Try our beta test site

Efficacy Study of GS010 for Treatment of Vision Loss From 7 Months to 1 Year From Onset in LHON Due to the ND4 Mutation (REVERSE)

This study is ongoing, but not recruiting participants.
Sponsor:
Information provided by (Responsible Party):
GenSight Biologics
ClinicalTrials.gov Identifier:
NCT02652780
First received: January 7, 2016
Last updated: February 22, 2017
Last verified: February 2017
  Purpose
The goal of this clinical trial is to assess the effectiveness of GS010, a gene therapy, in improving the visual outcome in patients with LHON due to the G11778A ND4 mitochondrial mutation when vision loss is present for more than six months and up to one year.

Condition Intervention Phase
Optic, Atrophy, Hereditary, Leber
Genetic: GS010
Other: Sham Intravitreal Injection
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Participant, Care Provider, Investigator, Outcomes Assessor
Primary Purpose: Treatment
Official Title: Randomized, Double-Masked, Sham-Controlled Clinical Trial to Evaluate the Efficacy of a Single Intravitreal Injection of GS010 in Subjects Affected for More Than 6 Months and To 12 Months by LHON Due to the G11778A Mutation in the ND4 Gene

Resource links provided by NLM:


Further study details as provided by GenSight Biologics:

Primary Outcome Measures:
  • ETDRS visual acuity, utilizing derived LogMAR acuity [ Time Frame: 48 weeks after GS010/sham injection ]
    The primary endpoint will be the ETDRS visual acuity (quantitative score) at Week 48 after intravitreal injection. The subjects' LogMAR scores, which are derived from the number of letters they read on the ETDRS chart, will be used for statistical analysis purposes. The change from baseline in each eye will be the primary response of interest.


Secondary Outcome Measures:
  • ETDRS visual acuity, utilizing derived LogMAR acuity [ Time Frame: 96 weeks after GS010/sham injection ]
    ETDRS visual acuity (quantitative score) over the follow-up period and at Week 96 after intravitreal injection. Change from baseline of the LogMAR scores will be used for statistical analysis purposes.

  • Responder Analysis: Improvement from Baseline by 15 ETDRS letters or having Visual Acuity >20/200 at 48 and 96 weeks [ Time Frame: 48 and 96 weeks after GS010/sham injection ]
    Response status to treatment at Week 48 and 96 after intravitreal injection will be determined. Responder will be defined by an improvement of at least 15 letters in the visual acuity score obtained with ETDRS or being greater than a Snellen acuity equivalent of 20/200. The number of GS010-treated eyes that qualify as responders will be compared to the number of sham-treated eyes that qualify as responders.

  • High Resolution Spectral Domain Optical Coherence Tomography to measure the optic nerve retinal nerve fiber layer (RNFL) thickness and the thickness/volume of the retinal layers of the macula [ Time Frame: 48 and 96 weeks after GS010/sham injection ]
    Measure of parameters of high resolution SD-OCT of the posterior pole and optic nerve at Week 48 and Week 96.Total average and quadrant thickness of the RNFL will be evaluated. The various layers of the retina, including the retinal ganglion cell layer and inner plexiform layer, will be analyzed and the thickness/volume will be evaluated.

  • Humphrey Visual Field 30-2 [ Time Frame: 48 and 96 weeks after GS010/sham injection ]
    Measure of the standardized automated visual fields obtained with HVF Analyzer II. Mean Deviation (MD) in decibels of sensitivity will be used at Week 48 and Week 96.

  • Pelli-Robson Contrast Sensitivity [ Time Frame: 48 and 96 weeks after GS010/sham injection ]
    Measure of contrast sensitivity with the Pelli-Robson chart at Week 48 and Week 96.

  • Farnsworth-Munsell Color 100 Hue Vision Test [ Time Frame: 48 and 96 weeks after GS010/sham injection ]
    Measure of color vision with the Farnsworth-Munsell 100 Hue color vision test at Week 48 and Week 96.

  • Adverse Events and Serious Adverse Events [ Time Frame: Continuous over 96 week study period ]
    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.

  • Immune Responses [ Time Frame: 96 week study period ]

    Results of immune response evaluations:

    Time course of neutralizing antibodies against AAV2 vector and cellular immune response against AAV2 vector and ND4 protein.


  • Blood Bio-dissemination of AAV2 Vector DNA [ Time Frame: Two weeks post GS010 administration ]
    Blood bio-dissemination two weeks after injection of GS010. The presence of AAV2 vector DNA in the blood of subjects will be tested for and quantified utilizing quantitative PCR.


Other Outcome Measures:
  • Better-Seeing Eye Comparison [ Time Frame: 48 and 96 weeks after GS010/sham injection ]
    The better seeing-eye of each patient will be determined at visit 1, prior to randomization. A pre-determined algorithm of criteria in a hierarchy will be used to determine the better seeing-eye based on vision testing results (e.g. visual acuity, SD-OCT, contrast sensitivity). A minimization method will be employed in the randomization process to ensure, as best as possible, an even distribution of better seeing-eyes to receipt of GS010 and sham. Better-seeing eyes that received GS010 will be compared to better-seeing eyes that received sham. A similar analysis will be done for worse-seeing eyes.

  • Quality of Life: Visual Functioning Questionnaire-25 [ Time Frame: 48 and 96 weeks after GS010/sham injection ]
    Visual Functioning Questionnaire-25.

  • Quality of Life: 36-Item Short Form Health Survey, version 2 Questionnaire [ Time Frame: 48 and 96 weeks after GS010/sham injection ]
    36-Item Short Form Health Survey, version 2 Questionnaire.


Estimated Enrollment: 36
Actual Study Start Date: January 2016
Estimated Study Completion Date: January 2019
Estimated Primary Completion Date: January 2018 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: GS010-treated Eyes
Each subject will have one eye randomly selected to receive a single injection of GS010 and the other eye will receive a sham injection. GS010-treated Eyes: GS010 is a recombinant adeno-associated viral vector serotype 2 (rAAV2/2) containing the wild-type ND4 gene (rAAV2/2-ND4). Subjects will receive a single dose of GS010 in one of their randomly selected eyes, via intravitreal injection containing 9E10 viral genomes in 90μL balanced salt solution (BSS) plus 0.001% Pluronic F68®.
Genetic: GS010

Both eyes of each subject will receive standard antiseptic preparation, administration of topical local ocular anesthetic agents and will undergo pupillary dilation. Administration of an intra-ocular pressure lowering agent will precede treatment for every subject.

GS010-treated Eyes: GS010 is a recombinant adeno-associated viral vector serotype 2 (rAAV2/2) containing the wild-type ND4 gene (rAAV2/2-ND4). Subjects will receive a single dose of GS010 in one of their randomly selected eyes, via intravitreal injection containing 9E10 viral genomes in 90μL balanced salt solution (BSS) plus 0.001% Pluronic F68®.

Other Names:
  • Lenadogene Nolparvovec
  • rAAV2/2-ND4
Sham Comparator: Sham-treated Eyes
Each subject will have one eye randomly selected to receive GS010 and the other eye will receive a sham injection. Eyes receiving sham injection will undergo the same preparatory procedures as eyes receiving GS010 injection, including pupillary dilation, topical anti-infection and topical anesthetic procedures. Sham Intravitreal injection will be performed by applying pressure to the eye at the location of a typical intravitreal injection procedure using the blunt end of a syringe without a needle.
Other: Sham Intravitreal Injection

Both eyes of each subject will receive standard antiseptic preparation, administration of topical local ocular anesthetic agents and will undergo pupillary dilation. Administration of an intra-ocular pressure lowering agent will precede treatment for every subject.

Sham-treated Eyes: One eye of each subject will undergo sham injection. Sham Intravitreal injection will be performed by applying pressure to the eye at the location of a typical intravitreal injection procedure using the blunt end of a syringe without a needle.


  Eligibility

Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

Selection Criteria:

Subjects must meet all the following criteria at the Screening Visit (Visit 1) in order to be included into the study.

  1. Age 18 years or older.
  2. Onset of vision loss based on medically documented history or subject testimony, in both eyes for 181 and ≤365 days in duration.
  3. Each eye of the subject maintaining visual ability to allow at least for counting of the examiner's fingers at any distance.
  4. Female subjects (if of childbearing potential) must agree to use effective methods of birth control up to 6 months after IVT injection and male subjects must agree to use condoms for up to 6 months after IVT injection.
  5. Ability to obtain adequate pupillary dilation to permit thorough ocular examination and testing.
  6. Signed written informed consent.

Inclusion Criteria:

Subjects included in the study must satisfy all the following criteria at the Inclusion Visit (Visit 2).

  1. 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.
  2. Review of all selection criteria to ensure continued compliance.
  3. Have a negative test for infection with human immunodeficiency virus (HIV).
  4. Have a negative pregnancy test for women of childbearing potential (a woman who is two years post-menopausal or surgically sterile is not considered to be of childbearing potential).

Exclusion Criteria:

Non-Selection Criteria:

Subjects who meet at least one of the following criteria at the Screening Visit (Visit 1) will not be included into the study.

  1. Any known allergy or hypersensitivity to GS010 or its constituents.
  2. Contraindication to IVT injection.
  3. IVT drug delivery to either eye within 30 days prior to the Screening Visit (Visit 1).
  4. Previous vitrectomy in either eye.
  5. Narrow angle in either eye contra-indicating pupillary dilation.
  6. Presence of disorders of the ocular media, such as the cornea and lens, which may interfere with visual acuity and other ocular assessments during the study period.
  7. Vision disorders, other than LHON, involving visual disability or with the potential to cause further vision loss during the trial period.
  8. Causes of optic neuropathy other than LHON and glaucoma.
  9. Subjects with known mutations of other genes involved in pathological retinal or optic nerve conditions.
  10. Presence of ocular or systemic disease, other than LHON, whose pathology or associated treatments might affect the retina or the optic nerve.
  11. History of amblyopia associated with a Snellen visual acuity equivalent of worse than 20/80 (equivalent to 6/24 at 6 meters, decimal acuity 0.25, LogMAR +0.6) in the affected eye.
  12. Presence of ocular conditions, which in the opinion of the Investigator will prevent good quality SD-OCT imaging from being obtained.
  13. Presence, in either eye, of uncontrolled glaucoma, defined as an IOP greater than 25 mmHg, despite maximal medical therapy with IOP-lowering agents.
  14. Active ocular inflammation or history of idiopathic or autoimmune-associated uveitis.
  15. Subjects participating in another clinical trial and receiving an IMP within 90 days prior to the Screening Visit (Visit 1).
  16. Previous treatment with an ocular gene therapy product.
  17. Subjects who have undergone ocular surgery of clinical relevance (per Investigator opinion) within 90 days preceding the Screening Visit (Visit 1).
  18. Female Subjects who are or who intend to breast feed during the trial period.

Exclusion Criteria:

Subjects who meet at least one of the following criteria at the Inclusion Visit (Visit 2) will not be included in the study.

  1. Any non-selection criteria which may have appeared after the screening visit.
  2. Subjects taking idebenone who have not completely discontinued the idebenone at least 7 days prior to Visit 2. If the subject has not discontinued idebenone at least 7 days prior to Visit 2, the visit may be delayed until the 7-day period is complete.
  3. Presence, at the time of study inclusion, of infectious conjunctivitis, keratitis, scleritis or endophthalmitis in either eye.
  4. Presence of systemic illness, including alcohol and drug abuse (except nicotine), or medically significant abnormal laboratory values that are deemed by the Investigator to preclude the subject's safe participation in the study.
  5. Presence of illness or disease that, in the opinion of the Investigator, include symptoms and/or the associated treatments that can alter visual function, for instance cancers or pathology of the central nervous system.
  6. Any medical or psychological condition that, in the opinion of the Investigator, may compromise the safe participation of the subject in the study or would preclude compliance with the study protocol or ability of the subject to successfully complete the study.
  7. Subjects unable or unwilling to comply with the protocol requirements.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT02652780

Locations
United States, California
Doheny Eye Center, University of California, Los Angeles
Los Angeles, California, United States
United States, Georgia
Department of Ophthalmology, Emory University School of Medicine
Atlanta, Georgia, United States, 30322
United States, Pennsylvania
Neuro Ophthalmologic Associates, Wills Eye Hospital, Thomas Jefferson University
Philadelphia, Pennsylvania, United States, 19107
France
Centre National Hospitalier d'Ophtalmologie des Quinze-Vingt
Paris, France
Germany
Department of Neurology, University of Munich, Friedrich-Baur-Institute
Munich, Germany, 80336
Italy
IRCCS Istituto delle Scienze Neurologiche di Bologna, UOC Clinica Neurologica, Ospedale Bellaria
Bologna, Italy
United Kingdom
Moorfields Eye Hospital NHS Foundation Trust
London, United Kingdom, EC1V 2PD
Sponsors and Collaborators
GenSight Biologics
Investigators
Principal Investigator: Patrick Yu Wai Man, MDPhDFRCOpht Moorfields Eye Hospital NHS Foundation Trust
  More Information

Additional Information:
Responsible Party: GenSight Biologics
ClinicalTrials.gov Identifier: NCT02652780     History of Changes
Other Study ID Numbers: GS-LHON-CLIN-03B
2015-001266-26 ( EudraCT Number )
Study First Received: January 7, 2016
Last Updated: February 22, 2017
Individual Participant Data  
Plan to Share IPD: No

Keywords provided by GenSight Biologics:
Leber Hereditary Optic Neuropathy
Leber Hereditary Optic Atrophy
Heredity Optic Atrophy
Eye Diseases
Hereditary Eye Diseases
Inborn Genetic Disease
Genetic Therapy
Intravitreal Injections
Mitochondrial Disease
AAV2 Vectors
Nervous System Diseases
Neurodegenerative Disease
Heredodegenerative Disorders of the Nervous System

Additional relevant MeSH terms:
Atrophy
Pathological Conditions, Anatomical
Anesthetics
Central Nervous System Depressants
Physiological Effects of Drugs

ClinicalTrials.gov processed this record on March 28, 2017