A Safety Study of Retinal Gene Therapy for Choroideremia With Administration of BIIB111

Study Overview
=================
Brief Summary
-----------------
The objective of the study is to evaluate the safety of bilateral, sequential sub-retinal administration of a single dose of BIIB111 in adult male participants with Choroideremia (CHM).

Detailed Description
-----------------
This study was previously posted by NightstaRx Ltd. In October 2020, sponsorship of the trial was transferred to Biogen.

Official Title
-----------------
An Open-Label Safety Study of Retinal Gene Therapy for Choroideremia With Bilateral, Sequential Administration of Adeno-Associated Viral Vector (AAV2) Encoding Rab Escort Protein 1 (REP1)

Conditions
-----------------
Choroideremia

Intervention / Treatment
-----------------
* Drug: BIIB111


Participation Criteria
=================
Eligibility Criteria
-----------------
Key Inclusion Criteria: Are willing and able to give informed consent for participation in the study to have both eyes treated. Have documentation of a genetically-confirmed diagnosis of CHM. Have active disease clinically visible within the macular region of both eyes. Have a BCVA of ≥34 ETDRS letters (20/200 or better Snellen acuity) in both eyes, or in the untreated eye, if the other eye was previously treated with BIIB111* *If previously treated with BIIB111 in an antecedent study, participants may be eligible for participation following Sponsor approval. For participants who received treatment with BIIB111 in an antecedent study, have biological samples available to complete an adequate immunology profile. Key Exclusion Criteria: Have a history of amblyopia or inflammatory disorder in either eye. Are unwilling to use barrier contraception methods or abstain from sexual intercourse for a period of 3 months following treatment with BIIB111 in either eye. Have had previous intraocular surgery performed within 3 months of the Screening Visit in either eye. Have any other significant ocular or non-ocular disease/disorder which, in the opinion of the investigator, may either put the participants at risk because of participation in the study, or may influence the results of the study or the participant's ability to participate in the study. This includes but is not limited to a potential participants: with a contraindication to oral corticosteroid (e.g., prednisolone/prednisone) with clinically significant cataract in either eye who, in the clinical opinion of the Investigator, is not an appropriate candidate for sub-retinal surgery. Have participated in another research study involving an investigational product in the past 12 weeks or received a gene/cell-based therapy at any time previously, except if treated within an antecedent study with BIIB111. NOTE: Other protocol defined Inclusion/Exclusion criteria may apply

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
Male

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: BIIB111<br>Participants will receive a single dose of sub-retinal injection of BIIB111 in each eye at Day 0 separated by an interval of <6 months, 6-12 months, or >12 months. | Drug: BIIB111<br>* Administered as specified in the treatment arm.<br>* Other names: AAV2-REP1;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean Best-Corrected Visual Acuity (BCVA) as Measured by the Early Treatment of Diabetic Retinopathy Study (ETDRS) Chart in Letters at Month 12 | BCVA was assessed for both eyes using the ETDRS visual acuity (VA) chart. BCVA test should be performed prior to pupil dilation, and distance refraction should be carried out before BCVA is measured. Initially, letters are read at a distance of 4 meters from the chart. If <20 letters are read at 4 meters, testing at 1 meter should be performed. BCVA is reported as number of letters read correctly by the participant using the ETDRS Scale (ranging from 0 to 100 letters) in the study eyes. The lower the number of letters read correctly on the eye chart, the worse the vision (or visual acuity). An increase in the number of letters read correctly means that vision has improved. | Month 12 | 
| Ophthalmic Examination Assessment: Mean Intraocular Pressure (IOP) at Month 12 | IOP, the fluid pressure inside the eye was measured and reported in millimeters mercury (mmHg). | Month 12 | 
| Ophthalmic Examination Assessment: Number of Participants With Clinically Significant Abnormalities in Slit Lamp Examination | Slit lamp examinations of study eyes included examination of Cornea, Conjunctiva, Iris, Lens, and Anterior Segment. | Baseline, Month 12 | 
| Ophthalmic Examination Assessment: Number of Participants With Clinically Significant Abnormalities in Dilated Ophthalmoscopy | Dilated Ophthalmoscopy examination of study eyes included examination of Vitreous, Macula, Peripheral retina, Choroid, and Optic nerve. | Baseline, Month 12 | 
| Ophthalmic Examination Assessment: Number of Participants With Lens Opacity Grading | The following lens opacity grades are reported for categories 1-4: Nuclear Opalescence grade, Nuclear Color grade, Cortical Cataract grade, and Posterior Cataract grade. Opacification severity is graded on a decimal scale, scores can range from 0.1 (no opacity) to 6.9 (maximum opacity) for the Nuclear Opalescence and Nuclear Color grades; and scores can range from 0.1 (lens clear) to 5.9 (lens unclear) for the Cortical and Posterior Cataract grades. Category 1 includes values 1, 1.0 and 0.x, Category 2 includes values 2, 2.0 and 1.x, Category 3 includes values 3, 3.0 and 2.x, and Category 4 includes values 4, 4.0, 3.x and any values above 4. For each opacification type the higher grading scores indicate greater severity. | Month 12 | 
| Spectral Domain Optical Coherence Tomography (SD-OCT): Foveal Subfield Thickness at Month 12 | SD-OCT was used to assess change in foveal subfield thickness. The measurements were taken after dilation of the participant's pupil. | Month 12 | 
| SD-OCT: Total Macular Volume at Month 12 | SD-OCT was used to assess change in total macular volume. The measurements were taken after dilation of the participant's pupil. | Month 12 | 
| SD-OCT: Central Horizontal Ellipsoid Width at Month 12 | SD-OCT was used to assess change in central horizontal ellipsoid width. The measurements were taken after dilation of the participant's pupil. | Month 12 | 
| SD-OCT: Central Ellipsoid Area at Month 12 | SD-OCT was used to assess change in central ellipsoid area. The measurements were taken after dilation of the participant's pupil. | Month 12 | 
| SD-OCT: Square Root of Central Ellipsoid Area at Month 12 | SD-OCT was used to assess change in square root of central ellipsoid area. The measurements were taken after dilation of the participant's pupil. | Month 12 | 
| SD-OCT: Choroidal Thickness at Foveal Center at Month 12 | SD-OCT was used to assess change in choroidal thickness. The measurements were taken after dilation of the participant's pupil. | Month 12 | 
| Fundus Autofluorescence (AF): Mean Total Area of Preserved Autofluorescence at Month 12 | Fundus AF was used to assess the total area of preserved AF. Areas of preserved AF were identified as well-demarcated regions of relative hyper autofluorescence (hyper AF) compared with the background areas of surrounding atrophy. | Month 12 | 
| AF: Mean Square Root of Total Area of Preserved AF at Month 12 | Fundus AF was used to assess the square root of total area of preserved AF. Areas of preserved AF were identified as well-demarcated regions of relative hyper AF compared with the background areas of surrounding atrophy. | Month 12 | 
| AF: Mean Distance From Foveal Center to Nearest Border of Preserved AF at Month 12 | Fundus AF was used to assess the distance from foveal center to nearest border of preserved AF. | Month 12 | 
| Fundus Photography: Number of Participants With Retinal Pigment Epithelium (RPE) Hyperplasia as Per Severity | Number of participants with RPE hyperplasia are reported for severity grades: mild, moderate, severe. | Month 12 | 
| Fundus Photography: Number of Participants With Retinal Arteriolar Narrowing as Per Severity | Number of participants with retinal arteriolar narrowing are reported for severity grades: mild, moderate, severe. | Month 12 | 
| Fundus Photography: Number of Participants With Retinal Vessel Sheathing as Per Severity | Number of participants with retinal vessel sheathing are reported for severity grades: mild, moderate, severe. | Month 12 | 
| Fundus Photography: Number of Participants With Optic Atrophy/Pallor as Per Severity | Number of participants with optic atrophy/pallor are reported for severity grades: mild, moderate, severe. | Month 12 | 
| Fundus Photography: Number of Participants With Optic Disc Swelling as Per Severity | Number of participants with optic disc swelling are reported for severity grades: mild, moderate, severe. | Month 12 | 
| Microperimetry: Retinal Mean Sensitivity at Month 12 | Microperimetry was conducted to assess retinal mean sensitivity within the macula. Retinal mean sensitivity to light was measured in decibels in multiple spots across the central and peripheral retina (entire visual field). Higher numbers (decibels) indicate higher retinal sensitivity. | Month 12 | 
| Microperimetry: Bivariate Contour Ellipse Area 63% at Month 12 | Microperimetry was conducted to assess bivariate contour ellipse area 63%. | Month 12 | 
| Microperimetry: Bivariate Contour Ellipse Area 95% at Month 12 | Microperimetry was conducted to assess bivariate contour ellipse area 95%. | Month 12 | 
| Microperimetry: Fixation Losses (in Percentage) at Month 12 | Microperimetry was conducted to assess fixation losses (in percentage) which samples the optic nerve blind spot for positive responses. | Month 12 | 
| Percentage of Participants With at Least One Treatment-Emergent Adverse Event (TEAE) | An AE is any unfavourable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of the study drug/surgical procedure, whether or not related to the investigational product or with the surgical procedure. TEAEs are defined as AEs starting on or after the day of the first surgery. | Day 0 (surgery) in period 1 up to last follow up visit in period 2 (approximately 2 years) | 
| Number of Participants With Vector Shedding Post-treatment at Month 3 | Tears (for both eyes- oculus dexter [OD] and oculus sinister [OS]), blood, urine and saliva samples were collected and tested using an appropriate assay for evidence of vector shedding. Participants with positive result for vector shredding post treatment are reported. | Baseline, at Month 3 | 
| Number of Participants With Anti-drug Antibodies Post-treatment at Month 12 | Participants with antibodies to the REP-1 transgenic product are reported. | Month 12 | 
| Vital Signs: Change From Baseline in Blood Pressure at Month 12 | Change from baseline in Systolic and diastolic blood pressures (BP) (millimeters of mercury [mmHg]) were reported. | Baseline, Month 12 | 
| Vital Signs: Change From Baseline in Pulse Rate at Month 12 | Change from baseline in pulse rate (beats per minute) were reported. | Baseline, Month 12 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in BCVA as Measured by the ETDRS Chart | BCVA was assessed for both eyes using the ETDRS VA chart. BCVA test should be performed prior to pupil dilation, and distance refraction should be carried out before BCVA is measured. Initially, letters are read at a distance of 4 meters from the chart. If <20 letters are read at 4 meters, testing at 1 meter should be performed. BCVA is reported as number of letters read correctly by the participant using the ETDRS Scale (ranging from 0 to 100 letters) in the study eyes. The lower the number of letters read correctly on the eye chart, the worse the vision (or VA). An increase in the number of letters read correctly means that vision has improved. | Baseline, Month 12 | 
| AF: Change From Baseline in Total Area of Preserved Autofluorescence at Month 12 | Fundus AF was used to assess change in total area of preserved AF. Areas of preserved AF were identified as well-demarcated regions of relative hyper autofluorescence (hyper AF) compared with the background areas of surrounding atrophy. Here negative values indicate decline in total area of preserved autofluoroscence. | Baseline, Month 12 | 
| AF: Change From Baseline in Square Root of Total Area of Preserved AF at Month 12 | Fundus AF was used to assess change in square root of total area of preserved AF. Areas of preserved AF were identified as well-demarcated regions of relative hyper AF compared with the background areas of surrounding atrophy. Here negative values indicate decline in total area of preserved autofluoroscence. | Baseline, Month 12 | 
| AF: Change From Baseline in Distance From Foveal Center to Nearest Border of Preserved AF at Month 12 | Fundus Autofluoroscence was used to assess change in distance from foveal center to nearest border of preserved autofluoroscence. Here negative values indicate decline in total area of preserved autofluoroscence. | Baseline, Month 12 | 
| SD-OCT: Change From Baseline in Foveal Subfield Thickness at Month 12 | SD-OCT was used to assess change in foveal subfield thickness. The measurements were taken after dilation of the participant's pupil. A negative change from baseline indicates decline in foveal subfield thickness. | Baseline, Month 12 | 
| SD-OCT: Change From Baseline in Total Macular Volume at Month 12 | SD-OCT was used to assess change in total macular volume. The measurements were taken after dilation of the participant's pupil. A negative change from baseline indicates decline in total macular volume. | Baseline, Month 12 | 
| SD-OCT: Change From Baseline in the Central Horizontal Ellipsoid Width at Month 12 | SD-OCT was used to assess change in central horizontal ellipsoid width. The measurements were taken after dilation of the participant's pupil. A negative change from baseline indicates decline in central horizontal ellipsoid width. | Baseline, Month 12 | 
| SD-OCT: Change From Baseline in Central Ellipsoid Area at Month 12 | SD-OCT was used to assess change in central ellipsoid area. The measurements were taken after dilation of the participant's pupil. A negative change from baseline indicates decline in central ellipsoid area. | Baseline, Month 12 | 
| SD-OCT: Change From Baseline in Square Root of Central Ellipsoid Area at Month 12 | SD-OCT was used to assess change in square root of central ellipsoid area. The measurements were taken after dilation of the participant's pupil. A negative change from baseline indicates decline in square root of central ellipsoid area. | Baseline, Month 12 | 
| SD-OCT: Change From Baseline in the Choroidal Thickness at Foveal Center at Month 12 | SD-OCT was used to assess change in choroidal thickness. The measurements were taken after dilation of the participant's pupil. A negative change from baseline indicates decline in choroidal thickness. | Baseline, Month 12 | 
| Microperimetry: Change From Baseline in Retinal Mean Sensitivity at Month 12 | Microperimetry was conducted to assess change in retinal mean sensitivity within the macula. Retinal mean sensitivity to light was measured in decibels in multiple spots across the central and peripheral retina (entire visual field). Higher numbers (decibels) indicate higher retinal sensitivity. A negative change from baseline indicates decline in retinal sensitivity. | Baseline, Month 12 | 
| Microperimetry: Change From Baseline in Bivariate Contour Ellipse Area 63% at Month 12 | Microperimetry was conducted to assess change in bivariate contour ellipse area 63%. A negative change from baseline indicates decline in bivariate contour ellipse area 63%. | Baseline, Month 12 | 
| Microperimetry: Change From Baseline in the Bivariate Contour Ellipse Area 95% at Month 12 | Microperimetry was conducted to assess change in bivariate contour ellipse area 95%. A negative change from baseline indicates decline in bivariate contour ellipse area 95%. | Baseline, Month 12 | 
| Microperimetry: Change From Baseline in Fixation Losses (in Percentage) at Month 12 | Microperimetry was conducted to assess change in fixation losses (in percentage) which samples the optic nerve blind spot for positive responses. A negative change from baseline indicates decline in fixation losses. | Baseline, Month 12 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
CHM, AAV, NightstaRx, NSR-REP1, Gene Therapy, REP1, Timrepigene Emparvovec