Clinical Trial Results:
An open label Phase 2 clinical trial of retinal gene therapy for choroideremia using an adeno-associated viral vector (AAV2) encoding Rab-escort protein 1 (REP1)
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Summary
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EudraCT number |
2015-001383-18 |
Trial protocol |
GB |
Global end of trial date |
23 Jul 2021
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Results information
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Results version number |
v1(current) |
This version publication date |
28 Oct 2022
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First version publication date |
28 Oct 2022
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Other versions |
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Summary report(s) |
BCVA ETDRS Scores, Full Dataset BCVA ETDRS Score Change from Baseline BCVA ETDRS Score Change from Baseline, Between Eye Comparison BCVA ETDRS Score Change from Baseline by Surgery site |
Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
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Trial identification
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Sponsor protocol code |
REGENERATE (PID 11351)
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT02407678 | ||
WHO universal trial number (UTN) |
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Sponsors
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Sponsor organisation name |
University of Oxford
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Sponsor organisation address |
Joint Research Office, Boundary Brook House, Churchill Drive, Oxford, United Kingdom, OX3 7LQ
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Public contact |
Research Governance, Ethics & Assurance Team, Research Services, ctrg@admin.ox.ac.uk
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Scientific contact |
Ophthalmology Trials Unit, Nuffield Laboratory of Ophthalmology, trials@eye.ox.ac.uk
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
No
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Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
03 Mar 2022
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Is this the analysis of the primary completion data? |
Yes
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Primary completion date |
23 Jul 2021
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Global end of trial reached? |
Yes
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Global end of trial date |
23 Jul 2021
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Was the trial ended prematurely? |
No
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General information about the trial
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Main objective of the trial |
Investigation of the efficacy and safety of a single subretinal injection of a recombinant adeno-associated virus serotype 2 (AAV2) vector encoding Rab-escort protein 1 (REP1), designated as AAV2-REP1, in subjects with a confirmed diagnosis of choroideremia over a 2-year assessment period following treatment.
Efficacy was primarily quantified by tracking the comparative change from baseline in best corrected visual acuity (BCVA) in the treated eye and untreated contralateral eye (control eye), measured by the number of letters read on an Early Treatment Diabetic Retinopathy Study (ETDRS) chart.
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Protection of trial subjects |
The method of vector administration was refined in an antecedent Phase 1/2 interventional study (EudraCT 2009-014617-27) where initial detachment of the retina was effected as a first step by injecting a small volume of balanced salt solution underneath the retina through a very fine needle that is narrower than a human hair, thereby creating a small fluid-filled blister or bleb under the retina. This was followed by injection of an exact dose of the adeno-associated viral (AAV) vector suspension into the subretinal fluid as a second step. The small area of retinal detachment is temporary and disappears over about 24 hours as the fluid gets slowly absorbed by the retina. This type of surgery normally lasts about an hour, and the operation itself (without administration of the gene therapy) is a routine procedure for patients with conditions such as retinal detachment.
The benefit of the preceding two-step procedure is that the slightly unpredictable part of the procedure (the retinal detachment) is completed before any AAV vector is administered to the subject. This allows for the management of any surgical complications without concerns about AAV vector dissemination.
An additional safety feature introduced in this Phase 2 interventional study was the use of an ophthalmic operating microscope with an integrated optical coherence tomography (OCT) scanner for conducting the retinal surgery. This special operating microscope shows a cross section of the retina in real time to the surgeon, thereby permitting administration of the gene therapy to be conducted far more precisely, safely and reliably.
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Background therapy |
In order to minimise postoperative inflammation, subjects were given a 45 day course of oral prednisolone, starting 3 days before surgery at a daily dose of 1 mg per kg of body weight (rounded to the nearest multiple of 5 mg), and gradually tapering off to 5 mg over the course of the next 42 days. | ||
Evidence for comparator |
Not applicable: no comparator was used in the study. | ||
Actual start date of recruitment |
16 Aug 2016
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Long term follow-up planned |
Yes
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Long term follow-up rationale |
Safety, Efficacy | ||
Long term follow-up duration |
5 Years | ||
Independent data monitoring committee (IDMC) involvement? |
Yes
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Population of trial subjects
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Number of subjects enrolled per country |
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Country: Number of subjects enrolled |
United Kingdom: 30
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Worldwide total number of subjects |
30
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EEA total number of subjects |
0
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Number of subjects enrolled per age group |
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In utero |
0
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Preterm newborn - gestational age < 37 wk |
0
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Newborns (0-27 days) |
0
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Infants and toddlers (28 days-23 months) |
0
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Children (2-11 years) |
0
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Adolescents (12-17 years) |
0
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Adults (18-64 years) |
30
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From 65 to 84 years |
0
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85 years and over |
0
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Recruitment
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Recruitment details |
A total of 30 subjects were recruited over the period 2016-2019, comprising 12 subjects recruited and treated at Oxford Eye Hospital and 18 subjects recruited and treated at Moorfields Eye Hospital (London). | |||||||||
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Pre-assignment
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Screening details |
Subjects were males aged 18 years or older with: • A clinical diagnosis of choroideremia and a molecular diagnosis of a null mutation in the gene encoding REP1. • Active disease visible clinically within the macula region. • BCVA better than or equal to 6/60 (20/200) in the eye to be treated. | |||||||||
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Period 1
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Period 1 title |
Overall study (overall period)
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Is this the baseline period? |
Yes | |||||||||
Allocation method |
Not applicable
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Blinding used |
Not blinded | |||||||||
Blinding implementation details |
This was an open label study with no masking. However, in order to minimise bias evaluation of the treated eye and untreated contralateral eye (control eye), ophthalmic assessments were conducted by an appropriately qualified masked observer once the subjects' treated eyes had regained their normal appearance and function following the surgical procedure.
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Arms
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Are arms mutually exclusive |
No
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Arm title
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Cohort 1 | |||||||||
Arm description |
Cohort 1 comprised all subjects that participated in the study, and compared changes in BCVA and other measures of visual function in the treated eye against baseline values. | |||||||||
Arm type |
Experimental | |||||||||
Investigational medicinal product name |
AAV2-REP1
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Suspension for injection
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Routes of administration |
Subretinal use
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Dosage and administration details |
AAV2-REP1 vector suspension (10e12 vector particles per mL) was supplied by Nightstar Therapeutics. Up to 0.1 mL of AAV2-REP1 vector suspension, corresponding to a dose of up to 10e11 vector particles, was administered to the treated eye by subretinal injection.
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Arm title
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Cohort 2 | |||||||||
Arm description |
Cohort 2 comprised the subset of subjects having symmetrical disease for whom selection of the treated eye was randomized, and compared changes in BCVA and other measures of visual function in the treated eye and the untreated contralateral (control) eye. Note that randomization was not used for assigning treatment (versus placebo/standard care as in randomized controlled trials), but solely for selection of the eye to be treated in these subjects for whom the progress of retinal degeneration was relatively symmetrical for both eyes, defined as a difference in BCVA of no more than one line of letters measured on an ETDRS chart, and no more than 25% difference in the area of surviving retinal pigment epithelium measured by fundus autofluorescence. | |||||||||
Arm type |
Experimental | |||||||||
Investigational medicinal product name |
AAV2-REP1
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Suspension for injection
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Routes of administration |
Subretinal use
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Dosage and administration details |
AAV2-REP1 vector suspension (10e12 vector particles per mL) was supplied by Nightstar Therapeutics. Up to 0.1 mL of AAV2-REP1 vector suspension, corresponding to a dose of up to 10e11 vector particles, was administered to the treated eye by subretinal injection.
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Baseline characteristics reporting groups
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Reporting group title |
Overall study
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Reporting group description |
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End points reporting groups
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Reporting group title |
Cohort 1
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Reporting group description |
Cohort 1 comprised all subjects that participated in the study, and compared changes in BCVA and other measures of visual function in the treated eye against baseline values. | ||
Reporting group title |
Cohort 2
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Reporting group description |
Cohort 2 comprised the subset of subjects having symmetrical disease for whom selection of the treated eye was randomized, and compared changes in BCVA and other measures of visual function in the treated eye and the untreated contralateral (control) eye. Note that randomization was not used for assigning treatment (versus placebo/standard care as in randomized controlled trials), but solely for selection of the eye to be treated in these subjects for whom the progress of retinal degeneration was relatively symmetrical for both eyes, defined as a difference in BCVA of no more than one line of letters measured on an ETDRS chart, and no more than 25% difference in the area of surviving retinal pigment epithelium measured by fundus autofluorescence. | ||
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End point title |
BCVA change from baseline in treated eye [1] | ||||||||||||
End point description |
Change from baseline in BCVA (measured as change in ETDRS letters) in the treated eye. [Statistical analysis: 95% Confidence Interval of the mean change based on t-test.]
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End point type |
Primary
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End point timeframe |
The 24-month assessment period following treatment.
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| Notes [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: Statistical analysis is provided in the attached PDF file "BCVA ETDRS Score Change from Baseline", with additional information provided in the attached PDF file "BCVA ETDRS Score Change from Baseline by Surgery site". |
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| No statistical analyses for this end point | |||||||||||||
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End point title |
BCVA change from baseline in treated eye compared with control eye [2] [3] | ||||||||
End point description |
Change from baseline in BCVA (measured as change in ETDRS letters) in the treated eye compared with the control eye. [Statistical analysis: 95% Confidence Intervals of the least squares mean difference from the untreated eye. The ANCOVA (analysis of covariance) model includes the least squares mean difference in BCVA (treated eye versus control eye) as a factor and baseline BCVA as a covariate (p-value 0.059).]
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End point type |
Primary
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End point timeframe |
The 24-month assessment period following treatment.
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| Notes [2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: Statistical analysis is provided in the attached PDF file "BCVA ETDRS Score Change from Baseline, Between Eye Comparison". [3] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: Statistical analysis is provided in the attached PDF file "BCVA ETDRS Score Change from Baseline, Between Eye Comparison". |
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| No statistical analyses for this end point | |||||||||
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End point title |
Safety [4] | ||||||
End point description |
Serious Adverse Events (SAEs) related to the study drug (AAV2-REP1 vector) and/or the surgical procedure (vitrectomy, retinal detachment and subretinal injection of the vector suspension).
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End point type |
Secondary
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End point timeframe |
The 24-month assessment period following treatment.
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| Notes [4] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: Serious adverse events are detailed in the "Adverse events" section of the report. |
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| No statistical analyses for this end point | |||||||
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Adverse events information
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Timeframe for reporting adverse events |
The recording and follow-up of all adverse events was carried out until the end of the study, corresponding to the date of the last subject's final follow-up visit at the end of the 2-year assessment period following treatment.
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Assessment type |
Systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
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Reporting groups
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Reporting group title |
All subjects
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Reporting group description |
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| Frequency threshold for reporting non-serious adverse events: 5% | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Substantial protocol amendments (globally) |
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| Were there any global substantial amendments to the protocol? Yes | |||
Date |
Amendment |
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15 Feb 2016 |
Version number of the Investigational Medicinal Product Dossier (IMPD) updated from 1.0 to 2.0 following approval by the Medicines and Healthcare products Regulatory Agency (MHRA) of requested corrections. |
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12 May 2016 |
Version number of the IMPD updated from 2.0 to 3.0 following the addition of supplementary vector stability/potency data required for MHRA approval of a 12-month extension of the AAV2-REP1 vector shelf life to 29 June 2017. |
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14 Dec 2016 |
Version numbers of the Protocol, Participant Information Sheet (PIS) and Informed Consent Form (ICF) updated from 2.0 to 3.0 following MHRA and research ethics committee approval of:
• Change of the Principal Investigator at the Moorfields Eye Hospital site.
• Amendments and clarifications to the schedule of assessments, and other clarifications in regard to data management for the study. |
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06 Feb 2017 |
Version numbers of the Protocol, PIS and ICF updated from 3.0 to 4.0 following MHRA and research ethics committee approval of amendments to the schedule of assessments (vital signs, immunology, fundus photography and refraction/BVCA). |
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05 Apr 2017 |
Version number of the Protocol updated from 4.0 to 5.0 following MHRA and research ethics committee approval of an amendment to the inclusion criterion specifying that candidates must have BCVA better than or equal to 6/60 (20/200) in the treated eye. |
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25 May 2017 |
Version number of the IMPD updated from 3.0 to 4.0 following the addition of supplementary vector stability/potency data required for MHRA approval of a 12-month extension of the AAV2-REP1 vector shelf life to 29 June 2018. |
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10 Nov 2017 |
Version number of the Protocol updated from 5.0 to 6.0 and the version number of the PIS updated from 4.0 to 5.0 following MHRA and research ethics approval of:
• Extension of the oral prednisolone course.
• Amendment permitting a total volume of no less than 0.2 mL of the AAV2-REP1 vector to be loaded into the injection system.
• Amendment to the Conflict of Interest Statement. |
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12 Sep 2018 |
Version number of the Investigator Brochure (IB) updated from 1.0 to 2.0 following MHRA and research ethics committee approval of the inclusion of safety data from other studies (NCT01461213, NCT02077361). Version number of the IMPD updated from 4.0 to 5.0 following the addition of supplementary vector stability/potency data required for MHRA approval of a 12-month extension of the AAV2-REP1 vector shelf life to 29 June 2019. |
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29 Jul 2020 |
Version number of the IB updated from 2.0 to 3.0 following MHRA and research ethics committee approval of the inclusion of clinical data from preceding/parallel studies (NCT01461213, NCT02077361, NCT02553135, NCT02671539), this study (NCT02407678) and studies sponsored by Nightstar Therapeutics (NCT03496012, NCT03507686). The Reference Safety Information now includes “visual acuity reduced” as an expected risk of treatment. Version number of the Protocol updated from 6.0 to 7.0 following following MHRA and research ethics committee approval of updates to the Safety Reporting section to include parameters for determining the clinical significance of changes in BCVA. |
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Interruptions (globally) |
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| Were there any global interruptions to the trial? No | |||
Limitations and caveats |
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| Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||
| None reported | |||
