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

Leber Hereditary Optic Neuropathy Clinical Trial

— REFLECT  

Official title:

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

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT03293524
• Other study ID #: GS-LHON-CLIN-05
• Secondary ID: 2017-002187-40
• Status: Active, not recruiting
• Phase: Phase 3
• Start date: March 12, 2018
• Est. completion date: June 30, 2024

Study information

• Verified date: August 2022
• Source: GenSight Biologics
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

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.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 90
• Est. completion date: June 30, 2024
• Est. primary completion date: June 30, 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 15 Years and older

Eligibility

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).

Related Conditions & MeSH terms

• Leber Hereditary Optic Neuropathy
• Optic Atrophy, Hereditary, Leber
• Optic Nerve Diseases

Intervention

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.

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.

Locations

Country	Name	City	State
Belgium	Universitair Ziekenhuis Gent	Gent
France	CHNO Les Quinze Vingts	Paris
Italy	IRCCS Istituto delle Scienze Neurologiche di Bologna UOC Clinica Neurologica	Bologna
Spain	Hospital Universitario Ramon y Cajal	Madrid
Taiwan	Taipei Veterans General Hospital	Taipei
United Kingdom	Moorfields Eye Hospital	London	Greater London
United States	Emory Healthcare - The Emory Clinic	Atlanta	Georgia
United States	University of Colorado Health Eye Center	Aurora	Colorado
United States	Massachusetts Eye and Ear Infirmary	Boston	Massachusetts
United States	Vanderbilt Eye Institute	Nashville	Tennessee
United States	Icahn School of Medicine at Mount Sinai	New York	New York
United States	Doheny Eye Center UCLA Pasadena	Pasadena	California
United States	Wills Eye Institute - Ocular Oncology Service	Philadelphia	Pennsylvania

Sponsors (1)

Lead Sponsor	Collaborator
GenSight Biologics

Countries where clinical trial is conducted

United States,  Belgium,  France,  Italy,  Spain,  Taiwan,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	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
Other	Physical examinations	Results of physical examinations	At 2-Years post baseline treatment
Other	Electrocardiograms	Results of Electrocardiograms (ECGs)	At 2-Years post baseline treatment
Other	Laboratory results	Results of laboratory tests from blood collection	At 2-Years post baseline treatment
Other	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
Other	Blood Bio-dissemination of AAV2 Vector DNA	Results of bio-dissemination testing up to 4-weeks post-treatment	up to 4 weeks post-treatment
Primary	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	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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

External Links

•   GenSight Biologics website