A Study to Evaluate 0.003% AR-15512 Safety and Drop Attributes: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for A Study to Evaluate 0.003% AR-15512 Safety and Drop Attributes (NCT06660290), a randomized phase 3 study. The primary outcome is Percentage of Subjects With Ocular Treatment-Emergent Adverse Events Attributed to Study Intervention.

2. Clinical Question

The central statistical question is descriptive: how often was an ocular treatment-emergent adverse event attributed to 0.003% AR-15512, compared with artificial tears, among participants in the safety population? The registry reports 3.6% for AR-15512 and 0.0% for artificial tears. Its comparison data correspond to 2 events among 55 subjects for AR-15512 and 0 among 55 for artificial tears.

This is a safety endpoint, not a measure of symptom improvement or treatment benefit. The endpoint concerns events that occurred or worsened on or after the day an intervention was initiated and were attributed to the study intervention. The record specifies that the AR-15512 percentage combines all instillation variations. It does not provide separate endpoint results for the individual variations, so their event rates cannot be compared using the posted primary result.

The study is described as randomized and crossover, but the clinical question remains limited to the posted adverse-event percentages and their uncertainty. The record does not report a prespecified hypothesis test for this endpoint. The estimate and interval therefore describe the posted safety comparison; they do not establish a treatment effect or resolve whether the observed difference reflects a reproducible pattern.

3. Trial Design

The registry identifies NCT06660290 as a Phase 3b study titled “A Study to Evaluate 0.003% AR-15512 Safety and Drop Attributes.” It was randomized, single-masked, and used a crossover model. The listed condition is dry eye disease. The sponsor is Alcon Research, and the record marks the study as completed. Enrollment was 55.

The interventions were 0.003% AR-15512 ophthalmic solution and artificial tears. The brief summary identifies the comparator as REFRESH® Classic. The registry describes four sequences of AR-15512 instillation variations: Sequence 1, Sequence 2, Sequence 3, and Sequence 4. Each sequence gives a different ordering of the variations 512-RT, 512-COLD, 512-RT-EC, and 512-COLD-EC. Each description also mentions one drop of artificial tears in the right eye before the AR-15512 variations. The details of eye-by-eye alternation are not reported in the registry record.

A crossover design means that the study plan involves participants receiving interventions in a sequence rather than assigning each participant to only one intervention throughout. General statistical interpretation of crossover data can depend on the order of interventions, timing, and whether effects from an earlier intervention could influence observations after a later one. The registry record does not report the washout arrangements, period durations, sequence allocation counts, or analysis accounting for sequence or period.

The primary safety observation window was up to Day 1 post drop instillation. Although the registry gives study start and primary completion dates, those dates do not by themselves describe the duration of each participant’s observation. Detailed eligibility criteria, the masking role, and the reason for selecting the design are not reported in the registry record.

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: This reporting group includes all randomized subjects (55).

Overall Study

Analysis population for the primary outcome, as defined in the registry: Safety Analysis Set: All subjects who received at least one dose of artificial tears or one dose of 0.003% AR-15512. AEs for 0.003% AR-15512 are reported by intervention (all instillation variations combined) as specified in the protocol and statistical analysis plan.

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: Full Analysis Set: All subjects who have received at least one dose of artificial tears and one dose of 0.003% AR-15512 instillation variation and who have at least one rating of the Rating Sensation Assessment.

6. Primary Endpoint

The registry lists the primary outcome as Percentage of Subjects With Ocular Treatment-Emergent Adverse Events Attributed to Study Intervention, measured over Up to Day 1 post drop instillation.

The primary endpoint is the percentage of subjects with ocular treatment-emergent adverse events attributed to study intervention, measured up to Day 1 post drop instillation. The registry defines treatment-emergent adverse events as events that occurred or worsened on or after the day study intervention was initiated. For the safety population, a subject could qualify by receiving at least one dose of artificial tears or at least one dose of 0.003% AR-15512.

This endpoint is used to describe the frequency of reported ocular adverse events after exposure to the interventions. It is a binary participant-level outcome: a subject is counted as having an event or not having an event under the endpoint definition. The percentage communicates how common the recorded outcome was in the stated safety population; it does not describe severity, duration, or the total number of all symptoms unless those are separately reported.

The record reports AR-15512 adverse events across all instillation variations combined, as specified in its protocol and statistical analysis plan. Consequently, the primary percentage does not distinguish among 512-RT, 512-COLD, 512-RT-EC, and 512-COLD-EC. The registry says no hypothesis testing was prespecified for this endpoint. The result should therefore be read as a descriptive safety summary rather than as a prespecified test of a difference between interventions.

7. Results Posted in the Registry

• 0.003% AR-15512: 3.6% (2/55) versus 0.0% (0/55) on control; risk difference 3.6 percentage points (95% CI -1.3 to 8.6); unadjusted two-proportion z-test p = 0.154.

8. Statistical Interpretation

9. Statistical Methods Explained

What does a percentage of subjects with an event represent?

For a binary endpoint, each subject is classified according to whether the event definition was met. The percentage is the proportion of the analysis population counted as having the event. It describes how frequently the event was observed in that population and over the stated observation window. It is not an event rate per unit of time, and it does not necessarily represent the total number of individual event episodes if a subject could have more than one.

Here, the outcome is the percentage of subjects with ocular treatment-emergent adverse events attributed to the intervention. The registry defines treatment-emergent events by when they occurred or worsened, and specifies attribution to study intervention. The safety population includes subjects receiving at least one dose of either artificial tears or 0.003% AR-15512. The record reports 55 subjects for each intervention and gives the endpoint percentages as 3.6% and 0.0%.

What is a risk difference?

A risk difference expresses the difference between two event proportions on the absolute proportion scale. It retains the same basic units as the event proportion, rather than expressing a relative change. A value of zero corresponds to equal proportions; values on either side indicate the direction of the estimated difference according to the comparison’s ordering. The posted estimate is 0.036 for 0.003% AR-15512 relative to artificial tears. Its confidence interval is -0.013 to 0.086.

The interval’s negative and positive limits indicate that the data do not pin down the direction of the difference with precision. This is an uncertainty statement about the estimate under the calculation used, not a probability that a particular treatment effect is true. General interpretation of a confidence interval depends on the method and assumptions used to construct it. The calculation method is not reported in the registry record.

How should the p-value be read?

A p-value is a measure of how unusual data at least as incompatible with a specified null model would be if that model and the test assumptions held. It is not the probability that the null hypothesis is true, nor does it measure the size or clinical importance of a difference. The registry posts an unadjusted p-value of 0.154, while also stating that hypothesis testing was not prespecified for this endpoint. The precise test and its assumptions are not reported in the registry record. The p-value is therefore best treated as supplementary descriptive information rather than as evidence from a prespecified confirmatory test.

Why does a small event count affect interpretation?

When events are sparse, each observed event can have a substantial influence on the estimated percentage and the comparison. Estimates can therefore be imprecise, even when the displayed percentages look simple. A confidence interval communicates this uncertainty more directly than the point estimate alone. General statistical methods for sparse binary outcomes can differ in their behavior, particularly when one group has no observed events. The registry does not state which interval or test methods were used, so no method-specific property should be assumed.

What does the crossover design add?

In a crossover study, interventions are administered to participants in a sequence, allowing observations from more than one intervention within the study plan. General analysis may need to account for the fact that measurements from the same participant are related; they are not necessarily independent as if they came from unrelated participants. Period effects, sequence effects, and carryover can also matter in some crossover settings. Their relevance and handling depend on the design and analysis plan. The registry identifies a crossover model and four sequences, but it does not report the analysis method, washout details, or results by sequence or period. It is not possible to determine from the posted summary whether these features were modeled.

What is the role of the planning illustrations?

Sample-size planning asks how many participants might be needed to detect a specified effect under chosen assumptions. The registry’s planning illustration is explicitly based on the observed effect, uses a two-sided significance level of 0.05 and equal allocation, and applies a normal approximation. It describes the effect to detect as a stated fraction of the observed effect. Such calculations are planning illustrations, not observed power and not evidence that the original trial was designed around the observed result. The registry does not report the trial’s own sample-size justification. The design basis and any original planning assumptions are not reported in the registry record.

In general, planning calculations depend on assumptions about the effect size, variability or event frequency, allocation, test, and desired power. Changing those assumptions changes the resulting planning requirement. For a crossover study, planning may also depend on within-participant variability and design features, but those elements are not specified in the registry’s stated illustration. No additional planning values or underlying study design justification should be inferred from the posted endpoint result.

10. Confidence Intervals and Precision

The point estimate for the risk difference is 0.036. Its 95% confidence interval extends from -0.013 to 0.086. The interval is the key precision measure for the reported comparison: it shows a range of values compatible with the data under the method used to calculate it and the assumptions behind that method.

Because the interval crosses zero, it includes no difference as well as possible differences in either direction. The result does not tightly determine the direction or size of the underlying contrast. The observed percentages, 3.6% for 0.003% AR-15512 and 0.0% for artificial tears, are point summaries; they should not be read without the interval or the underlying event counts. The comparison data report 2 events among 55 subjects in the AR-15512 group and 0 among 55 in the artificial-tears group.

General statistical interpretation: a confidence interval is not a guarantee that the true value lies within the particular interval, and it is not a range of individual participants’ outcomes. Its coverage interpretation depends on repeated use of the same method under its assumptions. The interval method is not reported in the registry record. The study’s crossover structure also means the analysis method may matter to uncertainty, but the record does not describe how the interval accounts for that design.

The interval should not be used to claim equivalence. Equivalence requires a prespecified margin and an analysis directed to that question; neither is reported in the registry record. Nor does the interval alone determine whether a difference is clinically important. A clinical threshold for interpreting this safety endpoint is not reported in the registry record.

11. Multiplicity, Missing Data and Analysis Populations

The registry states that no hypothesis testing was prespecified for the primary endpoint. It reports one primary outcome measure and no posted secondary outcome measures. The record does not report a multiplicity adjustment, a testing hierarchy, or a family of confirmatory hypotheses. Without those details, there is no basis for asserting how multiple comparisons, if any, were controlled. The four AR-15512 instillation variations are combined in the primary safety report, and separate inferential comparisons for those variations are not reported.

The primary population is the Safety Analysis Set: subjects who received at least one dose of artificial tears or at least one dose of 0.003% AR-15512. The record gives 55 subjects for each intervention. It does not report whether every participant contributed data to every sequence or intervention, the number excluded from any analysis, or the handling of participants with incomplete exposure or follow-up.

Missing-data methods are not reported in the registry record. In particular, it does not state how missing adverse-event information, withdrawal, or incomplete observation within the up to Day 1 post drop instillation window was handled. It also does not report sensitivity analyses for missing outcomes. These omissions limit assessment of whether the posted percentages represent complete event ascertainment for the full safety population.

The crossover model raises general questions about paired observations, sequence, period, and possible carryover, but the analysis population and model used for the primary comparison are not described beyond the safety-set definition. The registry does not report an intention-to-treat population or a separate per-protocol analysis. Therefore, the result can be interpreted as the posted safety summary, but the analysis details needed to assess alternative populations or model choices are not available in the registry record.

12. 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.

The registry’s adverse-event summary lists zero serious adverse events and zero other attributed adverse events for Pretreatment, Artificial Tears, and 0.003% AR-15512. It also lists zero deaths in each of those groups. These counts are safety-summary entries and should be read according to their labels; they do not mean that no adverse event of any kind occurred under every endpoint definition.

The primary endpoint separately reports ocular treatment-emergent adverse events attributed to study intervention: 3.6% for 0.003% AR-15512 and 0.0% for artificial tears. The comparison data give 2 events for AR-15512 and 0 for artificial tears. The record does not explain the relationship between this primary endpoint and the adverse-event summary’s zero other attributed events. Because the endpoint definitions or counting rules may differ, the two summaries should not be merged or treated as interchangeable.

Zero observed serious events is a statement about what was recorded in the registry’s safety summary for these groups. It is not proof that the risk of a serious event is zero. The number of subjects and the short endpoint timeframe also frame the scope of the observation, without establishing the frequency of uncommon events beyond the study. Serious-event term details are not reported in the registry record.

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

The posted findings describe the observed safety outcome in this study: ocular treatment-emergent adverse events attributed to 0.003% AR-15512 were reported for 3.6% of subjects, compared with 0.0% for artificial tears. The comparison summary gives 2 events among 55 subjects for AR-15512 and 0 among 55 for artificial tears. These results apply to the registry’s stated safety population and the endpoint window up to Day 1 post drop instillation.

The risk-difference estimate and its interval describe uncertainty around the observed contrast. The interval from -0.013 to 0.086 includes zero and values on either side, so the result does not establish a clear direction for the underlying difference. The registry says no hypothesis testing was prespecified for this endpoint; the posted p-value of 0.154 should not be elevated into a confirmatory conclusion. Nor does the result establish that the interventions are equivalent.

The findings do not measure symptom relief, efficacy, or any broader clinical outcome. They do not determine the rate of adverse events outside the reported observation window, and they do not provide separate percentages for the four AR-15512 instillation variations. A combined percentage cannot show whether the variations had similar or different event patterns.

These results also do not establish how well the findings generalize beyond the study population and design. The registry record does not report detailed eligibility criteria, sequence-specific results, or a full statistical model for the crossover comparison. In general, observed outcomes in a study are not automatically estimates for every population, setting, or exposure schedule.

The appropriate reading is limited: the registry reports a small observed proportion for the combined AR-15512 variations and no observed primary endpoint events for artificial tears, with uncertainty around the comparison. That is a description of the posted data, not a medical recommendation or a determination of treatment benefit or harm.

14. Why This Trial Matters Statistically

This trial illustrates why safety percentages should be considered alongside event counts and uncertainty. A percentage alone can make a sparse outcome look more definitive than it is. The underlying comparison counts are 2 and 0, and the risk-difference interval spans -0.013 to 0.086. Together, those summaries convey both what was observed and how much uncertainty remains about the contrast.

The crossover design is another important statistical feature. General analysis of crossover data can depend on within-participant relationships and on sequence or period effects. The registry identifies four sequences and combines all AR-15512 instillation variations in the primary report, but does not report sequence-specific results or the model used for the comparison. This leaves readers unable to assess how those design features were handled from the record alone.

The endpoint is explicitly descriptive in the registry: no hypothesis testing was prespecified. This distinction matters because a posted p-value can be mistaken for the result of a planned confirmatory test. The analysis should be read in light of its stated purpose, with emphasis on the event percentages, counts, and confidence interval rather than a threshold-based declaration.

The registry also demonstrates the value of keeping endpoint-specific results distinct from broader safety summaries. The primary outcome reports 2 AR-15512 events, while the adverse-event group summary lists zero other attributed events. The record does not explain the relationship between these summaries, so transparent definitions and analysis details are important for interpreting safety data accurately.

15. 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.
• Participant counts were reconstructed from posted percentages and arm sizes, so small rounding differences are possible.

The registry record leaves important details of the design and analysis unreported. It does not give the detailed eligibility criteria, the rationale for the enrollment target, or the study’s original sample-size justification. The planning illustration is based on the observed effect and should not be mistaken for the basis of the trial’s design.

Although the study is identified as a randomized, single-masked crossover trial, the record does not describe the identity of the masked party, the washout arrangements, period durations, or the number of participants assigned to each sequence. The sequence descriptions list different orderings of the instillation variations, but the available descriptions do not fully state the eye-by-eye schedule. No results by sequence, period, or individual variation are reported.

The primary endpoint has a short stated timeframe, up to Day 1 post drop instillation. The record does not describe longer-term safety follow-up for this outcome. The event count is sparse, and the confidence interval is broad enough to include values below and above zero. This limits precision in estimating the difference.

The statistical method for the interval and unadjusted p-value is not reported. The registry also does not describe missing-data handling, sensitivity analyses, or a crossover-specific model. Although it defines the safety analysis set, it does not report the handling of incomplete exposure or follow-up. Finally, the record does not explain why the primary endpoint reports 2 AR-15512 events while the adverse-event group summary lists zero other attributed events for that intervention. These limitations constrain interpretation of the posted result and do not establish that the analyses were incorrect.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: A Study to Evaluate 0.003% AR-15512 Safety and Drop Attributes — NCT06660290.
• Registry record last updated 2026-03-17; status last verified 2026-03.
• Results first posted 2026-03-17.
• 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.

19. Record Summary

NCT06660290 is a completed randomized, single-masked, Phase 3b crossover study sponsored by Alcon Research. It enrolled 55 subjects with dry eye disease and evaluated 0.003% AR-15512 ophthalmic solution and artificial tears, identified in the brief summary as REFRESH® Classic.

The primary endpoint was the percentage of subjects with ocular treatment-emergent adverse events attributed to study intervention, up to Day 1 post drop instillation. The endpoint result was 3.6% for 0.003% AR-15512 and 0.0% for artificial tears; the comparison data report 2 and 0 events, respectively, among 55 subjects per intervention. The risk difference was 0.036, with a 95% confidence interval from -0.013 to 0.086 and an unadjusted p-value of 0.154. No hypothesis testing was prespecified for this endpoint.

The registry reports the AR-15512 result across all instillation variations combined. It lists zero serious adverse events and zero deaths in the adverse-event group summaries. Detailed crossover analysis methods and missing-data handling are not reported in the registry record.