Clinical Trial Results:
A Randomised, Open Label, Outcomes-Assessor Masked, Prospective, Parallel Controlled Group, Phase 3 Clinical Trial of Retinal Gene Therapy for Choroideremia Using an Adeno-Associated Viral Vector (AAV2) Encoding Rab Escort Protein 1 (REP1) [STAR]
Summary
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EudraCT number |
2015-003958-41 |
Trial protocol |
DE FI DK NL |
Global end of trial date |
01 Dec 2020
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Results information
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Results version number |
v1(current) |
This version publication date |
16 Dec 2021
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First version publication date |
16 Dec 2021
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Other versions |
Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
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Trial identification
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Sponsor protocol code |
273CH301 (NSR-REP-01)
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT03496012 | ||
WHO universal trial number (UTN) |
- | ||
Sponsors
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Sponsor organisation name |
Biogen
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Sponsor organisation address |
225 Binney Street, Cambridge, United States, 02142
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Public contact |
Biogen Study Medical Director, Biogen, clinicaltrials@biogen.com
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Scientific contact |
Biogen Study Medical Director, Biogen, clinicaltrials@biogen.com
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
No
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Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
01 Dec 2020
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Is this the analysis of the primary completion data? |
No
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Global end of trial reached? |
Yes
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Global end of trial date |
01 Dec 2020
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Was the trial ended prematurely? |
No
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General information about the trial
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Main objective of the trial |
The objective of the study is to evaluate the efficacy and safety of a single sub-retinal injection of BIIB111 in subjects with choroideremia (CHM).
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Protection of trial subjects |
Written informed consent was obtained from each subject or subject’s legally authorized representative, as applicable, prior to evaluations performed for eligibility. Subjects or the subject’s legally authorized representative were given adequate time to review the information in the informed consent/assent and were allowed to ask, and have answered, questions concerning all portions of the conduct of the study.
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Background therapy |
Subjects who received BIIB111 (timrepigene emparvovec) were given a 21-day course of oral corticosteroid (e.g., prednisolone/prednisone). The schedule was as follows: 1 milligram per kilogram/day (mg/kg/day) prednisolone/prednisone for a total of 10 days, (beginning 2 days before the vector injection, on the day of injection, and then for 7 days), followed by 0.5 mg/kg/day for 7 days, then 0.25 mg/kg/day for 2 days and 0.125 mg/kg/day for 2 days (21 days in total). Weight captured at Visit 1 (Screening/Baseline) was used to calculate the required dose during the 21-day course, and all doses were rounded to the nearest 1 mg. | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
11 Dec 2017
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Long term follow-up planned |
No
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Independent data monitoring committee (IDMC) involvement? |
Yes
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Population of trial subjects
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Number of subjects enrolled per country |
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Country: Number of subjects enrolled |
Canada: 8
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Country: Number of subjects enrolled |
Denmark: 2
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Country: Number of subjects enrolled |
Finland: 18
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Country: Number of subjects enrolled |
Germany: 32
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Country: Number of subjects enrolled |
Netherlands: 5
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Country: Number of subjects enrolled |
United Kingdom: 13
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Country: Number of subjects enrolled |
United States: 74
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Country: Number of subjects enrolled |
France: 17
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Worldwide total number of subjects |
169
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EEA total number of subjects |
74
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Number of subjects enrolled per age group |
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In utero |
0
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Preterm newborn - gestational age < 37 wk |
0
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Newborns (0-27 days) |
0
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Infants and toddlers (28 days-23 months) |
0
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Children (2-11 years) |
0
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Adolescents (12-17 years) |
0
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Adults (18-64 years) |
148
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From 65 to 84 years |
21
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85 years and over |
0
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Recruitment
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Recruitment details |
Subjects were enrolled at the investigative sites in the United States, Germany, Finland, France, the United Kingdom, Canada, Netherlands, and Denmark from 11 December 2017 to 01 December 2020. | ||||||||||||||||||||||||||||
Pre-assignment
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Screening details |
A total of 169 subjects with Choroideremia were randomized in the study (66 subjects in Untreated Control Group; 34 subjects in BIIB111 Low Dose group and 69 subjects in BIIB111 High Dose group). Of which, 161 subjects completed the study. | ||||||||||||||||||||||||||||
Period 1
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Period 1 title |
Overall Study
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Is this the baseline period? |
No | ||||||||||||||||||||||||||||
Allocation method |
Randomised - controlled
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Blinding used |
Not blinded | ||||||||||||||||||||||||||||
Blinding implementation details |
Subjects were dose blinded.
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Arms
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Are arms mutually exclusive |
Yes
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Arm title
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Untreated Control Group | ||||||||||||||||||||||||||||
Arm description |
Subjects received no sham surgery or study medication to allow for a controlled comparison. | ||||||||||||||||||||||||||||
Arm type |
No intervention | ||||||||||||||||||||||||||||
Investigational medicinal product name |
No investigational medicinal product assigned in this arm
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Arm title
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BIIB111 Low Dose | ||||||||||||||||||||||||||||
Arm description |
Followed by vitrectomy and retinal detachment in the study eye, subjects received a single administration of low dose (1.0 × 10^10 genome particle [gp]) BIIB111 (timrepigene emparvovec) by sub-retinal injection on Day 0 (surgery day). | ||||||||||||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||||||||||||
Investigational medicinal product name |
Timrepigene Emparvovec
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Investigational medicinal product code |
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Other name |
AAV2-REP1
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Pharmaceutical forms |
Suspension for injection
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Routes of administration |
Intraocular use
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Dosage and administration details |
Administered as specified in the treatment arm.
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Arm title
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BIIB111 High Dose | ||||||||||||||||||||||||||||
Arm description |
Followed by vitrectomy and retinal detachment in the study eye, subjects received a single administration of high dose (1.0 × 10^11 gp) BIIB111 (timrepigene emparvovec) by sub-retinal injection on Day 0 (surgery day). | ||||||||||||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||||||||||||
Investigational medicinal product name |
Timrepigene Emparvovec
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Investigational medicinal product code |
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Other name |
AAV2-REP1
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Pharmaceutical forms |
Suspension for injection
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Routes of administration |
Intraocular use
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Dosage and administration details |
Administered as specified in the treatment arm.
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Period 2
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Period 2 title |
Intent to Treat (ITT) Period
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Is this the baseline period? |
Yes [1] | ||||||||||||||||||||||||||||
Allocation method |
Randomised - controlled
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Blinding used |
Not blinded | ||||||||||||||||||||||||||||
Blinding implementation details |
Subjects were dose blinded.
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Arms
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Are arms mutually exclusive |
Yes
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Arm title
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Untreated Control Group | ||||||||||||||||||||||||||||
Arm description |
Subjects received no sham surgery or study medication to allow for a controlled comparison. | ||||||||||||||||||||||||||||
Arm type |
No intervention | ||||||||||||||||||||||||||||
Investigational medicinal product name |
No investigational medicinal product assigned in this arm
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Arm title
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BIIB111 Low Dose | ||||||||||||||||||||||||||||
Arm description |
Followed by vitrectomy and retinal detachment in the study eye, subjects received a single administration of low dose (1.0 × 10^10 genome particle [gp]) BIIB111 (timrepigene emparvovec) by sub-retinal injection on Day 0 (surgery day). | ||||||||||||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||||||||||||
Investigational medicinal product name |
Timrepigene Emparvovec
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Investigational medicinal product code |
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Other name |
AAV2-REP1
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Pharmaceutical forms |
Suspension for injection
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Routes of administration |
Intraocular use
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Dosage and administration details |
Administered as specified in the treatment arm.
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Arm title
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BIIB111 High Dose | ||||||||||||||||||||||||||||
Arm description |
Followed by vitrectomy and retinal detachment in the study eye, subjects received a single administration of high dose (1.0 × 10^11 gp) BIIB111 (timrepigene emparvovec) by sub-retinal injection on Day 0 (surgery day). | ||||||||||||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||||||||||||
Investigational medicinal product name |
Timrepigene Emparvovec
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Investigational medicinal product code |
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Other name |
AAV2-REP1
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Pharmaceutical forms |
Suspension for injection
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Routes of administration |
Intraocular use
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Dosage and administration details |
Administered as specified in the treatment arm.
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Notes [1] - Period 1 is not the baseline period. It is expected that period 1 will be the baseline period. Justification: Baseline data is reported for ITT population so ITT period is selected as baseline period. |
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Notes [2] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same. Justification: Baseline data is reported for ITT population but not randomized population. |
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Baseline characteristics reporting groups
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Reporting group title |
Untreated Control Group
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Reporting group description |
Subjects received no sham surgery or study medication to allow for a controlled comparison. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
BIIB111 Low Dose
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Reporting group description |
Followed by vitrectomy and retinal detachment in the study eye, subjects received a single administration of low dose (1.0 × 10^10 genome particle [gp]) BIIB111 (timrepigene emparvovec) by sub-retinal injection on Day 0 (surgery day). | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
BIIB111 High Dose
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Reporting group description |
Followed by vitrectomy and retinal detachment in the study eye, subjects received a single administration of high dose (1.0 × 10^11 gp) BIIB111 (timrepigene emparvovec) by sub-retinal injection on Day 0 (surgery day). | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
Untreated Control Group
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Reporting group description |
Subjects received no sham surgery or study medication to allow for a controlled comparison. | ||
Reporting group title |
BIIB111 Low Dose
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Reporting group description |
Followed by vitrectomy and retinal detachment in the study eye, subjects received a single administration of low dose (1.0 × 10^10 genome particle [gp]) BIIB111 (timrepigene emparvovec) by sub-retinal injection on Day 0 (surgery day). | ||
Reporting group title |
BIIB111 High Dose
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Reporting group description |
Followed by vitrectomy and retinal detachment in the study eye, subjects received a single administration of high dose (1.0 × 10^11 gp) BIIB111 (timrepigene emparvovec) by sub-retinal injection on Day 0 (surgery day). | ||
Reporting group title |
Untreated Control Group
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Reporting group description |
Subjects received no sham surgery or study medication to allow for a controlled comparison. | ||
Reporting group title |
BIIB111 Low Dose
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Reporting group description |
Followed by vitrectomy and retinal detachment in the study eye, subjects received a single administration of low dose (1.0 × 10^10 genome particle [gp]) BIIB111 (timrepigene emparvovec) by sub-retinal injection on Day 0 (surgery day). | ||
Reporting group title |
BIIB111 High Dose
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Reporting group description |
Followed by vitrectomy and retinal detachment in the study eye, subjects received a single administration of high dose (1.0 × 10^11 gp) BIIB111 (timrepigene emparvovec) by sub-retinal injection on Day 0 (surgery day). |
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End point title |
Percentage of Subjects with a ≥15 -Letter Improvement from Baseline in Best Corrected Visual Acuity (BCVA) at Month 12 as Measured by the Early Treatment of Diabetic Retinopathy Study (ETDRS) Chart | ||||||||||||||||||||||||
End point description |
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 to be reported as number of letters read correctly by the subject using the ETDRS Scale (ranging from 0 to 100 letters) in the study and fellow 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. ITT Population included all randomized subjects who received the study treatment (or the phone call for those in the untreated control group) and have at least one post-treatment BCVA measurement.
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End point type |
Primary
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End point timeframe |
Month 12
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Statistical analysis title |
Study Eyes of Control Group vs BIIB111 Low Dose | ||||||||||||||||||||||||
Comparison groups |
Untreated Control Group v BIIB111 Low Dose
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Number of subjects included in analysis |
96
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||||||||||||||
P-value |
= 0.354 | ||||||||||||||||||||||||
Method |
Fisher exact | ||||||||||||||||||||||||
Parameter type |
Difference in Proportions | ||||||||||||||||||||||||
Point estimate |
2.9
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Confidence interval |
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level |
95% | ||||||||||||||||||||||||
sides |
2-sided
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lower limit |
-3.1 | ||||||||||||||||||||||||
upper limit |
15 | ||||||||||||||||||||||||
Statistical analysis title |
Study Eyes of Control Group vs BIIB111 High Dose | ||||||||||||||||||||||||
Comparison groups |
Untreated Control Group v BIIB111 High Dose
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Number of subjects included in analysis |
127
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||||||||||||||
P-value |
= 0.245 | ||||||||||||||||||||||||
Method |
Fisher exact | ||||||||||||||||||||||||
Parameter type |
Difference in proportions | ||||||||||||||||||||||||
Point estimate |
4.6
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Confidence interval |
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level |
95% | ||||||||||||||||||||||||
sides |
2-sided
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lower limit |
-1.4 | ||||||||||||||||||||||||
upper limit |
12.8 |
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End point title |
Change from Baseline in BCVA at Month 12 Measured by the ETDRS Chart | ||||||||||||||||||||
End point description |
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 to be reported as number of letters read correctly by the subject using the ETDRS Scale (ranging from 0 to 100 letters) in the study and fellow 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. ITT Population included all randomized participants who received the study treatment (or the phone call for those in the untreated control group) and have at least one post-treatment BCVA measurement. 'Number Analyzed’ signifies number of participants analyzed at the specified timepoint in this outcome measure.
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End point type |
Secondary
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End point timeframe |
Baseline, Month 12
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No statistical analyses for this end point |
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End point title |
Percentage of Subjects with a ≥10 -Letter Improvement from Baseline in BCVA at Month 12 Measured by the ETDRS Chart | ||||||||||||||||||||||||
End point description |
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 to be reported as number of letters read correctly by the subject using the ETDRS Scale (ranging from 0 to 100 letters) in the study and fellow 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. ITT Population included all randomized participants who received the study treatment (or the phone call for those in the untreated control group) and have at least one post-treatment BCVA measurement.
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End point type |
Secondary
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End point timeframe |
Month 12
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Statistical analysis title |
Study Eyes of Control Group vs BIIB111 Low Dose | ||||||||||||||||||||||||
Comparison groups |
Untreated Control Group v BIIB111 Low Dose
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Number of subjects included in analysis |
96
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||||||||||||||
Method |
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Parameter type |
Difference in proportions | ||||||||||||||||||||||||
Point estimate |
16
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Confidence interval |
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level |
95% | ||||||||||||||||||||||||
sides |
2-sided
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lower limit |
5.3 | ||||||||||||||||||||||||
upper limit |
32.2 | ||||||||||||||||||||||||
Statistical analysis title |
Study Eyes of Control Group vs BIIB111 High Dose | ||||||||||||||||||||||||
Comparison groups |
Untreated Control Group v BIIB111 High Dose
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Number of subjects included in analysis |
127
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||||||||||||||
Method |
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Parameter type |
Difference in proportions | ||||||||||||||||||||||||
Point estimate |
12.2
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Confidence interval |
|||||||||||||||||||||||||
level |
95% | ||||||||||||||||||||||||
sides |
2-sided
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lower limit |
3.5 | ||||||||||||||||||||||||
upper limit |
23 |
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End point title |
Percentage of Subjects with No Decrease from Baseline in BCVA or a Decrease from Baseline in BCVA of <5 ETDRS Letters at Month 12 Measured by the EDRS Chart | ||||||||||||||||||||||||
End point description |
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 to be reported as number of letters read correctly by the subject using the ETDRS Scale (ranging from 0 to 100 letters) in the study and fellow 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. ITT Population included all randomized participants who received the study treatment (or the phone call for those in the untreated control group) and have at least one post-treatment BCVA measurement.
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End point type |
Secondary
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End point timeframe |
Month 12
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Statistical analysis title |
Study Eyes of Control Group vs BIIB111 Low Dose | ||||||||||||||||||||||||
Comparison groups |
Untreated Control Group v BIIB111 Low Dose
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||||||||||||||||||||||||
Number of subjects included in analysis |
96
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||||||||||||||
Method |
|||||||||||||||||||||||||
Parameter type |
Difference in proportions | ||||||||||||||||||||||||
Point estimate |
2.8
|
||||||||||||||||||||||||
Confidence interval |
|||||||||||||||||||||||||
level |
95% | ||||||||||||||||||||||||
sides |
2-sided
|
||||||||||||||||||||||||
lower limit |
-17.2 | ||||||||||||||||||||||||
upper limit |
21 | ||||||||||||||||||||||||
Statistical analysis title |
Study Eyes of Control Group vs BIIB111 High Dose | ||||||||||||||||||||||||
Comparison groups |
Untreated Control Group v BIIB111 High Dose
|
||||||||||||||||||||||||
Number of subjects included in analysis |
127
|
||||||||||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||||||||||
Analysis type |
superiority | ||||||||||||||||||||||||
Method |
|||||||||||||||||||||||||
Parameter type |
Difference in proportions | ||||||||||||||||||||||||
Point estimate |
15.3
|
||||||||||||||||||||||||
Confidence interval |
|||||||||||||||||||||||||
level |
95% | ||||||||||||||||||||||||
sides |
2-sided
|
||||||||||||||||||||||||
lower limit |
0.3 | ||||||||||||||||||||||||
upper limit |
30.1 |
|
|||||||||||||||||||||||||||||||||||||||||
End point title |
Change from Baseline in BCVA at Months 4 and 8 Measured by the ETDRS Chart | ||||||||||||||||||||||||||||||||||||||||
End point description |
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 to be reported as number of letters read correctly by the subject using the ETDRS Scale (ranging from 0 to 100 letters) in the study and fellow 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. ITT Population included all randomized subjects who received the study treatment (or the phone call for those in the untreated control group) and have at least one post-treatment BCVA measurement. Here n=number of subjects analyzed at the specified timepoint in this outcome measure.
|
||||||||||||||||||||||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||||||||||||||||||||||
End point timeframe |
Baseline, Months 4 and 8
|
||||||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||||
End point title |
Change from Baseline in Total Area of Preserved Autofluorescence (AF) at Month 12 | ||||||||||||||||
End point description |
Fundus Autofluoroscence was used to assess change in total area of preserved autofluoroscence. A negative change from baseline indicate decline in total area of preserved autofluoroscence. ITT Population included all randomized subjects who received the study treatment (or the phone call for those in the untreated control group) and have at least one post-treatment BCVA measurement. ‘Number of Subjects Analyzed’ signifies number of subjects analyzed in this outcome measure.
|
||||||||||||||||
End point type |
Secondary
|
||||||||||||||||
End point timeframe |
Baseline, Month 12
|
||||||||||||||||
|
|||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||||
End point title |
Change from Baseline in Distance from Foveal Center to Nearest Border of Preserved AF at Month 12 | ||||||||||||||||
End point description |
Fundus Autofluoroscence was used to assess change in distance from foveal center (FC) to nearest border of preserved autofluoroscence. ITT Population included all randomized subjects who received the study treatment (or the phone call for those in the untreated control group) and have at least one post-treatment BCVA measurement. ‘Number of Subjects Analyzed’ signifies number of subjects analyzed in this outcome measure.
|
||||||||||||||||
End point type |
Secondary
|
||||||||||||||||
End point timeframe |
Baseline, Month 12
|
||||||||||||||||
|
|||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||||
End point title |
Change from Baseline in the Foveal Subfield Thickness Using Spectral Domain Optical Coherence Tomography (SD-OCT) at Month 12 | ||||||||||||||||
End point description |
SD-OCT was used to assess change in foveal subfield thickness. The measurements were taken after dilation of the subject’s pupil. A negative change from baseline indicates decline in foveal subfield thickness. ITT Population included all randomized subjects who received the study treatment (or the phone call for those in the untreated control group) and have at least one post-treatment BCVA measurement. ‘Number of Subjects Analyzed’ signifies number of subjects analyzed in this outcome measure.
|
||||||||||||||||
End point type |
Secondary
|
||||||||||||||||
End point timeframe |
Baseline, Month 12
|
||||||||||||||||
|
|||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||||
End point title |
Change from Baseline in the Total Macular Volume Using SD-OCT at Month 12 | ||||||||||||||||
End point description |
SD-OCT was used to assess change in total macular volume. The measurements were taken after dilation of the subject’s pupil. A negative change from baseline indicates decline in total macular volume. ITT Population included all randomized subjects who received the study treatment (or the phone call for those in the untreated control group) and have at least one post-treatment BCVA measurement. ‘Number of Subjects Analyzed’ signifies number of subjects analyzed in this outcome measure.
|
||||||||||||||||
End point type |
Secondary
|
||||||||||||||||
End point timeframe |
Baseline, Month 12
|
||||||||||||||||
|
|||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||||
End point title |
Change from Baseline in the Central Horizontal Ellipsoid Width Using SD-OCT at Month 12 | ||||||||||||||||
End point description |
SD-OCT was used to assess change in central horizontal ellipsoid width. The measurements were taken after dilation of the subject’s pupil. A negative change from baseline indicates decline in central horizontal ellipsoid width. ITT Population included all randomized subjects who received the study treatment (or the phone call for those in the untreated control group) and have at least one post-treatment BCVA measurement. ‘Number of Subjects Analyzed’ signifies number of subjects analyzed in this outcome measure.
|
||||||||||||||||
End point type |
Secondary
|
||||||||||||||||
End point timeframe |
Baseline, Month 12
|
||||||||||||||||
|
|||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||||
End point title |
Change from Baseline in the Central Ellipsoid Area Using SD-OCT at Month 12 | ||||||||||||||||
End point description |
SD-OCT was used to assess change in central ellipsoid area. The measurements were taken after dilation of the subject’s pupil. A negative change from baseline indicates decline in central ellipsoid area. ITT Population included all randomized subjects who received the study treatment (or the phone call for those in the untreated control group) and have at least one post-treatment BCVA measurement. ‘Number of Subjects Analyzed’ signifies number of subjects analyzed in this outcome measure.
|
||||||||||||||||
End point type |
Secondary
|
||||||||||||||||
End point timeframe |
Baseline, Month 12
|
||||||||||||||||
|
|||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||||
End point title |
Change from Baseline in the Choroidal Thickness Using SD-OCT at Month 12 | ||||||||||||||||
End point description |
SD-OCT was used to assess change in choroidal thickness. The measurements were taken after dilation of the subject’s pupil. A negative change from baseline indicates decline in choroidal thickness. ITT Population included all randomized subjects who received the study treatment (or the phone call for those in the untreated control group) and have at least one post-treatment BCVA measurement. ‘Number of Subjects Analyzed’ signifies number of subjects analyzed in this outcome measure.
|
||||||||||||||||
End point type |
Secondary
|
||||||||||||||||
End point timeframe |
Baseline, Month 12
|
||||||||||||||||
|
|||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||||
End point title |
Change from Baseline in the Mean Retinal Sensitivity Microperimetry Variable at Month 12 | ||||||||||||||||
End point description |
Microperimetry was used to assess change in mean retinal sensitivity. A negative change from baseline indicates decline in retinal sensitivity. ITT Population included all randomized subjects who received the study treatment (or the phone call for those in the untreated control group) and have at least one post-treatment BCVA measurement. ‘Number of Subjects Analyzed’ signifies number of subjects analyzed in this outcome measure.
|
||||||||||||||||
End point type |
Secondary
|
||||||||||||||||
End point timeframe |
Baseline, Month 12
|
||||||||||||||||
|
|||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||||
End point title |
Change from Baseline in the Bivariate Contour Ellipse Area 63% Microperimetry Variable at Month 12 | ||||||||||||||||
End point description |
Microperimetry was used to assess change in bivariate contour ellipse area 63%. A negative change from baseline indicates decline in bivariate contour ellipse area 63%. ITT Population included all randomized subjects who received the study treatment (or the phone call for those in the untreated control group) and have at least one post-treatment BCVA measurement. ‘Number of Subjects Analyzed’ signifies number of subjects analyzed in this outcome measure.
|
||||||||||||||||
End point type |
Secondary
|
||||||||||||||||
End point timeframe |
Baseline, Month 12
|
||||||||||||||||
|
|||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||||
End point title |
Change from Baseline in the Bivariate Contour Ellipse Area 95% Microperimetry Variable at Month 12 | ||||||||||||||||
End point description |
Microperimetry was used to assess change in bivariate contour ellipse area 95%. A negative change from baseline indicates decline in bivariate contour ellipse area 95%. ITT Population included all randomized subjects who received the study treatment (or the phone call for those in the untreated control group) and have at least one post-treatment BCVA measurement. ‘Number of Subjects Analyzed’ signifies number of subjects analyzed in this outcome measure.
|
||||||||||||||||
End point type |
Secondary
|
||||||||||||||||
End point timeframe |
Baseline, Month 12
|
||||||||||||||||
|
|||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||||
End point title |
Change from Baseline in Contrast Sensitivity Score at Month 12 | ||||||||||||||||
End point description |
Change in contrast sensitivity was assessed by Pelli-Robson chart which uses a single large letter size (20/60 optotype), with contrast varying across groups of letters (6 per line), whose contrast varies from high to low. Subjects read letters, starting with highest contrast, until they are unable to read 2 or 3 letters in a single group. Score is assigned based on contrast of last group in which 2 or 3 letters were correctly read. Score is a measure of subject`s log contrast sensitivity ranging from 0-2.25 ( 0 is no letters read and 2.25 is all letters read). Total CS score=[(total letters correct-3) x 0.05]. A negative change and a positive change from baseline indicates a worsening and an improvement in contrast sensitivity respectively. ITT Population=all randomized subjects who received study treatment (phone call for untreated control group) and have at least 1 post-treatment BCVA measurement. ‘Number of Subjects Analyzed’=number of subjects analyzed in this outcome measure.
|
||||||||||||||||
End point type |
Secondary
|
||||||||||||||||
End point timeframe |
Baseline, Month 12
|
||||||||||||||||
|
|||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||||
End point title |
Change from Baseline in Colour Vision Total Error Score at Month 12 | ||||||||||||||||
End point description |
Colour vision total error scores were assessed on the Farnsworth Munsell 100 Hue Sort Test. Farnsworth Munsell 100 Hue Test requires placing 100 colour palettes in the correct order based upon colour hue. Scores are determined by the frequency and severity of any displacement in the correct order. One error equates to one misplaced hue, by one step or position. An error score of 0 indicates no errors in ordering the hues while error score greater than 500 indicates virtually no color discrimination. A Total Error Score of 0 to 128 could be seen in a normal population. ITT Population included all randomized subjects who received the study treatment (or the phone call for those in the untreated control group) and have at least one post-treatment BCVA measurement. ‘Number of Subjects Analyzed’ signifies number of subjects analyzed in this outcome measure.
|
||||||||||||||||
End point type |
Secondary
|
||||||||||||||||
End point timeframe |
Baseline, Month 12
|
||||||||||||||||
|
|||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||||
End point title |
Change from Baseline in Reading Speed Test at Month 12 | ||||||||||||||||
End point description |
The reading speed was calculated using the following formula: [number of words in the text - number of misread words] / reading time x 60. The number of misread words and reading time is collected. A negative change from baseline indicates decline in reading speed. ITT Population included all randomized subjects who received the study treatment (or the phone call for those in the untreated control group) and have at least one post-treatment BCVA measurement. ‘Number of Subjects Analyzed’ signifies number of subjects analyzed in this outcome measure.
|
||||||||||||||||
End point type |
Secondary
|
||||||||||||||||
End point timeframe |
Baseline, Month 12
|
||||||||||||||||
|
|||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||||
End point title |
Change from Baseline in the 25-Item Visual Function Questionnaire (VFQ-25) Composite Scores at Month 12 | ||||||||||||||||
End point description |
VFQ-25 consists of a base set of 25 vision-targeted questions representing 11 vision-related constructs, plus an additional single-item general health rating question. All items are scored so that a high score represents better functioning. Each item is then converted to a 0 to 100 scale so that the lowest and highest possible scores are set at 0 and 100 points, respectively. A score of 0 represents the worst outcome and 100 represents the best outcome. A negative change from baseline indicates decline in VFQ-25 score. ITT Population included all randomized subjects who received the study treatment (or the phone call for those in the untreated control group) and have at least one post-treatment BCVA measurement. ‘Number of Subjects Analyzed’ signifies number of subjects analyzed in this outcome measure.
|
||||||||||||||||
End point type |
Secondary
|
||||||||||||||||
End point timeframe |
Baseline, Month 12
|
||||||||||||||||
|
|||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Adverse events information
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Timeframe for reporting adverse events |
From Signing of Informed Consent through End of Study (Up to 12 months)
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Adverse event reporting additional description |
Safety population included all randomized subjects who either received study treatment BIIB111 (timrepigene emparvovec) or a post-randomization study visit (control group). Subjects were analyzed according to their actual treatment received.
|
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Assessment type |
Systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary used for adverse event reporting
|
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Dictionary name |
MedDRA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
23.1
|
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Reporting groups
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Untreated Control Group
|
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Reporting group description |
Subjects received no sham surgery or study medication to allow for a controlled comparison. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
BIIB111 Low Dose
|
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Reporting group description |
Followed by vitrectomy and retinal detachment in the study eye, subjects received a single administration of low dose (1.0 × 10^10 gp) BIIB111 (timrepigene emparvovec) by sub-retinal injection on Day 0 (surgery day). | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
BIIB111 High Dose
|
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Reporting group description |
Followed by vitrectomy and retinal detachment in the study eye, subjects received a single administration of high dose (1.0 × 10^11 gp) BIIB111 (timrepigene emparvovec) by sub-retinal injection on Day 0 (surgery day). | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Frequency threshold for reporting non-serious adverse events: 5% | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Substantial protocol amendments (globally) |
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Were there any global substantial amendments to the protocol? Yes | |||
Date |
Amendment |
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10 Nov 2015 |
Removed treatment of the timrepigene emparvovec fellow eye in 4 to 6 subjects. Removed requirement for conducting the International Speed Reading Test in countries where validated translations were not available. |
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26 Feb 2016 |
Changed volume of timrepigene emparvovec subretinal injection from 0.05 mL to 0.1 mL (containing 1 x 1011 vg). Changed VA inclusion criterion for the study eye, from BCVA of 34 to 78 letters to a BCVA of 34 to 73. Removed randomization method for selection of the ‘Study eye’, and replaced with a requirement for the investigator to use clinical judgment (in collaboration with the subject) to select the ‘Study eye’, which was generally the worse eye. Clarification of management of Screening Identification and inclusion of Screen Failure data. Removed reference to an Interactive Voice/Web Response System for purposes of treatment randomization. Included prednisone (in addition to prednisolone) as the corticosteroid of choice in the 21-day perioperative period. Added requirement that subjects must have had a genetically confirmed diagnosis of CHM prior to the Screening Visit (Visit 1). Visit windows for Visits 7, 8, and 9 decreased from ± 21 days to ± 14 days. |
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01 Aug 2017 |
Updated title to reflect changes in study design. Changed choice of study control and randomization to a parallel, untreated control 3-arm study design (high-dose, low-dose, untreated-control). Increased sample size from 100 to 140 subjects. Increased the ETDRS BCVA letter improvement from 10 to 15 for the primary endpoint. Amended the key secondary endpoint to utilize Study NSR-CHM-OS1 (NIGHT study) as an historical control. |
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15 Mar 2019 |
Changes to statistical aspects of the study: Increased the sample size from 140 to 160 subjects; Changed the secondary endpoint from a historical comparison to prospective within-study assessments. Risk-benefit assessment was added to clarify vision loss as a known possible AE, therefore precluding it from SUSAR reporting; definition of SAEs associated with vision loss was also clarified. Other changes involved defining Day 0 for untreated subjects to assure that the duration of follow-up was equal for both treated and untreated subjects. |
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Interruptions (globally) |
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Were there any global interruptions to the trial? No | |||
Limitations and caveats |
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Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||
None reported |