Neuro-Ophthalmology Clinical Trials

 

Emory Eye Center’s neuro-ophthalmology team is very active in clinical research, including as a major focus of the neuro-ophthalmology fellowship program.

Dr. Newman and Dr. Biousse have led numerous research projects in the fields of hereditary optic neuropathies, optic nerve diseases, vascular diseases, increased intracranial pressure, and education. Dr. Peragallo is the principal investigator for studies of various neuro-ophthalmologic disorders in children. Dr. Beau Bruce, a neuro-ophthalmologist currently working primarily at the Centers for Disease Control and Prevention, has an adjunct appointment in Emory’s Department of Ophthalmology. He brings special expertise in epidemiology, statistics, and clinical trials to the team.

Our neuro-ophthalmologists have numerous international connections and collaborate closely with Emory’s Global Ophthalmology physicians.

 

Current

RESCUE: 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 6 Months or Less by Leber Hereditary Optic Neuropathy Due to the G11778A Mutation in the Mitochondrial NADH Dehydrogenase 4 Gene

REVERSE: 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 Months by Leber Hereditary Optic Neuropathy Due to the G11778A Mutation in the Mitochondrial NADH Dehydrogenase 4 Gene

Long-term Follow-up of ND4 LHON Subjects Treated With GS010 Ocular Gene Therapy in the RESCUE or REVERSE Phase III Clinical Trials
PI: Nancy Newman, MD
Coordinator: Debbie Gibbs, Lindy DuBois
Status: Closed to Recruitment

General Summary:
Leber Hereditary Optic Neuropathy (LHON) is due to a defect (mutation) in a mitochondrial gene that you were born with. Genes are pieces of DNA that hold genetic information about you and they determine, for example, the color of your eyes, height and skin color. A defect in a gene can lead to a malfunction of cells and/or organs. Mitochondria are small structures contained in most cells which are responsible for the production of a cell’s energy and they contain their own DNA. Your condition (LHON) is due to a specific defect in your mitochondrial ND4 gene.

This gene contains the code (like a recipe) for a protein which is essential for the proper functioning of the mitochondria of your retinal ganglion cells. Retinal ganglion cells are nerve cells and are part of the retina of the eye. Retinal ganglion cells give rise to the optic nerve, which carries all visual information from the eye to the brain. When the ND4 gene defect is present, the protein is not produced correctly and therefore the retinal ganglion cell and the optic nerve function gradually decline and your central vision is affected. Eventually the retinal ganglion cells die and the body is unable to regenerate them. The loss of central vision is sudden and painless.

Usually one eye is first affected and then later the other eye is also affected. Both men and women are affected but men are about 4 times more likely to develop the condition. To date, there is no cure or proven treatment for LHON. In the European Union a drug named idebenone has been approved under exceptional circumstances as there is some evidence that it may work in a certain group of patients with LHON.

Clinical Summary:
The purpose of this study is to evaluate the safety of the GS010 treatment and see if it is able to improve vision or prevent further vision loss caused by LHON from the ND4 gene mutation. This will be done by various tests and assessments of your eyes and vision. The investigational (study) drug that you will receive in this study is currently referred to as GS010. Investigational means that the drug has not been approved for marketing by any regulatory agencies, such as the FDA, anywhere in the world. GenSight Biologics distributes the medication and is funding the study by providing the medicine, paying for the treatment and all the testing procedures during all the visits.

The study is designed so that all subjects receive the experimental drug in one eye. This study is a (1) double-masked (2) sham-controlled study. This means that subjects will receive the study medication in one eye and a sham injection in the other eye. This will randomly be determined and you will not know which eye receives the study medication or which eye receives the sham injection. The study medication is injected into the eye after the eye is made numb by anesthetic eye drops. The sham injection is performed by numbing the eye, then placing pressure on the eye with a blunt end of a syringe without a needle.

The treatment studies (RESCUE and REVERSE) consist of 12 visits over 96 weeks (about 2 years). Enrollment has been completed.
The Long-term Follow-up study will allow these subjects to be followed for an additional 3 years if they choose to participate. Only patients in either RESCUE or REVERSE may be enrolled.

Inclusion Criteria:
1. At least 15 years of age
2. Each eye must have the ability to at least see examiner’s fingers at any distance
3. Female subjects of child-bearing potential must agree to use effective methods of birth control up to 6 months after study treatment; Male subjects must agree to use condoms for up to 6 months after study treatment
4. Female subjects of child-bearing potential must have a negative pregnancy test
5. Negative test for HIV
6. Ability to have eyes dilated

RESCUE subjects must have vision loss in one or both eyes for 6 months or less due to Leber Hereditary Optic Neuropathy (LHON)

REVERSE subjects must have vision loss due to Leber Hereditary Optic Neuropathy for more than 6 months

Exclusion Criteria:
1. Known allergy to study drug
2. Unable to have intravitreal (eye) injection
3. Intravitreal injection in either eye 30 days prior to screening visit
4. Previous vitrectomy in either eye
5. Visual disorders other than LHON
6. Known gene disorders involving retina or optic nerve conditions
7. Amblyopia worse than 20/80
8. Uncontrolled glaucoma
9. Ocular inflammation or history of idiopathic or autoimmune-associated uveitis
10. Receipt of any study drug within 90 days of screening visit
11. Previous treatment with ocular gene therapy
12. Ocular surgery of clinical relevance within 90 days of screening
13. Females who are or intend to breast feed during the trial period
14. Subjects taking idebenone who have not discontinued within 7 days prior to Visit 2
15. Infectious conjunctivitis, keratitis, scleritis, or endophthalmitis in either eye
16. Systemic illness, including alcohol and drug abuse (except nicotine), or medically significant abnormal lab values which are deemed by Investigator to preclude the subject’s safe participation in the study
17. Presence of disease or treatment that may alter visual function
18. Any medical or psychological condition that may compromise safe participation

Contact Name: Lindy DuBois
Phone Number: (404) 778-4443; ldubois@emory.edu
Posted: 07-02-2018

 

REFLECT: 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
PI: Nancy Newman, MD
Coordinator: Debbie Gibbs, Lindy DuBois
Status: active July 2018

General Summary:
The disorder is the same as is described for RESCUE and REVERSE.

Clinical Summary:
The purpose of this study is to evaluate the safety of the GS010 treatment and see if it is able to improve vision or prevent further vision loss caused by LHON from the ND4 gene mutation. This will be done by various tests and assessments of your eyes and vision, which will be described in more detail later. The investigational (study) drug that you will receive in this study is currently referred to as GS010. Investigational means that the drug has not been approved for marketing by any regulatory agencies, such as the FDA, anywhere in the world. GenSight Biologics distributes the medication and is funding the study by providing the medicine, paying for the treatment and all the testing procedures during all the visits.

The study is designed so that all subjects receive the experimental drug in at least one eye. This study is a (1) placebo-controlled, (2) double-masked study. This means that:

(1) Subjects may receive placebo injection in one eye. This will be randomly determined and you will not be made aware if you are receiving placebo or not. The placebo is a sterile solution without therapeutic action prepared for injection into the eye.

Inclusion Criteria:
Both men and women, aged at least 15 years, may participate in this study. At least one of your eyes must have visual acuity loss and the loss of your vision must have started less than 1 year ago. Additionally, your doctor will assess your other medical history to establish if there are any reasons that you may not be advised, or allowed, to participate. It is crucial that you tell your doctor all your past and present medical history. You must also be willing to undergo the intravitreal injection preparation and procedure in both eyes, as described below. In addition, you will need to have an HIV test and if you are female of childbearing potential, a blood sample will be collected for a pregnancy test. Female subjects (of childbearing potential) must agree to use effective methods of birth control for up to 6 months after Treatment Visit(s) 3 and male subjects must agree to use condoms for up to 6 months after Treatment Visit(s) 3. There may be other reasons you may not participate in the study.

Exclusion Criteria:
1. 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.
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, Visit 2 may be delayed until the 7-day period is complete as long as the study visit windows are adhered to.
3. Presence of active infectious conjunctivitis, keratitis, scleritis or endophthalmitis in either eye.
4. Presence of alcoholism, alcohol dependence, or alcohol or drug abuse (excluding nicotine).
5. Presence of systemic illness or medically significant abnormal laboratory values that are deemed by the Investigator to preclude the subject’s safe participation in the study.
6. Any medical or psychological condition that, in the opinion of the Investigator, may lead to non-tolerance of the treatment regimen, may compromise the safe participation of the subject in the study or would preclude comp

Contact Name: Debbie Gibbs; (404) 778-5815; dgibbs@emory.edu
Posted: 06-14-2018

 

External Natural History Controlled, Open-Label Intervention Study to Assess the Efficacy and Safety of Long-Term Treatment with Idebenone (Raxone®) in Leber’s Hereditary Optic Neuropathy (LHON) (LEROS)
PI: Nancy Newman, MD
Coordinator: Deborah Gibbs, COMT, CCRC, CCRP
Status: Recruiting

General Summary:
The study will be an open-label interventional study requiring 125 patients enrolled ≤1 year after the onset of symptoms to complete the 12 month treatment period (for evaluation of the primary endpoint), and 125 patients enrolled >1 year after the onset of symptoms to complete the 12 month treatment period (for evaluation of the secondary endpoints in these patients).

This multinational study is conducted with one protocol for sites under the IND (U.S. sites) in compliance with the IND requirements contained in 21 CFR 312, and a different version of the protocol for foreign sites not under the IND. As the intent is to pool the data from U.S. and foreign sites, it is ensured, as required, that the protocol versions are very similar or identical.

Patient eligibility for enrollment will be determined during the Baseline (Visit 1). Beginning at Baseline (Visit 1), the patient will receive study medication to take at home and will undergo regular assessments in the clinic throughout the study period until Visit 8 (Month 24) at which time the study medication is withdrawn. For all patients, there will be a final follow-up 28-35 days after study medication withdrawal. Patients enrolled in the study will commence study medication intake on the first day after the Baseline visit.

Clinical Summary:
Patients will be enrolled to receive 900 mg idebenone (2 tablets 3 times daily with meals) for 24 months. Starting with Baseline/Visit 1 sufficient study medication will be dispensed to last until the next visit. The patient will take the first dose of study medication on Day 1, the day of the Baseline Visit (or as instructed by the site investigator / study nurse).

The duration of study participation for each individual patient will be approximately 25 months and comprise 9 study visits (V1-V9). Before any study-specific procedures are undertaken, the patient (and parent/legal guardian if required) will have been thoroughly informed by the investigator of the purpose of the study, the relevant procedures and of patient rights and responsibilities. Patient information will be distributed in writing and signatures of consent obtained on the consent form. (See also Section 10.3).

Patient enrolled in the study will receive study medication at Baseline/Visit 1; the first study medication intake is on the day of the Baseline/Visit 1 (or as instructed by the site investigator / study nurse). During the 24 month treatment period, visits take place at Month 1, Month 3, Month 6, Month 9, Month 12, Month 18 and Month 24. Visit 8 (Month 24) is the endpoint of treatment. Visit 9 is a follow-up, 28-35 days after study medication discontinuation. Physical examination and measurement of vital signs will be undertaken at Baseline/Visit 1 and then at Visit 4/Month 6, Visit 6/Month 12, Visit 7/Month 18 and Visit 8/Month 24. Safety blood and urine and safety assessments will be done at each visit.

A urine or serum pregnancy test will be performed for WCBP when clinically indicated. Assessment of VA (assessed by ETDRS charts and reported in logMAR value) will be done at every visit.

During the Baseline visit the diagnosis of LHON will be confirmed and other eye diseases excluded. This will require fundus exam with dilated pupils to be performed at the Baseline visit and every 12 months thereafter. Blood sample will be taken for the genetic analysis, if the genetic diagnosis of the patient is not confirmed at the Baseline visit. The report from the genetic analysis should be on file prior to Visit 4.
Should the genetic diagnosis reveal that a patient does not harbour a LHON-specific mtDNA mutation, the patient will be withdrawn from the study.

It should be noted however that the VA outcomes for patients carrying one of the three major LHON-specific mtDNA mutations (G3460A, G11778A or T14484A) will be used in the primary analyses.

Inclusion Criteria:
The following criteria should be assessed during Baseline Visit. If any does not apply, the patient must not be included in the study:
1. Impaired visual acuity in affected eyes due to LHON
2. No explanation for visual loss besides LHON
3. Age ≥ 12 years
4. Onset of symptoms ≤5 years prior to Baseline
5. Confirmation of either G11778A, G3460A or T14484C LHON mtDNA (for the ITT population, not required for enrolment)
6. Written informed consent obtained from the patient
7. Ability and willingness to comply with study procedures and visits
8. Women of Childbearing Potential (WCBP) who have a negative urine or serum pregnancy test at Baseline visit and who are willing to use a highly effective contraceptive measure and maintain it until treatment discontinuation.

Exclusion Criteria:
The following criteria should be checked during Baseline Visit. If any applies, the patient must not be included in the study:
1. Patient has provided natural history data to the Case Record Survey (SNT-CRS-002)
2. Any previous use of idebenone
3. Any other cause of visual impairment (e.g. glaucoma, diabetic retinopathy, AIDS related visual impairment, cataract, macular degeneration, etc.) or any active ocular disorder (uveitis, infections, inflammatory retinal disease, thyroid eye disease, etc.)
4. Known history of clinically significant elevations (greater than 3 times the upper limit of normal) of AST, ALT or creatinine
5. Patient has a condition or is in a situation which, in an investigator’s opinion may put the patient at significant risk, may confound study results or may interfere significantly with the patient’s participation in the study
6. Participation in another clinical trial of any investigational drug within 3 months prior to Baseline
7. Hypersensitivity to the active substance or to any of the following excipients: Lactose monohydrate, Microcrystalline cellulose, Croscarmellose sodium, Povidone K25, Magnesium stearate, Colloidal silica, Macrogol 3350, Poly(vinyl alcohol), Talc, Titanium dioxide, Sunset yellow FCF (E110).
8. Women who are pregnant or have a positive pregnancy test at Baseline visit
9. Women who are breastfeeding

Contact: Deborah Gibbs; (404) 778-5815; dgibbs@emory.edu
Posted: 01-24-2018

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