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

Sponsor

GenSight Biologics (Industry)

Overall Status

Active, not recruiting

CT.gov ID

NCT03293524

Collaborator

(none)

Enrollment

Locations

Arms

75.6

Anticipated Duration (Months)

6.9

Patients Per Site

0.1

Patients Per Site Per Month

Study Details

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

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

Anticipated 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 :

Mar 12, 2018

Anticipated Primary Completion Date :

Jun 30, 2024

Anticipated Study Completion Date :

Jun 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 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.

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

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.

Outcome Measures

Primary Outcome Measures

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

Best-Corrected Visual Acuity (BCVA) reported with LogMAR - 2 years [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.
Responder Analysis [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: 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 [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
Humphrey Visual Field (HVF) parameter [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
Pelli Robson Low Vision Contrast Sensitivity parameter [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
Quality of Life: Visual Functioning Questionnaire-25 [at 1.5-Year and 2-Years post baseline treatment]
Visual Functioning Questionnaire-25 at 1.5 and 2-years post-treatment
Quality of Life: 36-Item Short Form Health Survey, version 2 Questionnaire [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

Adverse events (AEs) and serious adverse events (SAEs) [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.
Physical examinations [At 2-Years post baseline treatment]
Results of physical examinations
Electrocardiograms [At 2-Years post baseline treatment]
Results of Electrocardiograms (ECGs)
Laboratory results [At 2-Years post baseline treatment]
Results of laboratory tests from blood collection
Immune response evaluations [Up to 2-Years post baseline treatment]
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
Blood Bio-dissemination of AAV2 Vector DNA [up to 4 weeks post-treatment]
Results of bio-dissemination testing up to 4-weeks post-treatment

Eligibility Criteria

Criteria

Ages Eligible for Study:

15 Years and Older

Sexes Eligible for Study:

All

Accepts 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).

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Doheny Eye Center UCLA Pasadena	Pasadena	California	United States	91105
2	University of Colorado Health Eye Center	Aurora	Colorado	United States	80045
3	Emory Healthcare - The Emory Clinic	Atlanta	Georgia	United States	30322
4	Massachusetts Eye and Ear Infirmary	Boston	Massachusetts	United States	02114
5	Icahn School of Medicine at Mount Sinai	New York	New York	United States	10029
6	Wills Eye Institute - Ocular Oncology Service	Philadelphia	Pennsylvania	United States	19107
7	Vanderbilt Eye Institute	Nashville	Tennessee	United States	37232
8	Universitair Ziekenhuis Gent	Gent		Belgium	9000
9	CHNO Les Quinze Vingts	Paris		France	75012
10	IRCCS Istituto delle Scienze Neurologiche di Bologna UOC Clinica Neurologica	Bologna		Italy	40139
11	Hospital Universitario Ramon y Cajal	Madrid		Spain	28034
12	Taipei Veterans General Hospital	Taipei		Taiwan	11217
13	Moorfields Eye Hospital	London	Greater London	United Kingdom	EC1V 2PD