Clinical Trials Register

Summary
EudraCT Number:	2015-001266-26
Sponsor's Protocol Code Number:	GS-LHON-CLIN-03B
National Competent Authority:	Germany - PEI
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2015-08-11
Trial results	View results

Index
A. PROTOCOL INFORMATION
B. SPONSOR INFORMATION
C. APPLICANT IDENTIFICATION
D. IMP IDENTIFICATION
D.8 INFORMATION ON PLACEBO
E. GENERAL INFORMATION ON THE TRIAL
F. POPULATION OF TRIAL SUBJECTS
G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
P. END OF TRIAL

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A. Protocol Information

A.1

Member State Concerned

Germany - PEI

A.2

EudraCT number

2015-001266-26

A.3

Full title of the trial

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

A.3.1

Title of the trial for lay people, in easily understood, i.e. non-technical, language

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

A.4.1

Sponsor's protocol code number

GS-LHON-CLIN-03B

A.7

Trial is part of a Paediatric Investigation Plan

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	GENSIGHT-BIOLOGICS
B.1.3.4	Country	France
B.3.1 and B.3.2	Status of the sponsor	Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	GENSIGHT-BIOLOGICS
B.4.2	Country	France
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	GENSIGHT-BIOLOGICS
B.5.2	Functional name of contact point	Regulatory Affairs Director
B.5.3	Address:
B.5.3.1	Street Address	74 rue du Faubourg Saint-Antoine
B.5.3.2	Town/ city	PARIS
B.5.3.3	Post code	75012
B.5.3.4	Country	France
B.5.4	Telephone number	0033176217220
B.5.5	Fax number	0033143142592
B.5.6	E-mail	ipengue@gensight-biologics.com

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	No
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	Yes
D.2.5.1	Orphan drug designation number	EU/3/11/860
D.3 Description of the IMP
D.3.1	Product name	Recombinant AAV vector serotype 2 containing the human wild type mitochondrial ND4 gene
D.3.2	Product code	GS010
D.3.4	Pharmaceutical form	Suspension for injection
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravitreal use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	pending
D.3.9.1	CAS number	1640969-63-6
D.3.9.2	Current sponsor code	rAAv2/2-ND4
D.3.9.3	Other descriptive name	RAAV2/2-ND4 VECTOR
D.3.9.4	EV Substance Code	SUB129740
D.3.10	Strength
D.3.10.1	Concentration unit	titre titre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	1E12
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	No
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	Yes
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	Yes
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	Yes
D.3.11.10	Medicinal product containing genetically modified organisms	Yes
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No

D.8 Information on Placebo

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

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

E.1.1.1

Medical condition in easily understood language

LHON: Genetic disease of the optic nerve which leads to visual loss and development of blindness

E.1.1.2

Therapeutic area

Diseases [C] - Eye Diseases [C11]

MedDRA Classification

E.1.3

Condition being studied is a rare disease

Yes

E.2 Objective of the trial

E.2.1

Main objective of the trial

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

E.2.2

Secondary objectives of the trial

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

E.2.3

Trial contains a sub-study

E.3

Principal 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).

E.4

Principal 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, 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.

E.5 End points

E.5.1

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.

E.5.1.1

Timepoint(s) of evaluation of this end point

Full analysis = 48 weeks

E.5.2

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.

E.5.2.1

Timepoint(s) of evaluation of this end point

Secondary endpoints will be assessed 48 and 96 weeksafter the
injection of GS010.

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

E.6.3

Therapy

E.6.4

Safety

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

E.6.7

Pharmacodynamic

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

E.7.1.3.1

Other trial type description

E.7.2

Therapeutic exploratory (Phase II)

E.7.3

Therapeutic confirmatory (Phase III)

Yes

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

Yes

E.8.1.1

Randomised

Yes

E.8.1.2

Open

E.8.1.3

Single blind

E.8.1.4

Double blind

Yes

E.8.1.5

Parallel group

Yes

E.8.1.6

Cross over

E.8.1.7

Other

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

E.8.2.2

Placebo

E.8.2.3

Other

Yes

E.8.2.3.1

Comparator description

sham-controlled

E.8.2.4

Number of treatment arms in the trial

E.8.3

The trial involves single site in the Member State concerned

Yes

E.8.4

The trial involves multiple sites in the Member State concerned

E.8.5

The trial involves multiple Member States

Yes

E.8.5.1

Number of sites anticipated in the EEA

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

Yes

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.6.3

If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned

France

Germany

Italy

United Kingdom

United States

E.8.7

Trial has a data monitoring committee

Yes

E.8.8

Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial

LVLS

E.8.9 Initial estimate of the duration of the trial

E.8.9.1

In the Member State concerned years

E.8.9.1

In the Member State concerned months

E.8.9.1

In the Member State concerned days

E.8.9.2

In all countries concerned by the trial years

E.8.9.2

In all countries concerned by the trial months

E.8.9.2

In all countries concerned by the trial days

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

Yes

F.1.1

Number of subjects for this age range:

F.1.1.1

In Utero

F.1.1.2

Preterm newborn infants (up to gestational age < 37 weeks)

F.1.1.3

Newborns (0-27 days)

F.1.1.4

Infants and toddlers (28 days-23 months)

F.1.1.5

Children (2-11years)

F.1.1.6

Adolescents (12-17 years)

Yes

F.1.1.6.1

Number of subjects for this age range:

F.1.2

Adults (18-64 years)

Yes

F.1.2.1

Number of subjects for this age range:

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

F.2 Gender

F.2.1

Female

Yes

F.2.2

Male

Yes

F.3 Group of trial subjects

F.3.1

Healthy volunteers

F.3.2

Patients

Yes

F.3.3

Specific vulnerable populations

Yes

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

Yes

F.3.3.3

Pregnant women

F.3.3.4

Nursing women

F.3.3.5

Emergency situation

F.3.3.6

Subjects incapable of giving consent personally

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

F.4.2

For a multinational trial

F.4.2.1

In the EEA

F.4.2.2

In the whole clinical trial

F.5

Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)

Standard follow-up of LHON patients

G. Investigator Networks to be involved in the Trial

N. Review by the Competent Authority or Ethics Committee in the country concerned

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2016-01-21

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2015-10-06

P. End of Trial
P.	End of Trial Status	Completed

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IMP with orphan designation in the indication
Orphan Designation Number:
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