A Phase III gene therapy clinical trial in LHON Subjects Affected for more than 7months or more

• Register: EUCTR
• Last refreshed on: 30 April 2019
• Main ID: EUCTR2015-001266-26-DE
• Date of registration: 11/08/2015
• Prospective Registration: Yes
• Primary sponsor: GENSIGHT-BIOLOGICS
• Public title: A Phase III gene therapy clinical trial in LHON Subjects Affected for more than 7months or more
• Scientific title: A Randomized, Double-Masked, Sham-Controlled, Pivotal Clinical Trial to Evaluate the Efficacy of a Single Intravitreal Injection of GS010 (rAAV2/2-ND4) in Subjects Affected for more than 6 months and to 12 mounths by Leber Hereditary Optic Neuropathy Due to the G11778A Mutation in the Mitochondrial NADH Dehydrogenase 4 Gene
• Date of first enrolment: 21/01/2016
• Target sample size: 40
• Recruitment status: Not Recruiting
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2015-001266-26
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: yes; Randomised: yes; Open: no; Single blind: no; Double blind: yes; Parallel group: yes; Cross over: no; Other: no; If controlled, specify comparator, Other Medicinial Product: no; Placebo: no; Other: yes; Other specify the comparator: sham-controlled; Number of treatment arms in the trial: 2
• Phase: Human pharmacology (Phase I): no Therapeutic exploratory (Phase II): no Therapeutic confirmatory - (Phase III): yes Therapeutic use (Phase IV): no

Countries of recruitment

France, Germany, Italy, United Kingdom, United States

Contacts

• Name: Regulatory Affairs Director
• Affiliation: GENSIGHT-BIOLOGICS

• Name: Regulatory Affairs Director
• Affiliation: GENSIGHT-BIOLOGICS

Key inclusion & exclusion criteria

Inclusion criteria:
Selection Criteria:
1. Age 15 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).
Are the trial subjects under 18? yes
Number of subjects for this age range: 7
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 38
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 2

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 and well-controlled glaucoma, 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, includ

Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes

Health Condition(s) or Problem(s) studied

Leber Hereditary Optic Neuropathy due to mutations in the mitochondrial NADH Dehydrogenase 4 gene

Therapeutic area: Diseases [C] - Eye Diseases [C11]

Intervention(s)

Product Name: Recombinant AAV vector serotype 2 containing the human wild type mitochondrial ND4 gene
Product Code: GS010
Pharmaceutical Form: Suspension for injection
INN or Proposed INN: pending
CAS Number: 1640969-63-6
Current Sponsor code: rAAv2/2-ND4
Other descriptive name: RAAV2/2-ND4 VECTOR
Concentration unit: titre titre
Concentration type: equal
Concentration number: 1E12-

Primary Outcome(s)

Primary end point(s): The primary endpoint will be the ETDRS visual acuity (quantitative
score) at Week 48 after IVT 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 Objective: Evaluate the efficacy of GS010 compared with sham over the follow-up
period and at Week 96 in the change from baseline of the LogMAR
Verify whether the efficacy at Week 48 and at Week 96 of GS010
compared with sham and measured by the change from baseline in the
LogMAR is dependent upon the treatment of the better- or worse seeingeye
Verify whether the rate of responders at Week 48 and 96 is dependent
upon the treatment received and whether the magnitude of the
treatment effect is dependent the treatment of the better- or worse
seeing eye at entry
Assess the effect of GS010 on parameters measured with high resolution
spectral-domain optical coherence tomography (SD-OCT).
Assess the effect of GS010 on standardized automated visual fields
obtained with the Humphrey Visual Field (HVF) Analyzer II
Assess the effect of GS010 on contrast sensitivity measured with the
Pelli-Robson chart
Assess the effect of GS010 on color vision measure with the Farnsworth-
Munsell 100 Hue color test

Main Objective: To evaluate the efficacy of GS010 compared with sham at Week 48 in the change from baseline of the Log of the Minimal Angle of Resolution (LogMAR) in subjects affected for more than 6 months and to 12 months

Timepoint(s) of evaluation of this end point: Full analysis = 48 weeks

Secondary Outcome(s)

Timepoint(s) of evaluation of this end point: Secondary endpoints will be assessed 48 and 96 weeksafter the
injection of GS010.

Secondary end point(s): • ETDRS visual acuity (quantitative score) over the follow-up period
and at Week 96 after IVT injection. Change from baseline of the LogMAR
scores will be used for statistical analysis purposes.
• Response status to treatment at Week 48 and 96 after IVT injection.
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.
• Measure of parameters of high resolution SD-OCT of the posterior
pole and optic nerve at Week 48 and Week 96 .
• 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.
• Measure of contrast sensitivity with the Pelli-Robson chart at Week
48 and Week 96.
• Measure of color vision with the Farnsworth-Munsell 100 Hue color
vision test at Week 48 and Week 96.

Secondary ID(s)

GS-LHON-CLIN-03B

Source(s) of Monetary Support

GENSIGHT-BIOLOGICS

Ethics review

Status: Approved
Approval date:
Contact: