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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 more than 6 Months and to 12 months by Leber Hereditary Optic Neuropathy Due to the G11778A Mutation in the Mitochondrial NADH Dehydrogenase 4 Gene

    Summary
    EudraCT number
    		 2015-001266-26
    Trial protocol
    		 DE   GB   IT  
    Global end of trial date
    19 Dec 2018

    Results information
    Results version number
    		 v1
    This version publication date
    27 Dec 2019
    First version publication date
    27 Dec 2019
    Other versions
    		 v2

    Trial information

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    Trial identification
    Sponsor protocol code
    GS-LHON-CLIN-03B
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02652780
    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 176217233, ipengue@gensight-biologics.com
    Scientific contact
    Regulatory Affairs Director, GENSIGHT-BIOLOGICS, 0033 176217233, 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
    07 May 2019
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    11 Jan 2018
    Global end of trial reached?
    Yes
    Global end of trial date
    19 Dec 2018
    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 logarithm of the minimal angle of resolution (LogMAR) in participants affected for more than 6 months and up to 12 months by Leber hereditary optic 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
    22 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 States: 20
    Country: Number of subjects enrolled
    United Kingdom: 2
    Country: Number of subjects enrolled
    France: 5
    Country: Number of subjects enrolled
    Germany: 6
    Country: Number of subjects enrolled
    Italy: 4
    Worldwide total number of subjects
    37
    EEA total number of subjects
    17
    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)
    32
    From 65 to 84 years
    1
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 A total of 37 participants were enrolled across 7 sites in 4 European countries and the United States. The right eye of each participant was randomly allocated either GS010 or Sham in a 1:1 ratio. The left eye of each participant received the other treatment not allocated to the right eye at the same visit.

    Pre-assignment
    Screening details
    		 A total of 49 participants were screened, with 12 resulting in screen failures. 37 participants were randomized and received study treatment.

    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
    Blinding implementation details
    An unmasked team at the site performed all procedures on Day 0 (treatment day) and Day 1 and focused follow-up of ocular AEs commencing on Day 0 and 1 until resolution of the AE or the determination that no further clinical evolution is expected. The unmasked team includes the injecting investigator(s), allied medical professionals who assist with IVT injection and ophthalmic technicians/optometrists who perform vision testing on Day 1. The Principal Investigator remained masked until study end.

    Arms
    Arm title
    		 Overall trial: All participants
    Arm description
    		 All participants who were enrolled and received both study treatments, GS010 and Sham. Participants were randomly assigned to receive GS010 in either the right or left eye. The same participants also received the sham comparator in the eye not assigned to GS010 at the same visit. GS010: Either the right or left eye received one single dose of GS010 via an intravitreal (IVT) injection containing 9E10 viral genomes in 90 μl balanced salt solution (BSS) plus 0.001% Pluronic F68®. Sham procedure: Either the right or left eye (the eye not randomly assigned to GS010) received the 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
    Dosage: 9E10 vg/eye (volume of injection of 90µL) 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
    The 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
    37
    Completed
    37

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Overall trial
    Reporting group description
    		 All participants who were enrolled and randomized, and who received both treatments, GS010 and Sham.

    Reporting group values
    		 Overall trial Total
    Number of subjects
    		 37 37
    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)
    		 32 32
        From 65-84 years
    		 1 1
        85 years and over
    		 0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 34.2 ± 15.2 -
    Gender categorical
    Units: Subjects
        Female
    		 8 8
        Male
    		 29 29
    Weight
    Units: kg
        arithmetic mean (standard deviation)
    		 80.1 ± 21.0 -
    Height
    Units: cm
        arithmetic mean (standard deviation)
    		 174.4 ± 7.8 -

    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. Participants were randomly assigned to receive GS010 in either the right or left eye. The same participants also received the sham comparator in the eye not assigned to GS010 at the same visit. GS010: Either the right or left eye received one single dose of GS010 via an intravitreal (IVT) injection containing 9E10 viral genomes in 90 μl balanced salt solution (BSS) plus 0.001% Pluronic F68®. Sham procedure: Either the right or left eye (the eye not randomly assigned to GS010) received the 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 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.

    Subject analysis set title
    Sham comparator
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    All 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.

    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
    Early Treatment Diabetic Retinopathy Study (ETDRS) visual acuity LogMAR score 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 0.1 LogMAR = 5 ETDRS letters 15 ETDRS letters = 0.3 LogMAR A negative change from baseline indicates an improvement in visual acuity.
    End point type
    Primary
    End point timeframe
    Baseline and Week 48
    End point values
    		 GS010 treatment Sham comparator
    Number of subjects analysed
    37
    37
    Units: LogMAR
        least squares mean (standard error)
    -0.219 ± 0.055
    -0.211 ± 0.055
    Statistical analysis title
    		 Difference between GS010 Eyes and Sham Eyes
    Statistical analysis description
    The analysis compared GS010 treated eyes to Sham eyes of all 37 intent-to-treat participants.
    Comparison groups
    GS010 treatment v Sham comparator
    Number of subjects included in analysis
    74
    Analysis specification
    Pre-specified
    Analysis type
    		 other [1]
    P-value
    		 = 0.8783 [2]
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (net)
    Point estimate
    -0.008
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.119
         upper limit
    		 0.102
    Notes
    [1] - A mixed model of analysis of covariance (ANCOVA) was used with change from baseline at week 48 as the response, and participants, eyes of the participant as random factor, treatment and baseline LogMAR value as covariates in the model.
    [2] - P-value is used to assess the significance of the difference between All-GS010 and All-Sham with respect to change of LogMAR from baseline using Wilcoxon Signed-Rank test.

    Secondary: Change from Baseline in ETDRS Visual Acuity (Quantitative Score) at Week 96

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    End point title
    		 Change from Baseline in ETDRS Visual Acuity (Quantitative Score) at Week 96
    End point description
    Early Treatment Diabetic Retinopathy Study (ETDRS) visual acuity LogMAR score 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 0.1 LogMAR = 5 ETDRS letters 15 ETDRS letters = 0.3 LogMAR A negative change from baseline indicates an improvement in visual acuity.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 96
    End point values
    		 GS010 treatment Sham comparator
    Number of subjects analysed
    37
    37
    Units: LogMAR score
        least squares mean (standard deviation)
    -0.308 ± 0.068
    -0.259 ± 0.068
    No statistical analyses for this end point

    Secondary: Number of Eye Responders to Treatment at Week 48 and Week 96

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    End point title
    		 Number of Eye Responders to Treatment at Week 48 and Week 96
    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 (a score of at least 1 letter). Definition 2: An eye responder was defined by an ETDRS score of at least 20 letters compared to baseline.
    End point type
    Secondary
    End point timeframe
    Baseline; Week 48 and Week 96
    End point values
    		 GS010 treatment Sham comparator
    Number of subjects analysed
    37
    37
    Units: Participants
        Week 48 Definition 1
    7
    5
        Week 48 Definition 2
    10
    13
        Week 96 Definition 1
    12
    6
        Week 96 Definition 2
    17
    19
    No statistical analyses for this end point

    Secondary: Number of Subject Responders to Treatment at Week 48 and Week 96

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    End point title
    		 Number of Subject Responders to Treatment at Week 48 and Week 96
    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, is at least 15 letters better than the sham eye, or whose treated eye has a logarithm of the minimal angle of resolution (LogMAR) acuity of at least 0.3 LogMAR better than the sham eye.
    End point type
    Secondary
    End point timeframe
    Week 48 and Week 96
    End point values
    		 Overall trial: All participants
    Number of subjects analysed
    37
    Units: Participants
        Week 48
    37
        Week 96
    37
    No statistical analyses for this end point

    Secondary: Change from Baseline in GCL Macular Volume at Week 48 and Week 96

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    End point title
    		 Change from Baseline in GCL Macular Volume at Week 48 and Week 96
    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 and Week 96
    End point values
    		 GS010 treatment Sham comparator
    Number of subjects analysed
    36 [3]
    36 [4]
    Units: mm^3
    least squares mean (standard error)
        Week 48
    -0.003 ± 0.012
    -0.038 ± 0.012
        Week 96
    -0.018 ± 0.012
    -0.031 ± 0.012
    Notes
    [3] - Week 48 N = 36 Week 96 N = 36 All participants with data at baseline and Week 48 or Week 96.
    [4] - Week 48 N = 36 Week 96 N = 36 All participants with data at baseline and Week 48 or Week 96.
    No statistical analyses for this end point

    Secondary: Change from Baseline in RNFL Temporal Quadrant Thickness at Week 48 and Week 96

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    End point title
    		 Change from Baseline in RNFL Temporal Quadrant Thickness at Week 48 and Week 96
    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 and Week 96
    End point values
    		 GS010 treatment Sham comparator
    Number of subjects analysed
    37 [5]
    36 [6]
    Units: µm
    least squares mean (standard error)
        Week 48
    -0.562 ± 0.988
    -3.354 ± 1.017
        Week 96
    -1.791 ± 0.974
    -2.042 ± 0.951
    Notes
    [5] - Week 48 N = 37 Week 96 N = 35 All participants with data at baseline and Week 48 or Week 96.
    [6] - Week 48 N = 35 Week 96 N = 36 All participants with data at baseline and Week 48 or Week 96.
    No statistical analyses for this end point

    Secondary: Change from Baseline in Papillomacular Bundle Thickness at Week 48 and Week 96

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    End point title
    		 Change from Baseline in Papillomacular Bundle Thickness at Week 48 and Week 96
    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 and Week 96
    End point values
    		 GS010 treatment Sham comparator
    Number of subjects analysed
    37 [7]
    36 [8]
    Units: µm
    least squares mean (standard error)
        Week 48
    1.6 ± 1.3
    -1.0 ± 1.4
        Week 96
    1.2 ± 1.3
    0.7 ± 1.3
    Notes
    [7] - Week 48 N = 37 Week 96 N = 35 All participants with data at baseline and Week 48 or Week 96.
    [8] - Week 48 N = 35 Week 96 N = 36 All participants with data at baseline and Week 48 or Week 96.
    No statistical analyses for this end point

    Secondary: Change from Baseline in ETDRS Total Macular Volume at Week 48 and Week 96

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    End point title
    		 Change from Baseline in ETDRS Total Macular Volume at Week 48 and Week 96
    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 and Week 96
    End point values
    		 GS010 treatment Sham comparator
    Number of subjects analysed
    36 [9]
    36 [10]
    Units: mm^3
    least squares mean (standard error)
        Week 48
    -0.104 ± 0.046
    -0.224 ± 0.046
        Week 96
    -0.200 ± 0.037
    -0.265 ± 0.037
    Notes
    [9] - Week 48 N = 36 Week 96 N = 36 All participants with data at baseline and Week 48 or Week 96.
    [10] - Week 48 N = 36 Week 96 N = 36 All participants with data at baseline and Week 48 or Week 96.
    No statistical analyses for this end point

    Secondary: Change From Baseline in the Foveal Threshold Sensitivities Obtained With HVF Analyzer II at Week 48 and Week 96

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    End point title
    		 Change From Baseline in the Foveal Threshold Sensitivities Obtained With HVF Analyzer II at Week 48 and Week 96
    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 and Week 96
    End point values
    		 GS010 treatment Sham comparator
    Number of subjects analysed
    9 [11]
    11 [12]
    Units: decibel (dB)
    arithmetic mean (standard deviation)
        Week 48: Foveal Threshold Sensitivity
    0.7 ± 8.9
    -0.5 ± 11.9
        Week 96: Foveal Threshold Sensitivity
    1.3 ± 8.0
    2.4 ± 10.8
    Notes
    [11] - Week 48 N = 9 Week 96 N = 8
    [12] - Week 48 N = 11 Week 96 N = 9
    No statistical analyses for this end point

    Secondary: Visual Field Mean Deviation in Decibels of Sensitivity Obtained With HVF Analyzer II at Week 48 and Week 96

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    End point title
    		 Visual Field Mean Deviation in Decibels of Sensitivity Obtained With HVF Analyzer II at Week 48 and Week 96
    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 and Week 96
    End point values
    		 GS010 treatment Sham comparator
    Number of subjects analysed
    37
    37
    Units: decibels (dB)
    arithmetic mean (standard deviation)
        Baseline MD
    -25.99 ± 8.37
    -24.94 ± 9.70
        Week 48 MD
    -22.83 ± 9.43
    -22.94 ± 9.80
        Week 96 MD
    -23.22 ± 8.98
    -22.43 ± 9.39
    No statistical analyses for this end point

    Secondary: Change from Baseline in Contrast Sensitivity at Week 48 and Week 96

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    End point title
    		 Change from Baseline in Contrast Sensitivity at Week 48 and Week 96
    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. A score of 2.0 log of contrast sensitivity (LogCS) units, which represents a normal sensitivity contrast, indicates that 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 positive change from baseline indicates 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
    37
    37
    Units: LogCS score
    least squares mean (standard error)
        Week 48
    0.19 ± 0.05
    0.09 ± 0.05
        Week 96
    0.22 ± 0.06
    0.12 ± 0.06
    No statistical analyses for this end point

    Secondary: Change from Baseline in Color Vision at Week 48 and Week 96

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    End point title
    		 Change from Baseline in Color Vision at Week 48 and Week 96
    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 movable 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 was derived by counting the number of caps misplaced. 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
    24 [13]
    25 [14]
    Units: total error score
    arithmetic mean (standard deviation)
        Week 48
    -30.0 ± 255.0
    -44.3 ± 182.2
        Week 96
    -10.3 ± 247.3
    -61.0 ± 188.9
    Notes
    [13] - Week 48 N = 24 Week 96 N = 23
    [14] - Week 48 N = 25 Week 96 N = 24
    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)
    Adverse event reporting additional description
    Because participants received both treatment and sham procedure simultaneously, adverse events (AEs) are reported overall for systemic and ocular AEs. Reported events include AEs associated with sham procedure.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    20.1
    Reporting groups
    Reporting group title
    All participants
    Reporting group description
    		 All participants who were randomized and received study treatment, GS010 and Sham.

    Serious adverse events
    		 All participants
    Total subjects affected by serious adverse events
         subjects affected / exposed
    3 / 37 (8.11%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    0
    Cardiac disorders
    Acute myocardial infarction
         subjects affected / exposed
    1 / 37 (2.70%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Eye disorders
    Retinal tear
    Additional description: This event occurred only in an eye receiving the sham procedure.
         subjects affected / exposed
    1 / 37 (2.70%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal disorders
    Intestinal perforation
         subjects affected / exposed
    1 / 37 (2.70%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Infections and infestations
    Diverticulitis
         subjects affected / exposed
    1 / 37 (2.70%)
         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
    		 All participants
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    37 / 37 (100.00%)
    Investigations
    Gamma-glutamyl transferase increased
         subjects affected / exposed
    8 / 37 (21.62%)
         occurrences all number
    11
    Alanine aminotransferase increased
         subjects affected / exposed
    4 / 37 (10.81%)
         occurrences all number
    4
    Aspartate aminotransferase increased
         subjects affected / exposed
    2 / 37 (5.41%)
         occurrences all number
    2
    Injury, poisoning and procedural complications
    Arthropod bite
         subjects affected / exposed
    2 / 37 (5.41%)
         occurrences all number
    2
    Vascular disorders
    Hypertension
         subjects affected / exposed
    2 / 37 (5.41%)
         occurrences all number
    2
    Nervous system disorders
    Headache
         subjects affected / exposed
    4 / 37 (10.81%)
         occurrences all number
    8
    Paraesthesia
         subjects affected / exposed
    2 / 37 (5.41%)
         occurrences all number
    2
    Immune system disorders
    Drug hypersensitivity
         subjects affected / exposed
    2 / 37 (5.41%)
         occurrences all number
    2
    Social circumstances
    Alcohol use
         subjects affected / exposed
    2 / 37 (5.41%)
         occurrences all number
    2
    Eye disorders
    Anterior chamber cell
         subjects affected / exposed
    9 / 37 (24.32%)
         occurrences all number
    11
    Autoimmune uveitis
    Additional description: The verbatim AE term is "intermediate uveitis". 1/14 affected participants experienced this event only in sham-treated eyes.
         subjects affected / exposed
    14 / 37 (37.84%)
         occurrences all number
    15
    Cataract
    Additional description: 1/4 affected participants experienced this event only in sham-treated eyes
         subjects affected / exposed
    4 / 37 (10.81%)
         occurrences all number
    4
    Conjunctival haemorrhage
    Additional description: 3/6 affected participants experienced this event only in sham-treated eyes.
         subjects affected / exposed
    6 / 37 (16.22%)
         occurrences all number
    7
    Conjunctival hyperaemia
         subjects affected / exposed
    6 / 37 (16.22%)
         occurrences all number
    7
    Dry eye
    Additional description: 1/2 affected participants experienced this event only in sham-treated eyes.
         subjects affected / exposed
    2 / 37 (5.41%)
         occurrences all number
    3
    Iridocyclitis
    Additional description: 1/15 affected participants experienced this event only in sham-treated eyes.
         subjects affected / exposed
    15 / 37 (40.54%)
         occurrences all number
    17
    Iritis
         subjects affected / exposed
    2 / 37 (5.41%)
         occurrences all number
    2
    Keratic precipitates
         subjects affected / exposed
    13 / 37 (35.14%)
         occurrences all number
    16
    Eye pain
    Additional description: 1/3 affected participants experienced this event only in sham-treated eyes.
         subjects affected / exposed
    3 / 37 (8.11%)
         occurrences all number
    4
    Intraocular pressure increased
    Additional description: 1/11 affected participants experienced this event only in sham-treated eyes.
         subjects affected / exposed
    11 / 37 (29.73%)
         occurrences all number
    13
    Vitritis
         subjects affected / exposed
    6 / 37 (16.22%)
         occurrences all number
    6
    Vitreous floaters
         subjects affected / exposed
    2 / 37 (5.41%)
         occurrences all number
    3
    Vitreous detachment
         subjects affected / exposed
    2 / 37 (5.41%)
         occurrences all number
    2
    Vitreal cells
    Additional description: 1/7 affected participants experienced this event only in sham-treated eyes.
         subjects affected / exposed
    7 / 37 (18.92%)
         occurrences all number
    7
    Visual impairment
         subjects affected / exposed
    3 / 37 (8.11%)
         occurrences all number
    3
    Punctate keratitis
    Additional description: 4/15 affected participants experienced this event only in sham-treated eyes.
         subjects affected / exposed
    15 / 37 (40.54%)
         occurrences all number
    17
    Gastrointestinal disorders
    Abdominal pain upper
         subjects affected / exposed
    2 / 37 (5.41%)
         occurrences all number
    2
    Psychiatric disorders
    Depression
         subjects affected / exposed
    2 / 37 (5.41%)
         occurrences all number
    2
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    2 / 37 (5.41%)
         occurrences all number
    2
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    6 / 37 (16.22%)
         occurrences all number
    9

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    12 Jun 2015
    In Global Revision 1, the protocol was revised to incorporate the following: 1. Added 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-03A. a. The primary endpoint was to be the ETDRS score at 48 weeks compared to Baseline. b. 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 participants 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 EOS as last participants 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.
    23 Feb 2016
    In Global Revision 2, 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 participants age range to include paediatric participants aged 15 to 18 years and made corresponding changes to the informed consent process to include paediatric participants.
    07 Nov 2016
    In Global Revision 3, 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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