Safety and Efficacy Study in Subjects With Leber Congenital Amaurosis

NCT00999609 | Active Not Recruiting Phase 3 Results DMC FDA Drug

• 1 other identifier: AAV2-hRPE65v2-301
• Study Type: interventional
• Target: 31
• Locations: 1 country
• Sites: 2

Brief Summary

The study is a Phase 3, open-label, randomized controlled trial of gene therapy intervention by subretinal administration of AAV2-hRPE65v2 (voretigene neparvovec-rzyl). At least twenty-four subjects, three years of age or older, will be recruited. The intervention group will receive AAV2-hRPE65v2 at either The Children's Hospital of Philadelphia or University of Iowa to determine if it improves visual and retinal function in individuals with RPE65 gene mutations.

Conditions

Inherited Retinal Dystrophy Due to RPE65 Mutations; Leber Congenital Amaurosis

Keywords

Adeno-associated virus; AAV; Leber congenital amaurosis; RPE65; Gene therapy; Gene transfer; voretigene neparvovec-rzyl; Retinitis pigmentosa

Outcome Measures

Primary Outcomes (1)

• Multi-luminance Mobility Testing (MLMT), Bilateral

  The MLMT measures changes in functional vision, as assessed by the ability to navigate a course accurately and at a reasonable pace at different levels of environmental illumination. MLMT was assessed using both eyes at 1 or more of 7 levels of illumination, ranging from 400 lux (a brightly lit office) to 1 lux (a moonless summer night). Each light level was assigned a score code ranging from 0 to 6. A higher score indicated that a subject was able to pass the MLMT at a lower light level. A score of -1 was assigned to those who could not pass MLMT at 400 lux. The MLMT of each subject was videotaped and assessed by independent graders. The MLMT score was determined by the lowest light level at which the subject was able to pass the MLMT. The MLMT score change was defined as the difference between the score at Baseline and the score at Year 1. A positive MLMT score change from Baseline to Year 1 visit indicated that the subject was able to complete the MLMT at a lower light level.

  One year (change from baseline)

Secondary Outcomes (3)

• Full-field Light Sensitivity Threshold (FST) Testing: White Light

  One year (change from baseline)

• Multi-luminance Mobility Testing (Monocular)

  One year (change from baseline)

• Visual Acuity

  One year (change from baseline)

Study Arms (2)

AAV2-hRPE65v2,voretigene neparvovec-rzyl

EXPERIMENTAL

voretigene neparvovec rzyl, 1.5 E11 vector genomes, per eye, administered by subretinal injection in a volume of 0.3mL, 6-18 days apart

Biological: AAV2-hRPE65v2,voretigene neparvovec-rzyl

Control

NO INTERVENTION

No intervention

Interventions

AAV2-hRPE65v2,voretigene neparvovec-rzyl BIOLOGICAL

Subretinal administration of gene therapy vector AAV2-hRPE65v2 (1.5E11 vector genomes per eye) to both eyes via surgical procedures on separate days.

Also known as: AAV2-hRPE65v2, voretigene neparvovec-rzyl, gene therapy vector

AAV2-hRPE65v2,voretigene neparvovec-rzyl

Eligibility Criteria

• Age: 3 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• Willingness to adhere to protocol and long-term follow-up as evidenced by written informed consent or parental permission and subject assent (where applicable).
• Diagnosis of LCA due to RPE65 mutations; molecular diagnosis is to be performed, or confirmed, by a CLIA-approved laboratory.
• Age three years old or older.
• Visual acuity worse than 20/60 (both eyes) and/or visual field less than 20 degrees in any meridian as measured by a III4e isopter or equivalent (both eyes).
• Sufficient viable retinal cells as determined by non-invasive means, such as optical coherence tomography (OCT) and/or ophthalmoscopy. Must have either: 1) an area of retina within the posterior pole of \>100 µm thickness shown on OCT; 2) ≥ 3 disc areas of retina without atrophy or pigmentary degeneration within the posterior pole; or 3) remaining visual field within 30 degrees of fixation as measured by a III4e isopter or equivalent.
• Subjects must be evaluable on mobility testing (the primary efficacy endpoint) to be eligible for the study. Evaluable is defined as: 1) The ability to perform mobility testing within the luminance range evaluated in the study. Individuals must receive an accuracy score of ≤ 1 during screening mobility testing at 400 lux or less to be eligible; individuals with an accuracy score of \> 1 on all screening mobility test runs at 400 lux, or those who refuse to perform mobility testing at screening, will be excluded. 2) The inability to pass mobility testing at 1 lux. Individuals must fail screening mobility testing at 1 lux to be eligible; individuals that pass one or more screening mobility test runs at 1 lux will be excluded.

You may not qualify if:

• Unable or unwilling to meet requirements of the study, including receiving bilateral subretinal vector administrations.
• Any prior participation in a study in which a gene therapy vector was administered.
• Participation in a clinical study with an investigational drug in the past six months.
• Use of retinoid compounds or precursors that could potentially interact with the biochemical activity of the RPE65 enzyme; individuals who discontinue use of these compounds for 18 months may become eligible.
• Prior intraocular surgery within six months.
• Known sensitivity to medications planned for use in the peri-operative period.
• Pre-existing eye conditions or complicating systemic diseases that would preclude the planned surgery or interfere with the interpretation of study. Complicating systemic diseases would include those in which the disease itself, or the treatment for the disease, can alter ocular function. Examples are malignancies whose treatment could affect central nervous system function (for example: radiation treatment of the orbit; leukemia with CNS/optic nerve involvement). Subjects with diabetes or sickle cell disease would be excluded if they had any manifestation of advanced retinopathy (e.g., macular edema or proliferative changes). Also excluded would be subjects with immunodeficiency (acquired or congenital) as there could be susceptibility to opportunistic infection (such as CMV retinitis).
• Individuals of childbearing potential who are pregnant or unwilling to use effective contraception for four months following vector administration.
• Individuals incapable of performing mobility testing (the primary efficacy endpoint) for reason other than poor vision, including physical or attentional limitations.
• Any other condition that would not allow the potential subject to complete follow-up examinations during the course of the study or, in the opinion of the investigator, makes the potential subject unsuitable for the study.
• Subjects will not be excluded based on their gender, race, or ethnicity.

Sponsors & Collaborators

• Spark Therapeutics, Inc.: lead
• Children's Hospital of Philadelphia: collaborator
• University of Iowa: collaborator

Study Sites (2)

University of Iowa

Iowa City, Iowa, 52242, United States

Location

Children's Hospital of Philadelphia

Philadelphia, Pennsylvania, 19104, United States

Location

Related Publications (10)

• Maguire AM, Simonelli F, Pierce EA, Pugh EN Jr, Mingozzi F, Bennicelli J, Banfi S, Marshall KA, Testa F, Surace EM, Rossi S, Lyubarsky A, Arruda VR, Konkle B, Stone E, Sun J, Jacobs J, Dell'Osso L, Hertle R, Ma JX, Redmond TM, Zhu X, Hauck B, Zelenaia O, Shindler KS, Maguire MG, Wright JF, Volpe NJ, McDonnell JW, Auricchio A, High KA, Bennett J. Safety and efficacy of gene transfer for Leber's congenital amaurosis. N Engl J Med. 2008 May 22;358(21):2240-8. doi: 10.1056/NEJMoa0802315. Epub 2008 Apr 27.

  PMID: 18441370 BACKGROUND

• Maguire AM, High KA, Auricchio A, Wright JF, Pierce EA, Testa F, Mingozzi F, Bennicelli JL, Ying GS, Rossi S, Fulton A, Marshall KA, Banfi S, Chung DC, Morgan JI, Hauck B, Zelenaia O, Zhu X, Raffini L, Coppieters F, De Baere E, Shindler KS, Volpe NJ, Surace EM, Acerra C, Lyubarsky A, Redmond TM, Stone E, Sun J, McDonnell JW, Leroy BP, Simonelli F, Bennett J. Age-dependent effects of RPE65 gene therapy for Leber's congenital amaurosis: a phase 1 dose-escalation trial. Lancet. 2009 Nov 7;374(9701):1597-605. doi: 10.1016/S0140-6736(09)61836-5. Epub 2009 Oct 23.

  PMID: 19854499 BACKGROUND

• Chung DC, McCague S, Yu ZF, Thill S, DiStefano-Pappas J, Bennett J, Cross D, Marshall K, Wellman J, High KA. Novel mobility test to assess functional vision in patients with inherited retinal dystrophies. Clin Exp Ophthalmol. 2018 Apr;46(3):247-259. doi: 10.1111/ceo.13022. Epub 2017 Aug 31.

  PMID: 28697537 BACKGROUND

• Chung DC, Bertelsen M, Lorenz B, Pennesi ME, Leroy BP, Hamel CP, Pierce E, Sallum J, Larsen M, Stieger K, Preising M, Weleber R, Yang P, Place E, Liu E, Schaefer G, DiStefano-Pappas J, Elci OU, McCague S, Wellman JA, High KA, Reape KZ. The Natural History of Inherited Retinal Dystrophy Due to Biallelic Mutations in the RPE65 Gene. Am J Ophthalmol. 2019 Mar;199:58-70. doi: 10.1016/j.ajo.2018.09.024. Epub 2018 Sep 28.

  PMID: 30268864 BACKGROUND

• Ashtari M, Cyckowski LL, Monroe JF, Marshall KA, Chung DC, Auricchio A, Simonelli F, Leroy BP, Maguire AM, Shindler KS, Bennett J. The human visual cortex responds to gene therapy-mediated recovery of retinal function. J Clin Invest. 2011 Jun;121(6):2160-8. doi: 10.1172/JCI57377. Epub 2011 May 23.

  PMID: 21606598 RESULT

• Simonelli F, Maguire AM, Testa F, Pierce EA, Mingozzi F, Bennicelli JL, Rossi S, Marshall K, Banfi S, Surace EM, Sun J, Redmond TM, Zhu X, Shindler KS, Ying GS, Ziviello C, Acerra C, Wright JF, McDonnell JW, High KA, Bennett J, Auricchio A. Gene therapy for Leber's congenital amaurosis is safe and effective through 1.5 years after vector administration. Mol Ther. 2010 Mar;18(3):643-50. doi: 10.1038/mt.2009.277. Epub 2009 Dec 1.

  PMID: 19953081 RESULT

• Bennett J, Ashtari M, Wellman J, Marshall KA, Cyckowski LL, Chung DC, McCague S, Pierce EA, Chen Y, Bennicelli JL, Zhu X, Ying GS, Sun J, Wright JF, Auricchio A, Simonelli F, Shindler KS, Mingozzi F, High KA, Maguire AM. AAV2 gene therapy readministration in three adults with congenital blindness. Sci Transl Med. 2012 Feb 8;4(120):120ra15. doi: 10.1126/scitranslmed.3002865.

  PMID: 22323828 RESULT

• Russell S, Bennett J, Wellman JA, Chung DC, Yu ZF, Tillman A, Wittes J, Pappas J, Elci O, McCague S, Cross D, Marshall KA, Walshire J, Kehoe TL, Reichert H, Davis M, Raffini L, George LA, Hudson FP, Dingfield L, Zhu X, Haller JA, Sohn EH, Mahajan VB, Pfeifer W, Weckmann M, Johnson C, Gewaily D, Drack A, Stone E, Wachtel K, Simonelli F, Leroy BP, Wright JF, High KA, Maguire AM. Efficacy and safety of voretigene neparvovec (AAV2-hRPE65v2) in patients with RPE65-mediated inherited retinal dystrophy: a randomised, controlled, open-label, phase 3 trial. Lancet. 2017 Aug 26;390(10097):849-860. doi: 10.1016/S0140-6736(17)31868-8. Epub 2017 Jul 14.

  PMID: 28712537 RESULT

• Fischer MD, Simonelli F, Sahni J, Holz FG, Maier R, Fasser C, Suhner A, Stiehl DP, Chen B, Audo I, Leroy BP; PERCEIVE Study Group. Real-World Safety and Effectiveness of Voretigene Neparvovec: Results up to 2 Years from the Prospective, Registry-Based PERCEIVE Study. Biomolecules. 2024 Jan 17;14(1):122. doi: 10.3390/biom14010122.

  PMID: 38254722 DERIVED

• Bhadhuri A, Droschel D, Guldimann M, Jetschgo C, Banhazi J, Schwenkglenks M, Sutherland CS. Cost-effectiveness of voretigene neparvovec in the treatment of patients with inherited retinal disease with RPE65 mutation in Switzerland. BMC Health Serv Res. 2022 Jun 28;22(1):837. doi: 10.1186/s12913-022-08211-y.

  PMID: 35765055 DERIVED

MeSH Terms

Conditions

Leber Congenital Amaurosis; Retinitis Pigmentosa

Condition Hierarchy (Ancestors)

Eye Diseases, Hereditary; Eye Diseases; Retinal Diseases; Retinal Dystrophies; Retinal Degeneration; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities

Results Point of Contact

• Title: Clinical Director
• Organization: Spark Therapeutics

clinicaltrials@sparktx.com

Study Officials

• Albert M Maguire, MD

  Children's Hospital of Philadelphia

  PRINCIPAL INVESTIGATOR

• Stephen R Russell, MD

  University of Iowa

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: October 21, 2009
• First Posted: October 22, 2009
• Study Start: October 1, 2012
• Primary Completion: July 1, 2015
• Study Completion (Estimated): January 1, 2030
• Last Updated: April 23, 2025
• Results First Posted: March 26, 2018

Record last verified: 2025-04

Locations

US (2)