Efficacy & Safety Study of Bilateral IVT Injection of GS010 in LHON Subjects Due to the ND4 Mutation for up to 1 Year (REFLECT)

Efficacy and Safety of Bilateral Intravitreal Injection of GS010: A Randomized, Double-Masked, Placebo-Controlled Trial in Subjects Affected With G11778A ND4 Leber Hereditary Optic Neuropathy for Up to One Year

The goal of this clinical trial is to assess the efficacy and safety of GS010 gene therapy - (lenadogene nolparvovec) in subjects with LHON due to the G11778A ND4 mitochondrial mutation with a vision loss up to one year.

Study Overview

• Status: Completed
• Conditions: Leber Hereditary Optic Neuropathy
• Intervention / Treatment: Genetic: GS010; Drug: Placebo

Detailed Description

The REFLECT study is a Phase 3, international, multi-center, randomized, double-masked, placebo-controlled, clinical trial. The primary objective is to assess the efficacy of intravitreal (IVT) of GS010 compared to IVT of placebo in second-affected/not-yet-affected eyes at 1.5 years post-treatment, by analyzing the change from baseline of the visual acuity in ND4 LHON subjects with vision loss up to one year.

• Study Type: Interventional
• Enrollment (Actual): 98
• Phase: Phase 3

Expanded Access

No longer available outside the clinical trial. See expanded access record.

Contacts and Locations

Study Locations

• Belgium
  • Ghent, Belgium, 9000
    • Universitair Ziekenhuis Gent
• France
  • Paris
    • Paris, Paris, France, 75012
      • CHNO Les Quinze Vingts
• Italy
  • Bologna, Italy, 40139
    • IRCCS Istituto delle Scienze Neurologiche di Bologna (ISNB) Clinica Neurologica
• Spain
  • Madrid, Spain, 28034
    • Hospital Universitario Ramon y Cajal
• Taiwan
  • Taipei, Taiwan, 11217
    • Taipei Veterans General Hospital
• United Kingdom
  • Greater London
    • London, Greater London, United Kingdom, EC1V 2PD
      • Moorfields Eye Hospital
• United States
  • California
    • Pasadena, California, United States, 91105
      • Doheny Eye Center UCLA Pasadena
  • Colorado
    • Aurora, Colorado, United States, 80045
      • University of Colorado Health Eye Center
  • Georgia
    • Atlanta, Georgia, United States, 30322
      • Emory Healthcare - The Emory Clinic
  • Massachusetts
    • Boston, Massachusetts, United States, 02114
      • Massachusetts Eye and Ear Infirmary
  • New York
    • New York, New York, United States, 10029
      • Department of Ophthalmology, Icahn School of Medicine at Mount Sinai
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19107
      • Departments of Neurology and Ophthalmology, Wills Eye Hospital and Thomas Jefferson University
  • Tennessee
    • Nashville, Tennessee, United States, 37232
      • Vanderbilt Eye Institute

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 15 years and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Main Selection Criteria:

• Age 15 years or older on the date of signed informed consent.
• Clinically manifested vision loss due to ND4 LHON, to any extent, in at least one eye.
• Vision loss duration of ≤ 365 days (i.e. ≤ 1 year) in each affected eye at Inclusion Visit (Visit 2).

Main Non-Selection Criteria:

• Contraindication to intravitreal injection in any eye.
• Subjects refusing to discontinue idebenone.
• Previous vitrectomy in either eye.
• Narrow angle in any eye contra-indicating pupillary dilation.
• Presence of known/documented mutations, other than the G11778A ND4 LHON-causing mutation, which are known to cause pathology of the optic nerve, retina or afferent visual system.
• History of recurrent uveitis (idiopathic or immune-related) or active ocular inflammation.

Main Inclusion Criteria:

• Vision loss duration of ≤ 365 days (i.e. ≤ 1 year) in each affected eye at Inclusion Visit (Visit 2).
• Each eye of the subject must maintain at least Hand Motion (HM) visual acuity, as defined by the study's SOP for visual acuity testing.
• Documented results of genotyping showing the presence of the G11778A mutation in the ND4 gene and the absence of the other primary LHON-associated mutations (ND1 or ND6) in the subject's mitochondrial DNA.

Main Exclusion Criteria:

• Light Perception (LP) or No Light Perception (NLP) visual acuity in any eye, as defined by the study's standard operating procedure (SOP) for visual acuity testing.
• Presence of active infectious conjunctivitis, keratitis, scleritis or endophthalmitis in either eye.
• Presence of alcoholism, alcohol dependence, or alcohol or drug abuse (excluding nicotine).

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: GS010-GS010; Patients received single IVT injection of GS010 in both their first-affected eye and their second-affected/not-yet-affected eye at a droplet digital polymerase chain reaction (ddPCR) dose of 1.2/1.3E11 vg in 90 μL for each eye. Treatment could be performed either on a single day (1 IVT injection in each eye on Day 0) or on 2 consecutive days (1st IVT injection on Day -1 and 2nd IVT injection on Day 0).	Genetic: GS010; GS010 is a recombinant adeno-associated viral vector serotype 2 (rAAV2/2) containing the wild-type ND4 gene (rAAV2/2-ND4). GS010 was administrated via intravitreal injection containing 1.2/1.3E11 vg in 90 μL balanced sterile saline solution (BSSS).; Other Names: Lenadogene nolparvovec
Placebo Comparator: GS010-Placebo; Patients received single IVT injection of GS010 in their first-affected eye and placebo IVT injection in their second-affected/not-yet-affected eye. Patients received IVT lenadogene nolparvovec in their first-affected eye (ddPCR dose of 1.2/1.3E11 vg in a volume of 90 μL) and placebo IVT injection (volume of 90 μL) in their second-affected/not-yet-affected eye. Treatment could be performed either on a single day (1 IVT injection in each eye on Day 0) or on 2 consecutive days (1st IVT injection on Day -1 and 2nd IVT injection on Day 0).	Genetic: GS010; GS010 is a recombinant adeno-associated viral vector serotype 2 (rAAV2/2) containing the wild-type ND4 gene (rAAV2/2-ND4). GS010 was administrated via intravitreal injection containing 1.2/1.3E11 vg in 90 μL balanced sterile saline solution (BSSS).; Other Names: Lenadogene nolparvovec; Drug: Placebo; The placebo is a balanced sterile saline solution (BSSS) used for IVT. The placebo was administered via intravitreal injection in a volume of 90 μL.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline of the Best Corrected Visual Acuity (BCVA) Reported With Log of the Minimal Angle of Resolution (LogMAR) at 1.5 Years Post-treatment, in the Second Affected/Not-yet Affected Eyes	The primary efficacy endpoint was the change from baseline of BCVA reported with LogMAR at 1.5-year post-treatment, in the second-affected/not-yet-affected eyes of ND4 LHON patients with vision loss up to one year. LogMAR BCVA was used to represent BCVA.	at 1.5 years post-treatment, in the second-affected/not-yet affected eyes

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline of the BCVA Reported With LogMAR at 5 Years Post-treatment, in the Second Affected/Not-yet Affected Eyes	Change from baseline of BCVA reported with LogMAR at 5 years post-treatment, in the second-affected/not-yet-affected eyes of ND4 LHON patients with vision loss up to one year. LogMAR BCVA was used to represent BCVA.	at 5 years post-treatment, in the second-affected/not-yet affected eyes
Proportion of Patients Who Switched From Off-chart Eyes to On-chart Eyes at 5 Years Post-treatment	Proportion of patients with both eyes off-chart, defined as those patients unable to read letter on the ETDRS chart, who had at least one eye on-chart, defined as those patients able to read letters on the ETDRS chart (at either 4 meters or 1 meter) at 5 years	From baseline to 5 years post-treatment
Responder Analyses - Improvements From Nadir (Gainer Eyes) at 5 Years	Proportion of patients with an improvement of at least -0.3 LogMAR (≥ +15 ETDRS letters) from nadir to year 5 in at least one eye. Nadir was defined for each eye of each subject as the worst value observed from baseline to year 5	From nadir to 5 years post-treatment
Responder Analyses - Clinically Relevant Recovery From Nadir at 5 Years	Proportion of patients with clinically relevant recovery (CRR) from nadir that was defined as patient with a CRR in at least one eye - Patient with at least one eye which was on chart at nadir, and which had an improvement of at least -0.2 LogMAR from nadir, or which was off-chart at nadir but became on-chart	From nadir to 5 years post-treatment
Responder Analyses- Clinically Relevant Benefit at 5 Years	Proportion of patients who had clinically relevant stabilization (CRS), defined as eyes with LogMAR BCVA < 1 at baseline and at 5 years post-treatment or had a clinically relevant recovery (CRR) from nadir. The best response observed in either eye was considered.	From baseline nadir to 5 years post-treatment
Quality of Life Questionnaire: VFQ-25 - Composite Score	Change from baseline to 5 years follow up in the Visual Function Questionnaire (VFQ-25) composite score. The VFQ-25 is a patient-reported outcome instrument assessing vision-related quality of life and consists of a base set of 25 vision-targeted questions representing 11 vision-related constructs plus an additional single-item general health rating question. Each item was converted to a 0-100 scale for scoring, where 100 represents the best possible score on the measure and 0 represents the worst. Items within each subscale were averaged to create 12 subscale scores (11 subscales related to vision + 1 subscale related to general health). The vision-related subscale scores (excluding the general health rating question) were then averaged to calculate the composite score.	From baseline to 5 years post-treatment

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Adverse events (AEs) and serious adverse events (SAEs)	Adverse events (AEs) and serious adverse events (SAEs), including those that are treatment-emergent and non-treatment-emergent, throughout the study period and at each study visit. Incidence and severity of systemic and local (ocular) AEs and SAEs will be determined at each clinical site and for the entire study cohort.	up to 2-Years post baseline treatment
Physical examinations	Results of physical examinations	At 2-Years post baseline treatment
Electrocardiograms	Results of Electrocardiograms (ECGs)	At 2-Years post baseline treatment
Laboratory results	Results of laboratory tests from blood collection	At 2-Years post baseline treatment
Immune response evaluations	Results of immune response evaluations; Time course of the humoral immune response measured with Neutralizing Antibodies (Nab) against Adeno-associated virus vector 2 (AAV2); Time course of the cellular immune response against AAV2	Up to 2-Years post baseline treatment
Blood Bio-dissemination of AAV2 Vector DNA	Results of bio-dissemination testing up to 4-weeks post-treatment	up to 4 weeks post-treatment

Collaborators and Investigators

• Sponsor: GenSight Biologics
• Investigators: Principal Investigator: Nancy Newman, MD, Emory University Hospital Atlanta, Georgia, United States, 30322; Principal Investigator: Patrick Yu-Wai-Man, PhD, John van Geest Centre for Brain Repair, University of Cambridge, Cambridge, CB2 0PY, United Kingdom

Publications and helpful links

General Publications

• Carelli V, Newman NJ, Yu-Wai-Man P, Biousse V, Moster ML, Subramanian PS, Vignal-Clermont C, Wang AG, Donahue SP, Leroy BP, Sergott RC, Klopstock T, Sadun AA, Rebolleda Fernandez G, Chwalisz BK, Banik R, 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; the LHON Study Group. Indirect Comparison of Lenadogene Nolparvovec Gene Therapy Versus Natural History in Patients with Leber Hereditary Optic Neuropathy Carrying the m.11778G>A MT-ND4 Mutation. Ophthalmol Ther. 2023 Feb;12(1):401-429. doi: 10.1007/s40123-022-00611-x. Epub 2022 Nov 30.

Helpful Links

• GenSight Biologics website

Study record dates

Study Major Dates

• Study Start (Actual): March 12, 2018
• Primary Completion (Actual): July 23, 2024
• Study Completion (Actual): July 23, 2024

Study Registration Dates

• First Submitted: September 19, 2017
• First Submitted That Met QC Criteria: September 21, 2017
• First Posted (Actual): September 26, 2017

Study Record Updates

• Last Update Posted (Actual): April 16, 2026
• Last Update Submitted That Met QC Criteria: March 27, 2026
• Last Verified: March 1, 2026

More Information

Terms related to this study

• Keywords: Gene Therapy; Leber Hereditary Optic Atrophy; Leber Hereditary Optic Neuropathy; Eye Diseases; Hereditary Eye Diseases; Inherited retinal dystrophies or degeneration; Intravitreal Injections; Mitochondrial Disease; AAV2 Vectors; LHON; Hereditary Optic Atrophy
• Additional Relevant MeSH Terms: Nervous System Diseases; Genetic Diseases, Inborn; Metabolic Diseases; Neurodegenerative Diseases; Heredodegenerative Disorders, Nervous System; Optic Nerve Diseases; Cranial Nerve Diseases; Optic Atrophy; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Nutritional and Metabolic Diseases; Eye Diseases; Mitochondrial Diseases; Optic Atrophies, Hereditary; Eye Diseases, Hereditary; Optic Atrophy, Hereditary, Leber; Substandard Drugs; Pharmaceutical Preparations; Counterfeit Drugs
• Other Study ID Numbers: GS-LHON-CLIN-05; 2017-002187-40 (EudraCT Number)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No