A Safety Study of Retinal Gene Therapy for Choroideremia With Administration of BIIB111: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for A Safety Study of Retinal Gene Therapy for Choroideremia With Administration of BIIB111 (NCT03507686), a na phase 2 study. The primary outcome is Mean Best-Corrected Visual Acuity (BCVA) as Measured by the Early Treatment of Diabetic Retinopathy Study (ETDRS) Chart in Letters at Month 12.

2. Clinical Question

3. Trial Design

This was a Phase 2, open-label, single-group study of BIIB111 for choroideremia. The registry record lists Biogen as sponsor, enrollment of 66, and completed status. The recorded start date is 2017-11-29, and the primary completion date is 2022-06-29. These record details describe the study’s registration and timeline; they do not establish when any individual participant received treatment or completed follow-up.

BIIB111 was administered by sub-retinal injection as a single dose in each eye. The two eye administrations were sequential, separated by an interval of <6 months, 6-12 months, or >12 months. The design therefore involved treatment periods for a bilateral procedure, but no parallel control arm. Allocation was listed as not applicable and masking as none. With no randomized comparator, observed outcome values, if available, would describe participants in the study and would not by themselves isolate a treatment effect from other explanations.

The registry lists mean BCVA measured with the ETDRS chart at Month 12 as the primary outcome. It also lists secondary visual acuity, autofluorescence, and structural optical coherence tomography measures, including outcomes at Month 12. The record lists 42 outcome measures and zero analyses. It does not provide a protocol-level account of the analysis plan, sample-size justification, or any interim analyses. Those features should not be inferred from the study’s phase, enrollment, or endpoint list.

The safety data are reported separately for Treatment Period 1 and Treatment Period 2. Those periods are parts of a sequential bilateral intervention, not randomized arms. The registry record does not give enough detail to treat the period groups as independent or as a controlled comparison. Consequently, period-specific counts should be read as descriptive safety information within the study’s treatment sequence.

4. Participant Flow and Accounting

The registry reports how participants moved through each stage of the study. All counts below are exactly as posted; missing counts are not inferred from other stages.

Before assignment: A total of 66 unique male participants with Choroideremia were treated in the study. Of which 60 participants were treated in treatment Period 1 and 50 participants completed Period 1. 50 participants from Period 1 enrolled in Period 2 along with 6 unique participants who were treated in the first eye in a previous study (20150371 \[NCT02553135\], THOR-TUE-01 \[NCT02671539\]). 53 participants completed Period 2.

Treatment Period 1(Day 1 up to Month 12)

Reasons for not completing this period:

Treatment Period 2 (Month13 to Month24)

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: All Treated Subjects analysis set included all participants who completed the 'Day of Surgery' visit of Period 1 or 2. 'Overall number of participants analyzed' indicates the number of participants with data available for outcome measure analysis.

5. Baseline Characteristics

The table reproduces the baseline characteristics posted in the registry, which describe the participants analysed at baseline and help show whether the randomized groups were comparable.

Population: All Treated Subjects analysis set included all participants who completed the 'Day of Surgery' visit of Period 1 or 2. The baseline data were collected and reported for overall population of unique participants instead of period-wise treated population.

6. Primary Endpoint

The registry lists the primary outcome as Mean Best-Corrected Visual Acuity (BCVA) as Measured by the Early Treatment of Diabetic Retinopathy Study (ETDRS) Chart in Letters at Month 12, measured over Month 12.

The primary endpoint is mean best-corrected visual acuity (BCVA), measured in ETDRS chart letters at Month 12. BCVA is a standardized measure of how many letters a participant reads correctly on a visual acuity chart. The registry describes testing both eyes and notes that distance refraction is performed before measurement. Testing begins at a distance of 4 meters; if <20 letters are read at that distance, testing at 1 meter is performed. The scale ranges from 0 to 100 letters.

As described in the registry, fewer correctly read letters indicate worse visual acuity, while an increase in letters indicates improvement. BCVA is used in clinical research because it gives a structured, quantitative measure of visual function rather than relying only on a broad description of vision. A mean summarizes the measured values across participants in the analysis population; it does not show how much responses varied among individuals. The standard deviation, if reported, would describe that variation.

The registry record defines an All Treated Subjects analysis set as participants who completed the Day of Surgery visit of Period 1 or Period 2. It also says that the number analyzed is the number with data available for the outcome. However, it does not report the Month 12 mean, standard deviation, baseline-to-Month 12 change, confidence interval, or analyzed participant count for this primary endpoint. The endpoint’s measurement method is described, but its numerical result is not reported in the registry record.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

What does a mean describe? The primary endpoint is a mean, a summary of the observed ETDRS letter scores in the analysis population at Month 12. A mean can make a group’s results easier to describe, but it does not show whether individual participants had similar or widely varying scores. The registry identifies standard deviation as the dispersion measure for this endpoint, but reports no numerical mean or standard deviation. General explanation: standard deviation describes how spread out observations are around their mean; it is not the same as uncertainty in the estimated mean.

How should a confidence interval be understood? General explanation: a confidence interval expresses the statistical uncertainty around an estimate under the assumptions of the analysis. A narrower interval indicates greater precision, while a wider interval indicates less precision. The registry record does not report a confidence interval for the primary endpoint. Without one, the precision of any primary endpoint estimate cannot be assessed from this record. A confidence interval would also not resolve the design limitation that there is no randomized control group.

Why does the single-group design matter? The study is open-label and single-group, with allocation listed as not applicable and masking as none. There is no randomized control arm to provide a concurrent comparison. General explanation: in a single-group study, a before-and-after difference can describe change within participants, but it cannot by itself separate an intervention-related change from other changes over time or differences in measurement and follow-up. The registry does not report a primary change estimate, and does not report a controlled treatment contrast. The two treatment periods should not be interpreted as equivalent to randomized arms.

What is the role of analysis populations? The registry defines the All Treated Subjects analysis set as participants who completed the Day of Surgery visit of Period 1 or Period 2. It says that the overall number analyzed for an outcome is the number of participants with data available for that outcome. This definition tells readers who could be included according to the record, but the number analyzed for the primary outcome is not reported. General explanation: an analysis population definition helps clarify which participants contribute to a result; it does not by itself explain how missing observations were handled or whether analyses used all available observations.

What do the safety period counts mean? Safety outcomes are listed separately for Treatment Period 1 and Treatment Period 2. For each period, the record gives the number at risk and the number affected for serious adverse events and other adverse events, as well as deaths. These are descriptive counts. General explanation: a count of participants with an event does not convey the timing, duration, severity of every event, or causal relationship to an intervention. Period-specific groups also should not be treated as independent comparison arms unless the design and analysis establish that interpretation; the record describes sequential bilateral administration, not a randomized period comparison.

What does multiplicity mean in general? General explanation: when a study evaluates many outcomes or makes many statistical comparisons, the chance of at least one apparently notable result can rise if each is considered separately. Statistical plans may address this through prespecified priorities or adjustment methods. The registry lists 42 outcome measures, but does not report a multiplicity strategy. It would be inappropriate to assume that an adjustment was used, or that the listed outcomes were all tested in the same way.

How should planning calculations be read? The stated sample-size illustration uses a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation; its effect to detect is a stated fraction of the observed effect. It is described as planning based on an observed effect, not as the study’s own design. The record describes the actual study as single-group, so a hypothetical two-arm planning illustration is not a description of the trial’s allocation or a randomized comparison. General explanation: planning sample sizes depend on assumptions about the target effect, variability, and analysis; they are not observed power and do not establish that a study detected an effect. The registry record does not report the trial’s own sample-size justification.

What is not available for independent statistical review? The registry lists zero analyses and does not report a numerical primary endpoint result, uncertainty interval, p-value, missing-data method, or interim-analysis plan. These omissions prevent readers from checking how the registered endpoint was analyzed or how precise its estimate was. They should not be filled in by assumptions about common practice or by the study’s phase and enrollment.

10. Multiplicity, Missing Data and Analysis Populations

The registry lists 42 outcome measures and zero analyses. It identifies BCVA at Month 12 as the primary outcome and lists secondary measures involving visual acuity, autofluorescence, and structural imaging. The record does not report whether a multiplicity strategy was prespecified or applied. General statistical principle: evaluating many outcomes can increase the chance of a seemingly notable result arising by chance when each is assessed separately. Without a reported plan, readers should not assume that results were adjusted, prioritized in a particular way, or tested as a single family.

The record defines the All Treated Subjects analysis set as participants who completed the Day of Surgery visit of Period 1 or Period 2. It further defines the number analyzed for an outcome as the participants with data available for that outcome. The number analyzed for the primary endpoint is not reported. The registry does not describe how missing Month 12 observations were handled, whether any imputation was used, or how participants without outcome data were treated in analyses. Those details are not reported in the registry record.

General explanation: missing outcome data can affect both the amount of information available and the interpretation of an estimate, especially if data availability is related to participant characteristics or outcomes. A count of participants with available data would clarify the analysis denominator, but would not by itself explain why data were missing. Since the registry record supplies neither the primary endpoint estimate nor its analyzed count and missing-data approach, the impact of missing data cannot be evaluated from this record.

11. Safety Results

The registry reports serious adverse events as affected participants divided by participants at risk.

Deaths

Other (non-serious) adverse events

Participants with at least one non-serious event at or above the registry's 5% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: visual acuity reduced (16.7%), noninfective retinitis (3.3%), macular hole (1.8%), retinal degeneration (1.8%), tractional retinal detachment (1.8%).

Safety results are reported separately for Treatment Period 1 and Treatment Period 2. In Period 1, 12 of 60 participants at risk were affected by serious adverse events; 59 of 60 were affected by other adverse events, and deaths were 0. In Period 2, 8 of 56 participants at risk were affected by serious adverse events; 53 of 56 were affected by other adverse events, and deaths were 1. These are period-specific participant counts, not a randomized comparison of treatments.

The record lists serious adverse event terms and percentages: visual acuity reduced, 16.7%; noninfective retinitis, 3.3%; macular hole, 1.8%; retinal degeneration, 1.8%; tractional retinal detachment, 1.8%; and appendicitis, 1.8%. The percentages should be read as reported, not converted into counts. The record does not give enough detail to determine event timing, whether one participant experienced multiple events, or the relationship of each event to BIIB111.

One death is recorded in Treatment Period 2. The registry record does not report its cause or causal attribution, so it should not be interpreted as treatment-related on the basis of this count alone. Likewise, a serious adverse event is a safety classification, not by itself proof that the intervention caused the event. The two periods belong to sequential bilateral treatment and should not be read as independent control and treatment groups.

12. What the Result Does, and Does Not, Mean

The registry record establishes that a Phase 2, open-label, single-group study evaluated bilateral, sequential BIIB111 administration in adult male participants with choroideremia. It defines the primary visual-acuity endpoint as mean ETDRS letters at Month 12 and describes how BCVA was measured. It also reports adverse-event counts by treatment period. These details support an understanding of the study’s aims and recorded outcomes.

The record does not report a numerical Month 12 primary endpoint result, a change from baseline, the primary analysis count, or a measure of precision. Therefore, it does not show how much visual acuity changed on average or how uncertain an estimate might be. An outcome definition is not an outcome finding, and the absence of a numerical result in the registry should not be interpreted as no change or as a positive or negative result.

The design also limits what can be concluded about causation. Because there was no randomized comparator and the study was open-label, a group-level outcome cannot establish what would have happened over the same period without treatment. General statistical principle: an observed change in a single group can have multiple explanations; a concurrent randomized comparator helps distinguish a treatment contrast from changes that may occur for other reasons. The registry record does not provide such a contrast.

The safety figures describe participants affected during the listed treatment periods. They do not, on their own, identify the cause of an event or provide a like-for-like comparison between periods. The record gives one death in Period 2 but does not report its causal relationship to the intervention. No conclusion about causation should be drawn from the count alone.

Accordingly, the registry supports a descriptive account of the trial design, its endpoint definition, and its recorded safety counts. It does not support a numerical conclusion about the primary visual-acuity outcome or a controlled estimate of treatment effect. Those distinctions are important when separating what the registry documents from conclusions that would require additional results and analysis details.

13. Why This Trial Matters Statistically

This trial illustrates why a clearly defined endpoint and a reported numerical result are both necessary for statistical interpretation. The registry specifies BCVA in ETDRS letters at Month 12 and explains the direction of the scale. That definition allows readers to understand what the measure represents. Yet without the observed mean, its variability, and the number analyzed, readers cannot assess the magnitude or precision of the primary result from the registry record.

The single-group, open-label design also makes the distinction between description and comparison especially important. A study can record measurements after intervention and describe safety events, but those observations alone do not create a randomized contrast. General statistical principle: causal interpretation depends on a design and analysis that address what would have happened under a meaningful alternative. The record identifies no control arm, so the treatment periods should not be treated as if they posted one.

The sequential bilateral intervention creates a further interpretive consideration: safety information is organized by treatment period, but the record does not establish that these period groups are independent or comparable as randomized arms. Reading period-specific counts descriptively avoids an unsupported comparison.

Finally, a registry record is informative about registered aims, definitions, and posted results, but the amount of detail can vary. In this record, the listed endpoint and safety figures can be described, while numerical primary efficacy results, analysis details, and the sample-size justification are not reported. Recognizing that boundary is part of sound statistical practice: it prevents an endpoint description, enrollment figure, or adverse-event count from being mistaken for evidence of an unreported treatment effect.

14. Limitations

• The posted summary statistics are the only data these results rest on; patient-level data, full protocols and statistical analysis plans are not available.
• Recalculated results are simple, unadjusted calculations from posted summaries. They do not replace the sponsor's prespecified analysis.

The registry record has several limitations for interpreting this study’s results. Most importantly, it does not report the numerical result for the primary endpoint, mean BCVA at Month 12. It also does not report the primary endpoint’s standard deviation, confidence interval, baseline-to-Month 12 change, or analyzed participant count. The record therefore does not permit evaluation of the outcome’s magnitude or precision.

The study is open-label and single-group, with no randomized control group. This prevents a controlled treatment comparison in the registered design. The sequential treatment-period safety entries do not supply a like-for-like control comparison. The record does not report whether the same participants contributed to both period summaries, so the period groups should not be assumed to be independent.

The registry defines the All Treated Subjects population but does not describe missing-data methods or report how many participants had available primary endpoint data. It lists 42 outcome measures and zero analyses, but does not report a multiplicity approach. The statistical analysis plan, sample-size justification, and interim analyses are not reported in the registry record.

The safety entries provide counts and selected serious adverse event terms, but the record does not describe event-level timing or causal attribution for the listed findings. The single death in Period 2 is not accompanied by a reported causal relationship in the record. These limitations restrict interpretation to descriptive information and do not support claims about treatment causation or an unreported visual-acuity effect.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: A Safety Study of Retinal Gene Therapy for Choroideremia With Administration of BIIB111 — NCT03507686.
• Registry record last updated 2024-02-23; status last verified 2023-08.
• Results first posted 2023-09-18.
• Data retrieved from ClinicalTrials.gov on 2026-11-09.
• Group sizes, means, event counts and sponsor-reported p-values are reproduced as posted. Effect estimates, confidence intervals and p-values not attributed to the sponsor are independently calculated from the posted summary statistics.

18. Record Summary

The registry record describes NCT03507686, a completed Phase 2, open-label, single-group study sponsored by Biogen. It enrolled 66 adult male participants with choroideremia and evaluated a single sub-retinal dose of BIIB111 in each eye, administered sequentially. The recorded study start date is 2017-11-29, and the primary completion date is 2022-06-29.

The primary outcome was mean BCVA in ETDRS letters at Month 12. The record explains the measure and defines the All Treated Subjects analysis set, but does not report a numerical primary outcome result or its precision. It lists 42 outcome measures and zero analyses. Safety counts are given separately for Treatment Period 1 and Treatment Period 2, including one death in Period 2; causal attribution is not reported. The study has no randomized control group, so the treatment-period entries are descriptive, not a controlled comparison.