An Open Label Clinical Trial of Retinal Gene Therapy for Choroideremia

• ClinicalTrials.gov Identifier: NCT02077361
• Recruitment Status: Active, not recruiting
• First Posted: March 4, 2014
• Last Update Posted: February 16, 2021
• Sponsor: Ian M. MacDonald
• Collaborators: Alberta Innovates Health Solutions; Canada Foundation for Innovation; Canadian Institutes of Health Research (CIHR); Choroideremia Research Foundation Canada; Foundation Fighting Blindness; Imperial College London; University of Oxford
• Information provided by (Responsible Party): Ian M. MacDonald, University of Alberta

Study Description

Brief Summary:

A project has been developed in Edmonton, Alberta, Canada to enable male patients with choroideremia to access a clinical trial that replaces the defective gene with a normal copy. This experiment is designed to show that the transfer of a normal copy of the gene to the eye is not only safe but may improve the sight of patients. Only Canadian subjects who meet criteria will be recruited.

Condition or disease	Intervention/treatment	Phase
Choroideremia	Genetic: rAAV2.REP1 vector	Phase 1; Phase 2

Detailed Description:

This is an open label study involving a total of 6 male patients. Screening and patient medical records will determine patient eligibility. Patients will receive a subretinal injection of the rAAV2.REP1 vector by a trained vitreoretinal surgeon in one eye. Each patient will be followed up for 24 months after treatment to assess the primary and secondary endpoints of this study using a number of outcome measures. However, further follow-up will continue after the study on an annual basis for a minimum of ten years. Data will continue to be analyzed by members of the study group after this study is complete.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 6 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: An Open Label Clinical Trial of Retinal Gene Therapy for Choroideremia Using an Adeno-associated Viral Vector (AAV2) Encoding Rab-escort Protein-1 (REP1)
• Study Start Date: April 2015
• Actual Primary Completion Date: August 30, 2017
• Estimated Study Completion Date: September 1, 2025

Arms and Interventions

Arm	Intervention/treatment
Experimental: Open Label; Patients will receive a subretinal injection of 0.10 ml of the rAAV2.REP1 vector drug substance. It is a colourless opalescent frozen liquid with no visible particles. Each patient will be given a one-time dose in one eye. It is the same vector used in the United Kingdom Phase I/II trial logged at: http://clinicaltrials.gov/ct2/show/NCT01461213.	Genetic: rAAV2.REP1 vector; No additional details needed.

Outcome Measures

Primary Outcome Measures :

1. Number of patients with ocular and systemic adverse events [ Time Frame: 2 years ]
   This is assessed by standard ocular examinations and vector dissemination and inflammation assays.

Secondary Outcome Measures :

1. Changes in visual field [ Time Frame: Baseline and up to 2 years following vector delivery ]
   This is assessed by Goldmann perimetry and microperimetry; measurements before and after vector delivery are compared.
2. Changes in visual function [ Time Frame: Baseline and 2 years following vector delivery ]
   This is assessed by multifocal electrophysiology, full field scotopic threshold, spectral domain optical coherent tomography, fundus photography and fundus autofluorescence; measurements before and after vector delivery are compared.

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: Male
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

• The research subject is willing and able to give informed consent for participation in the study.
• Male aged 18 years or above.
• Diagnosed with choroideremia (with genotyping or evidence of lack of the gene product with immunohistochemistry) and in good health.
• Active degeneration of the retina (the expectation of significant decline in visual function without any intervention over the subsequent 5 years) with OCT (optical coherent tomography) changes visible within the macula.
• Willingness to allow his general physician and ophthalmologist, if appropriate, to be notified of participation in the study.

Exclusion Criteria:

The participant may not enter the study if ANY of the following apply.

• Female or child research subject (under the age of 18).
• Men unwilling to use barrier contraception methods, if relevant.
• Previous history of retinal surgery or ocular inflammatory disease (uveitis).
• Grossly asymmetrical retinal disease or other ocular morbidity which might confound adopting the fellow eye as a long-term comparator.
• Any other significant systemic disease or disorder which, in the opinion of the investigator, may either put the research subject at risk because of participation in the study, or may influence the result of the study, or the research subject's ability to participate in the study. This would include a contraindication to oral prednisolone, such as a history of gastric ulcer).
• Research subjects who have participated in another research study involving an investigational product within the past year.

Contacts and Locations

Locations

Canada, Alberta

University of Alberta

Edmonton, Alberta, Canada, T6G 2E1

Sponsors and Collaborators

Ian M. MacDonald

Alberta Innovates Health Solutions

Canada Foundation for Innovation

Canadian Institutes of Health Research (CIHR)

Choroideremia Research Foundation Canada

Foundation Fighting Blindness

Imperial College London

University of Oxford

Investigators

• Principal Investigator: Ian M MacDonald, MD, CM; University of Alberta

More Information

Additional Information:

Study Website: Click here for more information about the study. 

Choroideremia Overview 

Publications:

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.

Hauswirth WW, Aleman TS, Kaushal S, Cideciyan AV, Schwartz SB, Wang L, Conlon TJ, Boye SL, Flotte TR, Byrne BJ, Jacobson SG. Treatment of leber congenital amaurosis due to RPE65 mutations by ocular subretinal injection of adeno-associated virus gene vector: short-term results of a phase I trial. Hum Gene Ther. 2008 Oct;19(10):979-90. doi: 10.1089/hum.2008.107.

Bainbridge JW, Smith AJ, Barker SS, Robbie S, Henderson R, Balaggan K, Viswanathan A, Holder GE, Stockman A, Tyler N, Petersen-Jones S, Bhattacharya SS, Thrasher AJ, Fitzke FW, Carter BJ, Rubin GS, Moore AT, Ali RR. Effect of gene therapy on visual function in Leber's congenital amaurosis. N Engl J Med. 2008 May 22;358(21):2231-9. doi: 10.1056/NEJMoa0802268. Epub 2008 Apr 27.

Bennicelli J, Wright JF, Komaromy A, Jacobs JB, Hauck B, Zelenaia O, Mingozzi F, Hui D, Chung D, Rex TS, Wei Z, Qu G, Zhou S, Zeiss C, Arruda VR, Acland GM, Dell'Osso LF, High KA, Maguire AM, Bennett J. Reversal of blindness in animal models of leber congenital amaurosis using optimized AAV2-mediated gene transfer. Mol Ther. 2008 Mar;16(3):458-65. doi: 10.1038/sj.mt.6300389. Epub 2008 Jan 22.

MacLaren RE. An analysis of retinal gene therapy clinical trials. Curr Opin Mol Ther. 2009 Oct;11(5):540-6. Review.

MacLaren RE, Groppe M, Barnard AR, Cottriall CL, Tolmachova T, Seymour L, Clark KR, During MJ, Cremers FP, Black GC, Lotery AJ, Downes SM, Webster AR, Seabra MC. Retinal gene therapy in patients with choroideremia: initial findings from a phase 1/2 clinical trial. Lancet. 2014 Mar 29;383(9923):1129-37. doi: 10.1016/S0140-6736(13)62117-0. Epub 2014 Jan 16.

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Brooks SP, Benjaminy S, Bubela T. Participant perspectives on a phase I/II ocular gene therapy trial (NCT02077361). Ophthalmic Genet. 2019 Jun;40(3):276-281. doi: 10.1080/13816810.2019.1630843. Epub 2019 Jul 4.

• Responsible Party: Ian M. MacDonald, Professor, Department of Ophthalmology and Visual Sciences, University of Alberta
• ClinicalTrials.gov Identifier: NCT02077361
• Other Study ID Numbers: Pro00028599; File # 9427-U0180-84C ( Other Identifier: Health Canada )
• First Posted: March 4, 2014
• Last Update Posted: February 16, 2021
• Last Verified: February 2021

Keywords provided by Ian M. MacDonald, University of Alberta:

choroideremia; gene therapy; gene transfer

Additional relevant MeSH terms:

Choroideremia; Eye Diseases, Hereditary; Eye Diseases; Choroid Diseases; Uveal Diseases; Genetic Diseases, Inborn; Genetic Diseases, X-Linked