Achromatopsia
Conditions
Keywords
Achromatopsia, CNGA3, CNGB3
Brief summary
This is a longer-term follow-up study of patients with achromatopsia associated with defects in CNGA3 who participated in a clinical trial in which they received AAV-CNGA3 retinal gene therapy, or of patients with achromatopsia associated with defects in CNGB3 who participated in a clinical trial in which they received AAV-CNGB3 retinal gene therapy.
Detailed description
The follow-up study is designed to collect data on the longer-term safety and efficacy of AAV-CNGA3 retinal gene therapy and AAV-CNGB3 retinal gene therapy.
Interventions
BIOLOGICALPrior exposure to AAV-CNGA3 or AAV-CNGB3
Participants previously received AAV-CNGA3 or AAV-CNGB3 in an open-label, Phase 1/2 dose escalation trial for adults and children with achromatopsia owing to defects in CNGA3 or CNGB3, respectively.
Sponsors
MeiraGTx UK II Ltd
Study design
Observational model
COHORT
Time perspective
PROSPECTIVE
Eligibility
Sex/Gender
ALL
Age
3 Years to 100 Years
Healthy volunteers
No
Inclusion criteria
Inclusion in the study will be limited to individuals who: 1. Are able to give informed consent or assent, with or without the guidance of their parent(s)/guardian(s), where appropriate 2. Received AAV2/8-hCARp.hCNGB3 or AAV2/8-hG1.7p.coCNGA3 by intraocular administration in the prior open-label, Phase I/II, dose escalation study (EudraCT 2016-002290-35 or EudraCT 2018-003431-29) 3. Are willing to adhere to the protocol and long-term follow-up Individuals will be excluded who: Are unwilling or unable to meet the requirements of the study
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Incidence of Adverse Events Related to the Treatment | 5 Years | The primary outcome measure is the longer-term safety of treatment with AAV-CNGA3 or AAV-CNGB3, assessed by the absence of IMP-related adverse events. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Improvements in Visual Function as Assessed by Visual Acuity at Month 60 | 60 months | Change from baseline to Month 60 in best corrected visual acuity (BCVA) using Early Treatment Diabetic Retinopathy Study (ETDRS) chart letter score in the treated eye. The direction of improvement from baseline is an increase in the number of ETDRS letters read over time. |
| Improvements in Retinal Function as Assessed by Static Perimetry at Month 12 | 12 months | Change from baseline to Month 12 in contrast sensitivity in the treated eye. The direction of improvement is an increase in sensitivity. |
| Improvements in Retinal Function as Assessed by Static Perimetry at Month 60 | 60 months | Change from baseline to Month 60 in contrast sensitivity in the treated eye. The direction of improvement is an increase in sensitivity. |
| Improvements in Visual Function as Assessed by Visual Acuity at Month 12 | 12 months | Change from baseline to Month 12 in best corrected visual acuity (BCVA) using Early Treatment Diabetic Retinopathy Study (ETDRS) chart letter score in the treated eye. The direction of improvement from baseline is an increase in the number of ETDRS letters read over time. |
| Quality of Life at Month 60 Measured by QoL Questionnaires in Children and Adolescents | 60 months | Change from baseline to Month 60 in EuroQol-5D-Y Visual Analogue Scale (EQ-VAS) in children and adolescents. EQ-VAS uses a scale from 0 to 100, where 0 represents the worst imaginable health state and 100 represents the best imaginable health state. A positive change from baseline reflects improvement, and a negative change from baseline reflects worsening. |
| Quality of Life at Month 12 Measured by QoL Questionnaires in Adults | 12 months | Change from baseline to Month 12 in EuroQol-5D-5L Visual Analogue Scale (EQ-VAS) in adults. EQ-VAS uses a scale from 0 to 100, where 0 represents the worst imaginable health state and 100 represents the best imaginable health state. A positive change from baseline reflects improvement, and a negative change from baseline reflects worsening. |
| Quality of Life at Month 60 Measured by QoL Questionnaires in Adults | 60 months | Change from baseline to Month 60 in EuroQol-5D-5L Visual Analogue Scale (EQ-VAS) in adults. EQ-VAS uses a scale from 0 to 100, where 0 represents the worst imaginable health state and 100 represents the best imaginable health state. A positive change from baseline reflects improvement, and a negative change from baseline reflects worsening. |
| Quality of Life at Month 12 Measured by QoL Questionnaires in Children and Adolescents | 12 months | Change from baseline to Month 12 in EuroQol-5D-Y Visual Analogue Scale (EQ-VAS) in children and adolescents. EQ-VAS uses a scale from 0 to 100, where 0 represents the worst imaginable health state and 100 represents the best imaginable health state. A positive change from baseline reflects improvement, and a negative change from baseline reflects worsening. |
Countries
United Kingdom, United States
Participant flow
Recruitment details
Participants were recruited from medical centers in the United Kingdom (UK) and the United States (US). A total of 34 participants were enrolled in the study.
Participants by arm
| Arm | Count |
|---|---|
| Low Dose AAV-CNGA3 or AAV-CNGB3 Subretinal administration of a single low dose of adeno-associated virus AAV-CNGA3 or AAV-CNGB3
AAV gene therapy for defects in the CNGA3 or CNGB3 gene, respectively. | 6 |
| Intermediate Dose AAV-CNGA3 or AAV-CNGB3 Subretinal administration of a single intermediate dose of adeno-associated virus AAV-CNGA3 or AAV-CNGB3
AAV gene therapy for defects in the CNGA3 or CNGB3 gene, respectively. | 15 |
| Other Dose AAV-CNGA3 or AAV-CNGB3 Subretinal administration of a single other dose (between the intermediate and high dose) of adeno-associated virus AAV-CNGA3 or AAV-CNGB3
AAV gene therapy for defects in the CNGA3 or CNGB3 gene, respectively. | 3 |
| High Dose AAV-CNGA3 or AAV-CNGB3 Subretinal administration of a single high dose of adeno-associated virus AAV-CNGA3 or AAV-CNGB3
AAV gene therapy for defects in the CNGA3 or CNGB3 gene, respectively. | 10 |
| Total | 34 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Early Termination | 2 | 6 | 0 | 4 |
| Overall Study | Lost to Follow-up | 0 | 0 | 2 | 0 |
| Overall Study | Patient withdrew as they could no longer participate, as they had moved to Canada | 0 | 0 | 1 | 0 |
| Overall Study | Sponsor's decision | 0 | 1 | 0 | 0 |
| Overall Study | The patient decided to withdraw via email | 1 | 0 | 0 | 0 |
| Overall Study | The patient was unresponsive to contact | 0 | 0 | 0 | 4 |
| Overall Study | The patient wished to participate no longer | 0 | 1 | 0 | 0 |
| Overall Study | Withdrawal by Subject | 0 | 1 | 0 | 0 |
Baseline characteristics
| Characteristic | Low Dose AAV-CNGA3 or AAV-CNGB3 | Intermediate Dose AAV-CNGA3 or AAV-CNGB3 | Other Dose AAV-CNGA3 or AAV-CNGB3 | High Dose AAV-CNGA3 or AAV-CNGB3 | Total |
|---|---|---|---|---|---|
| Age, Categorical <=18 years | 3 Participants | 11 Participants | 3 Participants | 5 Participants | 22 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 3 Participants | 4 Participants | 0 Participants | 5 Participants | 12 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants | 2 Participants | 2 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 6 Participants | 15 Participants | 3 Participants | 8 Participants | 32 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 2 Participants | 1 Participants | 0 Participants | 2 Participants | 5 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 4 Participants | 14 Participants | 3 Participants | 8 Participants | 29 Participants |
| Region of Enrollment United Kingdom | 6 participants | 14 participants | 1 participants | 8 participants | 29 participants |
| Region of Enrollment United States | 0 participants | 1 participants | 2 participants | 2 participants | 5 participants |
| Sex: Female, Male Female | 3 Participants | 10 Participants | 3 Participants | 4 Participants | 20 Participants |
| Sex: Female, Male Male | 3 Participants | 5 Participants | 0 Participants | 6 Participants | 14 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 6 | 0 / 15 | 0 / 3 | 0 / 10 | 0 / 34 |
| other Total, other adverse events | 1 / 6 | 4 / 15 | 3 / 3 | 2 / 10 | 10 / 34 |
| serious Total, serious adverse events | 0 / 6 | 1 / 15 | 0 / 3 | 1 / 10 | 2 / 34 |
Outcome results
Primary
Incidence of Adverse Events Related to the Treatment
The primary outcome measure is the longer-term safety of treatment with AAV-CNGA3 or AAV-CNGB3, assessed by the absence of IMP-related adverse events.
Time frame: 5 Years
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Low Dose AAV-CNGA3 or AAV-CNGB3 | Incidence of Adverse Events Related to the Treatment | 1 Participants |
| Intermediate Dose AAV-CNGA3 or AAV-CNGB3 | Incidence of Adverse Events Related to the Treatment | 2 Participants |
| Other Dose AAV-CNGA3 or AAV-CNGB3 | Incidence of Adverse Events Related to the Treatment | 0 Participants |
| High Dose AAV-CNGA3 or AAV-CNGB3 | Incidence of Adverse Events Related to the Treatment | 0 Participants |
Secondary
Improvements in Retinal Function as Assessed by Static Perimetry at Month 12
Change from baseline to Month 12 in contrast sensitivity in the treated eye. The direction of improvement is an increase in sensitivity.
Time frame: 12 months
Population: 31 of the 34 participants had contrast sensitivity data available at both baseline and Month 12 in the treated eye.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Low Dose AAV-CNGA3 or AAV-CNGB3 | Improvements in Retinal Function as Assessed by Static Perimetry at Month 12 | -0.08 LogCS |
| Intermediate Dose AAV-CNGA3 or AAV-CNGB3 | Improvements in Retinal Function as Assessed by Static Perimetry at Month 12 | -0.17 LogCS |
| Other Dose AAV-CNGA3 or AAV-CNGB3 | Improvements in Retinal Function as Assessed by Static Perimetry at Month 12 | 0.12 LogCS |
| High Dose AAV-CNGA3 or AAV-CNGB3 | Improvements in Retinal Function as Assessed by Static Perimetry at Month 12 | 0.03 LogCS |
Secondary
Improvements in Retinal Function as Assessed by Static Perimetry at Month 60
Change from baseline to Month 60 in contrast sensitivity in the treated eye. The direction of improvement is an increase in sensitivity.
Time frame: 60 months
Population: 15 of the 34 participants had contrast sensitivity data available at both baseline and Month 60 in the treated eye.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Low Dose AAV-CNGA3 or AAV-CNGB3 | Improvements in Retinal Function as Assessed by Static Perimetry at Month 60 | -0.19 LogCS |
| Intermediate Dose AAV-CNGA3 or AAV-CNGB3 | Improvements in Retinal Function as Assessed by Static Perimetry at Month 60 | -0.11 LogCS |
| High Dose AAV-CNGA3 or AAV-CNGB3 | Improvements in Retinal Function as Assessed by Static Perimetry at Month 60 | -0.12 LogCS |
Secondary
Improvements in Visual Function as Assessed by Visual Acuity at Month 12
Change from baseline to Month 12 in best corrected visual acuity (BCVA) using Early Treatment Diabetic Retinopathy Study (ETDRS) chart letter score in the treated eye. The direction of improvement from baseline is an increase in the number of ETDRS letters read over time.
Time frame: 12 months
Population: 32 of the 34 participants performed the visual acuity assessment at baseline and Month 12.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Low Dose AAV-CNGA3 or AAV-CNGB3 | Improvements in Visual Function as Assessed by Visual Acuity at Month 12 | -0.6 Number of ETDRS letters |
| Intermediate Dose AAV-CNGA3 or AAV-CNGB3 | Improvements in Visual Function as Assessed by Visual Acuity at Month 12 | 0.2 Number of ETDRS letters |
| Other Dose AAV-CNGA3 or AAV-CNGB3 | Improvements in Visual Function as Assessed by Visual Acuity at Month 12 | 3.5 Number of ETDRS letters |
| High Dose AAV-CNGA3 or AAV-CNGB3 | Improvements in Visual Function as Assessed by Visual Acuity at Month 12 | 4.0 Number of ETDRS letters |
Secondary
Improvements in Visual Function as Assessed by Visual Acuity at Month 60
Change from baseline to Month 60 in best corrected visual acuity (BCVA) using Early Treatment Diabetic Retinopathy Study (ETDRS) chart letter score in the treated eye. The direction of improvement from baseline is an increase in the number of ETDRS letters read over time.
Time frame: 60 months
Population: 16 of the 34 participants performed the visual acuity assessment at baseline and Month 60.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Low Dose AAV-CNGA3 or AAV-CNGB3 | Improvements in Visual Function as Assessed by Visual Acuity at Month 60 | 3.3 Number of ETDRS letters |
| Intermediate Dose AAV-CNGA3 or AAV-CNGB3 | Improvements in Visual Function as Assessed by Visual Acuity at Month 60 | 0.1 Number of ETDRS letters |
| High Dose AAV-CNGA3 or AAV-CNGB3 | Improvements in Visual Function as Assessed by Visual Acuity at Month 60 | -0.3 Number of ETDRS letters |
Secondary
Quality of Life at Month 12 Measured by QoL Questionnaires in Adults
Change from baseline to Month 12 in EuroQol-5D-5L Visual Analogue Scale (EQ-VAS) in adults. EQ-VAS uses a scale from 0 to 100, where 0 represents the worst imaginable health state and 100 represents the best imaginable health state. A positive change from baseline reflects improvement, and a negative change from baseline reflects worsening.
Time frame: 12 months
Population: Two adult participants had EuroQol-5D-5L EQ-VAS data available at both baseline and Month 12. For this study outcome, adults are participants aged ≥16 years in the UK and aged ≥18 years in the US.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| High Dose AAV-CNGA3 or AAV-CNGB3 | Quality of Life at Month 12 Measured by QoL Questionnaires in Adults | 0.5 Units on a scale |
Secondary
Quality of Life at Month 12 Measured by QoL Questionnaires in Children and Adolescents
Change from baseline to Month 12 in EuroQol-5D-Y Visual Analogue Scale (EQ-VAS) in children and adolescents. EQ-VAS uses a scale from 0 to 100, where 0 represents the worst imaginable health state and 100 represents the best imaginable health state. A positive change from baseline reflects improvement, and a negative change from baseline reflects worsening.
Time frame: 12 months
Population: Eleven pediatric participants had EuroQol-5D-Y EQ-VAS data available at both baseline and Month 12. For this study outcome, pediatric participants are participants aged \<16 years in the UK and aged \<18 years in the US.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Intermediate Dose AAV-CNGA3 or AAV-CNGB3 | Quality of Life at Month 12 Measured by QoL Questionnaires in Children and Adolescents | 4.3 Units on a scale |
| Other Dose AAV-CNGA3 or AAV-CNGB3 | Quality of Life at Month 12 Measured by QoL Questionnaires in Children and Adolescents | 9.5 Units on a scale |
| High Dose AAV-CNGA3 or AAV-CNGB3 | Quality of Life at Month 12 Measured by QoL Questionnaires in Children and Adolescents | -12.0 Units on a scale |
Secondary
Quality of Life at Month 60 Measured by QoL Questionnaires in Adults
Change from baseline to Month 60 in EuroQol-5D-5L Visual Analogue Scale (EQ-VAS) in adults. EQ-VAS uses a scale from 0 to 100, where 0 represents the worst imaginable health state and 100 represents the best imaginable health state. A positive change from baseline reflects improvement, and a negative change from baseline reflects worsening.
Time frame: 60 months
Population: One adult participant had EuroQol-5D-5L EQ-VAS data available at both baseline and Month 60. For this study outcome, adults are participants aged ≥16 years in the UK and aged ≥18 years in the US.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Low Dose AAV-CNGA3 or AAV-CNGB3 | Quality of Life at Month 60 Measured by QoL Questionnaires in Adults | 0.0 Units on a scale |
Secondary
Quality of Life at Month 60 Measured by QoL Questionnaires in Children and Adolescents
Change from baseline to Month 60 in EuroQol-5D-Y Visual Analogue Scale (EQ-VAS) in children and adolescents. EQ-VAS uses a scale from 0 to 100, where 0 represents the worst imaginable health state and 100 represents the best imaginable health state. A positive change from baseline reflects improvement, and a negative change from baseline reflects worsening.
Time frame: 60 months
Population: Two pediatric participants had EuroQol-5D-Y EQ-VAS data available at both baseline and Month 60. For this study outcome, pediatric participants are participants aged \<16 years in the UK and aged \<18 years in the US.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Intermediate Dose AAV-CNGA3 or AAV-CNGB3 | Quality of Life at Month 60 Measured by QoL Questionnaires in Children and Adolescents | 0.0 Units on a scale |