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Study of RS1 Ocular Gene Transfer for X-linked Retinoschisis

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ClinicalTrials.gov Identifier: NCT02317887
Recruitment Status : Recruiting
First Posted : December 17, 2014
Last Update Posted : September 19, 2019
Sponsor:
Information provided by (Responsible Party):
National Institutes of Health Clinical Center (CC) ( National Eye Institute (NEI) )

Tracking Information
First Submitted Date  ICMJE December 16, 2014
First Posted Date  ICMJE December 17, 2014
Last Update Posted Date September 19, 2019
Actual Study Start Date  ICMJE February 11, 2015
Estimated Primary Completion Date July 31, 2023   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: September 18, 2019)
  • Retinal function [ Time Frame: Day 1, Day 7, Day 14, Month 1, Month 2, Month 3, Month 4, Month 6, Month 9, Month12, Month 18, Year 2, Year 3, Year 4, Year 5 ]
    maintenance of retinal function
  • Ocular structure [ Time Frame: Day 1, Day 7, Day 14, Month 1, Month 2, Month 3, Month 4, Month 6, Month 9, Month12, Month 18, Year 2, Year 3, Year 4, Year 5 ]
    maintenance of ocular structure
  • Occurence of AEs [ Time Frame: Day 1, Day 7, Day 14, Month 1, Month 2, Month 3, Month 4,Month 6, Month 9, Month 12, Month 18, Year 2, Year 3, Year 4, Year 5 ]
    number and severity of adverse events that differ clinically from the normal progression of XLRS
Original Primary Outcome Measures  ICMJE
 (submitted: December 16, 2014)
  • Retinal function [ Time Frame: Multiple ]
  • Ocular structure [ Time Frame: Multiple ]
  • Occurence of AEs [ Time Frame: Multiple ]
Change History Complete list of historical versions of study NCT02317887 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: September 18, 2019)
  • ERG [ Time Frame: Months 1, 3, 6, 12, 18, and annually at years 2-5 ]
    Change in ERG combined response amplitudes from average of baseline 1 and 2
  • OCT imaging [ Time Frame: Months 1, 2, 3, 4, 6, 9, 18 and annually at years 2-5 ]
    Change in retinal structure compared to average of baseline 1 and 2
  • Anti-AAV antibodies [ Time Frame: Day 7, Day 14, Months 1, 2, 3, 6, 9, 12, 18 and annually at years 2-5 ]
    formation of circulating systemic anti-AAV or anti-RS1 antibodies
  • Visual function [ Time Frame: Days 1, 7, 14, Months 1, 2, 3, 4, 6, 9, 12, 18 and annually at years 2-5 ]
    Mean median and distribution of change in BCVA compared to average of baseline 1 and 2
Original Secondary Outcome Measures  ICMJE
 (submitted: December 16, 2014)
  • ERG [ Time Frame: Multiple ]
  • OCT imaging [ Time Frame: Multiple ]
  • Anti-AAV antibodies [ Time Frame: Multiple ]
  • Visual function [ Time Frame: Multiple ]
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Study of RS1 Ocular Gene Transfer for X-linked Retinoschisis
Official Title  ICMJE 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 Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Phase 2
Study Design  ICMJE Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Retinoschisis
  • X-Linked
Intervention  ICMJE Biological: RS1 AAV Vector
Gene transfer by intravitreal injection of the RS1 AAV vector (AAV8-scRS/IRBPhRS)
Study Arms  ICMJE
  • Experimental: Group 1
    1e9 vg/eye
    Intervention: Biological: RS1 AAV Vector
  • Experimental: Group 2
    1e10 vg/eye
    Intervention: Biological: RS1 AAV Vector
  • Experimental: Group 3
    1e11 vg/eye
    Intervention: Biological: RS1 AAV Vector
  • Experimental: Group 4
    1e11 vg/eye
    Intervention: Biological: RS1 AAV Vector
  • Experimental: Group 5
    Not to exceed 3e11 vg/eye
    Intervention: Biological: RS1 AAV Vector
  • Experimental: Group 6
    Not to exceed 6e11 vg/eye
    Intervention: Biological: RS1 AAV Vector
Publications * Cukras C, Wiley HE, Jeffrey BG, Sen HN, Turriff A, Zeng Y, Vijayasarathy C, Marangoni D, Ziccardi L, Kjellstrom S, Park TK, Hiriyanna S, Wright JF, Colosi P, Wu Z, Bush RA, Wei LL, Sieving PA. Retinal AAV8-RS1 Gene Therapy for X-Linked Retinoschisis: Initial Findings from a Phase I/IIa Trial by Intravitreal Delivery. Mol Ther. 2018 Sep 5;26(9):2282-2294. doi: 10.1016/j.ymthe.2018.05.025. Epub 2018 Jul 7.

*   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 Recruiting
Estimated Enrollment  ICMJE
 (submitted: November 3, 2015)
24
Original Estimated Enrollment  ICMJE
 (submitted: December 16, 2014)
100
Estimated Study Completion Date  ICMJE July 31, 2023
Estimated Primary Completion Date July 31, 2023   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE
  • 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<1.3 x 10(3)/micro liters).
  • Participant has used any biologic immunosuppressive agents within the last three months (within the last six months for rituximab or cyclophosphamide).

STUDY EYE ELIGIBILITY CRITERIA:

The participant must have at least one eye meeting all inclusion criteria and none of the exclusion criteria listed below.

STUDY EYE INCLUSION CRITERIA:

  • The study eye must have a best-corrected E-ETDRS visual acuity letterscore of less than or equal to 63 (i.e., worse than or equal to 20/63). The visual acuity from the first baseline visit (Baseline 1) will be used for eligibility determination in case of a change in visual acuity at the second baseline visit (Baseline 2).
  • Electroretinogram in the study eye with a scotopic combined response demonstrating a subnormal b wave, consistent with retinoschisis.

STUDY EYE EXCLUSION CRITERIA:

  • The study eye has a history of other ocular disease likely to contribute significantly to visual loss or likely to present special risks (e.g., optic neuropathy, advanced glaucoma, uveitis, large bullous schisis cavities or bullous retinal detachment precluding safe intravitreal injection).
  • The study eye has lens, cornea, or other media opacities precluding adequate visualization and testing of the retina.
  • The study eye has undergone intraocular surgery within six months prior to enrollment.
  • The study eye is receiving topical carbonic anhydrase inhibitor, or has received topical carbonic anhydrase inhibitors in the past three months.

STUDY EYE SELECTION CRITERIA:

If both eyes of a participant meet the study eye eligibility criteria, the choice of study eye will be determined as follows:

  • The eye with the worse visual acuity will be selected as the study eye.
  • If both eyes have the same visual acuity, the choice of study eye will be determined at the discretion of the investigator in consultation with the participant.
Sex/Gender  ICMJE
Sexes Eligible for Study: Male
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Patti Sherry, C.R.N.O. (301) 435-4529 patti.sherry@nih.gov
Contact: Henry E Wiley, M.D. (301) 451-4260 wileyhe@mail.nih.gov
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02317887
Other Study ID Numbers  ICMJE 150038
15-EI-0038
Has Data Monitoring Committee Not Provided
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 National Institutes of Health Clinical Center (CC) ( National Eye Institute (NEI) )
Study Sponsor  ICMJE National Eye Institute (NEI)
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Henry E Wiley, M.D. National Eye Institute (NEI)
PRS Account National Institutes of Health Clinical Center (CC)
Verification Date September 16, 2019

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