Efficacy Study of GS010 for Treatment of Vision Loss From 7 Months to 1 Year From Onset in LHON Due to the ND4 Mutation (REVERSE) (REVERSE)

• ClinicalTrials.gov Identifier: NCT02652780
• Recruitment Status: Completed
• First Posted: January 12, 2016
• Results First Posted: January 23, 2020
• Last Update Posted: January 23, 2020
• Sponsor: GenSight Biologics
• Information provided by (Responsible Party): GenSight Biologics

• Study Type: Interventional
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor); Primary Purpose: Treatment
• Condition: Optic, Atrophy, Hereditary, Leber
• Interventions: Biological: GS010; Device: Sham Intravitreal Injection
• Enrollment: 37

Participant Flow

Recruitment Details
Pre-assignment Details

Arm/Group Title	All Participants
Arm/Group Description	All participants who were enrolled and received both study treatments, GS010 and Sham. All participants in the study received both GS010 and the sham procedure simultaneously. Participants were randomly assigned to receive GS010 in either the right or left eye. The same participants also received the sham procedure in the eye not assigned to GS010, at the same study visit. 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: 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.
Period Title: Overall Study
Started	37
Completed	37
Not Completed	0

Baseline Characteristics

Arm/Group Title		All Participants
Arm/Group Description		All participants who were enrolled and received both study treatments, GS010 and Sham. All participants in the study received both GS010 and the sham procedure simultaneously. Participants were randomly assigned to receive GS010 in either the right or left eye. The same participants also received the sham procedure in the eye not assigned to GS010, at the same study visit. 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: 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.
Overall Number of Baseline Participants		37
Baseline Analysis Population Description		[Not Specified]
Age, Categorical; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	37 participants
	<=18 years	4 10.8%
	Between 18 and 65 years	32 86.5%
	>=65 years	1 2.7%
Age, Continuous; Mean (Standard Deviation); Unit of measure: Years
	Number Analyzed	37 participants
		34.2 (15.2)
Sex: Female, Male; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	37 participants
	Female	8 21.6%
	Male	29 78.4%
Race and Ethnicity Not Collected [1]; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	0 participants
		[1] Measure Analysis Population Description: Race and Ethnicity were not collected from any participant.
Region of Enrollment; Measure Type: Count of Participants; Unit of measure: Participants
United States	Number Analyzed	37 participants
		20 54.1%
United Kingdom	Number Analyzed	37 participants
		2 5.4%
France	Number Analyzed	37 participants
		5 13.5%
Germany	Number Analyzed	37 participants
		6 16.2%
Italy	Number Analyzed	37 participants
		4 10.8%
Weight; Mean (Standard Deviation); Unit of measure: Kilograms
	Number Analyzed	37 participants
		80.1 (21.0)
Height; Mean (Standard Deviation); Unit of measure: Centimetres
	Number Analyzed	37 participants
		174.4 (7.8)

Outcome Measures

1. Primary Outcome

Title	Change From Baseline in ETDRS Visual Acuity (Quantitative Score) at Week 48
Description	Visual acuity was derived from the Early Treatment Diabetic Retinopathy Study (ETDRS) chart. The visual acuity logarithm of the minimal angle of resolution (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 A lower LogMAR score denotes better visual acuity and a negative change from baseline indicates an improvement in visual acuity. Change = (Week 48 score - Baseline score).
Time Frame	Baseline and Week 48

Outcome Measure Data

Analysis Population Description

All participants and all eyes that received study treatments, with data at both Baseline and the applicable post-dose visit (Week 48). All participants received both GS010 and Sham simultaneously.

Arm/Group Title	GS010-treated Eyes	Sham-treated Eyes
Arm/Group Description:	All eyes that received the study treatment, GS010. Each participant was randomly assigned GS010 in either the right or left eye. The eye assigned to GS010 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. The same participants also received the sham procedure in the right or left eye, which was not assigned to receive GS010, at the same study visit.	All eyes that received the Sham. Each participant was randomly assigned GS010 in either the right or left eye, the eye not assigned GS010 received the sham procedure. The eye assigned to the Sham received one single sham intravitreal (IVT) injection, which 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. The same participants also received GS010 in the right or left eye, which did not receive the Sham, at the same study visit.
Overall Number of Participants Analyzed	37	37
Overall Number of Units Analyzed; Type of Units Analyzed: Eyes	37	37
Least Squares Mean (Standard Error); Unit of Measure: LogMAR
	-0.219 (0.055)	-0.211 (0.055)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	GS010-treated Eyes, Sham-treated Eyes
	Comments	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. 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.
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.8783
	Comments	[Not Specified]
	Method	ANCOVA
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-0.008
	Confidence Interval	(2-Sided) 95%; -0.119 to 0.102
	Estimation Comments	[Not Specified]

2. Secondary Outcome

Title	Change From Baseline in ETDRS Visual Acuity (Quantitative Score) at Week 96
Description	Visual acuity was derived from the Early Treatment Diabetic Retinopathy Study (ETDRS) chart. The visual acuity logarithm of the minimal angle of resolution (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 A lower LogMAR score denotes better visual acuity and a negative change from baseline indicates an improvement in visual acuity. Change = (Week 96 score - Baseline score).
Time Frame	Baseline and Week 96

Outcome Measure Data

Analysis Population Description

All participants and all eyes that received study treatments, with data at both Baseline and the applicable post-dose visit (Week 96). All participants received both GS010 and Sham simultaneously.

Arm/Group Title	GS010-treated Eyes	Sham-treated Eyes
Arm/Group Description:	All eyes that received the study treatment, GS010. Each participant was randomly assigned GS010 in either the right or left eye. The eye assigned to GS010 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. The same participants also received the sham procedure in the right or left eye, which was not assigned to receive GS010, at the same study visit.	All eyes that received the Sham. Each participant was randomly assigned GS010 in either the right or left eye, the eye not assigned GS010 received the sham procedure. The eye assigned to the Sham received one single sham intravitreal (IVT) injection, which 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. The same participants also received GS010 in the right or left eye, which did not receive the sham procedure, at the same study visit.
Overall Number of Participants Analyzed	37	37
Least Squares Mean (Standard Error); Unit of Measure: LogMAR
	-0.308 (0.068)	-0.259 (0.068)

3. Secondary Outcome

Title	Number of Eye Responders to Treatment at Week 48 and Week 96
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 improvement of the ETDRS score of at least 20 letters compared to Baseline.
Time Frame	Baseline; Week 48 and Week 96

Outcome Measure Data

Analysis Population Description

All participants and all eyes that received study treatments, with data at both Baseline and the applicable post-dose visit (Week 48 or Week 96). All participants received both GS010 and Sham simultaneously.

Arm/Group Title	GS010-treated Eyes	Sham-treated Eyes
Arm/Group Description:	All eyes that received the study treatment, GS010. Each participant was randomly assigned GS010 in either the right or left eye. The eye assigned to GS010 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. The same participants also received the sham procedure in the right or left eye, which was not assigned to receive GS010, at the same study visit.	All eyes that received the Sham. Each participant was randomly assigned GS010 in either the right or left eye, the eye not assigned GS010 received the sham procedure. The eye assigned to the Sham received one single sham intravitreal (IVT) injection, which 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. The same participants also received GS010 in the right or left eye, which did not receive the sham procedure, at the same study visit.
Overall Number of Participants Analyzed	37	37
Overall Number of Units Analyzed; Type of Units Analyzed: Eyes	37	37
Count of Units; Unit of Measure: Eyes
Definition 1: Week 48	7 18.9%	5 13.5%
Definition 1: Week 96	12 32.4%	6 16.2%
Definition 2: Week 48	10 27.0%	13 35.1%
Definition 2: Week 96	17 45.9%	19 51.4%

4. Secondary Outcome

Title	Number of Subject Responders to Treatment at Week 48 and Week 96
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.
Time Frame	Week 48 and Week 96

Outcome Measure Data

Analysis Population Description

All participants that received study treatments, with data at the applicable post dose visit (Week 48 or Week 96). All participants received both GS010 and Sham simultaneously.

Arm/Group Title	All Participants
Arm/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 (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: 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.
Overall Number of Participants Analyzed	37
Measure Type: Count of Participants; Unit of Measure: Participants
Week 48	37 100.0%
Week 96	37 100.0%

5. Secondary Outcome

Title	Change From Baseline in GCL Macular Volume at Week 48 and Week 96
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).
Time Frame	Baseline and Week 48; Baseline and Week 96

Outcome Measure Data

Analysis Population Description

All participants and all eyes that received study treatments, with data at both Baseline and the applicable post-dose visit (Week 48 or Week 96). All participants received both GS010 and Sham simultaneously.

Arm/Group Title	GS010-treated Eyes	Sham-treated Eyes
Arm/Group Description:	All eyes that received the study treatment, GS010. Each participant was randomly assigned GS010 in either the right or left eye. The eye assigned to GS010 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. The same participants also received the sham procedure in the right or left eye, which was not assigned to receive GS010, at the same study visit.	All eyes that received the Sham. Each participant was randomly assigned GS010 in either the right or left eye, the eye not assigned GS010 received the sham procedure. The eye assigned to the Sham received one single sham intravitreal (IVT) injection, which 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. The same participants also received GS010 in the right or left eye, which did not receive the sham procedure, at the same study visit.
Overall Number of Participants Analyzed	36	36
Overall Number of Units Analyzed; Type of Units Analyzed: Eyes	36	36
Least Squares Mean (Standard Error); Unit of Measure: mm^3
Week 48	-0.003 (0.012)	-0.038 (0.012)
Week 96	-0.018 (0.012)	-0.031 (0.012)

6. Secondary Outcome

Title	Change From Baseline in RNFL Temporal Quadrant Thickness at Week 48 and Week 96
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).
Time Frame	Baseline and Week 48; Baseline and Week 96

Outcome Measure Data

Analysis Population Description

All participants and all eyes that received study treatments, with data at both Baseline and the applicable post-dose visit (Week 48 or Week 96). All participants received both GS010 and Sham simultaneously.

Arm/Group Title		GS010-treated Eyes	Sham-treated Eyes
Arm/Group Description:		All eyes that received the study treatment, GS010. Each participant was randomly assigned GS010 in either the right or left eye. The eye assigned to GS010 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. The same participants also received the sham procedure in the right or left eye, which was not assigned to receive GS010, at the same study visit.	All eyes that received the Sham. Each participant was randomly assigned GS010 in either the right or left eye, the eye not assigned GS010 received the sham procedure. The eye assigned to the Sham received one single sham intravitreal (IVT) injection, which 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. The same participants also received GS010 in the right or left eye, which did not receive the sham procedure, at the same study visit.
Overall Number of Participants Analyzed		37	36
Overall Number of Units Analyzed; Type of Units Analyzed: Eyes		37	36
Least Squares Mean (Standard Error); Unit of Measure: µm
Week 48	Number Analyzed	37 Eyes	35 Eyes [1]
		-0.562 (0.988)	-3.354 (1.017)
Week 96	Number Analyzed	35 Eyes [1]	36 Eyes
		-1.791 (0.974)	-2.042 (0.951)

[1]

35 participants

7. Secondary Outcome

Title	Change From Baseline in Papillomacular Bundle Thickness at Week 48 and Week 96
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).
Time Frame	Baseline and Week 48; Baseline and Week 96

Outcome Measure Data

Analysis Population Description

All participants and all eyes that received study treatments, with data at both Baseline and the applicable post-dose visit (Week 48 or Week 96). All participants received both GS010 and Sham simultaneously.

Arm/Group Title		GS010-treated Eyes	Sham-treated Eyes
Arm/Group Description:		All eyes that received the study treatment, GS010. Each participant was randomly assigned GS010 in either the right or left eye. The eye assigned to GS010 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. The same participants also received the sham procedure in the right or left eye, which was not assigned to receive GS010, at the same study visit.	All eyes that received the Sham. Each participant was randomly assigned GS010 in either the right or left eye, the eye not assigned GS010 received the sham procedure. The eye assigned to the Sham received one single sham intravitreal (IVT) injection, which 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. The same participants also received GS010 in the right or left eye, which did not receive the sham procedure, at the same study visit.
Overall Number of Participants Analyzed		37	36
Overall Number of Units Analyzed; Type of Units Analyzed: Eyes		37	36
Least Squares Mean (Standard Error); Unit of Measure: µm
Week 48	Number Analyzed	37 Eyes	35 Eyes [1]
		1.6 (1.3)	-1.0 (1.4)
Week 96	Number Analyzed	35 Eyes [1]	36 Eyes
		1.2 (1.3)	0.7 (1.3)

[1]

35 participants

8. Secondary Outcome

Title	Change From Baseline in ETDRS Total Macular Volume at Week 48 and Week 96
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).
Time Frame	Baseline and Week 48; Baseline and Week 96

Outcome Measure Data

Analysis Population Description

All participants and all eyes that received study treatments, with data at both Baseline and the applicable post-dose visit (Week 48 or Week 96). All participants received both GS010 and Sham simultaneously.

Arm/Group Title	GS010-treated Eyes	Sham-treated Eyes
Arm/Group Description:	All eyes that received the study treatment, GS010. Each participant was randomly assigned GS010 in either the right or left eye. The eye assigned to GS010 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. The same participants also received the sham procedure in the right or left eye, which was not assigned to receive GS010, at the same study visit.	All eyes that received the Sham. Each participant was randomly assigned GS010 in either the right or left eye, the eye not assigned GS010 received the sham procedure. The eye assigned to the Sham received one single sham intravitreal (IVT) injection, which 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. The same participants also received GS010 in the right or left eye, which did not receive the sham procedure, at the same study visit.
Overall Number of Participants Analyzed	36	36
Overall Number of Units Analyzed; Type of Units Analyzed: Eyes	36	36
Least Squares Mean (Standard Error); Unit of Measure: mm^3
Week 48	-0.104 (0.046)	-0.224 (0.046)
Week 96	-0.200 (0.037)	-0.265 (0.037)

9. Secondary Outcome

Title	Change From Baseline in the Foveal Threshold Sensitivities Obtained With HVF Analyzer II at Week 48 and Week 96
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.
Time Frame	Baseline and Week 48; Baseline and Week 96

Outcome Measure Data

Analysis Population Description

All participants and all eyes that received study treatments, with data at both Baseline and the applicable post-dose visit (Week 48 or Week 96). All participants received both GS010 and Sham simultaneously.

Arm/Group Title		GS010-treated Eyes	Sham-treated Eyes
Arm/Group Description:		All eyes that received the study treatment, GS010. Each participant was randomly assigned GS010 in either the right or left eye. The eye assigned to GS010 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. The same participants also received the sham procedure in the right or left eye, which was not assigned to receive GS010, at the same study visit.	All eyes that received the Sham. Each participant was randomly assigned GS010 in either the right or left eye, the eye not assigned GS010 received the sham procedure. The eye assigned to the Sham received one single sham intravitreal (IVT) injection, which 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. The same participants also received GS010 in the right or left eye, which did not receive the sham procedure, at the same study visit.
Overall Number of Participants Analyzed		9	11
Overall Number of Units Analyzed; Type of Units Analyzed: Eyes		9	11
Mean (Standard Deviation); Unit of Measure: decibels (dB)
Week 48	Number Analyzed	9 Eyes	11 Eyes
		0.7 (8.9)	-0.5 (11.9)
Week 96	Number Analyzed	8 Eyes [1]	9 Eyes [2]
		1.3 (8.0)	2.4 (10.8)

[1]

8 participants

[2]

9 participants

10. Secondary Outcome

Title	Visual Field Mean Deviation in Decibels of Sensitivity Obtained With HVF Analyzer II at Week 48 and Week 96
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.
Time Frame	Baseline, Week 48 and Week 96

Outcome Measure Data

Analysis Population Description

All participants and all eyes that received study treatments, with data at both Baseline and the applicable post-dose visit (Week 48 or Week 96). All participants received both GS010 and Sham simultaneously.

Arm/Group Title	GS010-treated Eyes	Sham-treated Eyes
Arm/Group Description:	All eyes that received the study treatment, GS010. Each participant was randomly assigned GS010 in either the right or left eye. The eye assigned to GS010 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. The same participants also received the sham procedure in the right or left eye, which was not assigned to receive GS010, at the same study visit.	All eyes that received the Sham. Each participant was randomly assigned GS010 in either the right or left eye, the eye not assigned GS010 received the sham procedure. The eye assigned to the Sham received one single sham intravitreal (IVT) injection, which 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. The same participants also received GS010 in the right or left eye, which did not receive the sham procedure, at the same study visit.
Overall Number of Participants Analyzed	37	37
Overall Number of Units Analyzed; Type of Units Analyzed: Eyes	37	37
Mean (Standard Deviation); Unit of Measure: decibels (dB)
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)

11. Secondary Outcome

Title	Change From Baseline in Contrast Sensitivity at Week 48 and Week 96
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 positive change from baseline indicates improvement in symptoms.
Time Frame	Baseline and Week 48; Baseline and Week 96

Outcome Measure Data

Analysis Population Description

All participants and all eyes that received study treatments, with data at both Baseline and the applicable post-dose visit (Week 48 or Week 96). All participants received both GS010 and Sham simultaneously.

Arm/Group Title	GS010-treated Eyes	Sham-treated Eyes
Arm/Group Description:	All eyes that received the study treatment, GS010. Each participant was randomly assigned GS010 in either the right or left eye. The eye assigned to GS010 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. The same participants also received the sham procedure in the right or left eye, which was not assigned to receive GS010, at the same study visit.	All eyes that received the Sham. Each participant was randomly assigned GS010 in either the right or left eye, the eye not assigned GS010 received the sham procedure. The eye assigned to the Sham received one single sham intravitreal (IVT) injection, which 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. The same participants also received GS010 in the right or left eye, which did not receive the sham procedure, at the same study visit.
Overall Number of Participants Analyzed	37	37
Overall Number of Units Analyzed; Type of Units Analyzed: Eyes	37	37
Least Squares Mean (Standard Error); Unit of Measure: LogCS
Week 48	0.19 (0.05)	0.09 (0.05)
Week 96	0.22 (0.06)	0.12 (0.06)

12. Secondary Outcome

Title	Change From Baseline in Color Vision
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.
Time Frame	Baseline and Week 48; Baseline and Week 96

Outcome Measure Data

Analysis Population Description

All participants and all eyes that received study treatments, with data at both Baseline and the applicable post-dose visit (Week 48 or Week 96). All participants received both GS010 and Sham simultaneously.

Arm/Group Title		GS010-treated Eyes	Sham-treated Eyes
Arm/Group Description:		All eyes that received the study treatment, GS010. Each participant was randomly assigned GS010 in either the right or left eye. The eye assigned to GS010 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. The same participants also received the sham procedure in the right or left eye, which was not assigned to receive GS010, at the same study visit.	All eyes that received the Sham. Each participant was randomly assigned GS010 in either the right or left eye, the eye not assigned GS010 received the sham procedure. The eye assigned to the Sham received one single sham intravitreal (IVT) injection, which 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. The same participants also received GS010 in the right or left eye, which did not receive the sham procedure, at the same study visit.
Overall Number of Participants Analyzed		24	25
Overall Number of Units Analyzed; Type of Units Analyzed: Eyes		24	25
Mean (Standard Deviation); Unit of Measure: score on a scale
Week 48	Number Analyzed	24 Eyes	25 Eyes
		-30.0 (255.0)	-44.3 (182.2)
Week 96	Number Analyzed	23 Eyes [1]	24 Eyes [2]
		-10.3 (247.3)	-61.0 (188.9)

[1]

23 participants

[2]

24 participants

Adverse Events

Time Frame	From first dose to end of study (a maximum of 96 weeks)
Adverse Event Reporting 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.
Arm/Group Title	All Participants
Arm/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 (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: 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.
All-Cause Mortality
	All Participants
	Affected / at Risk (%)
Total	0/37 (0.00%)
Serious Adverse Events
	All Participants
	Affected / at Risk (%)	# Events
Total	3/37 (8.11%)
Cardiac disorders
Acute myocardial infarction † 1	1/37 (2.70%)	1
Eye disorders
Retinal tear † 1 [1]	1/37 (2.70%)	1
Gastrointestinal disorders
Intestinal perforation † 1	1/37 (2.70%)	1
Infections and infestations
Diverticulitis † 1	1/37 (2.70%)	1
1 Term from vocabulary, MedDRA 20.1; † Indicates events were collected by systematic assessment; [1] This event occurred only in an eye receiving the sham procedure.
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	5%
	All Participants
	Affected / at Risk (%)	# Events
Total	37/37 (100.00%)
Eye disorders
Anterior chamber cell † 1	9/37 (24.32%)	11
Autoimmune uveitis † 1 [1]	14/37 (37.84%)	15
Cataract † 1 [2]	4/37 (10.81%)	4
Conjunctival haemorrhage † 1 [3]	6/37 (16.22%)	7
Conjunctival hyperaemia † 1	6/37 (16.22%)	7
Dry eye † 1 [4]	2/37 (5.41%)	3
Iridocyclitis † 1 [5]	15/37 (40.54%)	17
Iritis † 1	2/37 (5.41%)	2
Keratic precipitates † 1	13/37 (35.14%)	16
Eye pain † 1 [6]	3/37 (8.11%)	4
Intraocular pressure increased † 1 [7]	11/37 (29.73%)	13
Vitritis † 1	6/37 (16.22%)	6
Vitreous floaters † 1	2/37 (5.41%)	3
Vitreous detachment † 1	2/37 (5.41%)	2
Vitreal cells † 1 [8]	7/37 (18.92%)	7
Visual impairment † 1	3/37 (8.11%)	3
Punctate keratitis † 1 [9]	15/37 (40.54%)	17
Gastrointestinal disorders
Abdominal pain upper † 1	2/37 (5.41%)	2
Immune system disorders
Drug hypersensitivity † 1	2/37 (5.41%)	2
Infections and infestations
Nasopharyngitis † 1	6/37 (16.22%)	9
Injury, poisoning and procedural complications
Arthropod bite † 1	2/37 (5.41%)	2
Investigations
Gamma-glutamyl transferase increased † 1	8/37 (21.62%)	11
Alanine aminotransferase increased † 1	4/37 (10.81%)	4
Aspartate aminotransferase increased † 1	2/37 (5.41%)	2
Musculoskeletal and connective tissue disorders
Arthralgia † 1	2/37 (5.41%)	2
Nervous system disorders
Headache † 1	4/37 (10.81%)	8
Paraesthesia † 1	2/37 (5.41%)	2
Psychiatric disorders
Depression † 1	2/37 (5.41%)	2
Social circumstances
Alcohol use † 1	2/37 (5.41%)	2
Vascular disorders
Hypertension † 1	2/37 (5.41%)	2
1 Term from vocabulary, MedDRA 20.1; † Indicates events were collected by systematic assessment; [1] The verbatim AE term is "intermediate uveitis". 1/14 affected participants experienced this event only in sham-treated eyes.; [2] 1/4 affected participants experienced this event only in sham-treated eyes; [3] 3/6 affected participants experienced this event only in sham-treated eyes.; [4] 1/2 affected participants experienced this event only in sham-treated eyes.; [5] 1/15 affected participants experienced this event only in sham-treated eyes.; [6] 1/3 affected participants experienced this event only in sham-treated eyes.; [7] 1/11 affected participants experienced this event only in sham-treated eyes.; [8] 1/7 affected participants experienced this event only in sham-treated eyes.; [9] 4/15 affected participants experienced this event only in sham-treated eyes.

Limitations and Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

Results Point of Contact

• Name/Title: Regulatory Affairs
• Organization: GenSight Biologics
• Phone: 176217220 ext 0033
• EMail: ipengue@gensight-biologics.com

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Newman NJ, Yu-Wai-Man P, Carelli V, Biousse V, Moster ML, Vignal-Clermont C, Sergott RC, Klopstock T, Sadun AA, Girmens JF, La Morgia C, DeBusk AA, Jurkute N, Priglinger C, Karanjia R, Josse C, Salzmann J, Montestruc F, Roux M, Taiel M, Sahel JA. Intravitreal Gene Therapy vs. Natural History in Patients With Leber Hereditary Optic Neuropathy Carrying the m.11778G>A ND4 Mutation: Systematic Review and Indirect Comparison. Front Neurol. 2021 May 24;12:662838. doi: 10.3389/fneur.2021.662838. eCollection 2021.

• Responsible Party: GenSight Biologics
• ClinicalTrials.gov Identifier: NCT02652780
• Other Study ID Numbers: GS-LHON-CLIN-03B; 2015-001266-26 ( EudraCT Number )
• First Submitted: January 7, 2016
• First Posted: January 12, 2016
• Results First Submitted: December 13, 2019
• Results First Posted: January 23, 2020
• Last Update Posted: January 23, 2020