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

• ClinicalTrials.gov Identifier: NCT03293524
• Recruitment Status: Active, not recruiting
• First Posted: September 26, 2017
• Last Update Posted: August 3, 2022
• Sponsor: GenSight Biologics
• Information provided by (Responsible Party): GenSight Biologics

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.

Condition or disease	Intervention/treatment	Phase
Leber Hereditary Optic Neuropathy	Genetic: GS010; Drug: Placebo	Phase 3

Expanded Access : An investigational treatment associated with this study is available outside the clinical trial.   More info ...

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 Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 90 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• 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
• Actual Study Start Date: March 12, 2018
• Estimated Primary Completion Date: June 30, 2024
• Estimated Study Completion Date: June 30, 2024

Arms and Interventions

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 Name: 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 Name: 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.

Outcome Measures

Primary Outcome Measures :

1. Best-Corrected Visual Acuity (BCVA) reported using Log of the Minimal Angle of Resolution (LogMAR) - 1 year [ Time Frame: at 1.5 Year post baseline treatment ]
   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 :

1. Best-Corrected Visual Acuity (BCVA) reported with LogMAR - 2 years [ Time Frame: at 1.5-Year and 2-Years post baseline treatment ]
   Change from baseline in LogMAR BCVA at each timepoint of the follow-up period and at 2 years post-treatment.
2. Responder Analysis [ Time Frame: at 1.5-Year and 2-Years post baseline treatment ]

   Response status at each timepoint of the follow-up period and at 2 years post-treatment. Definitions of responder eyes include:

   1. Eyes whose LogMAR BCVA improves (i.e. decreases) by ≥ 0.3 LogMAR (equivalent to a gain of ≥ 15 ETDRS letters) compared to baseline.
   2. 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.
   3. Eyes whose LogMAR visual acuity is < 1.0 (i.e. better than LogMAR 1.0, equivalent to better than Snellen acuity of 20/200).
3. Spectral-Domain - Optical Coherence Tomography (SD-OCT) parameter [ Time Frame: at 1.5-Year and 2-Years post baseline treatment ]
   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
4. Humphrey Visual Field (HVF) parameter [ Time Frame: at 1.5-Year and 2-Years post baseline treatment ]
   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
5. Pelli Robson Low Vision Contrast Sensitivity parameter [ Time Frame: at 1.5-Year and 2-Years post baseline treatment ]
   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
6. Quality of Life: Visual Functioning Questionnaire-25 [ Time Frame: at 1.5-Year and 2-Years post baseline treatment ]
   Visual Functioning Questionnaire-25 at 1.5 and 2-years post-treatment
7. Quality of Life: 36-Item Short Form Health Survey, version 2 Questionnaire [ Time Frame: at 1.5-Year and 2-Years post baseline treatment ]
   36-Item Short Form Health Survey, version 2 Questionnaire at 1 and 2-years post-treatment.

Other Outcome Measures:

1. Adverse events (AEs) and serious adverse events (SAEs) [ Time Frame: up to 2-Years post baseline treatment ]
   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.
2. Physical examinations [ Time Frame: At 2-Years post baseline treatment ]
   Results of physical examinations
3. Electrocardiograms [ Time Frame: At 2-Years post baseline treatment ]
   Results of Electrocardiograms (ECGs)
4. Laboratory results [ Time Frame: At 2-Years post baseline treatment ]
   Results of laboratory tests from blood collection
5. Immune response evaluations [ Time Frame: Up to 2-Years post baseline treatment ]

   Results of immune response evaluations

   1. Time course of the humoral immune response measured with Neutralizing Antibodies (Nab) against Adeno-associated virus vector 2 (AAV2)
   2. Time course of the cellular immune response against AAV2
6. Blood Bio-dissemination of AAV2 Vector DNA [ Time Frame: up to 4 weeks post-treatment ]
   Results of bio-dissemination testing up to 4-weeks post-treatment

Eligibility Criteria

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

Criteria

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).

Contacts and Locations

Locations

United States, California

Doheny Eye Center UCLA Pasadena

Pasadena, California, United States, 91105

United States, Colorado

University of Colorado Health Eye Center

Aurora, Colorado, United States, 80045

United States, Georgia

Emory Healthcare - The Emory Clinic

Atlanta, Georgia, United States, 30322

United States, Massachusetts

Massachusetts Eye and Ear Infirmary

Boston, Massachusetts, United States, 02114

United States, New York

Icahn School of Medicine at Mount Sinai

New York, New York, United States, 10029

United States, Pennsylvania

Wills Eye Institute - Ocular Oncology Service

Philadelphia, Pennsylvania, United States, 19107

United States, Tennessee

Vanderbilt Eye Institute

Nashville, Tennessee, United States, 37232

Belgium

Universitair Ziekenhuis Gent

Gent, Belgium, 9000

France

CHNO Les Quinze Vingts

Paris, France, 75012

Italy

IRCCS Istituto delle Scienze Neurologiche di Bologna UOC Clinica Neurologica

Bologna, Italy, 40139

Spain

Hospital Universitario Ramon y Cajal

Madrid, Spain, 28034

Taiwan

Taipei Veterans General Hospital

Taipei, Taiwan, 11217

United Kingdom

Moorfields Eye Hospital

London, Greater London, United Kingdom, EC1V 2PD

Sponsors and Collaborators

GenSight Biologics

Investigators

• Principal Investigator: Nancy Newman, MD; Emory University Hospital Atlanta, Georgia, United States, 30322

More Information

Additional Information:

GenSight Biologics website 

• Responsible Party: GenSight Biologics
• ClinicalTrials.gov Identifier: NCT03293524
• Other Study ID Numbers: GS-LHON-CLIN-05; 2017-002187-40 ( EudraCT Number )
• First Posted: September 26, 2017
• Last Update Posted: August 3, 2022
• Last Verified: August 2022

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by GenSight Biologics:

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

Additional relevant MeSH terms:

Optic Nerve Diseases; Optic Atrophy, Hereditary, Leber; Nervous System Diseases; Cranial Nerve Diseases; Eye Diseases; Optic Atrophies, Hereditary; Optic Atrophy; Heredodegenerative Disorders, Nervous System; Neurodegenerative Diseases; Eye Diseases, Hereditary; Genetic Diseases, Inborn; Mitochondrial Diseases; Metabolic Diseases