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History of Changes for Study: NCT02781480
Clinical Trial of Gene Therapy for the Treatment of Leber Congenital Amaurosis (LCA) (OPTIRPE65)
Latest version (submitted June 17, 2021) on ClinicalTrials.gov
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Study Record Versions
Version A B Submitted Date Changes
1 May 23, 2016 None (earliest Version on record)
2 May 31, 2016 Recruitment Status, Study Status, Contacts/Locations and Oversight
3 April 25, 2017 Oversight, Sponsor/Collaborators, Study Identification, Study Status, Contacts/Locations and Study Design
4 August 16, 2017 Arms and Interventions, Outcome Measures, Study Status, Study Design, Study Description, Eligibility and Study Identification
5 September 7, 2017 Outcome Measures, Study Status and Study Description
6 December 15, 2017 Contacts/Locations and Study Status
7 July 15, 2019 Recruitment Status, Study Status, Contacts/Locations, Study Design, IPDSharing and Oversight
8 March 10, 2021 Study Status, Outcome Measures, Document Section and Results
9 April 9, 2021 Study Status, Outcome Measures and Study Design
10 June 17, 2021 Adverse Events and Study Status
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Study NCT02781480
Submitted Date:  May 23, 2016 (v1)

Open or close this module Study Identification
Unique Protocol ID: 15/0587
Brief Title: Clinical Trial of Gene Therapy for the Treatment of Leber Congenital Amaurosis (LCA) (OPTIRPE65)
Official Title: An Open-label, Multi-centre, Phase I/II Dose Escalation Trial of an Adeno Associated Of an Adeno-Associated Virus Vector (AAV2/5-OPTIRPE65) for Gene Therapy of Adults And Children With Retinal Dystrophy Associated With Defects in RPE65 (LCA)
Secondary IDs:
Open or close this module Study Status
Record Verification: April 2016
Overall Status: Not yet recruiting
Study Start: April 2016
Primary Completion: April 2018 [Anticipated]
Study Completion:
First Submitted: April 28, 2016
First Submitted that
Met QC Criteria:
May 23, 2016
First Posted: May 24, 2016 [Estimate]
Last Update Submitted that
Met QC Criteria:
May 23, 2016
Last Update Posted: May 24, 2016 [Estimate]
Open or close this module Sponsor/Collaborators
Sponsor: University College, London
Responsible Party: Sponsor
Collaborators: Medical Research Council
MeiraGTx UK II Ltd
Open or close this module Oversight
U.S. FDA-regulated Drug:
U.S. FDA-regulated Device:
Data Monitoring: Yes
Open or close this module Study Description
Brief Summary:

The inherited retinal dystrophies are a clinically and genetically heterogeneous group of conditions, which often present in childhood.Inherited retinal degenerations cause sight impairment in approximately 1 in 3000 people in the Western world. There are currently no effective treatments.

Leber congenital amaurosis (LCA) is a severe, early-onset form of inherited retinal degeneration involving both rod and cone photoreceptors. LCA is caused by mutations in one of at least 19 different genes.Mutations in RPE65, which is expressed in the retinal pigment epithelium (RPE), are responsible in 3 to 16 % of people affected. The RPE65 gene encodes a 65-kDa retinal pigment epithelium (RPE)-specific protein that is required for the conversion of vitamin A to 11-cis-retinal by the RPE and is essential for the regeneration of the rod visual pigment

Proof of principle studies for RPE65 gene replacement therapy has been demonstrated with the use of recombinant adeno-associated virus serotype 2 (rAAV2/2) vectors in animal models. Furthermore clinical trials of gene replacement therapy in RPE65 associated LCA (RPE65-LCA) have shown significant promise. All three clinical trials showed improvement in visual function over the first year, however longer term follow up Proof of principle studies for RPE65 gene replacement therapy has been demonstrated with the use of recombinant adeno-associated virus serotype 2 (rAAV2/2) vectors in animal models. Furthermore clinical trials of gene replacement therapy in RPE65 associated LCA (RPE65-LCA) have shown significant promise. All three clinical trials showed improvement in visual function over the first year, however longer term follow up demonstrated progressive visual loss and that initial improvements were not maintained.

Greater efficacy was noted in animal models. The relatively lower efficacy of treatment in participants was most likely due to insufficient production of RPE65 protein from AAV2/2 hRPE65 in the human eye.

Having identified the maximal tolerated AAV2/2 vector dose in the previous clinical trial, an optimized therapeutic vector to drive more efficient transgene expression and increase the availability of RPE65 for affected humans has been developed.

The aim of this trial is to determine the safety of the new optimised AAV2/5 vector in humans and to explore its potential efficacy.

Detailed Description:

This trial will take place across 2 sites (Moorfields Eye Hospital in the UK and University of Michigan Kellogg Eye Centre in the US). Up to 27 patients will be recruited.

The trial will involve a dose escalation phase, where up to 18 adult participants will be administered one of 3 different doses (low, intermediate or high) of using a 3+3 design. Dose escalation will be undertaken in adults, based on an escalation rule around dose-limiting events (DLEs).

Up to 9 children aged 3 or above will then be included once an acceptable safety profile has been established in adults. Review of safety data will be undertaken by the IDMC prior to each dose escalation.

The trial will involve 13 visits that occur during an approximate 9 to 12 month period. Delivery of the vector to the subretinal space will be performed following a standard surgical vitrectomy.

Subjects will be asked to consider enrolling onto a separate long-term follow-up study that will continue to monitor the safety of the intervention after this study ends, for a period of 5 years.

Assessments that will be undertaken depending on age, co-operation and ability to undertake the test include (see schedule of assessments):

  • Medical history, ocular examination, visual acuity testing, contrast sensitivity, reading speed, colour fundus photography, fundus autofluorescence, SDOCT imaging, adaptive optics imaging, mesopic and scotopic microperimetry
  • Electrophysiological assessments incorporating the protocols recommended by the International Society for Clinical Electrophysiology of Vision (ISCEV). Full-field electroretinogram (FFERG) - a measure of global retinal function - will not be undertaken if previously documented to be undetectable - the majority of patients will have undetectable FFERG. Pattern ERG (PERG) and multifocal ERG (mfERG) will be undertaken on an annual basis to determine change in central retinal function over time (often residual central function till late in disease) - but will not be repeated once found to be undetectable.
  • Visual Field Testing. The Octopus 900 perimeter will be used. Static full-field testing will be undertaken employing the GATE strategy, and size V test targets. Further analysis will be undertaken to model the entire hill-of-vision which will enhance the information obtained with full-field static perimetry.
  • Vision guided mobility. This will be assessed by measuring the ability of each subject to navigate a simple route in a range of controlled illuminances.
  • QoL questionnaires (IVI_A, IVI_C and EQ5D-5L)
  • Blood tests to confirm mutation within the RPE65 gene, bio distribution of the vector and evaluation of immune responses, biochemistry and haematology.
Open or close this module Conditions
Conditions: Leber Congenital Amaurosis
Keywords:
Open or close this module Study Design
Study Type: Interventional
Primary Purpose: Treatment
Study Phase: Phase 1
Interventional Study Model: Single Group Assignment
Number of Arms: 1
Masking: None (Open Label)
Allocation: N/A
Enrollment: 27 [Anticipated]
Open or close this module Arms and Interventions
Arms Assigned Interventions
AAV2/5 OPTIRPE65
Genetic: AAV2/5 OPTIRPE65
Open or close this module Outcome Measures
Primary Outcome Measures:
1. Number of participants with treatment-related ocular adverse events graded as III & IV in CTCAE Version 4.0 grading scale.
[ Time Frame: 1 year ]

The primary outcome is safety of subretinal administration of AAV2/5-OPTIRPE65.

Safety is defined as the absence of ocular Grade III (sustained reduction of visual acuity to counting fingers or less, severe unresponsive inflammation, infective endophthalmitis) or Grade IV (loss of light perception, ocular malignancy) adverse events and severe non-ocular Suspected Unexpected Serious Adverse Reaction. Safety will be assessed for 6 months after the intervention.

Secondary Outcome Measures:
1. Number of participants with improvement in visual function as shown in several visual assessments including Visual Acuity & Visual Mobility & also retinal function as shown in electroretinography (ERG) assessments.
[ Time Frame: 1 year ]

The secondary outcomes are measures of the efficacy of the intervention, which will be performed on an individual participant basis and will be descriptive in nature. Any improvement in patient's visual function from baseline that is greater that the test-retest variation for that test and is sustained for at least two consecutive assessments.
2. Number of participants with improvement in visual function as shown in several visual assessments including Visual Acuity & Visual Mobility & also retinal function as shown in electroretinography (ERG) assessments.
[ Time Frame: 1 year ]

Any improvement in patient's retinal function from baseline that is measurable by electroretinography (ERG).
Open or close this module Eligibility
Minimum Age: 3 Years
Maximum Age:
Sex: All
Gender Based:
Accepts Healthy Volunteers: No
Criteria:

Inclusion Criteria:

  • Are aged 3 years or older (although participants who are aged 3-15 will only be enrolled once the maximum tolerated dose (MTD) has been established)
  • Have early-onset severe retinal dystrophy consistent with RPE65 deficiency
  • Have homozygous or compound heterozygous missense or null mutations in RPE65
  • Have functional or structural evidence of photoreceptor preservation
  • Are able to give informed consent or assent, with the guidance of their parent/guardian where appropriate: children aged 3-6 years will not be asked to provide assent.
  • Are able to undertake age-appropriate clinical assessments at the trial sites as specified in the protocol
  • If female and of child bearing potential, are willing to use an effective form of birth control (hormonal or barrier method of birth control; or abstinence) for up to 3 months prior to ATIMP administration, and at least 12 months following ATIMP administration; a total of 15 months (Section 4.1.5, Assessment and Management of Risk)
  • If male, are willing to use barrier and spermicide form of contraceptive or maintain sexual abstinence for up to 3 months prior to ATIMP administration, and at least 12 months following ATIMP administration; a total of 15 months
  • Females of childbearing potential will have a negative pregnancy test within 7 days prior to ATIMP administration. Participants are considered not of childbearing potential if they are pre-pubescent, surgically sterile (i.e. they have undergone a hysterectomy or bilateral oophorectomy) or post-menopausal
  • Are willing to give consent for the use of blood and blood components collected throughout the trial for the investigation of immune responses to the ATIMP

Exclusion Criteria:

  • Are females who are pregnant or breastfeeding
  • Have contraindications for transient immune-suppression by systemic corticosteroids (including hypertension, diabetes mellitus, tuberculosis, renal impairment, osteoporosis, gastric ulceration, severe affective disorder) or are immunocompromised
  • Have a previous (within 5 years) history of gastric or duodenal ulceration, hiatus hernia, gastro-oesophageal reflux or are using non-steroidal anti-inflammatory drugs on a regular basis at the time of screening
  • Have a known allergy to any of the non-investigational drugs to be used in the trial as defined in Section 5.4.1
  • Have participated in another research study involving an investigational medicinal therapy for ocular disease within the last 6 months
  • Have any other condition that the PI considers makes them inappropriate for entry into the trial
  • Are unwilling to consider the possibility of entry into a subsequent longer term
Open or close this module Contacts/Locations
Locations:
Open or close this module IPDSharing
Plan to Share IPD:
Open or close this module References
Citations:
Links:
Available IPD/Information:

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