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Study of RS1 Ocular Gene Transfer for X-linked Retinoschisis

Descriptive Information
Brief Title † Study of RS1 Ocular Gene Transfer for X-linked Retinoschisis
Official Title † A Phase I/IIa Study of RS1 Ocular Gene Transfer for X-linked Retinoschisis
Brief Summary Background: - X-linked juvenile retinoschisis (XLRS) is caused by changes in the RS1 gene. These changes cause abnormal function of the eye protein retinoschisin. Without normal retinoschisin, the layers of the retina split and vision is lost. Researchers want to try to introduce a healthy RS1 gene into eye cells, to see if this helps retinal cells make healthy retinoschisin. They will put the gene in a virus. The gene and virus package is known as a gene transfer vector (AAV-RS1 vector). Objectives: - To see if the AAV-RS1 vector is safe to use in people. Eligibility: - Adults 18 and older with a mutation of the RS1 gene, 20/63 vision or worse in one eye, and XLRS. Design: - Participants will be screened with genetic tests to confirm XLRS. They will have a medical history and physical and eye exams. - At visits 1-2, participants will have some or all of the following: - Medical history - Physical exam - Blood and urine tests - Tuberculosis skin test - Eye exam - Vision tests (for one test an intravenous line will be placed in the arm. A dye will be injected that will travel to the blood vessels in the eye). - At visit 3, the AAV-RS1 vector will be injected with a needle in the study eye. Participants pupils will be dilated. They will get numbing eye drops. - Visits 4-13 will occur in the 18 months after gene transfer. Many of the above tests will be repeated. Participants will discuss any side effects. - Visits 14-17 will occur yearly between years 2 and 5. - After year 5, participants will be contacted yearly by phone for up to 15 years.
Detailed Description Objective: To evaluate the safety and tolerability of ocular AAV-RS1 vector (AAV8-scRS/IRBPhRS) gene transfer to the retina of participants affected with X-linked juvenile retinoschisis (XLRS). Study Population: Male participants affected with XLRS will receive ocular gene transfer. A maximum of up to 24 participants may be enrolled. Design: This is a Phase I/IIa, prospective, dose escalation, single-center study. One eye of each participant will receive the AAV-RS1 gene vector application by intravitreal injection. Participants will be closely monitored in conjunction with DSMC oversight. Participants will be followed for 18 months after which they will continue to be followed for up to 15 years after enrollment, or per FDA requirements, for further safety analysis. Outcome Measures: The primary outcome is the safety of ocular AAV-RS1 vector as determined from assessment of retinal function, ocular structure and occurrence of adverse events and laboratory tests. Secondary outcomes include changes in visual function, electroretinogram (ERG) responses, visual field measurements, retinal imaging with optical coherence tomography (OCT), and the formation of anti-AAV and anti-RS1 antibodies. Statistics: No formal sample size calculations are used in this Phase I/IIa dose-escalation study.
Study Phase Phase 1/Phase 2
Study Type † Interventional
Study Design †
Primary Outcome Measure † Retinal function
Secondary Outcome Measure † ERG
Condition † Gene Transfer
Intervention † BiologicalRS1 AAV Vector
Study Arms / Comparison Groups Group 1 Low Group 2 Medium Group 3 High
Publications *

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information
Recruitment Status † Biological
Estimated Enrollment † 24
Start Date † December 3, 2014
Completion Date December 31, 2017
Primary Completion Date December 31, 2017
Eligibility Criteria † - INCLUSION CRITERIA: - Participant is male with a mutation in the RS1 gene identified by genotyping. - Participant must be 18 years of age or older. - Participant must be able to understand and sign the informed consent. - Participant must be medically able to comply with the study treatment, study testing and procedures and follow-up visits. - Participant has at least one eye that meets the study eye criteria listed below. - Participant must agree not to receive live (attenuated) vaccines prior to dosing and for some duration following dosing. - Participant must agree to use effective barrier (male or female condom) of contraception before dosing and continuing one year after gene transfer. - If the participant's partner is able to become pregnant, a second form of effective contraception will be required before dosing and continuing one year after gene transfer. Effective methods of contraception for this study include: - hormonal contraception (birth control pills, injected hormones or vaginal ring), - intrauterine device, - barrier methods (condom or diaphragm) combined with spermicide, - surgical sterilization (hysterectomy or tubal ligation in partner or vasectomy). - Participant agrees to use appropriate sun protection when on immunomodulatory agents. EXCLUSION CRITERIA: - Participant is actively receiving another study medication/investigational product (IP). - Participant has previously enrolled in another gene therapy trial. - Participant is currently taking, or has taken in the last three months, a systemic carbonic anhydrase inhibitor prior to enrollment/baseline 1 testing. - Participant has any condition that significantly increases risk of systemic corticosteroids or systemic steroid-sparing immuno-modulatory agents, such as HIV, syphilis, tuberculosis, hepatitis B, hepatitis C, or diabetes mellitus (DM). - Participant has an underlying serious illness that impairs regular follow-up during the study. - Participant has had diagnosis or treatment of a malignancy (excluding non-melanoma skin cancer) within the previous five years. - Participant has pre-existing ocular tumors (excluding non-suspicious nevi). - Participant has a known allergy to fluorescein dye or other contraindications to obtaining a fluorescein angiogram. - Participant is on a medication that prevents safe administration of study related drugs. - Participant has uncontrolled hypertension. (Hypertension judged to be adequately controlled at baseline medical evaluation is not exclusionary.) - Participant has compromised renal function such that cyclosporine or cellcept would be contraindicated. - Participant has significant liver disease with elevated liver enzymes (greater than or equal to 2.5 times ULN). - Participant has low absolute neutrophil count (ANC
Gender All
Ages 18 Years - N/A
Accepts Healthy Volunteers No
Contacts †† Amy E Turriff, (301) 402-4175, turriffa@mail.nih.gov
Location Countries † United States
Administrative Information
NCT ID † NCT02317887
Organization ID 150038
Secondary IDs †† 15-EI-0038
Responsible Party Sponsor
Study Sponsor † National Eye Institute (NEI)
Collaborators ††
Investigators † Principal Investigator: Paul A Sieving, M.D., National Eye Institute (NEI)
Information Provided By
Verification Date April 7, 2017
First Received Date † December 16, 2014
Last Updated Date May 31, 2017
† Required WHO trial registration data element.
†† WHO trial registration data element that is required only if it exists.
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