; Week 72 and Week 96
    End point values
    GS010 treatment Sham comparator
    Number of subjects analysed
    36 [14]
    37 [15]
    Units: mm^3
    least squares mean (standard error)
        Week 48
    -0.578 ± 0.041
    -0.708 ± 0.040
        Week 72
    -0.686 ± 0.048
    -0.782 ± 0.048
        Week 96
    -0.720 ± 0.050
    -0.800 ± 0.050
    Notes
    [14] - ITT population. Week 48 N 36 Week 72 N 33 Week 96 N 33 Data at Baseline and the post-dose visit.
    [15] - ITT population. Week 48 N 37 Week 72 N 34 Week 96 N 33 Data at Baseline and the post-dose visit.
    No statistical analyses for this end point

    Secondary: Change From Baseline in the Foveal Threshold Sensitivities Obtained With HVF Analyzer II

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    End point title
    Change From Baseline in the Foveal Threshold Sensitivities Obtained With HVF Analyzer II
    End point description
    The assessment of standardized automated visual fields was measured using the Humphrey Visual Field (HVF) Analyzer II. Automated visual fields included the assessment of foveal threshold sensitivities. Foveal threshold sensitivity is measured in decibels (dB), which ranges from 0 dB to 50 dB. A sensitivity threshold of 0 dB indicates not being able to see the most intense perimetric stimulus, while higher dB indicates better/normal foveal vision. A positive change from baseline indicates an improvement of symptoms.
    End point type
    Secondary
    End point timeframe
    Baseline; Week 48; Week 72 and Week 96
    End point values
    GS010 treatment Sham comparator
    Number of subjects analysed
    11 [16]
    8 [17]
    Units: decibels (dB)
    arithmetic mean (standard deviation)
        Week 48
    3.5 ± 12.3
    -7.4 ± 12.8
        Week 72
    6.3 ± 7.8
    -5.1 ± 11.9
        Week 96
    3.3 ± 12.7
    1.4 ± 19.5
    Notes
    [16] - ITT population. Week 48 N 11 Week 72 N 7 Week 96 N 6 Data at Baseline and the post-dose visit.
    [17] - ITT population. Week 48 N 7 Week 72 N 7 Week 96 N 8 Data at Baseline and the post-dose visit.
    No statistical analyses for this end point

    Secondary: Visual Field Mean Deviation in Decibels of Sensitivity Obtained With HVF Analyzer II

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    End point title
    Visual Field Mean Deviation in Decibels of Sensitivity Obtained With HVF Analyzer II
    End point description
    The assessment of standardized automated visual fields was measured using the Humphrey Visual Field (HVF) Analyzer II. Automated visual fields included the assessment of the mean deviation (MD) in decibels (dB) of sensitivity.
    End point type
    Secondary
    End point timeframe
    Baseline; Week 48; Week 72 and Week 96
    End point values
    GS010 treatment Sham comparator
    Number of subjects analysed
    38 [18]
    38 [19]
    Units: decibels (dB)
    arithmetic mean (standard deviation)
        Baseline MD
    -16.26 ± 10.59
    -16.73 ± 11.48
        Week 48 MD
    -24.26 ± 9.37
    -23.76 ± 10.40
        Week 72 MD
    -23.33 ± 9.41
    -22.94 ± 10.11
        Week 96 MD
    -23.31 ± 9.41
    -22.70 ± 9.88
    Notes
    [18] - ITT set Baseline N 38 Week 48 N 37 Week 72 & Week 96 N 34 Data at Baseline and post-dose visit
    [19] - ITT set Baseline N 38 Week 48 N 37 Week 72 & Week 96 N 33 Data at Baseline and post-dose visit
    No statistical analyses for this end point

    Secondary: Change From Baseline in Contrast Sensitivity

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    End point title
    Change From Baseline in Contrast Sensitivity
    End point description
    The assessment of contrast sensitivity was measured using the Pelli-Robson chart. The chart uses letters arranged in groups whose contrast varies from high to low. Participants read the letters, starting with the highest contrast, until they are unable to read 2 or 3 letters in a single group. Each eye is assigned a score based on the contrast of the last group in which 2 or 3 letters were correctly read, ranging from 0 to 2.2 "log of contrast sensitivity" (LogCS) units. A score of 2.0 LogCS, represents a normal sensitivity contrast, and indicates the eye was able to detect 2 of the 3 letters with a contrast of 1 percent (contrast sensitivity = 100 percent or log 2). Scores less than 2.0 signify poorer contrast sensitivity. Pelli-Robson contrast sensitivity score of less than 1.5 is consistent with visual impairment and a score of less than 1.0 represents in visual disability. A negative change from baseline indicates worsening in symptoms.
    End point type
    Secondary
    End point timeframe
    Baseline; Week 48; Week 72 and Week 96
    End point values
    GS010 treatment Sham comparator
    Number of subjects analysed
    38 [20]
    38 [21]
    Units: LogCS
    least squares mean (standard error)
        Week 48
    -0.35 ± 0.07
    -0.33 ± 0.07
        Week 72
    -0.25 ± 0.07
    -0.28 ± 0.07
        Week 96
    -0.27 ± 0.07
    -0.25 ± 0.07
    Notes
    [20] - Intent-to-treat (ITT) population.
    [21] - Intent-to-treat (ITT) population.
    No statistical analyses for this end point

    Secondary: Change From Baseline in Color Vision

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    End point title
    Change From Baseline in Color Vision
    End point description
    The assessment of color vision was measured using the Farnsworth-Munsell 100-Hue Color Test. Each of the 4 trays consisted of 21 caps. Participants were asked to sort the randomly arranged caps following the hue order from the first to the last fixed caps. The total error score (TES) was derived by the frequency the caps were misplaced and the severity, or distance of the misplacement. Errors were made whenever caps were misplaced from the correct order. Error scores were calculated according to the distance between any two caps. The error score for each individual cap was the sum of the difference between the number of that cap and the numbers of the cap adjacent to it, minus 2. TES was the total sum of the error scores of the entire set of caps. The best possible score was 0 and there is no defined upper limit to the total error score range. A lower score indicates improved color discrimination ability. A negative change from baseline indicates an improvement in symptoms.
    End point type
    Secondary
    End point timeframe
    Baseline; Week 48 and Week 96
    End point values
    GS010 treatment Sham comparator
    Number of subjects analysed
    21 [22]
    21 [23]
    Units: Score on a scale
    arithmetic mean (standard deviation)
        Week 48
    133.1 ± 290.7
    235.6 ± 392.3
        Week 96
    97.7 ± 342.2
    213.5 ± 393.1
    Notes
    [22] - ITT population. Week 48 N 18 Week 96 N 21 Data at Baseline and post-dose visit.
    [23] - ITT population. Week 48 N 20 Week 96 N 21 Data at Baseline and post-dose visit.
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From first dose to the end of study (a maximum of 96 weeks)
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    20.1
    Reporting groups
    Reporting group title
    Overall trial: All participants
    Reporting group description
    All participants who were enrolled and received both study treatments, GS010 and sham. All participants received both GS010 and the sham procedure. The right eye of each participant was randomly assigned to receive either GS010 or the sham treatment. The left eye received the treatment which was not allocated to the right eye. GS010: One single intravitreal (IVT) injection containing 9E10 viral genomes in 90 µl balanced salt solution (BSS) plus 0.001% Pluronic F68®. The IVT injection was performed in the vitreous humor under local anaesthesia. Sham procedure: The sham IVT injection was performed by applying pressure to the eye at the location of a typical IVT injection procedure, using the blunt end of a syringe without a needle.

    Serious adverse events
    Overall trial: All participants
    Total subjects affected by serious adverse events
         subjects affected / exposed
    3 / 39 (7.69%)
         number of deaths (all causes)
    2
         number of deaths resulting from adverse events
    2
    Injury, poisoning and procedural complications
    Alcohol poisoning
         subjects affected / exposed
    1 / 39 (2.56%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Psychiatric disorders
    Alcohol withdrawal syndrome
         subjects affected / exposed
    1 / 39 (2.56%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Renal and urinary disorders
    Renal failure
         subjects affected / exposed
    1 / 39 (2.56%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Hepatobiliary disorders
    Alcoholic liver disease
         subjects affected / exposed
    1 / 39 (2.56%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Metabolism and nutrition disorders
    Malnutrition
         subjects affected / exposed
    1 / 39 (2.56%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Overall trial: All participants
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    38 / 39 (97.44%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    6 / 39 (15.38%)
         occurrences all number
    6
    Investigations
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    3 / 39 (7.69%)
         occurrences all number
    3
    Alanine aminotransferase increased
         subjects affected / exposed
    2 / 39 (5.13%)
         occurrences all number
    2
    Blood glucose increased
         subjects affected / exposed
    2 / 39 (5.13%)
         occurrences all number
    2
    Neutrophil count increased
         subjects affected / exposed
    2 / 39 (5.13%)
         occurrences all number
    2
    White blood cell count increased
         subjects affected / exposed
    2 / 39 (5.13%)
         occurrences all number
    2
    Intraocular pressure increased
    Additional description: 1/13 affected participants experienced this event in the sham-treated eyes.
         subjects affected / exposed
    13 / 39 (33.33%)
         occurrences all number
    14
    Social circumstances
    Alcohol use
         subjects affected / exposed
    2 / 39 (5.13%)
         occurrences all number
    3
    Nervous system disorders
    Headache
         subjects affected / exposed
    6 / 39 (15.38%)
         occurrences all number
    30
    Migraine
         subjects affected / exposed
    3 / 39 (7.69%)
         occurrences all number
    10
    Eye disorders
    Anterior chamber cell
         subjects affected / exposed
    6 / 39 (15.38%)
         occurrences all number
    8
    Anterior chamber flare
         subjects affected / exposed
    5 / 39 (12.82%)
         occurrences all number
    6
    Anterior chamber inflammation
         subjects affected / exposed
    3 / 39 (7.69%)
         occurrences all number
    5
    Autoimmune uveitis
    Additional description: The verbatim term for all events of “autoimmune uveitis” is “intermediate uveitis”.
         subjects affected / exposed
    15 / 39 (38.46%)
         occurrences all number
    19
    Chalazion
         subjects affected / exposed
    2 / 39 (5.13%)
         occurrences all number
    3
    Conjunctival haemorrhage
    Additional description: 1/7 affected participants experienced this event in the sham-treated eyes.
         subjects affected / exposed
    7 / 39 (17.95%)
         occurrences all number
    13
    Conjunctival hyperaemia
    Additional description: 4/5 affected participants experienced this event in the sham-treated eyes.
         subjects affected / exposed
    5 / 39 (12.82%)
         occurrences all number
    10
    Corneal disorder
         subjects affected / exposed
    2 / 39 (5.13%)
         occurrences all number
    2
    Eye irritation
    Additional description: 1/2 affected participants experienced this event in the sham-treated eyes.
         subjects affected / exposed
    2 / 39 (5.13%)
         occurrences all number
    3
    Eye pain
    Additional description: 1/3 affected participants experienced this event in sham-treated eyes.
         subjects affected / exposed
    3 / 39 (7.69%)
         occurrences all number
    8
    Foreign body sensation in eyes
    Additional description: 1/2 affected participants experienced this event in sham-treated eyes.
         subjects affected / exposed
    2 / 39 (5.13%)
         occurrences all number
    3
    Iridocyclitis
    Additional description: 2/18 affected participants experienced this event in the sham-treated eyes.
         subjects affected / exposed
    18 / 39 (46.15%)
         occurrences all number
    24
    Iris atrophy
         subjects affected / exposed
    3 / 39 (7.69%)
         occurrences all number
    3
    Iris transillumination defect
         subjects affected / exposed
    2 / 39 (5.13%)
         occurrences all number
    2
    Keratic precipitates
         subjects affected / exposed
    9 / 39 (23.08%)
         occurrences all number
    11
    Macular oedema
         subjects affected / exposed
    2 / 39 (5.13%)
         occurrences all number
    2
    Photopsia
         subjects affected / exposed
    2 / 39 (5.13%)
         occurrences all number
    2
    Punctate keratitis
    Additional description: 3/18 affected participants experienced this event in sham-treated eyes.
         subjects affected / exposed
    18 / 39 (46.15%)
         occurrences all number
    20
    Vitreal cells
         subjects affected / exposed
    3 / 39 (7.69%)
         occurrences all number
    4
    Vitreous disorder
         subjects affected / exposed
    3 / 39 (7.69%)
         occurrences all number
    3
    Vitreous floaters
         subjects affected / exposed
    3 / 39 (7.69%)
         occurrences all number
    3
    Vitritis
         subjects affected / exposed
    7 / 39 (17.95%)
         occurrences all number
    8
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    3 / 39 (7.69%)
         occurrences all number
    3
    Depression
         subjects affected / exposed
    2 / 39 (5.13%)
         occurrences all number
    2
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    7 / 39 (17.95%)
         occurrences all number
    7
    Ear infection
         subjects affected / exposed
    2 / 39 (5.13%)
         occurrences all number
    2
    Conjunctivitis
         subjects affected / exposed
    2 / 39 (5.13%)
         occurrences all number
    2

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    11 Jun 2015
    The protocol was revised to incorporate the following: 1. Added the newly-determined names of the current studies (RESCUE and REVERSE) to the protocol. 2. Updated the clinical and nonclinical safety profile of GS010. 3. The objectives, endpoints, and statistical analyses were revised to harmonize with Protocol GS-LHON-CLIN-03B. i. The primary endpoint (both studies) was to be the ETDRS score at 48 weeks compared to Baseline. ii. Secondary acuity endpoints in both studies were to include ETDRS at 96 weeks compared to Baseline, binary response to treatment at 48 and 96 weeks, and the comparison of the strategy of treating better versus worse seeing eyes. 4. Randomization was revised from the better-seeing eye to the right eye of each participant randomized with the left receiving the alternative. 5. Revised the randomization and unmasking methods from envelopes to an interactive voice recognition system. 6. Respiratory rate was removed from the measured vital signs. 7. Applanation tonometry was further specified as Goldmann applanation tonometry. 8. The color vision test was changed from the 15 Hue color test to the Farnsworth Munsell 100 Hue Color Test. 9. Added a section for Study Duration with a definition of End of Study as last subject’s last visit. 10. The data collected by the SD-OCT assessment were simplified. 11. More specific time frames were assigned to some secondary endpoints. 12. Added color fundus photos at Visit 1 for Baseline and Visits 4 to12 as necessary if the participant had vitreous inflammation. 13. Added all vision-related testing to Visit 1. 14. Specific instructions were added on establishing and maintaining the study masking and procedures for unmasking. 15. The timing of the primary analysis was revised so that the primary efficacy analysis can be performed after all participants complete Week 48. 16. Changed the term “patients” to “subjects” when referring to study participants.
    22 Feb 2016
    The protocol was revised to incorporate the following: 1. Added the ClinicalTrials.gov identifier for the trial. 2. Made refraction for BCVA required at each study follow-up visit regardless of change in visual acuity. 3. Required ND4 genotyping to be performed for all participants in an appropriately certified central study laboratory. 4. Clarified in the Schedule of Events that QoL questionnaires should be administered before visual acuity tests were conducted. 5. Clarified the non-selection criteria with regard to participants with well-controlled glaucoma. 6. Updated the appropriate post-reconstitution storage conditions for the investigational product. 7. Clarified the appropriate site personnel who could randomize participants. 8. Widened eligible participant age range to include pediatric participants aged 15 to 18 years and made corresponding changes to the informed consent process to include pediatric participants.
    07 Nov 2016
    The protocol was revised to incorporate the following: 1. Updated the job title of one of the study Sponsor contacts. 2. Added the performance of FAs to the protocol when the Investigator documented the initial presence of significant vitreous inflammation that also required treatment per the recommendation of the study DSMB. The FAs served to further characterize the observed vitreous inflammation and potentially guide management/treatment of the vitreous inflammation. 3. Clarified how the duration of vision loss should be calculated for the purpose of determining study eligibility. 4. Clarified which study visits should be conducted by the unmasked study team and how AEs should be followed up by the unmasked study team.

    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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