Efficacy Study of GS010 for the Treatment of Vision Loss up to 6 Months From Onset in LHON Due to the ND4 Mutation (RESCUE)

• ClinicalTrials.gov Identifier: NCT02652767
• Recruitment Status: Completed
• First Posted: January 12, 2016
• Results First Posted: January 28, 2020
• Last Update Posted: July 29, 2022
• 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: 39

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 receive 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: 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	39
Completed Week 48	38
Completed	35
Not Completed	4
Reason Not Completed
Death	2
Lost to Follow-up	1
Withdrawal by Subject	1

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 receive 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: 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		39
Baseline Analysis Population Description		[Not Specified]
Age, Continuous; Mean (Standard Deviation); Unit of measure: Years
	Number Analyzed	39 participants
		36.3 (15.5)
Sex: Female, Male; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	39 participants
	Female	7 17.9%
	Male	32 82.1%
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.
Weight; Mean (Standard Deviation); Unit of measure: Kilograms
	Number Analyzed	39 participants
		73.9 (17.8)
Height; Mean (Standard Deviation); Unit of measure: Centimeters
	Number Analyzed	39 participants
		174.5 (7.7)

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. 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).
Time Frame	Baseline and Week 48

Outcome Measure Data

Analysis Population Description

Intent-to-treat (ITT) population: All participants and all eyes that received study treatments, with data at both Baseline and the applicable post-dose visit. 1 participant was excluded from the ITT population due to receiving a smaller volume of study treatment than specified in the protocol. Participants received 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	38	38
Overall Number of Units Analyzed; Type of Units Analyzed: Eyes	38	38
Least Squares Mean (Standard Error); Unit of Measure: LogMAR
	0.380 (0.129)	0.392 (0.129)

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	0.8890
	Comments	[Not Specified]
	Method	ANCOVA
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-0.012
	Confidence Interval	(2-Sided) 95%; -0.182 to 0.158
	Estimation Comments	[Not Specified]

2. Secondary Outcome

Title	Change From Baseline in ETDRS Visual Acuity (Quantitative Score)
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 was imputed by the linear interpolation method.
Time Frame	Baseline; Week 72 and Week 96

Outcome Measure Data

Analysis Population Description

Intent-to-treat (ITT) population: All participants and all eyes that received study treatments, with data at both Baseline and the applicable post-dose visit. 1 participant was excluded from the ITT population due to receiving a smaller volume of study treatment than specified in the protocol. Participants received 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	38	38
Overall Number of Units Analyzed; Type of Units Analyzed: Eyes	38	38
Least Squares Mean (Standard Error); Unit of Measure: LogMAR
Week 72	0.192 (0.104)	0.216 (0.104)
Week 96	0.178 (0.120)	0.207 (0.120)

3. Secondary Outcome

Title	Number of Eye Responders to Treatment
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; Week 72 and Week 96

Outcome Measure Data

Analysis Population Description

Intent-to-treat (ITT) population: All participants and all eyes that received study treatments, with data at both Baseline and the applicable post-dose visit. 1 participant was excluded from the ITT population due to receiving a smaller volume of study treatment than specified in the protocol. Participants received 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	38	38
Overall Number of Units Analyzed; Type of Units Analyzed: Eyes	38	38
Count of Units; Unit of Measure: Eyes
Week 48 Definition 1	4 10.5%	3 7.9%
Week 48 Definition 2	9 23.7%	10 26.3%
Week 72 Definition 1	6 15.8%	5 13.2%
Week 72 Definition 2	11 28.9%	9 23.7%
Week 96 Definition 1	7 18.4%	5 13.2%
Week 96 Definition 2	13 34.2%	11 28.9%

4. Secondary Outcome

Title	Number of Subject Responders to Treatment
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. For the Week 96 analysis, if no score was available for Week 96, the score from the previous visit was used.
Time Frame	Week 48; Week 72 and Week 96

Outcome Measure Data

Analysis Population Description

Intent-to-treat (ITT) population: All participants that received study treatments, with data at the applicable post-dose visit. 1 participant was excluded from the ITT population due to receiving a smaller volume of study treatment than specified in the protocol. Participants received 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. All participants in the study received both GS010 and the sham procedure. 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 receive 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: 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	38
Measure Type: Count of Participants; Unit of Measure: Participants
Week 48	4 10.5%
Week 72	2 5.3%
Week 96	5 13.2%

5. Secondary Outcome

Title	Change From Baseline in GCL Macular Volume
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; Week 48; Week 72 and Week 96

Outcome Measure Data

Analysis Population Description

Intent -to-treat (ITT) population: All participants and all eyes that received study treatments, with data at both Baseline and the applicable post-dose visit. 1 participant was excluded from the ITT population due to receiving a smaller volume of study treatment than specified in the protocol. Participants received 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	37
Overall Number of Units Analyzed; Type of Units Analyzed: Eyes		36	37
Least Squares Mean (Standard Error); Unit of Measure: mm^3
Week 48	Number Analyzed	36 Eyes	37 Eyes
		-0.184 (0.014)	-0.207 (0.014)
Week 72	Number Analyzed	33 Eyes [1]	34 Eyes [2]
		-0.204 (0.015)	-0.226 (0.015)
Week 96	Number Analyzed	33 Eyes [1]	33 Eyes [1]
		-0.208 (0.015)	-0.221 (0.015)

[1]

33 participants

[2]

34 participants

6. Secondary Outcome

Title	Change From Baseline in RNFL Temporal Quadrant Thickness
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; Week 48; Week 72 and Week 96

Outcome Measure Data

Analysis Population Description

Intent-to-treat (ITT) population: All participants and all eyes that received study treatments, with data at both Baseline and the applicable post-dose visit. 1 participant was excluded from the ITT population due to receiving a smaller volume of study treatment than specified in the protocol. Participants received 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: µm
Week 48	Number Analyzed	37 Eyes	37 Eyes
		-22.8 (1.0)	-24.7 (1.0)
Week 72	Number Analyzed	34 Eyes [1]	34 Eyes [1]
		-25.5 (0.9)	-26.0 (0.9)
Week 96	Number Analyzed	32 Eyes [2]	33 Eyes [3]
		-24.2 (0.8)	-26.1 (0.8)

[1]

34 participants

[2]

32 participants

[3]

33 participants

7. Secondary Outcome

Title	Change From Baseline in RNFL Papillomacular Bundle Thickness
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; Week 48; Week 72 and Week 96

Outcome Measure Data

Analysis Population Description

Intent-to-treat (ITT) population: All participants and all eyes that received study treatments, with data at both Baseline and the applicable post-dose visit. 1 participant was excluded from the ITT population due to receiving a smaller volume of study treatment than specified in the protocol. Participants received 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: µm
Week 48	Number Analyzed	37 Eyes	37 Eyes
		-10.4 (1.0)	-12.4 (1.0)
Week 72	Number Analyzed	34 Eyes [1]	34 Eyes [1]
		-12.8 (1.0)	-13.1 (1.0)
Week 96	Number Analyzed	32 Eyes [2]	33 Eyes [3]
		-11.2 (1.0)	-13.3 (1.0)

[1]

34 participants

[2]

32 participants

[3]

33 participants

8. Secondary Outcome

Title	Change From Baseline in ETDRS Total Macular Volume
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; Week 48; Week 72 and Week 96

Outcome Measure Data

Analysis Population Description

Intent-to-treat (ITT) population: All participants and all eyes that received study treatments, with data at both Baseline and the applicable post-dose visit. 1 participant was excluded from the ITT population due to receiving a smaller volume of study treatment than specified in the protocol. Participants received 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	37
Overall Number of Units Analyzed; Type of Units Analyzed: Eyes		36	37
Least Squares Mean (Standard Error); Unit of Measure: mm^3
Week 48	Number Analyzed	36 Eyes	37 Eyes
		-0.578 (0.041)	-0.708 (0.040)
Week 72	Number Analyzed	33 Eyes [1]	34 Eyes [2]
		-0.686 (0.048)	-0.782 (0.048)
Week 96	Number Analyzed	33 Eyes [1]	33 Eyes [1]
		-0.720 (0.050)	-0.800 (0.050)

[1]

33 participants

[2]

34 participants

9. Secondary Outcome

Title	Change From Baseline in the Foveal Threshold Sensitivities Obtained With HVF Analyzer II
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; Week 48; Week 72 and Week 96

Outcome Measure Data

Analysis Population Description

Intent-to-treat (ITT) population: All participants and all eyes that received study treatments, with data at both Baseline and the applicable post-dose visit. 1 participant was excluded from the ITT population due to receiving a smaller volume of study treatment than specified in the protocol. Participants received 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		11	8
Overall Number of Units Analyzed; Type of Units Analyzed: Eyes		11	8
Mean (Standard Deviation); Unit of Measure: decibels (dB)
Week 48	Number Analyzed	11 Eyes	7 Eyes [1]
		3.5 (12.3)	-7.4 (12.8)
Week 72	Number Analyzed	7 Eyes [1]	7 Eyes [1]
		6.3 (7.8)	-5.1 (11.9)
Week 96	Number Analyzed	6 Eyes [2]	8 Eyes
		3.3 (12.7)	1.4 (19.5)

[1]

7 participants

[2]

6 participants

10. Secondary Outcome

Title	Visual Field Mean Deviation in Decibels of Sensitivity Obtained With HVF Analyzer II
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; Week 72 and Week 96

Outcome Measure Data

Analysis Population Description

Intent-to-treat (ITT) population: All participants and all eyes that received study treatments, with data at both Baseline and the applicable post-dose visit. 1 participant was excluded from the ITT population due to receiving a smaller volume of study treatment than specified in the protocol. Participants received 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		38	38
Overall Number of Units Analyzed; Type of Units Analyzed: Eyes		38	38
Mean (Standard Deviation); Unit of Measure: decibels (dB)
Baseline MD	Number Analyzed	38 Eyes	38 Eyes
		-16.26 (10.59)	-16.73 (11.48)
Week 48 MD	Number Analyzed	37 Eyes [1]	37 Eyes [1]
		-24.26 (9.37)	-23.76 (10.40)
Week 72 MD	Number Analyzed	34 Eyes [2]	33 Eyes [3]
		-23.33 (9.41)	-22.94 (10.11)
Week 96 MD	Number Analyzed	34 Eyes [2]	33 Eyes [3]
		-23.31 (9.41)	-22.70 (9.88)

[1]

37 participants

[2]

34 participants

[3]

33 participants

11. Secondary Outcome

Title	Change From Baseline in Contrast Sensitivity
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.
Time Frame	Baseline; Week 48; Week 72 and Week 96

Outcome Measure Data

Analysis Population Description

Intent-to-treat (ITT) population: All participants and all eyes that received study treatments, with data at both Baseline and the applicable post-dose visit. 1 participant was excluded from the ITT population due to receiving a smaller volume of study treatment than specified in the protocol. Participants received 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	38	38
Overall Number of Units Analyzed; Type of Units Analyzed: Eyes	38	38
Least Squares Mean (Standard Error); Unit of Measure: LogCS
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)

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 positive change from baseline indicates a worsening in symptoms.
Time Frame	Baseline; Week 48 and Week 96

Outcome Measure Data

Analysis Population Description

Intent-to-treat (ITT) population: All participants and all eyes that received study treatments, with data at both Baseline and the applicable post-dose visit. 1 participant was excluded from the ITT population due to receiving a smaller volume of study treatment than specified in the protocol. Participants received 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		21	21
Overall Number of Units Analyzed; Type of Units Analyzed: Eyes		21	21
Mean (Standard Deviation); Unit of Measure: score on a scale
Week 48	Number Analyzed	18 Eyes [1]	20 Eyes [2]
		133.1 (290.7)	235.6 (392.3)
Week 96	Number Analyzed	21 Eyes	21 Eyes
		97.7 (342.2)	213.5 (393.1)

[1]

18 participants

[2]

20 participants

Adverse Events

Time Frame	From first dose to end of study (a maximum of 96 weeks)
Adverse Event Reporting Description	Safety population: All participants who were randomized and received study treatments. Because all participants received both study treatment and the sham procedure simultaneously, adverse events (AEs) are reported overall for systemic and ocular events. Reported events include AEs associated with both GS010 and the sham procedure.
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 receive 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: 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	2/39 (5.13%)
Serious Adverse Events
	All Participants
	Affected / at Risk (%)
Total	3/39 (7.69%)
Hepatobiliary disorders
Alcoholic liver disease † 1	1/39 (2.56%)
Injury, poisoning and procedural complications
Alcohol poisoning † 1	1/39 (2.56%)
Metabolism and nutrition disorders
Malnutrition † 1	1/39 (2.56%)
Psychiatric disorders
Alcohol withdrawal syndrome † 1	1/39 (2.56%)
Renal and urinary disorders
Renal failure † 1	1/39 (2.56%)
1 Term from vocabulary, MedDRA 20.1; † Indicates events were collected by systematic assessment
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	5%
	All Participants
	Affected / at Risk (%)
Total	38/39 (97.44%)
Eye disorders
Anterior chamber cell † 1	6/39 (15.38%)
Anterior chamber flare † 1	5/39 (12.82%)
Anterior chamber inflammation † 1	3/39 (7.69%)
Autoimmune uveitis † 1 [1]	15/39 (38.46%)
Chalazion † 1	2/39 (5.13%)
Conjunctival haemorrhage † 1 [2]	7/39 (17.95%)
Conjunctival hyperaemia † 1 [3]	5/39 (12.82%)
Corneal disorder † 1	2/39 (5.13%)
Eye irritation † 1 [4]	2/39 (5.13%)
Eye pain † 1 [5]	3/39 (7.69%)
Foreign body sensation in eyes † 1 [6]	2/39 (5.13%)
Iridocyclitis † 1 [7]	18/39 (46.15%)
Iris atrophy † 1	3/39 (7.69%)
Iris transillumination defect † 1	2/39 (5.13%)
Keratic precipitates † 1	9/39 (23.08%)
Macular oedema † 1	2/39 (5.13%)
Photopsia † 1	2/39 (5.13%)
Punctate keratitis † 1 [8]	18/39 (46.15%)
Vitreal cells † 1	3/39 (7.69%)
Vitreous disorder † 1	3/39 (7.69%)
Vitreous floaters † 1	3/39 (7.69%)
Vitritis † 1	7/39 (17.95%)
Infections and infestations
Nasopharyngitis † 1	7/39 (17.95%)
Ear infection † 1	2/39 (5.13%)
Conjunctivitis † 1	2/39 (5.13%)
Investigations
Gamma-glutamyltransferase increased † 1	3/39 (7.69%)
Alanine aminotransferase increased † 1	2/39 (5.13%)
Blood glucose increased † 1	2/39 (5.13%)
Neutrophil count increased † 1	2/39 (5.13%)
White blood cell count increased † 1	2/39 (5.13%)
Intraocular pressure increased † 1 [9]	13/39 (33.33%)
Nervous system disorders
Headache † 1	6/39 (15.38%)
Migraine † 1	3/39 (7.69%)
Psychiatric disorders
Anxiety † 1	3/39 (7.69%)
Depression † 1	2/39 (5.13%)
Social circumstances
Alcohol use † 1	2/39 (5.13%)
Vascular disorders
Hypertension † 1	6/39 (15.38%)
1 Term from vocabulary, MedDRA 20.1; † Indicates events were collected by systematic assessment; [1] The verbatim term for all events of "autoimmune uveitis" is "intermediate uveitis".; [2] 1/7 affected participants experienced this event in the sham-treated eyes.; [3] 4/5 affected participants experienced this event in the sham-treated eyes.; [4] 1/2 affected participants experienced this event in the sham-treated eyes.; [5] 1/3 affected participants experienced this event in the sham treated eyes.; [6] 1/2 affected participants experienced this event in the sham treated eyes.; [7] 2/18 affected participants experienced this event in the sham-treated eyes.; [8] 3/18 affected participants experienced this event in the sham-treated eyes.; [9] 1/13 affected participants experienced this event in the 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: Magali Taiel CMO
• Organization: GenSight Biologics
• Phone: 1 76 21 72 26 ext 0033
• EMail: mtaiel@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.

Newman NJ, Yu-Wai-Man P, Carelli V, Moster ML, Biousse V, Vignal-Clermont C, Sergott RC, Klopstock T, Sadun AA, Barboni P, DeBusk AA, Girmens JF, Rudolph G, Karanjia R, Taiel M, Blouin L, Smits G, Katz B, Sahel JA; LHON Study Group. Efficacy and Safety of Intravitreal Gene Therapy for Leber Hereditary Optic Neuropathy Treated within 6 Months of Disease Onset. Ophthalmology. 2021 May;128(5):649-660. doi: 10.1016/j.ophtha.2020.12.012. Epub 2021 Jan 12.

• Responsible Party: GenSight Biologics
• ClinicalTrials.gov Identifier: NCT02652767
• Other Study ID Numbers: GS-LHON-CLIN-03A; 2015-001265-11 ( EudraCT Number )
• First Submitted: January 7, 2016
• First Posted: January 12, 2016
• Results First Submitted: January 17, 2020
• Results First Posted: January 28, 2020
• Last Update Posted: July 29, 2022