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Safety and Efficacy of rAAV2tYF-GRK1-RPGR in Subjects With X-linked Retinitis Pigmentosa Caused by RPGR Mutations

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ClinicalTrials.gov Identifier: NCT03316560
Recruitment Status : Recruiting
First Posted : October 20, 2017
Last Update Posted : March 12, 2021
Sponsor:
Information provided by (Responsible Party):
Applied Genetic Technologies Corp

Tracking Information
First Submitted Date  ICMJE October 10, 2017
First Posted Date  ICMJE October 20, 2017
Last Update Posted Date March 12, 2021
Actual Study Start Date  ICMJE April 16, 2018
Estimated Primary Completion Date August 2022   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: January 27, 2021)
  • Phase 1/2 Dose Escalation: Number and proportion of Adverse Events [ Time Frame: Day 0 - Month 36 ]
  • Phase 1/2 Dose Escalation: Number and proportion of participants experiencing abnormal clinically relevant hematology or clinical chemistry parameters. [ Time Frame: Day 0 - Month 36 ]
  • Phase 2 Dose Expansion: The difference in the proportion of responding eyes between treated and control eyes in low dose group and high dose group. [ Time Frame: Day 0 - Month 12 ]
Original Primary Outcome Measures  ICMJE
 (submitted: October 17, 2017)
  • Number of participants experiencing adverse events [ Time Frame: Day 0 - Month 36 ]
  • Number of participants experiencing abnormal clinically relevant hematology/clinical chemistry parameters [ Time Frame: Day 0 - Month 36 ]
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: January 27, 2021)
  • Phase 1/2 Dose Escalation: Changes from baseline in visual function as measured by mesopic microperimetry in the treated eye compared to the untreated eye [ Time Frame: Day 0 - Month 36 ]
  • Phase 1/2 Dose Escalation: Changes from baseline in visual acuity [ Time Frame: Day 0 - Month 36 ]
  • Phase 1/2 Dose Escalation: Changes from baseline in retinal structure as assessed by spectral-domain optical coherence tomography (SD-OCT) [ Time Frame: Day 0 - Month 36 ]
  • Phase 1/2 Dose Escalation: Changes from baseline in quality of life questionnaire responses [ Time Frame: Day 0 - Month 36 ]
  • Phase 2 Dose Expansion: Proportion of responding eyes in treated eyes versus control eyes in the low dose and high dose group measured by mobility test [ Time Frame: Day 0 - Month 12 ]
  • Phase 2 Dose Expansion: Proportion of responding eyes in treated eyes versus control eyes in the low dose and high dose group measured by visual function [ Time Frame: Day 0 - Month 12 ]
  • Phase 2 Dose Expansion: Difference in mean change from baseline in Visual Acuity in treated eyes versus control eyes in the low dose and high dose groups [ Time Frame: Day 0 - Month 12 ]
  • Phase 2 Dose Expansion: Difference in mean change from baseline in the EZ area, as measured by SD-OCT, in treated eyes versus control eyes in the low dose group and high dose group [ Time Frame: Day 0 - Month 12 ]
  • Phase 2 Dose Expansion: Changes from baseline in quality of life questionnaire responses [ Time Frame: Day 0 - Month 12 ]
Original Secondary Outcome Measures  ICMJE
 (submitted: October 17, 2017)
  • Changes from baseline in visual function by perimetry [ Time Frame: Day 0 - Month 36 ]
  • Changes from baseline in visual acuity by ETDRS [ Time Frame: Day 0 - Month 36 ]
  • Changes from baseline in retinal structure by OCT [ Time Frame: Day 0 - Month 36 ]
  • Changes from baseline in VFQ-25 quality of life questionnaire [ Time Frame: Day 0 - Month 36 ]
Current Other Pre-specified Outcome Measures
 (submitted: January 27, 2021)
  • Phase 1/2 Dose Escalation: Changes in antibody and T-cell responses to AAV and RPGR as measured quantitatively and by frequency of positive responses [ Time Frame: Day 0 - Month 36 ]
  • Phase 1/2 Dose Escalation: Presence of vector DNA and blood by qPCR assay [ Time Frame: Day 0 - Month 36 ]
  • Phase 2 Dose Expansion: Overall safety evaluation [ Time Frame: Day 0 - Month 12 ]
    The safety evaluation will be based on ophthalmic examinations, AE reporting, laboratory assessments, and physical examinations, as well as any safety information collected as a result of the efficacy assessments, as appropriate.
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Safety and Efficacy of rAAV2tYF-GRK1-RPGR in Subjects With X-linked Retinitis Pigmentosa Caused by RPGR Mutations
Official Title  ICMJE An Open-Label Dose Escalation Study to Evaluate the Safety and Efficacy of AGTC-501 (rAAV2tYF-GRK1-RPGR) in Subjects With X-linked Retinitis Pigmentosa Caused by RPGR Mutations
Brief Summary This study will evaluate the safety and efficacy of a recombinant adeno-associated virus vector (rAAV2tYF-GRK1-RPGR) in patients with X-linked retinitis pigmentosa caused by RPGR mutations. Approximately 42 participants will be enrolled in 2 study phases, 30 participants in the phase 1/2 dose escalation portion of the study, and 12 participants in the phase 2 dose expansion portion.
Detailed Description

This study includes a non-randomized, open-label, Phase 1/2 dose escalation portion, and a Phase 2 randomized, controlled, masked dose expansion portion.

Approximately 30 participants will be enrolled into the dose escalation portion of the study. Each participant will receive the study agent by subretinal injection in one eye on a single occasion. Enrollment will begin with the lowest dose and will proceed to higher doses only after review of safety data by a Data and Safety Monitoring Committee (DSMC). Within groups 1 through 3 and 5 and 6, enrollment of participants will be staggered by at least 2 weeks to allow adequate time for review of safety information by the investigators and sponsor. Within Group 4, enrollment of the first 3 pediatric participants will be staggered by at least 2 weeks to allow adequate time for review of safety information by the investigators and sponsor. Study agent administration will occur on Day 0. There are a total of 15 visits over approximately 36 months, and long-term follow-up evaluations annually at years 4 and 5.

After the phase 1/2 portion of the study is completed, approximately 12 participants, who were not part of the Phase 1/2 portion of the study, will be enrolled into the dose expansion portion of the study. These participants will be randomized in a 1:1 ratio to 1 of 2 treatment groups (i.e., Group 1 [low dose, 300 μL containing 1.2 x 1011 vg/mL] and Group 2 [high dose, 300 μL containing 1.1 x 1012 vg/mL]). Each participant will receive the assigned dose of AGTC-501 in one eye on a single occasion. Randomization to dose groups will be stratified by age (8-17 years, 18-50 years). To minimize bias in the assessment and reporting of outcomes, both the investigators and the study subjects will be masked to the dose of AGTC-501 received. Study agent administration will occur on Day 0. There are a total of 15 visits over approximately 24 months, and long-term follow-up evaluations annually at years 3, 4 and 5.

Safety will be measured by the number and proportion of participants experiencing ocular and non-ocular adverse events and abnormal clinically relevant hematology and clinical chemistry parameters. Efficacy will be measured by evaluation of changes in visual structure, function, and quality of life.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Single Group Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Condition  ICMJE X-Linked Retinitis Pigmentosa
Intervention  ICMJE Biological: rAAV2tYF-GRK1-RPGR
Adeno-associated virus vector expressing a human RPGR gene
Study Arms  ICMJE
  • Experimental: Group 1: Phase 1/2 Dose Escalation
    Male subjects at least 18 y/o treated with Dose 1 of rAAV2tYF-GRK1-RPGR study drug.
    Intervention: Biological: rAAV2tYF-GRK1-RPGR
  • Experimental: Group 2: Phase 1/2 Dose Escalation and Low Dose Group Phase 2 Dose Expansion

    Phase 1/2 Dose Escalation: male subjects at least 18 y/o treated with Dose 2 of rAAV2tYF-GRK1-RPGR study drug.

    Phase 2 Dose Expansion: male subjects at least 8 y/o treated with Dose 2 of rAAV2tYF-GRK1-RPGR study drug. This will be the low dose group for the phase 2 expansion.

    Intervention: Biological: rAAV2tYF-GRK1-RPGR
  • Experimental: Group 3 and Group 4 Phase 1/2 Dose Escalation
    Group 3 male subjects at least 18 y/o and Group 4 male subjects at least 6 y/o treated with Dose 3 of rAAV2tYF-GRK1-RPGR study drug.
    Intervention: Biological: rAAV2tYF-GRK1-RPGR
  • Experimental: Group 5 Phase 1/2 Dose Escalation and High Dose Group Phase 2 Dose Expansion

    Phase 1/2 Dose Escalation: male subjects at least 18 y/o treated with Dose 5 of rAAV2tYF-GRK1-RPGR study drug.

    Phase 2 Dose Expansion: male subjects at least 8 y/o treated with Dose 5 of rAAV2tYF-GRK1-RPGR study drug. This will be the high dose group for the phase 2 expansion.

    Intervention: Biological: rAAV2tYF-GRK1-RPGR
  • Experimental: Group 6 Phase 1/2 Dose Escalation
    Male subjects at least 18 y/o treated with Dose 6 of rAAV2tYF-GRK1-RPGR study drug.
    Intervention: Biological: rAAV2tYF-GRK1-RPGR
Publications * Not Provided

*   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: January 27, 2021)
42
Original Estimated Enrollment  ICMJE
 (submitted: October 17, 2017)
15
Estimated Study Completion Date  ICMJE August 2026
Estimated Primary Completion Date August 2022   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Phase 1/2 Dose Escalation Inclusion Criteria:

  • Male subjects with a documented RPGR mutation within exons 1-14 and/or ORF15 from a Clinical Laboratory Improvement Amendments (CLIA)-certified laboratory;
  • Clinical diagnosis of X-linked retinitis pigmentosa (XLRP);
  • Best-corrected visual acuity not better than 78 ETDRS letters (20/32) in the study eye;
  • Ability to perform tests of visual and retinal function and structure and ability to comply with other research procedures;
  • Detectable baseline mean macular sensitivity between 1-2 dB in both eyes, as measured by Microperimetry;
  • Good general health based on a complete physical examination and hematology and clinical chemistry studies performed at a pre-treatment evaluation;
  • At least 18 years of age for Groups 1-3, 5 and 6 and at least 6 years of age for Groups 4 and 7;
  • Has a parent or caregiver able to follow study instructions, comply with the protocol and attend study visits with the subject as required;
  • Signed informed consent and assent (if necessary) obtained before screening.
  • Have detectable Ellipsoid Zone (EZ) line during the pre-treatment period as assessed by OCT and confirmed by the CRC

Phase 1/2 Dose Escalation Exclusion Criteria:

  • Pre-existing eye conditions that would preclude the planned surgery or interfere with the interpretation of study endpoints or increase the risk of surgical complications (for example, glaucoma, corneal or lenticular opacities, diabetic retinopathy, retinal vasculitis);
  • Complicating systemic diseases (such as medical conditions causing immunosuppression or known sensitivity or allergy to medications planned for use in the peri-operative period) that would preclude the gene transfer or ocular surgery;
  • Use of anti-coagulant agents that may alter coagulation within 7 days prior to study agent administration;
  • Use of systemic corticosteroids or other immunosuppressive medications within 3 months prior to enrollment;
  • Subjects who are unwilling to use barrier contraception for 3 months following agent administration;
  • Any other condition that would prevent a subject from completing follow-up examinations during the course of the study;
  • Any other condition or reason that, in the opinion of the investigator, makes the subject unsuitable for the study;
  • Current, or recent (the longer of 90 days or 10 half-lives of the drug) participation, in any other research protocol involving investigational agents or therapies;
  • Previous receipt of any AAV gene therapy product;
  • Study personnel or family members of the study personnel;
  • Monocular or having BCVA less than 20/800 in the fellow eye.

Phase 2 Dose Expansion Inclusion Criteria:

  • Provide written informed consent or assent (per local regulation), prior to the conduct of any study-related procedure. Subjects who provide assent must have a parent, guardian, or legal representative provide written informed consent.
  • Be between 8 and 50 years of age (inclusive) at the time of informed consent and assent (as applicable).
  • Be male and have at least one documented pathogenic or likely pathogenic variant in the RPGR gene within exons 1-14 and/or ORF15 from Molecular Vision Laboratory (MVL), a CLIA-certified laboratory.
  • Have a clinical diagnosis of XLRP.
  • Be in good general health to withstand subretinal surgery and perioperative medications based on a complete physical examination and hematology and clinical chemistry evaluations performed at screening.
  • Be able and willing, as assessed by the investigator, to follow study instructions, complete study assessments, comply with the protocol, and attend study visits for the duration of the study.
  • If the subject has a parent or caregiver, the parent or caregiver must be able to follow study instructions, comply with the protocol, and attend study visits with the subject, as required.
  • Both eyes: Have a BCVA no better than 75 letters (20/32) and no worse than 35 letters (20/200) in both eyes based on an ETDRS chart at each screening visit. Pediatric subjects unable to read the ETDRS letters may utilize a tumbling "E" chart for BCVA assessments.
  • Both eyes: Be able to perform all tests of visual and retinal function and structure based on the subject's reliability, and fixation, per the investigator's discretion.
  • Both eyes: Have detectable baseline mean macular sensitivity measured by (MAIA) microperimetry, between 1-12 dB, as determined by the investigator and confirmed by the Central Reading Center (CRC), at each screening visit.
  • Both eyes: Have detectable EZ line as assessed by SD-OCT and confirmed by the CRC.

Phase 2 Dose Expansion Exclusion Criteria

  • Have other known disease-causing mutations documented in the subject's medical history or identified through a retinal dystrophy gene panel, that in the opinion of the investigator would interfere with the potential therapeutic effect of the study agent or the quality of the assessments.
  • For subjects with herpes simplex virus (HSV):

    1. Have history of oral or genital herpes and unable and/or unwilling to utilize prophylactic antiviral medication.
    2. Have a history of ocular herpes.
    3. Have active oral or genital herpes, or are currently receiving treatment for HSV infection.
  • Have complicating systemic diseases (e.g., medical conditions causing immunosuppression, active systemic infection) that would preclude the gene transfer or ocular surgery.
  • Have known sensitivity or allergy to systemic corticosteroids or other immunosuppressive medications.
  • Have used anti-coagulant agents that may alter coagulation (e.g., warfarin, heparin, apixaban, or high dose DHA [fish oil]) within 7 days prior to study treatment administration (ibuprofen, aspirin, or similar are acceptable).
  • Have received any vaccination/immunization within 28 days prior to screening and/or during screening with the exception of the influenza vaccine. Subjects should be excluded if they have received the influenza vaccine within 28 days prior to randomization.
  • Have used systemic corticosteroids or other immunosuppressive medications within 3 months prior to screening and/or intend to use during screening.
  • If sexually active or planning to become sexually active, are unwilling to use barrier contraception for 3 months following treatment administration.
  • Have any other condition or reason that, in the opinion of both the Medical Monitor and the investigator, would prevent a subject from completing study assessments during the course of the study.
  • Have any other condition or reason that, in the opinion of both the Medical Monitor and the investigator, makes the subject unsuitable for the study.
  • Are currently participating or recently participated in any other research protocol involving investigational agents or therapies, in the opinion of both the Medical Monitor and the investigator, would make the subject unsuitable for the study. Recent participation is defined as participation within 90 days of initial screening for this study OR within 10 half-lives of the investigational drug, whichever is longer.
  • Have previously received any AAV gene therapy product, stem cell therapy, cell-based therapy, or similar biologics.
  • Either Eye: Have pre-existing eye conditions that would preclude the planned surgery, interfere with the interpretation of study endpoints, or increase the risk of surgical complications (e.g., corneal opacities, diabetic retinopathy, retinal vasculitis, glaucoma).
  • Either Eye: Have significant media opacity impacting evaluation of the retina or vitreous. This includes cataracts considered to be a major contributor to reducing visual acuity and/or if the subject is likely to require cataract extraction within 3 months of study treatment administration.
  • Either Eye: Had intraocular surgery within 90 days of study treatment administration.
  • Either Eye: Have any active ocular/intraocular infection or inflammation (e.g., severe blepharitis, infectious conjunctivitis, keratitis, scleritis, endophthalmitis, idiopathic or autoimmuneassociated uveitis, or herpetic lesions).
  • Either Eye: Have a history of steroid-induced raised IOP of >25 mmHg following corticosteroid exposure, despite topical IOP-lowering pharmacologic therapy.
  • Either Eye: Have any artificial retinal implant or prosthesis.
  • Either Eye: Have highly variable baseline mean macular sensitivity of >2 dB between any of the 3 microperimetry assessments performed during screening.
  • Either Eye: Have absence of clear ocular media and/or inadequate pupil dilation to facilitate good quality OCT images.
  • Either Eye: Have any history of rhegmatogenous retinal detachment.
  • Either Eye: Have spherical equivalent > -10 diopters (D) of myopia, or absolute axial length beyond 30 mm at the investigator's or surgeon's discretion.
Sex/Gender  ICMJE
Sexes Eligible for Study: Male
Gender Based Eligibility: Yes
Ages  ICMJE 6 Years to 50 Years   (Child, Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Jill Dolgin, PharmD 833-770-2862 advocacy@agtc.com
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03316560
Other Study ID Numbers  ICMJE AGTC-RPGR-001
Has Data Monitoring Committee Yes
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
Plan to Share IPD: No
Responsible Party Applied Genetic Technologies Corp
Study Sponsor  ICMJE Applied Genetic Technologies Corp
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: Matthew Feinsod, MD Applied Genetics Technologies Corporation
PRS Account Applied Genetic Technologies Corp
Verification Date March 2021

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