Gene Therapy for Achromatopsia (CNGB3)

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Disease Information

Descriptive Information
Brief Title † Gene Therapy for Achromatopsia (CNGB3)
Official Title † An Open Label, Multi-centre, Phase I/II Dose Escalation Trial of a Recombinant Adeno-associated Virus Vector (AAV2/8-hCARp.hCNGB3) for Gene Therapy of Adults and Children With Achromatopsia Owing to Defects in CNGB3
Brief Summary Achromatopsia is a recessively inherited condition characterised by a lack of cone photoreceptor function resulting in impairment of colour vision and visual acuity, central scotoma often with eccentric fixation, disabling hypersensitivity to light (photophobia) and involuntary eye movements (pendular nystagmus). Children with CNGB3-related achromatopsia have profound sight impairment from birth or early infancy. The condition is currently untreatable, but there is a real possibility that a gene therapy could offer a significant benefit in terms of improved sight and quality of life (QOL), based on our own and others experience of ocular gene therapy trials )and pre-clinical data demonstrating improved outcome in CNGB3- related achromatopsia. Possible benefits of improved cone-photoreceptor function include improved visual acuity; improved colour perception; and relief from disabling photophobia. Although younger individuals may benefit most from gene supplementation therapy by virtue of their greater visual plasticity, it is anticipated that the intervention may offer benefit across a range of ages and the aim is to define this range. For this reason, participants of various ages will be included; children will be included only after an acceptable safety profile has been established in adults.
Detailed Description The purpose of this trial is to determine the safety and efficacy of subretinal administration of the ATIMP in participants with CNGB3-related achromatopsia. Since this is primarily a safety study and assessments of efficacy will be explored in nature, a control group won't be included and will only enrol patients with CNBG3 mutations. Since this is a rare disease, only a small number of participants (up to 27) will be recruited. This study will be conducted at two academic hospitals: one in the UK and one in the USA. In the dose escalation phase, up to 18 adult participants will be administered one of 3 different doses of the ATIMP in cohorts of 3 participants at a time. Based on toxicity data, the IDMC will make a recommendation on the dose to administer to the next cohort of 3 participants. The IDMC may recommend an additional 1 or 2 participants at a given dose before deciding how to proceed. Once an acceptable safety profile has been established in adults, up to 9 additional participants, who may be children or adults, will be included. The IDMC will agree the maximum tolerated dose in adults before recommending administering this dose to children. During the study the participants will make 13 visits to the study site over a period of six to nine months to measure parameters of safety and efficacy of the intervention. Participants will attend a screening visit to ensure eligibility for the study, three baseline visits to establish reference measurement, a visit where they will undergo an operation to deliver the normal CNGB3 gene to the eye and eight follow-up visits within the six months after the operation to make sure the operation is safe and to measure whether there are any improvements in sight. The visits before and after the operation are designed to ensure that the study will be able to determine safety and measure any positive benefit. At the screening visit participants will be asked to sign the consent form after which their eligibility to participate in the trial will be determined. They will be asked about their medical history, eye and medication history, be tested for pregnancy if appropriate and a blood sample will be taken to determine the genetic fault in the CNGB3 gene, if this has not been done previously. Images of the retina will be taken and the response of the eyes to light will be measured. Prior to ATIMP administration, participants will have three baselines visits to establish reference measurements. These baseline visits will include testing a blood sample for haematology, biochemistry and serology, tests to measure various aspects of visual function, imaging and scans to document the retina and tests of participants' ability to navigate a maze. The baseline visits will take 1 to 3 days depending on the number of tests scheduled for each visit. ATIMP administration will be performed by medical operation to deliver the normal gene to the retina. The operation will involve "keyhole" surgery under general anaesthetic to remove some of the vitreous jelly from the eye, and an injection of the virus vector under the retina. The operation will last between one and two hours. Assessments during the 6 months after ATIMP administration will measure the response of the participants' eye to the intervention. Visits will occur approximately 1 day, 3 days, 1 week, 2 weeks, 4 weeks, 6 weeks, 3 months and 6 months after the operation. Participants will be examined at each visit and tests will be performed to measure the safety and effect of the intervention. These will include detailed tests of sight, photographs, scans, measuring the electrical responses to light, mobility tests and blood tests. Each of these follow-up visits will take 1 to 3 days depending on the number of tests scheduled for each visit. Safety will be assessed on an ongoing basis in this trial. When the six months follow up time point has been reached in this study, participants will subsequently be invited to enrol in a separate follow-up study where they will be assessed for safety up to 60 months following ATIMP administration. Participants in the current study will be strongly encouraged to join the follow up study as part of their ongoing clinical review, though will be no obligation on their part to do so.
Study Phase Phase 1/Phase 2
Study Type † Interventional
Study Design †
Primary Outcome Measure † Incidence of Adverse Events related to the sub retinal administration of an AAV2/8 vector.
Secondary Outcome Measure † Improvement in the visual function
Condition † Achromatopsia
Intervention † GeneticAAV2/8 viral vector
Study Arms / Comparison Groups Intervention single arm Subretinal administration of an AAV2/8 viral vector in cohorts of 3 participants at a time.
Publications *

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information
Recruitment Status † Genetic
Estimated Enrollment † 18
Start Date † January 12, 2016
Completion Date December 2018
Primary Completion Date December 2018
Eligibility Criteria † Inclusion Criteria: - Are aged 3 years or older (children will be enrolled only once the MTD has been determined) - Are male or female - Have achromatopsia confirmed by a retinal specialist (CI or PI) - Have homozygous or compound heterozygous missense or null mutations in CNGB3 - Have evidence of relative photoreceptor survival at the macula, which will be assessed by OCT +/- AO - Are able to give informed consent or assent, with or without 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 at least 12 months following ATIMP administration) - If male, are willing to use barrier and spermicide form of contraceptive or maintain sexual abstinence for at least 12 months following ATIMP administration - 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 uncontrolled 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 - 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 CI/PI considers makes them inappropriate for entry into the trial - Have an ocular or systemic disorder that may preclude subretinal surgery and/or interfere with interpretation of the study results - Have had intraocular surgery within 6 months of screening - Are unwilling to consider the possibility of entry into a subsequent longer term follow up study
Gender All
Ages 3 Years - N/A
Accepts Healthy Volunteers No
Contacts †† Julie Bakobaki, MSc,
Location Countries † United Kingdom
Administrative Information
NCT ID † NCT03001310
Organization ID MGT006
Secondary IDs †† 2016-002290-35
Responsible Party Sponsor
Study Sponsor † MeiraGTx UK II Ltd
Collaborators †† EMAS
Investigators † Principal Investigator: James Bainbridge, Prof, Chief Investigator
Information Provided By
Verification Date February 2017
First Received Date † November 22, 2016
Last Updated Date February 22, 2017
† Required WHO trial registration data element.
†† WHO trial registration data element that is required only if it exists.
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