Gene Therapy for Blindness Caused by Choroideremia

Study Description

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Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

Brief Summary:

- Primary objective: To assess the safety and tolerability of the AAV.REP1 vector, administered at two different doses to the retina in 12 patients with a diagnosis of choroideremia.

- Secondary Objective: To identify any therapeutic benefit as evidenced by a slowing down of the retinal degeneration assessed by functional and anatomical methods in the treated eye compared to the control eye 24 months after gene delivery.

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

Detailed Description:

Detailed description may be found in the following scientific publication:

Retinal gene therapy in patients with choroideremia: initial findings from a phase 1/2 clinical trial, The Lancet, Volume 383, Issue 9923, Pages 1129 - 1137 (29 March 2014).

Links: www.thelancet.com/journals/lancet/article/PIIS0140-6736(13)62117-0/abstract ; http://dx.doi.org/doi:10.1016/S0140-6736(13)62117-0

Study Design

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Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

Study Type :	Interventional (Clinical Trial)
Actual Enrollment :	14 participants
Allocation:	Non-Randomized
Intervention Model:	Single Group Assignment
Masking:	None (Open Label)
Primary Purpose:	Treatment
Official Title:	An Open Label Dose Escalation Phase 1 Clinical Trial of Retinal Gene Therapy for Choroideraemia Using an Adeno-associated Viral Vector (AAV2) Encoding Rab-escort Protein 1 (REP1)
Study Start Date :	October 2011
Actual Primary Completion Date :	October 2017
Actual Study Completion Date :	October 2017

Arms and Interventions

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Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

Arm	Intervention/treatment
Experimental: Dose 1; Dose 1 = single subretinal injection of vector suspension containing approximately 10e10 rAAV2.REP1 genome particles. Six patients have now received Dose 1.	Drug: rAAV2.REP1; Single subretinal injection of rAAV2.REP1 vector suspension containing 10e12 genome particles per ml. Dose 1 = dose containing approximately 10e10 rAAV2.REP1 genome particles. Dose 2 = dose containing approximately 10e11 rAAV2.REP1 genome particles.; Other Name: Adeno-associated viral vector
Experimental: Dose 2; Dose 2 = single subretinal injection of vector suspension containing approximately 10e11 rAAV2.REP1 genome particles. Three patients thus far have received Dose 2.	Drug: rAAV2.REP1; Single subretinal injection of rAAV2.REP1 vector suspension containing 10e12 genome particles per ml. Dose 1 = dose containing approximately 10e10 rAAV2.REP1 genome particles. Dose 2 = dose containing approximately 10e11 rAAV2.REP1 genome particles.; Other Name: Adeno-associated viral vector

Outcome Measures

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Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

Primary Outcome Measures :

1. Visual acuity [ Time Frame: 6 months ]
   Best corrected visual acuity, following cataract surgery if indicated

Secondary Outcome Measures :

1. Microperimetry, OCT and fundus autofluorescence [ Time Frame: 24 months ]
   Structure function correlations at the margins of the retinal degeneration

Eligibility Criteria

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Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

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

Criteria

Inclusion Criteria:

• Participant is willing and able to give informed consent for participation in the study,
• Male aged 18 years or above,
• Diagnosed with choroideraemia and in good health,
• Active disease with SLO changes visible within the macula region,
• Willing to allow his or her General Practitioner and consultant, if appropriate, to be notified of participation in the study,
• Vision at least 6/60 or better in the study eye.

Exclusion Criteria:

• Female and child participants (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 disease or other ocular morbidity which might confound use of the fellow eye as a long-term control,
• Any other significant disease or disorder which, in the opinion of the Investigator, may either put the participants at risk because of participation in the study, or may influence the result of the study, or the participant's ability to participate in the study,
• Participants who have participated in another research study involving an investigational product in the previous 12 weeks.

Contacts and Locations

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Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

Locations

United Kingdom
Moorfields Eye Hospital NHS Foundation Trust
London, United Kingdom, EC1V 2PD
St Mary's Hospital, Central Manchester University Hospitals NHS Foundation Trust
Manchester, United Kingdom, M13 9WL
Oxford Radcliffe Hospitals NHS Trust
Oxford, United Kingdom, OX3 9DU
Eye Unit, Southampton University Hospitals NHS Trust
Southampton, United Kingdom, SO16 6YD

Sponsors and Collaborators

University of Oxford

Oxford University Hospitals NHS Trust

Moorfields Eye Hospital NHS Foundation Trust

University College, London

Manchester University NHS Foundation Trust

University of Manchester

University Hospital Southampton NHS Foundation Trust

University of Southampton

Investigators

Study Chair:	Robert E MacLaren, MB ChB DPhil	University of Oxford, Oxford Radcliffe Hospitals NHS Trust and Moorfields Eye Hospital
Principal Investigator:	Miguel C Seabra, MD PhD	Imperial College London
Principal Investigator:	Andrew R Webster, MD	UCL Institute of Ophthalmology and Moorfields Eye Hospital
Principal Investigator:	Susan M Downes, MD	Oxford University Hospitals NHS Trust
Principal Investigator:	Graeme C Black, MB BCh DPhil	University of Manchester and Central Manchester University Hospitals NHS Foundation Trust
Principal Investigator:	Andrew J Lotery, MD	University of Southampton and Southampton University Hospitals Trust
Principal Investigator:	Len W Seymour, PhD	University of Oxford
Principal Investigator:	Tanya Tolmachova, PhD	Imperial College London

More Information

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Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

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

Simunovic MP, Jolly JK, Xue K, Edwards TL, Groppe M, Downes SM, MacLaren RE. The Spectrum of CHM Gene Mutations in Choroideremia and Their Relationship to Clinical Phenotype. Invest Ophthalmol Vis Sci. 2016 Nov 1;57(14):6033-6039. doi: 10.1167/iovs.16-20230.

Xue K, Oldani M, Jolly JK, Edwards TL, Groppe M, Downes SM, MacLaren RE. Correlation of Optical Coherence Tomography and Autofluorescence in the Outer Retina and Choroid of Patients With Choroideremia. Invest Ophthalmol Vis Sci. 2016 Jul 1;57(8):3674-84. doi: 10.1167/iovs.15-18364.

Seitz IP, Zhour A, Kohl S, Llavona P, Peter T, Wilhelm B, Zrenner E, Ueffing M, Bartz-Schmidt KU, Fischer MD. Multimodal assessment of choroideremia patients defines pre-treatment characteristics. Graefes Arch Clin Exp Ophthalmol. 2015 Dec;253(12):2143-50. doi: 10.1007/s00417-015-2976-4. Epub 2015 Mar 7.

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.

Responsible Party:	University of Oxford
ClinicalTrials.gov Identifier:	NCT01461213 History of Changes
Other Study ID Numbers:	CHM09/01; 2009-014617-27 ( EudraCT Number )
First Posted:	October 28, 2011
Last Update Posted:	November 17, 2017
Last Verified:	November 2017

Keywords provided by University of Oxford:

Tapetoretinal degeneration, choroideraemia, X-linked; retinitis pigmentosa

Additional relevant MeSH terms:

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