Efficacy Study of GS010 for the Treatment of Vision Loss up to 6 Months From Onset in LHON Due to the ND4 Mutation (RESCUE)

• ClinicalTrials.gov Identifier: NCT02652767
• Recruitment Status: Completed
• First Posted: January 12, 2016
• Results First Posted: January 28, 2020
• Last Update Posted: July 29, 2022
• Sponsor: GenSight Biologics
• Information provided by (Responsible Party): GenSight Biologics

Tracking Information

• First Submitted Date: January 7, 2016
• First Posted Date: January 12, 2016
• Results First Submitted Date: January 17, 2020
• Results First Posted Date: January 28, 2020
• Last Update Posted Date: July 29, 2022
• Actual Study Start Date: February 23, 2016
• Actual Primary Completion Date: August 7, 2018 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: January 17, 2020)

Change From Baseline in ETDRS Visual Acuity (Quantitative Score) at Week 48 [ Time Frame: Baseline and Week 48 ]

Visual acuity was derived from the Early Treatment Diabetic Retinopathy Study (ETDRS) chart. Visual acuity is measured in "logarithm of the minimal angle of resolution" (LogMAR), which was derived from the number of letters participants could read on the ETDRS chart. 1 ETDRS line = 5 letters 1 ETDRS line = 0.1 LogMAR A lower LogMAR score denotes better visual acuity. A positive change from baseline indicates a worsening in symptoms. Change = (Week 48 score - Baseline score).

Original Primary Outcome Measures (submitted: January 8, 2016)

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.

Current Secondary Outcome Measures (submitted: January 17, 2020)

• Change From Baseline in ETDRS Visual Acuity (Quantitative Score) [ Time Frame: Baseline; Week 72 and Week 96 ]
  Visual acuity was derived from the Early Treatment Diabetic Retinopathy Study (ETDRS) chart. Visual acuity is measured in "logarithm of the minimal angle of resolution" (LogMAR), which was derived from the number of letters participants could read on the ETDRS chart. 1 ETDRS line = 5 letters 1 ETDRS line = 0.1 LogMAR A lower LogMAR score denotes better visual acuity. A positive change from baseline indicates a worsening in symptoms. Change = (Week 72 score - Baseline score) or (Week 96 score - Baseline score). Missing data was imputed by the linear interpolation method.
• Number of Eye Responders to Treatment [ Time Frame: Baseline; Week 48; Week 72 and Week 96 ]
  An eye was determined as a responder to treatment based on 2 different definitions. Definition 1: An eye responder was defined by an improvement of the Early Treatment Diabetic Retinopathy Study (ETDRS) visual acuity score of at least 15 letters compared to Baseline, or a final visual acuity greater than a Snellen acuity equivalent of 20/200 (a score of at least 1 letter). Definition 2: An eye responder was defined by an improvement of the ETDRS score of at least 20 letters compared to Baseline.
• Number of Subject Responders to Treatment [ Time Frame: Week 48; Week 72 and Week 96 ]
  A subject responder was defined as a participant whose Early Treatment Diabetic Retinopathy Study (ETDRS) score of the treated eye (that received GS010), was at least 15 letters better than the sham eye, or whose treated eye had a "logarithm of the minimal angle of resolution" (LogMAR) acuity score of at least 0.3 LogMAR better than the sham eye. For the Week 96 analysis, if no score was available for Week 96, the score from the previous visit was used.
• Change From Baseline in GCL Macular Volume [ Time Frame: Baseline; Week 48; Week 72 and Week 96 ]
  Ganglion cell layer (GCL) macular volume was measured as a parameter of spectral domain-optical coherence tomography (SD-OCT). SD-OCT was obtained with the Spectralis® OCT (Heidelberg Engineering).
• Change From Baseline in RNFL Temporal Quadrant Thickness [ Time Frame: Baseline; Week 48; Week 72 and Week 96 ]
  Retinal nerve fiber layer (RNFL) temporal quadrant thickness was measured as a parameter of spectral domain-optical coherence tomography (SD-OCT). SD-OCT was obtained with the Spectralis® OCT (Heidelberg Engineering).
• Change From Baseline in RNFL Papillomacular Bundle Thickness [ Time Frame: Baseline; Week 48; Week 72 and Week 96 ]
  Papillomacular bundle thickness was measured as a parameter of spectral domain-optical coherence tomography (SD-OCT). SD-OCT was obtained with the Spectralis® OCT (Heidelberg Engineering).
• Change From Baseline in ETDRS Total Macular Volume [ Time Frame: Baseline; Week 48; Week 72 and Week 96 ]
  Early Treatment Diabetic Retinopathy Study (ETDRS) total macular volume was measured as a parameter of spectral domain-optical coherence tomography (SD-OCT). SD-OCT was obtained with the Spectralis® OCT (Heidelberg Engineering).
• Change From Baseline in the Foveal Threshold Sensitivities Obtained With HVF Analyzer II [ Time Frame: Baseline; Week 48; Week 72 and Week 96 ]
  The assessment of standardized automated visual fields was measured using the Humphrey Visual Field (HVF) Analyzer II. Automated visual fields included the assessment of foveal threshold sensitivities. Foveal threshold sensitivity is measured in decibels (dB), which ranges from 0 dB to 50 dB. A sensitivity threshold of 0 dB indicates not being able to see the most intense perimetric stimulus, while higher dB indicates better/normal foveal vision. A positive change from baseline indicates an improvement of symptoms.
• Visual Field Mean Deviation in Decibels of Sensitivity Obtained With HVF Analyzer II [ Time Frame: Baseline; Week 48; Week 72 and Week 96 ]
  The assessment of standardized automated visual fields was measured using the Humphrey Visual Field (HVF) Analyzer II. Automated visual fields included the assessment of the mean deviation (MD) in decibels (dB) of sensitivity.
• Change From Baseline in Contrast Sensitivity [ Time Frame: Baseline; Week 48; Week 72 and Week 96 ]
  The assessment of contrast sensitivity was measured using the Pelli-Robson chart. The chart uses letters arranged in groups whose contrast varies from high to low. Participants read the letters, starting with the highest contrast, until they are unable to read 2 or 3 letters in a single group. Each eye is assigned a score based on the contrast of the last group in which 2 or 3 letters were correctly read, ranging from 0 to 2.2 "log of contrast sensitivity" (LogCS) units. A score of 2.0 LogCS, represents a normal sensitivity contrast, and indicates the eye was able to detect 2 of the 3 letters with a contrast of 1 percent (contrast sensitivity = 100 percent or log 2). Scores less than 2.0 signify poorer contrast sensitivity. Pelli-Robson contrast sensitivity score of less than 1.5 is consistent with visual impairment and a score of less than 1.0 represents in visual disability. A negative change from baseline indicates worsening in symptoms.
• Change From Baseline in Color Vision [ Time Frame: Baseline; Week 48 and Week 96 ]
  The assessment of color vision was measured using the Farnsworth-Munsell 100-Hue Color Test. Each of the 4 trays consisted of 21 caps. Participants were asked to sort the randomly arranged caps following the hue order from the first to the last fixed caps. The total error score (TES) was derived by the frequency the caps were misplaced and the severity, or distance of the misplacement. Errors were made whenever caps were misplaced from the correct order. Error scores were calculated according to the distance between any two caps. The error score for each individual cap was the sum of the difference between the number of that cap and the numbers of the cap adjacent to it, minus 2. TES was the total sum of the error scores of the entire set of caps. The best possible score was 0 and there is no defined upper limit to the total error score range. A lower score indicates improved color discrimination ability. A positive change from baseline indicates a worsening in symptoms.

Original Secondary Outcome Measures (submitted: January 8, 2016)

• 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.

• Current Other Pre-specified Outcome Measures: Not Provided

Original Other Pre-specified Outcome Measures (submitted: January 8, 2016)

• 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 scale.
• 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 quality of life scale.

Descriptive Information

• Brief Title: Efficacy Study of GS010 for the Treatment of Vision Loss up to 6 Months From Onset in LHON Due to the ND4 Mutation
• Official Title: A Randomized, Double-Masked, Sham-Controlled Clinical Trial to Evaluate the Efficacy of a Single Intravitreal Injection of GS010 in Subjects Affected for 6 Months or Less by LHON Due to the G11778A Mutation in the Mitochondrial ND4 Gene
• Brief Summary: The goal of this clinical trial is to assess the effectiveness of GS010, a gene therapy, in improving the visual outcome in participants with Leber Hereditary Optic Neuropathy (LHON) due to the G11778A ND4 mitochondrial mutation when vision loss is present for six months or less.
• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor); Primary Purpose: Treatment
• Condition: Optic, Atrophy, Hereditary, Leber

Intervention

• Biological: GS010

  Both eyes of each participant 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 participant.

  GS010-treated Eyes: GS010 is a recombinant adeno-associated viral vector serotype 2 (rAAV2/2) containing the wild-type ND4 gene (rAAV2/2-ND4). Participants 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
• Device: Sham Intravitreal Injection

  Both eyes of each participant 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 participant.

  Sham-treated Eyes: One eye of each participant 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.

Study Arms

• Experimental: GS010-treated Eyes
  Each participant 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). Participants 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®.
  Intervention: Biological: GS010
• Sham Comparator: Sham-treated Eyes
  Each participant 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.
  Intervention: Device: Sham Intravitreal Injection

Publications *

• Newman NJ, Yu-Wai-Man P, Carelli V, Biousse V, Moster ML, Vignal-Clermont C, Sergott RC, Klopstock T, Sadun AA, Girmens JF, La Morgia C, DeBusk AA, Jurkute N, Priglinger C, Karanjia R, Josse C, Salzmann J, Montestruc F, Roux M, Taiel M, Sahel JA. Intravitreal Gene Therapy vs. Natural History in Patients With Leber Hereditary Optic Neuropathy Carrying the m.11778G>A ND4 Mutation: Systematic Review and Indirect Comparison. Front Neurol. 2021 May 24;12:662838. doi: 10.3389/fneur.2021.662838. eCollection 2021.
• Newman NJ, Yu-Wai-Man P, Carelli V, Moster ML, Biousse V, Vignal-Clermont C, Sergott RC, Klopstock T, Sadun AA, Barboni P, DeBusk AA, Girmens JF, Rudolph G, Karanjia R, Taiel M, Blouin L, Smits G, Katz B, Sahel JA; LHON Study Group. Efficacy and Safety of Intravitreal Gene Therapy for Leber Hereditary Optic Neuropathy Treated within 6 Months of Disease Onset. Ophthalmology. 2021 May;128(5):649-660. doi: 10.1016/j.ophtha.2020.12.012. Epub 2021 Jan 12.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: January 17, 2020): 39
• Original Estimated Enrollment (submitted: January 8, 2016): 36
• Actual Study Completion Date: July 4, 2019
• Actual Primary Completion Date: August 7, 2018 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

Selection Criteria:

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

1. Age 15 years or older.
2. Onset of vision loss based on medically documented history or participant testimony, in at least one eye for ≤180 days in duration and if both eyes are affected the duration of vision loss in both eyes must be ≤180 days in duration.
3. Each eye of the participant maintaining visual ability to allow at least for counting of the examiner's fingers at any distance.
4. Female participants (if of childbearing potential) must agree to use effective methods of birth control up to 6 months after intravitreal (IVT) injection and male participants 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:

Participants 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 Leber Hereditary Optical Neuropathy (LHON)-associated mutations (ND1 or ND6) in the participant's mitochondrial DNA.
2. Review of all selection criteria to ensure continued compliance.
3. Have a negative test for infection with human immunodeficiency virus.
4. Have a negative pregnancy test for women of childbearing potential (a woman who is 2 years post-menopausal or surgically sterile is not considered to be of childbearing potential).

Exclusion Criteria:

Non-Selection Criteria:

Participants 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. Participants 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 intra-ocular pressure (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. Participants participating in another clinical trial and receiving an investigational medicinal product within 90 days prior to the Screening Visit (Visit 1).
16. Previous treatment with an ocular gene therapy product.
17. Participants who have undergone ocular surgery of clinical relevance (per Investigator opinion) within 90 days preceding the Screening Visit (Visit 1).
18. Female participants who are or who intend to breast feed during the trial period.

Exclusion Criteria:

Participants 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. Participants taking idebenone who have not completely discontinued the idebenone at least 7 days prior to Visit 2. If the participant 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 participant'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 participant in the study or would preclude compliance with the study protocol or ability of the participant to successfully complete the study.
7. Participants unable or unwilling to comply with the protocol requirements.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 15 Years and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: France, Germany, Italy, United Kingdom, United States

Administrative Information

• NCT Number: NCT02652767
• Other Study ID Numbers: GS-LHON-CLIN-03A; 2015-001265-11 ( EudraCT Number )
• Has Data Monitoring Committee: Yes
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Current Responsible Party: GenSight Biologics
• Original Responsible Party: Same as current
• Current Study Sponsor: GenSight Biologics
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Principal Investigator: Nancy J. Newman, MD; Department of Ophthalmology, Emory University School of Medicine

• PRS Account: GenSight Biologics
• Verification Date: January 2020