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 safety and efficacy of GS010, a gene therapy, in improving the retina functional & structural outcomes in subjects with LHON due to the G11778A ND4 mitochondrial mutation when vision loss duration is present up to one year.

Study Overview

• Status: Active, not recruiting
• Conditions: Leber Hereditary Optic Neuropathy
• Intervention / Treatment: Genetic: GS010; Drug: Placebo

Detailed Description

GS-LHON-CLIN-05 is a Phase III, global, multi-center randomized, double-masked for the primary analysis, placebo-controlled, clinical study. As LHON is a neurodegenerative disease, the goal is to administer GS010 as soon as possible upon confirmation of the LHON diagnosis and the causative mutation.

• Study Type: Interventional
• Enrollment (Anticipated): 90
• Phase: Phase 3

Expanded Access

Available outside the clinical trial. See expanded access record.

Contacts and Locations

Study Locations

• Belgium
  • Gent, Belgium, 9000
    • Universitair Ziekenhuis Gent
• France
  • Paris, France, 75012
    • CHNO Les Quinze Vingts
• Italy
  • Bologna, Italy, 40139
    • Irccs Istituto Delle Scienze Neurologiche Di Bologna Uoc 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
      • Icahn School of Medicine at Mount Sinai
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19107
      • Wills Eye Institute - Ocular Oncology Service
  • 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
• Genders Eligible for Study: All

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: Treatment Arm 1; Subjects will be randomized to treatment arm 1 or treatment arm 2 in a 1:1 allocation. Subjects in treatment arm 1 will receive intravitreal GS010 in both eyes.	Genetic: GS010; GS010 is a recombinant adeno-associated viral vector serotype 2 (rAAV2/2) containing the wild-type ND4 gene (rAAV2/2-ND4). GS010 will be administrated via intravitreal injection containing 9E10 viral genomes in 90μL balanced salt solution (BSS) as a single baseline intravitreal injection.; Other Names: Lenadogene nolparvovec
Placebo Comparator: Treatment Arm 2; Subjects will be randomized to treatment arm 1 or treatment arm 2 in a 1:1 allocation. Subjects in treatment arm 2 will receive GS010 in one eye and placebo intravitreal injection in the other eye.	Genetic: GS010; GS010 is a recombinant adeno-associated viral vector serotype 2 (rAAV2/2) containing the wild-type ND4 gene (rAAV2/2-ND4). GS010 will be administrated via intravitreal injection containing 9E10 viral genomes in 90μL balanced salt solution (BSS) as a single baseline intravitreal injection.; Other Names: Lenadogene nolparvovec; Drug: Placebo; The placebo is a BSS, sterile, apyrogenic solution and used for ocular surgery. The placebo will be administered via intravitreal injection in a volume of 90 μL.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Best-Corrected Visual Acuity (BCVA) reported using Log of the Minimal Angle of Resolution (LogMAR) - 1 year	The primary efficacy endpoint will be the change from baseline (Visit 2) BCVA reported with LogMAR at 1.5 years post-treatment in second affected/not yet affected eyes of ND4 LHON subjects with vision loss up to one year. The change from baseline (Visit 2) in second affected/not yet affected eyes receiving GS010 and placebo will be the primary response of interest. LogMAR BCVA will be used to represent BCVA.	at 1.5 Year post baseline treatment

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Best-Corrected Visual Acuity (BCVA) reported with LogMAR - 2 years	Change from baseline in LogMAR BCVA at each timepoint of the follow-up period and at 2 years post-treatment.	at 1.5-Year and 2-Years post baseline treatment
Responder Analysis	Response status at each timepoint of the follow-up period and at 2 years post-treatment. Definitions of responder eyes include: Eyes whose LogMAR BCVA improves (i.e. decreases) by ≥ 0.3 LogMAR (equivalent to a gain of ≥ 15 ETDRS letters) compared to baseline.; Eyes whose LogMAR BCVA does not increase (i.e. worsen) by ≥ 0.3 LogMAR (equivalent to eyes that lose ≤ 15 ETDRS letters) compared to baseline.; Eyes whose LogMAR visual acuity is < 1.0 (i.e. better than LogMAR 1.0, equivalent to better than Snellen acuity of 20/200).	at 1.5-Year and 2-Years post baseline treatment
Spectral-Domain - Optical Coherence Tomography (SD-OCT) parameter	Parameters measured with SD-OCT over time and at 1.5 and 2-years post baseline treatment. The change from baseline will be the response. Analysis will be performed mainly for second affected/not yet affected eyes treated with GS010 versus placebo and also for first affected eyes receiving GS010 as well	at 1.5-Year and 2-Years post baseline treatment
Humphrey Visual Field (HVF) parameter	Parameters measured with HVF 30-2 over time and at 1.5 and 2-years post baseline treatment. The change from baseline will be the response. Analysis will be performed mainly for second affected/not yet affected eyes treated with GS010 versus placebo and also for first affected eyes receiving GS010 as well	at 1.5-Year and 2-Years post baseline treatment
Pelli Robson Low Vision Contrast Sensitivity parameter	Parameters measured with Pelli Robson Low Vision Contrast Sensitivity over time and at 1.5 and 2-years post baseline treatment. The change from baseline will be the response. Analysis will be performed mainly for second affected/not yet affected eyes treated with GS010 versus placebo and also for first affected eyes receiving GS010 as well	at 1.5-Year and 2-Years post baseline treatment
Quality of Life: Visual Functioning Questionnaire-25	Visual Functioning Questionnaire-25 at 1.5 and 2-years post-treatment	at 1.5-Year and 2-Years post baseline treatment
Quality of Life: 36-Item Short Form Health Survey, version 2 Questionnaire	36-Item Short Form Health Survey, version 2 Questionnaire at 1 and 2-years post-treatment.	at 1.5-Year and 2-Years post baseline 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

Publications and helpful links

Helpful Links

• GenSight Biologics website

Study record dates

Study Major Dates

• Study Start (Actual): March 12, 2018
• Primary Completion (Anticipated): June 30, 2024
• Study Completion (Anticipated): June 30, 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): August 3, 2022
• Last Update Submitted That Met QC Criteria: August 2, 2022
• Last Verified: August 1, 2022

More Information

Terms related to this study

• Keywords: Gene Therapy; Heredity Optic Atrophy; Leber Hereditary Optic Atrophy; Leber Hereditary Optic Neuropathy; Eye Diseases; Hereditary Eye Diseases; Inherited retinal dystrophies or degeneration; Inborn Genetic Disease; Intravitreal Injections; Mitochondrial Disease; AAV2 Vectors; Nervous System Diseases; Neurodegenerative Disease; Heredodegenerative Disorders of the Nervous System; Physiological Effects of Drugs; Anesthetics; Atrophy; LHON; Central Nervous System Depressants; Pathological Conditions, Anatomical
• Additional Relevant MeSH Terms: Metabolic Diseases; Nervous System Diseases; Eye Diseases; Genetic Diseases, Inborn; Neurodegenerative Diseases; Eye Diseases, Hereditary; Heredodegenerative Disorders, Nervous System; Cranial Nerve Diseases; Optic Atrophies, Hereditary; Optic Atrophy; Mitochondrial Diseases; Optic Nerve Diseases; Optic Atrophy, Hereditary, Leber
• 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