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

Primary Purpose

Leber Hereditary Optic Neuropathy

Status

Active

Phase

Phase 3

Locations

International

Study Type

Interventional

Intervention

GS010

Placebo

About this trial

This is an interventional treatment trial for Leber Hereditary Optic Neuropathy focused on measuring Heredity Optic Atrophy, Leber Hereditary Optic Atrophy, Leber Hereditary Optic Neuropathy, LHON, Eye Diseases, Hereditary Eye Diseases, Inherited retinal dystrophies or degeneration, Inborn Genetic Disease, Gene Therapy, Intravitreal Injections, Mitochondrial Disease, AAV2 Vectors, Nervous System Diseases, Neurodegenerative Disease, Heredodegenerative Disorders of the Nervous System, Atrophy, Pathological Conditions, Anatomical, Anesthetics, Central Nervous System Depressants, Physiological Effects of Drugs

Eligibility Criteria

15 Years - undefined (Child, Adult, Older Adult)All SexesDoes not accept healthy volunteers

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).

Sites / Locations

Doheny Eye Center UCLA Pasadena
University of Colorado Health Eye Center
Emory Healthcare - The Emory Clinic
Massachusetts Eye and Ear Infirmary
Icahn School of Medicine at Mount Sinai
Wills Eye Institute - Ocular Oncology Service
Vanderbilt Eye Institute
Universitair Ziekenhuis Gent
CHNO Les Quinze Vingts
IRCCS Istituto delle Scienze Neurologiche di Bologna UOC Clinica Neurologica
Hospital Universitario Ramon y Cajal
Taipei Veterans General Hospital
Moorfields Eye Hospital

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Placebo Comparator

Arm Label

Treatment Arm 1

Treatment Arm 2

Arm Description

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.

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.

Outcomes

Primary Outcome Measures

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.

Secondary Outcome Measures

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.

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).

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

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

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

Quality of Life: Visual Functioning Questionnaire-25

Visual Functioning Questionnaire-25 at 1.5 and 2-years post-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.

Full Information

NCT ID

NCT03293524

First Posted

September 19, 2017

Last Updated

August 2, 2022

Sponsor

GenSight Biologics

1. Study Identification

Unique Protocol Identification Number

NCT03293524

Brief Title

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

Acronym

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

Study Type

Interventional

2. Study Status

Record Verification Date

August 2022

Overall Recruitment Status

Active, not recruiting

Study Start Date

March 12, 2018 (Actual)

Primary Completion Date

June 30, 2024 (Anticipated)

Study Completion Date

June 30, 2024 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

GenSight Biologics

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Yes

Studies a U.S. FDA-regulated Device Product

Data Monitoring Committee

Yes

5. Study Description

Brief 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.

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Leber Hereditary Optic Neuropathy

Keywords

Heredity Optic Atrophy, Leber Hereditary Optic Atrophy, Leber Hereditary Optic Neuropathy, LHON, Eye Diseases, Hereditary Eye Diseases, Inherited retinal dystrophies or degeneration, Inborn Genetic Disease, Gene Therapy, Intravitreal Injections, Mitochondrial Disease, AAV2 Vectors, Nervous System Diseases, Neurodegenerative Disease, Heredodegenerative Disorders of the Nervous System, Atrophy, Pathological Conditions, Anatomical, Anesthetics, Central Nervous System Depressants, Physiological Effects of Drugs

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 3

Interventional Study Model

Parallel Assignment

Masking

ParticipantInvestigator

Allocation

Randomized

Enrollment

90 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title

Treatment Arm 1

Arm Type

Experimental

Arm Description

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.

Arm Title

Treatment Arm 2

Arm Type

Placebo Comparator

Arm Description

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.

Intervention Type

Genetic

Intervention Name(s)

GS010

Other Intervention Name(s)

Lenadogene nolparvovec

Intervention Description

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.

Intervention Type

Drug

Intervention Name(s)

Placebo

Intervention Description

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.

Primary Outcome Measure Information:

Title

Best-Corrected Visual Acuity (BCVA) reported using Log of the Minimal Angle of Resolution (LogMAR) - 1 year

Description

Time Frame

at 1.5 Year post baseline treatment

Secondary Outcome Measure Information:

Title

Best-Corrected Visual Acuity (BCVA) reported with LogMAR - 2 years

Description

Change from baseline in LogMAR BCVA at each timepoint of the follow-up period and at 2 years post-treatment.

Time Frame