Clinical Trial: Clinical Trial of Gene Therapy for the Treatment of Leber Congenital Amaurosis (LCA)

Study Status: Recruiting
Recruit Status: Recruiting
Study Type: Interventional

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 Dystrop

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 not

Detailed Summary:

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 el
  Sponsor: MeiraGTx UK II Ltd
  

  Current Primary Outcome: 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.

  
  
  

  Original Primary Outcome: Same as current
  
  

  Current Secondary Outcome:

  • 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.
  • 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).
  
  
  

  Original Secondary Outcome: Same as current
  
  Information By: MeiraGTx UK II Ltd
  

  Dates:
  Date Received: April 28, 2016
  Date Started: April 2016
  Date Completion:
  Last Updated: April 25, 2017
  Last Verified: April 2017