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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)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03293524
Recruitment Status : Active, not recruiting
First Posted : September 26, 2017
Last Update Posted : February 8, 2021
Sponsor:
Information provided by (Responsible Party):
GenSight Biologics

Tracking Information
First Submitted Date  ICMJE September 19, 2017
First Posted Date  ICMJE September 26, 2017
Last Update Posted Date February 8, 2021
Actual Study Start Date  ICMJE March 12, 2018
Estimated Primary Completion Date June 30, 2024   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: July 21, 2020)
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.
Original Primary Outcome Measures  ICMJE
 (submitted: September 21, 2017)
Best-Corrected Visual Acuity (BCVA) reported using Log of the Minimal Angle of Resolution (LogMAR) - 1 year [ Time Frame: at 1-Year post baseline treatment ]
The primary endpoint will be the BCVA reported with LogMAR at 1-Year post-treatment in second affected/not yet affected eyes. The change from baseline in second affected/not yet affected eyes receiving GS010 and placebo will be the primary response of interest. LogMAR BCVA will be used for statistical purposes.
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: July 21, 2020)
  • 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.
  • 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).
  • 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
  • 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
  • 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
  • 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
  • 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.
Original Secondary Outcome Measures  ICMJE
 (submitted: September 21, 2017)
  • Best-Corrected Visual Acuity (BCVA) reported with LogMAR - 2 years [ Time Frame: at 2-Years post baseline treatment ]
    LogMAR BCVA at each timepoint of the follow-up period and at 2-years post-treatment, for second affected/not yet affected eyes receiving GS010 versus placebo and also for first affected eyes receiving GS010. The change from baseline of the LogMAR BCVA will be used for statistical analyses.
  • Responder Analysis [ Time Frame: at 1-Year and 2-Years post baseline treatment ]
    Response status over time and at 1 and 2-years post baseline treatment. Response status will be assessed for second affected/not yet affected eyes receiving GS010 versus placebo and also for first affected eyes receiving GS010. 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 eye 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).
  • Spectral-Domain - Optical Coherence Tomography (SD-OCT) parameter [ Time Frame: at 1-Year and 2-Years post baseline treatment ]
    Parameters measured with SD-OCT over time and at 1 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 [ Time Frame: at 1-Year and 2-Years post baseline treatment ]
    Parameters measured with HVF 30-2 over time and at 1 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 [ Time Frame: at 1-Year and 2-Years post baseline treatment ]
    Parameters measured with Pelli Robson Low Vision Contrast Sensitivity over time and at 1 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 [ Time Frame: at 1-Year and 2-Years post baseline treatment ]
    Visual Functioning Questionnaire-25 at 1 and 2-years post-treatment
  • Quality of Life: 36-Item Short Form Health Survey, version 2 Questionnaire [ Time Frame: at 1-Year and 2-Years post baseline treatment ]
    36-Item Short Form Health Survey, version 2 Questionnaire at 1 and 2-years post-treatment.
Current Other Pre-specified Outcome Measures
 (submitted: September 21, 2017)
  • 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.
  • Physical examinations [ Time Frame: At 2-Years post baseline treatment ]
    Results of physical examinations
  • Electrocardiograms [ Time Frame: At 2-Years post baseline treatment ]
    Results of Electrocardiograms (ECGs)
  • Laboratory results [ Time Frame: At 2-Years post baseline treatment ]
    Results of laboratory tests from blood collection
  • 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
  • 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
Original Other Pre-specified Outcome Measures Same as current
 
Descriptive Information
Brief Title  ICMJE Efficacy & Safety Study of Bilateral IVT Injection of GS010 in LHON Subjects Due to the ND4 Mutation for up to 1 Year
Official Title  ICMJE 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
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.
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Treatment
Condition  ICMJE Leber Hereditary Optic Neuropathy
Intervention  ICMJE
  • 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.
Study Arms  ICMJE
  • 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.
    Intervention: Genetic: GS010
  • 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.
    Interventions:
    • Genetic: GS010
    • Drug: Placebo
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Active, not recruiting
Estimated Enrollment  ICMJE
 (submitted: September 21, 2017)
90
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE June 30, 2024
Estimated Primary Completion Date June 30, 2024   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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).
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 15 Years and older   (Child, Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Belgium,   France,   Italy,   Spain,   Taiwan,   United Kingdom,   United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03293524
Other Study ID Numbers  ICMJE GS-LHON-CLIN-05
2017-002187-40 ( EudraCT Number )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE Not Provided
Responsible Party GenSight Biologics
Study Sponsor  ICMJE GenSight Biologics
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Nancy Newman, MD Emory University Hospital Atlanta, Georgia, United States, 30322
PRS Account GenSight Biologics
Verification Date January 2021

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP