This page provides an independent statistical analysis and educational interpretation of publicly reported results. ClinicalTrials.gov provides the official trial registry record. Numerical trial results on this page are restricted to the results posted in the ClinicalTrials.gov record; calculations added by Clinical Biostats are labelled as such.
1. Trial at a Glance
This page covers the registry results for Clinical Trial of Gene Therapy for the Treatment of Leber Congenital Amaurosis (LCA) (NCT02781480), a non-randomized phase 1, phase 2 study. The primary outcome is Overall Safety of Adeno-Associated Virus Vector (AAV-OPTIRPE65) - Number of Participants With a Safety Event.
| Feature | Registry value |
|---|---|
| ClinicalTrials.gov identifier | NCT02781480 |
| Phase | Phase 1, Phase 2 |
| Condition | Leber Congenital Amaurosis |
| Allocation | Non-Randomized |
| Design model | Sequential |
| Masking | None (open label) |
| Enrollment | 15 |
| Arms in the primary outcome | n/a |
| Lead sponsor | MeiraGTx UK II Ltd |
| Results posted | Yes |
2. Clinical Question
Population
Adults and children with retinal dystrophy associated with defects in RPE65, described in the trial title in connection with Leber congenital amaurosis. The registry lists Leber congenital amaurosis as the condition and records enrollment of 15 participants. Further eligibility criteria and details of the enrolled population are not reported in the registry record.
Intervention
AAV RPE65 gene therapy, administered subretinally as a single dose. The record describes low-dose, intermediate-dose, and high-dose groups. The brief summary identifies an AAV2/5 vector, while the registered outcome title refers to AAV-OPTIRPE65.
Comparator
There is no randomized control group described. The arms represent dose levels in a non-randomized, sequential design, not like-for-like treatment and control groups. The registry record does not report a placebo or untreated comparator.
Primary question
The registered primary question is how many participants experience a defined ATIMP-related safety event within 6 months. The definition includes specified ocular events and a serious non-ocular reaction. Although the registry lists this outcome measure, its result count is not reported in the registry record.
3. Trial Design
The registry describes an open-label, multi-centre Phase I/II trial of an adeno-associated virus vector for gene therapy in adults and children with retinal dystrophy associated with RPE65 defects. It is marked completed and non-randomized, with sequential allocation and no masking. Enrollment is listed as 15. The registered start is 2016-04, and primary completion is listed as 2018-12.
The intervention is AAV RPE65, described as a single subretinal administration at a low, intermediate, or high dose. These dose groups form the structure of the trial. Because allocation was not randomized and no control group is described, differences between groups should not be treated as randomized treatment effects. The groups may differ for reasons beyond dose, and the registry does not report enough detail to determine or adjust for such differences.
The record identifies one primary outcome measure: the number of participants with a safety event, assessed over 6 months. It does not report a statistical analysis for that outcome. Although the record gives an enrollment figure and adverse-event summaries by dose group, it does not state how many participants were included in the primary endpoint analysis or how missing observations were handled. Those details are not reported in the registry record.
The sequential, dose-escalation structure is relevant to interpretation: the trial was not designed as a randomized comparison among dose groups. The record does not describe the escalation rules, the timing of dose decisions, or any protocol-based criteria for moving between doses. Those elements are not reported in the registry record, so the design should be characterized only by the features explicitly registered.
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.
Overall Study
| Stage | Low Dose AAV-RPE65 | Intermediate Dose AAV-RPE65 | High Dose AAV-RPE65 |
|---|---|---|---|
| STARTED | 9 | 3 | 3 |
| COMPLETED | 9 | 3 | 3 |
| NOT COMPLETED | 0 | 0 | 0 |
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.
| Characteristic | Unit | Low Dose AAV-RPE65 | Intermediate Dose AAV-RPE65 | High Dose AAV-RPE65 | Total |
|---|---|---|---|---|---|
| Participants analysed | 9 | 3 | 3 | 15 | |
| Age, Continuous | years | 12.8 (SD 5.52) | 19.0 (SD 2.65) | 21.0 (SD 3.00) | 15.7 (SD 5.79) |
| Sex: Female, Male: Female | Participants | 7 | 2 | 0 | 9 |
| Sex: Female, Male: Male | Participants | 2 | 1 | 3 | 6 |
| Race/Ethnicity, Customized: Hispanic or Latino | Participants | 0 | 1 | 0 | 1 |
| Race/Ethnicity, Customized: Not Hispanic or Latino | Participants | 9 | 2 | 3 | 14 |
| Race/Ethnicity, Customized: Black or African American | Participants | 0 | 0 | 1 | 1 |
| Race/Ethnicity, Customized: Asian | Participants | 2 | 0 | 0 | 2 |
| Race/Ethnicity, Customized: White | Participants | 7 | 3 | 2 | 12 |
| Region of Enrollment: United States | participants | 2 | 0 | 0 | 2 |
| Region of Enrollment: United Kingdom | participants | 7 | 3 | 3 | 13 |
6. Primary Endpoint
The registry lists the primary outcome as Overall Safety of Adeno-Associated Virus Vector (AAV-OPTIRPE65) - Number of Participants With a Safety Event, measured over 6 months.
| Element | Registry entry |
|---|---|
| Result type | Count Of Participants |
| Measure of spread | not applicable |
| Unit | Participants |
| Endpoint classification | Binary Endpoint |
The primary endpoint is the number of participants with a defined safety event during 6 months. A safety event is specified as ATIMP-related and includes a reduction in visual acuity by 15 ETDRS letters or more, severe unresponsive inflammation, infective endophthalmitis, ocular malignancy, or a Grade III or above non-ocular suspected unexpected serious adverse reaction.
This is a composite endpoint: it groups different types of possible harm into one outcome. Such an endpoint can provide a broad summary of whether participants experienced at least one event meeting the stated definition. Its interpretation depends on the definition, the observation period, and whether events are judged related to the investigational medicinal product. The record states the relation criterion but does not report the process used to judge relatedness.
Counting participants is different from counting event episodes. A participant with multiple qualifying events may still contribute as one participant to a participant-count endpoint, depending on the outcome specification. The registry lists the parameter as a count of participants, but further rules for handling multiple events are not reported in the registry record.
In general, safety endpoints are used to describe events that may warrant attention during clinical evaluation. This endpoint does not itself establish whether an event was caused by treatment or whether risks differ across dose groups. The primary endpoint result count is not reported in the registry record, so the registered definition can be described, but its result cannot be interpreted from the posted record.
7. Why No Re-analysis Is Shown
8. Statistical Interpretation
The registry establishes the trial’s central safety question and the endpoint definition, but it does not report a result for the primary endpoint. The number of participants meeting the composite ATIMP-related safety definition is therefore not reported in the registry record. The adverse-event summaries do contain group-level counts for serious adverse events, other adverse events, and deaths; those summaries should not be substituted for the missing primary endpoint result because the registered primary endpoint has its own specific definition.
For serious adverse events, the record lists 0 affected participants among 9 at risk in the low-dose group, 2 among 3 in the intermediate-dose group, and 1 among 3 in the high-dose group. For other adverse events, it lists 5 among 9, 2 among 3, and 3 among 3, respectively. Deaths are listed as 0 in each group. These are descriptive counts in a small, non-randomized dose-escalation trial. They do not establish that dose caused a difference in event frequency.
The registry also identifies uveitis and reduced visual acuity among the top serious adverse-event terms, listing 66.7% and 33.3%, respectively. The denominator and the precise basis for these percentages are not reported in the registry record. They should not be read as rates among all participants or as estimates of treatment-attributable risk without that information.
With non-randomized allocation, participants in the dose groups are not guaranteed to be comparable. A numerical difference in observed counts could reflect dose, group composition, observation, or other factors. The registry does not report an adjusted analysis, a formal between-group test, or uncertainty estimates. No inferential conclusion about dose differences can therefore be drawn from the posted counts alone.
The record lists no statistical analyses. It also does not provide a primary endpoint estimate, confidence interval, or hypothesis test. In general, a confidence interval describes the range of values compatible with data under a statistical model and its assumptions; it would help convey precision if an appropriate estimate were available. No such interval is reported for the primary outcome in the registry record.
The posted counts remain useful as a description of recorded safety events by group, with the limits just noted. They should be kept distinct from the primary composite outcome and from any causal claim. The registry record does not report enough information to determine event attribution, completeness of follow-up, or the precision of the group-specific estimates.
9. Statistical Methods Explained
The registry identifies a count of participants with a safety event as the primary outcome. This is a binary-outcome framework at the participant level: each participant either meets the outcome definition during the stated period or does not. A count summarizes how many participants meet the definition, while a denominator is needed to understand that count relative to the participants assessed. The registry record does not report the primary endpoint counts or analysis denominators.
What does a participant count capture?
A participant count differs from an event count. One participant may experience more than one event, but a participant-based endpoint generally focuses on whether the person met the outcome definition, rather than how many episodes occurred. The registered parameter is a count of participants. The registry does not report detailed counting rules for multiple qualifying events, overlapping event categories, or events occurring after the observation window.
The endpoint is composite because it combines several defined types of ATIMP-related safety event. Composite outcomes can summarize multiple clinically relevant event types, but the components may differ in severity, frequency, and meaning. A single combined count does not show which component accounts for the result unless component-level results are also reported. The registry gives the component definitions but does not report the primary composite result or component-specific results for that endpoint.
Why does allocation matter?
The trial is described as non-randomized and sequential, with low-, intermediate-, and high-dose groups. Random allocation, in general, is intended to make comparison groups more similar on average with respect to measured and unmeasured characteristics. Without randomization, that protection is absent. Sequential dose escalation also means the groups are not described as contemporaneous randomized arms. A difference in event counts across the groups is therefore descriptive and cannot, by itself, be attributed to dose.
For a randomized comparison, an analysis might estimate a difference or ratio in event risk and quantify uncertainty. Here, the record does not report a registered inferential analysis or a causal comparison. No comparative effect estimate should be reconstructed from the posted counts, and no new estimate is reported in this interpretation.
What does precision mean for these counts?
In general, estimates based on a small number of observations can be imprecise. A confidence interval expresses uncertainty around an estimate under stated modeling assumptions; wider intervals indicate less precision. For binary outcomes, uncertainty depends on the observed event count and the denominator, among other features. The registry does not report a confidence interval for the primary endpoint, and the specific analysis population and denominator for that endpoint are not reported in the registry record.
Formal tests and intervals also depend on an analysis plan, including the estimand, model, handling of missing data, and assumptions. These details are not reported in the registry record. The number of registered analyses is 0, so there is no registry-listed statistical analysis to interpret alongside the outcome definition.
How should the planning illustrations be read?
The planning assumptions describe illustrations based on an observed effect, a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation. The effect to detect is described as a stated fraction of the observed effect. These assumptions are not a report of the trial’s original design or its statistical plan; the record does not report that plan. The illustrations are prospective planning scenarios, not observed power. In general, sample-size calculations depend on assumptions about the target effect, variability or event frequency, allocation, and analysis method. A planning result does not add evidence to the trial’s observed outcomes and does not overcome limitations such as non-randomized allocation or missing endpoint results.
For time-to-event outcomes, the record’s planning note says that illustrations use a total number of events. The registered primary endpoint is a participant count, not a time-to-event measure. No event-time analysis is reported for the primary endpoint. Consequently, a reader should distinguish any general planning calculations from the trial’s observed safety summaries and from an analysis of the primary outcome.
10. Multiplicity, Missing Data and Analysis Populations
The registry lists one primary outcome measure and no registered analyses. It does not report whether the protocol included additional secondary outcomes, planned subgroup analyses, interim analyses, or a strategy for controlling multiplicity. Multiplicity concerns arise when several outcomes, comparisons, or repeated analyses are evaluated; without the protocol or analysis plan, it is not possible to determine what adjustments, if any, were intended. These details are not reported in the registry record.
Missing-data handling is also not reported. The record does not state whether every participant was observed for the full 6 months, how incomplete follow-up was treated, or whether an endpoint was considered absent when a participant’s status was unknown. These choices matter for a participant-count endpoint because the denominator should correspond to participants whose outcome status can be assessed under the analysis rules.
The analysis population is not reported in the registry record. The enrollment figure and group-level adverse-event denominators do not establish which participants were included in the primary endpoint analysis. No intention-to-treat, per-protocol, safety, or other analysis set is identified for that endpoint. Such labels should not be inferred from the group summaries.
The registry also does not report sensitivity analyses for missing observations or alternative definitions of the composite outcome. Without these details, the robustness of any primary endpoint result cannot be assessed; in any case, that endpoint result is not reported in the registry record. The available information supports description of the registered outcome and the posted adverse-event counts, but not reconstruction of a prespecified inferential analysis.
11. Safety Results
The registry reports serious adverse events as affected participants divided by participants at risk.
| Arm | Participants with serious adverse events | Participants at risk | Percentage |
|---|---|---|---|
| Low Dose AAV-RPE65 | 0 | 9 | 0.0% |
| Intermediate Dose AAV-RPE65 | 2 | 3 | 66.7% |
| High Dose AAV-RPE65 | 1 | 3 | 33.3% |
Deaths
| Arm | Deaths (participants affected of at risk) |
|---|---|
| Low Dose AAV-RPE65 | 0 of 9 |
| Intermediate Dose AAV-RPE65 | 0 of 3 |
| High Dose AAV-RPE65 | 0 of 3 |
Other (non-serious) adverse events
Participants with at least one non-serious event at or above the registry's 5% reporting threshold.
| Arm | Participants affected of at risk |
|---|---|
| Low Dose AAV-RPE65 | 5 of 9 |
| Intermediate Dose AAV-RPE65 | 2 of 3 |
| High Dose AAV-RPE65 | 3 of 3 |
Most frequent serious adverse event terms
| Event term | Organ system | Low Dose AAV-RPE65 | Intermediate Dose AAV-RPE65 | High Dose AAV-RPE65 |
|---|---|---|---|---|
| Uveitis | Eye disorders | 0 of 9 | 2 of 3 | 1 of 3 |
| Visual acuity reduced | Eye disorders | 0 of 9 | 0 of 3 | 1 of 3 |
Most frequent non-serious adverse event terms
| Event term | Organ system | Low Dose AAV-RPE65 | Intermediate Dose AAV-RPE65 | High Dose AAV-RPE65 |
|---|---|---|---|---|
| Uveitis | Eye disorders | 3 of 9 | 1 of 3 | 1 of 3 |
| Visual acuity reduced | Eye disorders | 2 of 9 | 0 of 3 | 1 of 3 |
| Anterior chamber inflammation | Eye disorders | 0 of 9 | 0 of 3 | 1 of 3 |
| Hypotony of eye | Eye disorders | 1 of 9 | 0 of 3 | 0 of 3 |
| Blurred vision | Eye disorders | 0 of 9 | 1 of 3 | 0 of 3 |
| Intraocular pressure increased | Investigations | 1 of 9 | 0 of 3 | 0 of 3 |
| Visual field defect | Nervous system disorders | 0 of 9 | 1 of 3 | 0 of 3 |
Serious events with the highest arm-level rate: uveitis (66.7%), visual acuity reduced (33.3%).
The serious adverse-event summaries list affected participants and participants at risk within each dose group. The low-dose group has 0 serious adverse-event participants among 9 at risk; the intermediate-dose group has 2 among 3; and the high-dose group has 1 among 3. The corresponding other-adverse-event counts are 5 among 9, 2 among 3, and 3 among 3. Deaths are listed as 0 in each group.
These are descriptive summaries, not randomized comparisons. The group sizes are small, and allocation was non-randomized and sequential. The counts do not establish that the dose level caused an event or a difference between groups. The registry record does not report the event-level details, adjudication process, duration of observation for these summaries, or whether all listed events were considered related to treatment.
Uveitis and reduced visual acuity are listed among the top serious terms, with 66.7% and 33.3%. Their percentage denominator is not reported in the registry record. These term percentages should therefore be read as registry-listed summaries, not as participant-level risks. Serious adverse events also should not be equated with the primary composite safety endpoint, which has a separate ATIMP-related definition and no reported result count.
12. What the Result Does, and Does Not, Mean
The record documents a completed, open-label, non-randomized Phase I/II dose-escalation trial of AAV RPE65 gene therapy for retinal dystrophy associated with RPE65 defects. It specifies a safety endpoint and a 6-month timeframe, and reports adverse-event counts by dose group. These details describe the scope and recorded safety information for this trial.
The registered primary endpoint asks how many participants experienced an ATIMP-related event meeting a defined set of criteria. That count is not reported in the registry record. The adverse-event summaries give serious and other event counts, but those are not interchangeable with the primary composite outcome. The record does not provide the primary endpoint estimate, its denominator, or an uncertainty interval.
The posted group counts do not establish a causal effect of dose. The groups were not randomized, and the registry does not report a control arm or an adjusted analysis. In general, observed differences in a non-randomized study may reflect differences between participants or other influences as well as the intervention. The posted counts can be described as recorded events, but they cannot isolate a treatment effect.
Nor do the counts establish the absence of risk. A count of zero for a category in a group is a statement about the events recorded in that group, not proof that the event cannot occur. More broadly, the registry record does not report enough detail on follow-up completeness, event attribution, or analysis populations to determine how those factors affect the summaries.
The results therefore support a limited reading: the registry reports particular adverse-event counts across three dose groups and defines a primary safety outcome, but does not report that primary outcome’s result or an inferential comparison. The record does not establish efficacy, comparative safety, or a dose-response relationship.
13. Why This Trial Matters Statistically
This trial is statistically informative as an example of the distinction between a registered endpoint and the results actually available in a registry record. The primary outcome is clearly named and defined, but its participant count is not reported. The presence of other safety summaries does not fill that gap, because serious adverse events, other adverse events, and the specified ATIMP-related composite endpoint are distinct measures.
Its non-randomized, sequential design also illustrates why descriptive group summaries should not be mistaken for causal comparisons. Dose-group counts can communicate what was recorded, but groups created sequentially are not equivalent to randomized arms. Without randomization and a reported analysis addressing group differences, numerical contrasts cannot be interpreted as effects attributable to dose.
The trial further highlights the importance of denominators and outcome definitions. Counts are easier to interpret when the analysis population, follow-up completeness, event attribution, and counting rules are reported. Here, group denominators appear in the adverse-event summaries, but the primary endpoint’s analysis denominator and result are not reported. The listed serious-event term percentages also lack a reported denominator.
Finally, planning calculations and observed evidence answer different questions. Planning illustrations can show how assumptions about an effect and analysis method relate to a prospective sample-size scenario; they are not observed power and do not substitute for a reported outcome analysis. Keeping design, planning, and observed results separate is essential when reading an early-phase safety study.
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 main limitation for interpreting the registered primary question is that its outcome count is not reported in the registry record. The record lists the endpoint definition and observation period, but does not give the result, analysis denominator, or an uncertainty estimate. The posted adverse-event summaries cannot be treated as a substitute for that primary endpoint.
The non-randomized, sequential allocation limits comparisons across dose groups. No like-for-like control group is described, and the record does not report an adjusted comparison. Any differences in observed event counts could reflect features of the groups as well as dose. The registry does not provide enough information to assess baseline comparability or account for potential confounding.
The registry does not report the analysis population, missing-data rules, completeness of follow-up, event-attribution procedures, or detailed rules for counting multiple events. The denominator underlying the listed serious-event term percentages is also not reported. These omissions limit assessment of how completely and consistently outcomes were captured and how the summary figures should be interpreted.
Further protocol and statistical-plan details, including escalation criteria, planned analyses, and any multiplicity approach, are not reported in the registry record. The available record supports a description of the design, endpoint definition, and posted safety counts, but not a full appraisal of the planned analysis or a causal conclusion about dose.
15. Related Tutorials
16. Related Statistical Calculators
17. Sources
- ClinicalTrials.gov: Clinical Trial of Gene Therapy for the Treatment of Leber Congenital Amaurosis (LCA) — NCT02781480.
- Registry record last updated 2021-07-12; status last verified 2021-06.
- Results first posted 2021-04-08.
- 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.
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18. Record Summary
NCT02781480 is a completed, open-label, multi-centre Phase I/II trial of AAV RPE65 gene therapy in adults and children with retinal dystrophy associated with RPE65 defects. The design is registered as non-randomized and sequential, with low-, intermediate-, and high-dose groups. Enrollment is listed as 15.
The primary outcome is the number of participants with a defined ATIMP-related safety event over 6 months. The primary endpoint result and a registered statistical analysis are not reported in the registry record. Adverse-event summaries list serious events, other events, and deaths by group; those summaries are descriptive and do not establish a causal dose comparison.