CHM (Choroideremia) Gene Mutations, Choroideremia
Conditions
Keywords
Choroideremia, AAV, Gene therapy, CHM, Adeno-associated virus, Adeno-associated viral vector
Brief summary
This clinical study evaluates the safety and tolerability of AAV2-hCHM in participants with Choroideremia gene mutations.
Detailed description
The primary objective is to evaluate the safety and tolerability of subretinal administration of AAV2-hCHM, in an inter-subject group dose escalation in individuals with choroideremia, based on a comprehensive clinical monitoring plan. The secondary objectives are to define the dose of AAV2-hCHM required to achieve stable, or improved, visual function/functional vision and to assess development of immune responses to adeno-associated virus vector, serotype 2 (AAV2) and Rab escort protein 1 (REP-1).
Interventions
BIOLOGICALAAV2-hCHM
Comparison of different dosages of AAV2-hCHM
Sponsors
Spark Therapeutics, Inc.
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
MALE
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Male at least 18 years of age diagnosed with CHM gene mutation * Central visual field (VF) \<30° in any of the 24 meridians (using Goldmann perimetry III4e isopter) in the eye to be injected * Any evidence of functioning outer retinal cells within the central 10°
Exclusion criteria
* Previous history of ocular inflammatory disease (uveitis) * Prior intraocular surgery within six months * Participation in a previous gene therapy research trial within one year of enrollment or participation in any other ocular gene therapy trial * Participation in a clinical study with an investigational drug in the past six months * Grossly asymmetrical disease, or other eye morbidity, which may render the contralateral eye ineffective as a control * Visual acuity \<20/200 on standard Early Treatment of Diabetic Retinopathy Study (ETDRS) testing in the eye to be injected * Presence of disease which may preclude the participant from participation in this trial * Use of medications known to be neuroprotective or retino-toxic that could potentially interfere with the disease process and/or cause ocular adverse events; individuals who discontinue use of these compounds for 6 months may become eligible * Identification by the investigator as being unable or unwilling to perform/be compliant with study procedures.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | Up to 5 years | An adverse event (AE) was defined as any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. TEAEs were AEs that occurred on or after the day of study drug administration. A summary of other non-serious AEs and all serious AEs, regardless of causality is located in Reported AE section. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Anti-AAV2 Viral Capsid Antibody Titers That Rose Above Baseline At Least Once After Dosing | Up to 2 years | Number of participants who were found to have quantifiable levels (above 1.55 micrograms \[μg\]/milliliter \[mL\]) of Anti-AAV2 viral capsid antibodies titer in the blood at least 1 study visit up to 2 years were reported. |
| Number of Participants With Cellular Immune Response to AAV2 Through Interferon Gamma Enzyme-linked Immunosorbent Spot (ELISpot) Assay | Up to 2 years | Interferon gamma ELISpot assays were used to evaluate the cellular immune response to AAV2 antigen in collected peripheral blood mononuclear cell (PBMC) samples. Number of participants who demonstrated immune response to the AAV2 antigen were reported. |
| Number of Participants With Cellular Immune Response to Rab Escore Protein-1 (REP-1) Through Interferon Gamma ELISPOT Assay | Up to 2 years | Interferon gamma ELISpot assays were used to evaluate the cellular immune response to REP-1 antigen in collected PBMC samples. Number of participants who demonstrated immune response to the REP-1 antigen were reported. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Cohort 1: AAV2-hCHM Dose 1 Single, unilateral subretinal administration of a single low dose range of AAV2-hCHM. | 5 |
| Cohort 2: AAV2-hCHM Dose 2 Single, unilateral subretinal administration of a single high dose range of AAV2-hCHM. | 5 |
| Cohort 3 (Expansion Cohort): AAV2-hCHM Dose 2 Single, unilateral subretinal administration of a single high dose range of AAV2-hCHM. | 5 |
| Total | 15 |
Baseline characteristics
| Characteristic | Total | Cohort 1: AAV2-hCHM Dose 1 | Cohort 2: AAV2-hCHM Dose 2 | Cohort 3 (Expansion Cohort): AAV2-hCHM Dose 2 |
|---|---|---|---|---|
| Age, Continuous | 34.5 years STANDARD_DEVIATION 9.68 | 37.0 years STANDARD_DEVIATION 7.52 | 39.6 years STANDARD_DEVIATION 11.65 | 27.0 years STANDARD_DEVIATION 5 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 15 Participants | 5 Participants | 5 Participants | 5 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 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 |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 15 Participants | 5 Participants | 5 Participants | 5 Participants |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Male | 15 Participants | 5 Participants | 5 Participants | 5 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 5 | 0 / 5 | 0 / 5 |
| other Total, other adverse events | 5 / 5 | 5 / 5 | 5 / 5 |
| serious Total, serious adverse events | 1 / 5 | 2 / 5 | 2 / 5 |
Outcome results
Primary
Number of Participants With Treatment-Emergent Adverse Events (TEAEs)
An adverse event (AE) was defined as any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. TEAEs were AEs that occurred on or after the day of study drug administration. A summary of other non-serious AEs and all serious AEs, regardless of causality is located in Reported AE section.
Time frame: Up to 5 years
Population: FAS included all participants who received the investigational product.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Cohort 1: AAV2-hCHM Dose 1 | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | 5 Participants |
| Cohort 2: AAV2-hCHM Dose 2 | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | 5 Participants |
| Cohort 3 (Expansion Cohort): AAV2-hCHM Dose 2 | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | 5 Participants |
Secondary
Number of Participants With Anti-AAV2 Viral Capsid Antibody Titers That Rose Above Baseline At Least Once After Dosing
Number of participants who were found to have quantifiable levels (above 1.55 micrograms \[μg\]/milliliter \[mL\]) of Anti-AAV2 viral capsid antibodies titer in the blood at least 1 study visit up to 2 years were reported.
Time frame: Up to 2 years
Population: FAS included all participants who received the investigational product.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Cohort 1: AAV2-hCHM Dose 1 | Number of Participants With Anti-AAV2 Viral Capsid Antibody Titers That Rose Above Baseline At Least Once After Dosing | 0 Participants |
| Cohort 2: AAV2-hCHM Dose 2 | Number of Participants With Anti-AAV2 Viral Capsid Antibody Titers That Rose Above Baseline At Least Once After Dosing | 1 Participants |
| Cohort 3 (Expansion Cohort): AAV2-hCHM Dose 2 | Number of Participants With Anti-AAV2 Viral Capsid Antibody Titers That Rose Above Baseline At Least Once After Dosing | 3 Participants |
Secondary
Number of Participants With Cellular Immune Response to AAV2 Through Interferon Gamma Enzyme-linked Immunosorbent Spot (ELISpot) Assay
Interferon gamma ELISpot assays were used to evaluate the cellular immune response to AAV2 antigen in collected peripheral blood mononuclear cell (PBMC) samples. Number of participants who demonstrated immune response to the AAV2 antigen were reported.
Time frame: Up to 2 years
Population: FAS included all participants who received the investigational product.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Cohort 1: AAV2-hCHM Dose 1 | Number of Participants With Cellular Immune Response to AAV2 Through Interferon Gamma Enzyme-linked Immunosorbent Spot (ELISpot) Assay | 0 Participants |
| Cohort 2: AAV2-hCHM Dose 2 | Number of Participants With Cellular Immune Response to AAV2 Through Interferon Gamma Enzyme-linked Immunosorbent Spot (ELISpot) Assay | 0 Participants |
| Cohort 3 (Expansion Cohort): AAV2-hCHM Dose 2 | Number of Participants With Cellular Immune Response to AAV2 Through Interferon Gamma Enzyme-linked Immunosorbent Spot (ELISpot) Assay | 0 Participants |
Secondary
Number of Participants With Cellular Immune Response to Rab Escore Protein-1 (REP-1) Through Interferon Gamma ELISPOT Assay
Interferon gamma ELISpot assays were used to evaluate the cellular immune response to REP-1 antigen in collected PBMC samples. Number of participants who demonstrated immune response to the REP-1 antigen were reported.
Time frame: Up to 2 years
Population: FAS included all participants who received the investigational product.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Cohort 1: AAV2-hCHM Dose 1 | Number of Participants With Cellular Immune Response to Rab Escore Protein-1 (REP-1) Through Interferon Gamma ELISPOT Assay | 2 Participants |
| Cohort 2: AAV2-hCHM Dose 2 | Number of Participants With Cellular Immune Response to Rab Escore Protein-1 (REP-1) Through Interferon Gamma ELISPOT Assay | 0 Participants |
| Cohort 3 (Expansion Cohort): AAV2-hCHM Dose 2 | Number of Participants With Cellular Immune Response to Rab Escore Protein-1 (REP-1) Through Interferon Gamma ELISPOT Assay | 0 Participants |