A Clinical Trial of Retinal Gene Therapy for X-linked Retinitis Pigmentosa Using BIIB112

Study Overview
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Brief Summary
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The objective of the study is to evaluate the safety, tolerability and efficacy of a single sub-retinal injection of BIIB112 in participants with X-linked retinitis pigmentosa (XLRP).

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

Official Title
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A Dose Escalation (Phase 1), and Dose Expansion (Phase 2/3) Clinical Trial of Retinal Gene Therapy for X-linked Retinitis Pigmentosa Using an Adeno-Associated Viral Vector (AAV8) Encoding Retinitis Pigmentosa GTPase Regulator (RPGR)

Conditions
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X-Linked Retinitis Pigmentosa

Intervention / Treatment
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* Biological: BIIB112


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: Part 1: Participants with genetically confirmed diagnosis of XLRP (with RPGR mutation). Participant with active disease clinically visible within the macular region in both eyes. Part 2: - Participant with mean total retinal sensitivity in the study eye as assessed by microperimetry ≥ 0.1 dB and ≤8 dB. Key exclusion Criteria: Parts 1 and 2: Participant with history of amblyopia in either eye. Participated in a gene therapy trial previously or a clinical trial with an investigational drug in the past 12 weeks or received a gene/cell-based therapy at any time previously. NOTE: Other protocol defined Inclusion/Exclusion criteria may apply.

Ages Eligible for Study
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Minimum Age: 10 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Sequential Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part 1: BIIB112 Dose 1<br>Participants will receive a single Dose 1 of BIIB112 by sub-retinal injection on Day 0. | Biological: BIIB112<br>* Administered as specified in the treatment arm<br>* Other names: AAV8-RPGR;|
| Experimental: Part 1: BIIB112 Dose 2<br>Participants will receive a single Dose 2 of BIIB112 by sub-retinal injection on Day 0. | Biological: BIIB112<br>* Administered as specified in the treatment arm<br>* Other names: AAV8-RPGR;|
| Experimental: Part 1: BIIB112 Dose 3<br>Participants will receive a single Dose 3 of BIIB112 by sub-retinal injection on Day 0. | Biological: BIIB112<br>* Administered as specified in the treatment arm<br>* Other names: AAV8-RPGR;|
| Experimental: Part 1: BIIB112 Dose 4<br>Participants will receive a single Dose 4 of BIIB112 by sub-retinal injection on Day 0. | Biological: BIIB112<br>* Administered as specified in the treatment arm<br>* Other names: AAV8-RPGR;|
| Experimental: Part 1: BIIB112 Dose 5<br>Participants will receive a single Dose 5 of BIIB112 by sub-retinal injection on Day 0. | Biological: BIIB112<br>* Administered as specified in the treatment arm<br>* Other names: AAV8-RPGR;|
| Experimental: Part 1: BIIB112 Dose 6<br>Participants will receive a single Dose 6 of BIIB112 by sub-retinal injection on Day 0. | Biological: BIIB112<br>* Administered as specified in the treatment arm<br>* Other names: AAV8-RPGR;|
| Experimental: Part 2: BIIB112 High Dose<br>Participants will receive a single high dose of BIIB112 by sub-retinal injection. | Biological: BIIB112<br>* Administered as specified in the treatment arm<br>* Other names: AAV8-RPGR;|
| Experimental: Part 2: BIIB112 Low Dose<br>Participants will receive a single low dose of BIIB112 by sub-retinal injection. | Biological: BIIB112<br>* Administered as specified in the treatment arm<br>* Other names: AAV8-RPGR;|
| No Intervention: Part 2: Untreated Group<br>Participants will receive no intervention to allow for a controlled comparison. | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part 1: Number of Participants with Dose-Limiting Toxicities (DLTs) | DLTs are defined as any of the following events considered to be related to AAV8-RPGR: Sustained decrease in best-corrected visual acuity (BCVA) of ≥30 letters on the Early Treatment of Diabetic Retinopathy Study (ETDRS) chart compared to baseline (sustained is defined as lasting 48 hours or more until recovery, with recovery defined as visual acuity (VA) returning to within 10 letters of baseline VA. An exception is made for surgery-related events occurring in close temporal association {within <24 hours} of the surgery); Vitreous inflammation, vitritis (>Grade 3 using standardised Nussenblatt vitreous inflammation scale grading); Any clinically significant retinal damage observed that is not directly attributed to complications of surgery; Any clinically relevant suspected unexpected serious adverse reaction, with the exception of vision loss or vision threatening. | Up to Month 24 | 
| Part 1: Number of Participants with Treatment-Emergent Adverse Events (TEAEs) | An AE is any untoward medical occurrence in a participant or clinical investigation participant administered a pharmaceutical product and that does not necessarily have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal (investigational) product, whether or not related to the medicinal (investigational) product. | Up to Month 24 | 
| Part 2: Percentage of Study Eyes with ≥7 Decibels (dB) Improvement from Baseline at ≥5 of the 16 Central Loci of the 10-2 Grid Assessed by Macular Integrity Assessment (MAIA) Microperimetry | MAIA microperimetry assessment was measured in dB using a 10-2 grid of 68 points. Each point was labeled as '< 0', '0', or a positive integer. The point labeled as '< 0' was assigned a value of '-1' by MAIA in the calculation. Improvement in Retinal Sensitivity in center grid was defined as an increase from baseline of 7 or more decibels in any 5 or more points out of the 16 central points. | Months 12 | 
| Part 2: Number of Participants with TEAEs | An AE is any untoward medical occurrence in a participant or clinical investigation participant administered a pharmaceutical product and that does not necessarily have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal (investigational) product, whether or not related to the medicinal (investigational) product. | Up to Month 12 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Parts 1 and 2 : Percentage of Study Eyes with ≥7 dB Improvement from Baseline at ≥5 out of the 16 Central Loci in Microperimetry | MAIA microperimetry assessment was measured in dB using a 10-2 grid of 68 points. Each point was labeled as '< 0', '0' or a positive integer. The point labeled as '< 0' was assigned a value of '-1' by MAIA in the calculation. Improvement in Retinal Sensitivity in center grid was defined as an increase from baseline of 7 or more decibels in any 5 or more points out of the 16 central points. | Part 1: Month 1, 3, 6, 9, 12, 18 and 24; Part 2: Month 1, 2, 3, 6, 9, and 12 | 
| Parts 1 and 2: Percentage of Study Eyes with ≥7 dB Improvement from Baseline at ≥5 Out of the 68 Loci in Microperimetry | MAIA microperimetry assessment was measured in dB using a 10-2 grid of 68 points. Each point was labeled as '< 0', '0' or a positive integer. The point labeled as '< 0' was assigned a value of '-1' by MAIA in the calculation. Improvement in Retinal Sensitivity in whole grid was defined as an increase from baseline of 7 or more decibels in any 5 or more points of the grid as a whole (68 points). | Part 1: Month 1, 3, 6, 9, 12, 18 and 24; Part 2: Month 1, 2, 3, 6, 9, and 12 | 
| Parts 1 and 2: Change from Baseline in Mean Sensitivity of the 16 Central Loci | MAIA microperimetry assessment was measured in dB using a 10-2 grid of 68 points. Each point was labeled as '< 0', '0' or a positive integer. The point labeled as '< 0' is assigned a value of '-1' by MAIA in the calculation. Improvement in Retinal Sensitivity in center grid was defined as an increase from baseline of 7 or more decibels in any 5 or more points out of the 16 central points. Here negative values indicate a decline in retinal sensitivity. | Part 1: Month 1, 3, 6, 9, 12, 18 and 24; Part 2: Month 1, 2, 3, 6, 9, and 12 | 
| Parts 1 and 2: Change from Baseline in Mean Sensitivity of the 68 Central Loci | MAIA microperimetry assessment was measured in dB using a 10-2 grid of 68 points. Each point was labeled as '< 0', '0' or a positive integer. The point labeled as '< 0' is assigned a value of '-1' by MAIA in the calculation. Improvement in Retinal Sensitivity in whole grid was defined as an increase from baseline of 7 or more decibels in any 5 or more points of the grid as a whole (68 points). Here negative values indicate a decline in retinal sensitivity. | Part 1: Month 1, 3, 6, 9, 12, 18 and 24; Part 2: Month 1, 2, 3, 6, 9, and 12 | 
| Parts 1 and 2: Change from Baseline in Best Corrected Visual Acuity (BCVA) Score | BCVA was assessed using the ETDRS VA chart. Initially, letters were read at a distance of 4 meters from the chart. If <20 letters were read at 4 meters, testing at 1 meter was performed. BCVA was to be reported as number of letters read correctly by the subject. An increase in the number of letters read correctly means that vision has improved. | Part 1: Month 1, 3, 6, 9, 12, 18 and 24; Part 2: Month 1, 2, 3, 6, 9, and 12 | 
| Parts 1 and 2: Change from Baseline in Low Luminance Visual Acuity (LLVA) Score | LLVA was measured by placing a 2.0-log-unit neutral density filter over the front of each eye and having the subject read the normally illuminated ETDRS chart. Initially, letters were read at a distance of 4 meters from the chart. If <20 letters were read at 4 meters, testing at 1 meter was performed. LLVA was reported as number of letters read correctly by the subject. | Part 1: Month 1, 3, 6, 9, 12, 18, and 24; Part 2: Month 1, 3, 6, 9, and 12 | 
| Parts 1 and 2: Percentage of Eyes with a ≥15 Letters Increase from Baseline for BCVA | BCVA was assessed using the ETDRS VA chart. Initially, letters were read at a distance of 4 meters from the chart. If <20 letters were read at 4 meters, testing at 1 meter was performed. BCVA was to be reported as number of letters read correctly by the subject. An increase in the number of letters read correctly means that vision has improved. | Part 1: Month 1, 3, 6, 9, 12, 18, and 24; Part 2: Month 1, 2, 3, 6, 9, and 12 | 
| Parts 1 and 2: Percentage of Eyes with a ≥15 Letters Increase from Baseline for LLVA | LLVA was measured by placing a 2.0-log-unit neutral density filter over the front of each eye and having the subject read the normally illuminated ETDRS chart. Initially, letters were read at a distance of 4 meters from the chart. If <20 letters were read at 4 meters, testing at 1 meter was performed. LLVA was reported as number of letters read correctly by the subject. | Part 1: Month 1, 3, 6, 9, 12, 18, and 24; Part 2: Month 1, 3, 6, 9, and 12 | 
| Parts 1 and 2: Percentage of Eyes with a ≥10 Letters Increase from Baseline for BCVA | BCVA was assessed using the ETDRS VA chart. Initially, letters were read at a distance of 4 meters from the chart. If <20 letters were read at 4 meters, testing at 1 meter was performed. BCVA was to be reported as number of letters read correctly by the subject. An increase in the number of letters read correctly means that vision has improved. | Part 1: Month 1, 3, 6, 9, 12, 18, and 24; Part 2: Month 1, 2, 3, 6, 9, and 12 | 
| Parts 1 and 2: Percentage of Eyes with a ≥10 Letters Increase from Baseline for LLVA | LLVA was measured by placing a 2.0-log-unit neutral density filter over the front of each eye and having the subject read the normally illuminated ETDRS chart. Initially, letters were read at a distance of 4 meters from the chart. If <20 letters were read at 4 meters, testing at 1 meter was performed. LLVA was reported as number of letters read correctly by the subject. | Part 1: Month 1, 3, 6, 9, 12, 18, and 24; Part 2: Month 1, 3, 6, 9, and 12 | 
| Parts 1 and 2: Percentage of Eyes with a ≥5 Letters Increase from Baseline for BCVA | BCVA was assessed using the ETDRS VA chart. Initially, letters were read at a distance of 4 meters from the chart. If <20 letters were read at 4 meters, testing at 1 meter was performed. BCVA was to be reported as number of letters read correctly by the subject. An increase in the number of letters read correctly means that vision has improved. | Part 1: Month 1, 3, 6, 9, 12, 18, and 24; Part 2: Month 1, 2, 3, 6, 9, and 12 | 
| Parts 1 and 2: Percentage of Eyes with a ≥5 Letters Increase from Baseline for LLVA | LLVA was measured by placing a 2.0-log-unit neutral density filter over the front of each eye and having the subject read the normally illuminated ETDRS chart. Initially, letters were read at a distance of 4 meters from the chart. If <20 letters were read at 4 meters, testing at 1 meter was performed. LLVA was reported as number of letters read correctly by the subject. | Part 1: Month 1, 3, 6, 9, 12, 18, and 24; Part 2: Month 1, 3, 6, 9, and 12 | 
| Parts 1 and 2: Percentage of Eyes with a ≥15 Letters Loss from Baseline for BCVA | BCVA was assessed using the ETDRS VA chart. Initially, letters were read at a distance of 4 meters from the chart. If <20 letters were read at 4 meters, testing at 1 meter was performed. BCVA was to be reported as number of letters read correctly by the subject. An increase in the number of letters read correctly means that vision has improved. | Part 1: Month 1, 3, 6, 9, 12, 18, and 24; Part 2: Month 1, 2, 3, 6, 9, and 12 | 
| Parts 1 and 2: Percentage of Eyes with a ≥15 Letters Loss from Baseline for LLVA | LLVA was measured by placing a 2.0-log-unit neutral density filter over the front of each eye and having the subject read the normally illuminated ETDRS chart. Initially, letters were read at a distance of 4 meters from the chart. If <20 letters were read at 4 meters, testing at 1 meter was performed. LLVA was reported as number of letters read correctly by the subject. | Part 1: Month 1, 3, 6, 9, 12, 18, and 24; Part 2: Month 1, 3, 6, 9, and 12 | 
| Parts 1 and 2: Percentage of Eyes with a ≥10 Letters Loss from Baseline for BCVA | BCVA was assessed using the ETDRS VA chart. Initially, letters were read at a distance of 4 meters from the chart. If <20 letters were read at 4 meters, testing at 1 meter was performed. BCVA was to be reported as number of letters read correctly by the subject. An increase in the number of letters read correctly means that vision has improved. | Part 1: Month 1, 3, 6, 9, 12, 18, and 24; Part 2: Month 1, 2, 3, 6, 9, and 12 | 
| Parts 1 and 2: Percentage of Eyes with a ≥10 Letters Loss from Baseline for LLVA | LLVA was measured by placing a 2.0-log-unit neutral density filter over the front of each eye and having the subject read the normally illuminated ETDRS chart. Initially, letters were read at a distance of 4 meters from the chart. If <20 letters were read at 4 meters, testing at 1 meter was performed. LLVA was reported as number of letters read correctly by the subject. | Part 1: Month 1, 3, 6, 9, 12, 18, and 24; Part 2: Month 1, 3, 6, 9, and 12 | 
| Parts 1 and 2: Percentage of Eyes with a ≥5 Letters Loss from Baseline for BCVA | BCVA was assessed using the ETDRS VA chart. Initially, letters were read at a distance of 4 meters from the chart. If <20 letters were read at 4 meters, testing at 1 meter was performed. BCVA was to be reported as number of letters read correctly by the subject. An increase in the number of letters read correctly means that vision has improved. | Part 1: Month 1, 3, 6, 9, 12, 18, and 24; Part 2: Month 1, 2, 3, 6, 9, and 12 | 
| Parts 1 and 2: Percentage of Eyes with a ≥5 Letters Loss from Baseline for LLVA | LLVA was measured by placing a 2.0-log-unit neutral density filter over the front of each eye and having the subject read the normally illuminated ETDRS chart. Initially, letters were read at a distance of 4 meters from the chart. If <20 letters were read at 4 meters, testing at 1 meter was performed. LLVA was reported as number of letters read correctly by the subject. | Part 1: Month 1, 3, 6, 9, 12, 18, and 24; Part 2: Month 1, 3, 6, 9, and 12 | 
| Parts 1 and 2: Percentage of Eyes with Change from Baseline > -5 Letters for BCVA | BCVA was assessed using the ETDRS VA chart. Initially, letters were read at a distance of 4 meters from the chart. If <20 letters were read at 4 meters, testing at 1 meter was performed. BCVA was to be reported as number of letters read correctly by the subject. An increase in the number of letters read correctly means that vision has improved. | Part 1: Month 1, 3, 6, 9, 12, 18, and 24; Part 2: Month 1, 2, 3, 6, 9, and 12 | 
| Part 1 and 2: Percentage of Eyes with Change from Baseline > -5 Letters for LLVA | LLVA was measured by placing a 2.0-log-unit neutral density filter over the front of each eye and having the subject read the normally illuminated ETDRS chart. Initially, letters were read at a distance of 4 meters from the chart. If <20 letters were read at 4 meters, testing at 1 meter was performed. LLVA was reported as number of letters read correctly by the subject. | Part 1: Month 1, 3, 6, 9, 12, 18, and 24; Part 2: Month 1, 3, 6, 9, and 12 | 
| Part 1: Change from Baseline in Central Ellipsoid Area | Spectral Domain Optical Coherence Tomography (SD-OCT) was used to assess change in central ellipsoid area. | Month 1, 3, 6, 9, 12, 18 and 24 | 
| Part 1: Change from Baseline in Central Horizontal Ellipsoid Width | SD-OCT was used to assess change in central horizontal ellipsoid width. Here negative values indicate decline in central horizontal ellipsoid width. | Month 1, 3, 6, 9, 12, 18 and 24 | 
| Part 1: Change from Baseline in Fundus Autofluorescence- Total Area of Preserved Autofluoroscence | Fundus Autofluorescence was used to assess change in total area of preserved autofluorescence and distance from foveal center (FC) to nearest border of preserved autofluorescence. | Month 1, 3, 6, 12, 18 and 24 | 
| Part 1: Change from Baseline in Fundus Autofluorescence- Distance from Foveal Center (FC) to Nearest Border of Preserved Autofluorescence | Fundus Autofluorescence was used to assess change in distance from foveal center (FC) to nearest border of preserved autofluorescence. | Month 1, 3, 6, 9, 12, 18 and 24 | 
| Part 1: Change from Baseline in Volume of 30-Degree Hill of Vision | Visual field testing was performed to assess change in volume of 30-degree hill vision. Reliability Factor (RF)=number of false positive responses + number of false negative responses/number of false positive presentations + number of false negative presentations*100. If there are 0 responses, then RF value=0. RFpositive=number of false positive responses/number of false positive presentations*100. If RF≤ 20% measurement is considered reliable. If 20% < RF ≤ 25% and RFpositive ≤ 10% measurement is also considered reliable. Otherwise if 20% < RF ≤ 25% and RFpositive > 10%, or RF > 25%, measurement is not reliable. | Month 6, 12 and 24 | 
| Part 1: Change from Baseline in Volume of Full Field Hill of Vision | Visual field testing was performed to assess change in volume of full field hill vision. Reliability Factor (RF)=number of false positive responses + number of false negative responses/number of false positive presentations + number of false negative presentations*100. If there are 0 responses, then RF value=0. RFpositive=number of false positive responses/number of false positive presentations*100. If RF≤ 20% measurement is considered reliable. If 20% < RF ≤ 25% and RFpositive ≤ 10% measurement is also considered reliable. Otherwise if 20% < RF ≤ 25% and RFpositive > 10%, or RF > 25%, measurement is not reliable. | Month 6, 12, and 24 | 
| Part 1: Change from Baseline in Contrast Sensitivity | Change in contrast sensitivity (CS) was assessed by Pelli-Robson chart which uses a single large letter size (20/60 optotype), with contrast varying across groups of letters. Chart uses letters (6 per line), arranged in groups whose contrast varies from high to low. Subjects read the letters, starting with the highest contrast, until they are unable to read two or three letters in a single group. Each group has three letters of the same contrast level, so there are three trials per contrast level. Subject is assigned a score based on the contrast of the last group in which two or three letters were correctly read. Score is a measure of the subject's log contrast sensitivity ranging from 0-2.25, with 0 being no letters read, and 2.25 being all letters read. Total CS score = [(total # letters correct - 3) x 0.05]. | Month 3, 6, 12 and 24 | 
| Part 2: Change from Baseline in Volume of 30-Degree Hill of Vision Assessed by Octopus 900 | Visual field testing was performed to assess change in volume of 30-degree hill vision. Reliability Factor (RF)=number of false positive responses + number of false negative responses/number of false positive presentations + number of false negative presentations*100. If there are 0 responses, then RF value=0. RFpositive=number of false positive responses/number of false positive presentations*100. If RF≤ 20% measurement is considered reliable. If 20% < RF ≤ 25% and RFpositive ≤ 10% measurement is also considered reliable. Otherwise if 20% < RF ≤ 25% and RFpositive > 10%, or RF > 25%, measurement is not reliable. Here negative values indicate decline in the volume of 30-degree hill vision. | Baseline, Month 3, 6 and 12 | 
| Part 2: Change from Baseline in Volume of Full Field Hill of Vision Assessed by Octopus 900 | Visual field testing was performed to assess change in volume of full field hill vision. Reliability Factor (RF)=number of false positive responses + number of false negative responses/number of false positive presentations + number of false negative presentations*100. If there are 0 responses, then RF value=0. RFpositive=number of false positive responses/number of false positive presentations*100. If RF≤ 20% measurement is considered reliable. If 20% < RF ≤ 25% and RFpositive ≤ 10% measurement is also considered reliable. Otherwise if 20% < RF ≤ 25% and RFpositive > 10%, or RF > 25%, measurement is not reliable. Here negative values indicate decline in volume of full field hill vision. | Baseline, Month 3, 6 and 12 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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XLRP, Ophthalmology, Gene Therapy, Retinitis Pigmentosa GTPase Regulator (RPGR), AAV8