Safety and Efficacy of Nyxol (0.75% Phentolamine Ophthalmic Solution) to Reverse Pharmacologically-Induced Mydriasis (MIRA-3): Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Safety and Efficacy of Nyxol (0.75% Phentolamine Ophthalmic Solution) to Reverse Pharmacologically-Induced Mydriasis (MIRA-3) (NCT05134974), a randomized phase 3 study. The primary outcome is Percent of Subjects' Study Eyes With Pupil Diameter Returning to Baseline.

2. Clinical Question

The clinical question is whether phentolamine ophthalmic solution 0.75% can help reverse pharmacologically induced pupil dilation, and how its safety findings compare with those for the vehicle control. The registry describes a randomized, parallel-arm study in healthy subjects. It identifies phenylephrine as an emphasis among the mydriatic agents, and also describes objectives concerning return to baseline accommodation after cycloplegic agents tropicamide and Paremyd.

The primary outcome is the percentage of subjects’ study eyes whose pupil diameter returns to within 0.2 mm of baseline at 90 minutes. This makes the question specific to a measured pupil-diameter threshold and a stated assessment time. The primary outcome title and definition are present, but the numerical results for this endpoint are not reported in the registry record. The record also lists outcomes concerning pupil diameter change, accommodation, and best-corrected distance visual acuity under normal photopic lighting without glare conditions; numerical results for those outcomes are not reported in the registry record.

The intervention and vehicle are both described as eye drops given one hour after pharmacologically induced mydriasis, with the same stated number of drops in the study and non-study eyes. This comparison is intended to distinguish the effects observed with the active solution from those observed with its vehicle under the study conditions. Without posted primary endpoint results, the registry record does not establish the size or precision of a treatment difference for reversal of mydriasis.

Other stated objectives include safety, additional benefits of reversal, and systemic exposure assessed through pharmacokinetic sampling. The record does not give numerical pharmacokinetic findings or a complete account of the additional-benefit outcomes.

3. Trial Design

The registry identifies NCT05134974 as a completed phase 3 study sponsored by Opus Genetics, Inc. It describes random allocation and a parallel-arm model, with enrollment listed as 368. The study began on 2021-11-18 and had a primary completion date of 2022-03-18. These dates and enrollment describe the registry entry; the record does not report how many participants contributed data to each outcome or analysis.

The two listed interventions are phentolamine ophthalmic solution 0.75% and phentolamine ophthalmic solution vehicle. For each, the arm description specifies two drops in the study eye and one drop in the non-study eye, one hour after pharmacologically induced mydriasis. The record identifies the population as healthy subjects in the official title. More detailed eligibility criteria, including age range and other inclusion or exclusion rules, are not reported in the registry record.

The registry masking field says triple masking, whereas the official title describes the study as double-masked. The record does not explain this difference or identify which groups of people were masked. It also does not report the randomization sequence method, allocation concealment procedure, treatment adherence, or the handling of deviations from assigned treatment.

The brief summary describes evaluation across multiple mydriatic agents, with emphasis on phenylephrine, and evaluation of return to baseline accommodation after worsening with tropicamide and Paremyd. It also names safety, additional benefits, and pharmacokinetic sampling as objectives. The record does not specify how many participants were assigned to each arm for the efficacy outcomes or whether all participants received the same inducing agents and assessment schedule.

Five outcome measures are listed, but the registry reports no outcome analyses. Thus, the design and aims can be described, but the available record does not provide the outcome estimates required to assess the comparative efficacy results.

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

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.

6. Primary Endpoint

The registry lists the primary outcome as Percent of Subjects' Study Eyes With Pupil Diameter Returning to Baseline, measured over 90 minutes.

The primary endpoint is the percentage of subjects’ study eyes returning to a pupil diameter within 0.2 mm of baseline at 90 minutes. It is a threshold-based endpoint: an eye is counted as meeting the endpoint if its measured pupil diameter is close enough to its baseline value at the stated assessment time. The endpoint is expressed as a percentage of subjects, while the registry also identifies its measure type as a count of participants.

In general, a threshold endpoint can make a clinical question easier to interpret by distinguishing whether a predefined target was reached. It also compresses a continuous measurement, pupil diameter, into a yes-or-no classification for each subject’s study eye. That can make the result less informative about how far from baseline an eye was when it did not meet the threshold, or how close it was when it did. The separate listed outcome of pupil-diameter change from maximum may address a different aspect of the measurement, but its numerical findings are not reported in the registry record.

The 90-minute assessment gives the endpoint a specific time horizon. In general, results at one assessment time do not by themselves describe the full time course of pupil recovery. The registry lists the endpoint definition and timeframe but does not report its numerical result, group denominators for the efficacy analysis, or an estimated comparison between arms. The extent and precision of any difference in this primary endpoint therefore cannot be assessed from the registry record.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

Statistical interpretation begins by separating the study question, the outcome definition, and the result. The study question concerns a randomized comparison of phentolamine ophthalmic solution 0.75% with vehicle after pharmacologically induced mydriasis. The primary outcome definition concerns return of the study-eye pupil diameter to within 0.2 mm of baseline at 90 minutes. A numerical result would then be needed to estimate the observed group outcomes and their contrast. The registry record supplies the first two elements but does not report the primary outcome analysis.

What does randomization contribute?

In general, randomization assigns participants to treatment groups by chance. Its purpose is to reduce systematic differences between groups at assignment, including differences that may not have been measured. Randomization does not guarantee that groups are identical, and it does not replace reporting baseline characteristics, follow-up, outcome data, and the analysis method. The registry identifies the study as randomized but does not report the sequence-generation method, concealment procedure, baseline outcome data, or group-specific efficacy analysis denominators. The extent to which these details can be evaluated from the registry record is therefore limited.

A parallel-arm design means that participants are assigned to a group and the comparison is made between groups. In general, the primary analysis should reflect the randomized comparison in a clearly stated analysis population. The registry does not identify the population used for the primary outcome analysis, such as whether it included all randomized participants or only those with an observed endpoint. That information is important because exclusions after randomization can affect how well the comparison preserves the benefits of random assignment.

How should the primary endpoint be read?

The endpoint classifies whether a study eye reached a prespecified pupil-diameter threshold relative to baseline at a specified time. In general, categorical outcomes are often summarized as counts or proportions meeting the definition in each group. A comparison might then estimate an absolute difference or another contrast, with an interval that conveys uncertainty. Those are general descriptions of possible statistical summaries, not reported analyses for this study. The registry gives no primary outcome counts, proportions, treatment contrast, confidence interval, or p-value.

Converting a measured diameter into a threshold outcome has interpretive consequences. In general, participants just inside and just outside the threshold are classified differently, even if their measurements are close. A binary classification can be clear, but it omits detail about the distribution of continuous measurements. The listed pupil-diameter change outcome could provide complementary information, although its numerical results and precise analysis are not reported in the registry record.

What do uncertainty and significance mean?

In general, a confidence interval expresses uncertainty in an estimate under the assumptions of the analysis. It is not a guarantee that the true effect lies within a particular interval, and its width depends on such factors as the amount of information and variability in the data. A p-value, when reported, measures how incompatible the observed data are with a specified null model under its assumptions; it does not state the probability that the null hypothesis is true, nor does it measure clinical importance. Neither confidence intervals nor p-values for the primary endpoint are reported in the registry record.

Statistical significance and practical importance are distinct. A small estimated difference can be statistically distinguishable from a null value in sufficiently informative data, while an imprecise estimate can be compatible with a range of effects. Conversely, a result that does not meet a significance threshold does not establish equivalence. Since the primary endpoint estimate and its uncertainty are absent, none of these distinctions can be applied to the efficacy comparison in this registry entry.

What is reported about planning?

The planning description characterizes sample-size illustrations as based on the observed effect, using a two-sided significance level of 0.05, equal allocation between arms, and a normal approximation. It says the effect to detect is a stated fraction of the observed effect, and that the non-time-to-event illustrations are expressed as participants per arm. These are planning illustrations, not observed power. They do not establish the trial’s original design assumptions or show that the study had a particular probability of detecting an effect. A sample-size justification in the original protocol is not reported in the registry record. The record also does not provide numerical planning results in the registry record for interpretation.

In general, planning calculations depend on assumptions about the effect size, variability or event rate, significance threshold, allocation, and analysis. When an observed effect is used to construct an illustration after results are available, the calculation is not a substitute for a prospective design justification. The registry’s planning description does not supply the original protocol assumptions, and no conclusion about the adequacy of the trial’s design should be drawn from the illustration alone.

What analysis details are missing?

The registry does not report the statistical test or model for the primary endpoint, whether the comparison was adjusted for other variables, or how repeated assessments across agents or times were handled. It does not describe interim analyses, an estimand, or procedures for handling missing data. General methods for binary outcomes may include models or tests that estimate group differences, but selecting a suitable approach depends on the design, outcome structure, and prespecified analysis plan. Since the relevant plan and analysis are not reported, it would be inappropriate to infer which method was used.

The registry lists five outcome measures and names several objectives. In general, testing multiple outcomes, time points, or subgroups can increase the chance of at least one apparently notable result if no multiplicity strategy is used. The record does not report whether such a strategy was specified or applied. The primary endpoint itself is described in the record as having several categories or time points, and it is not reduced to one comparison in the posted results. No single primary contrast can therefore be reconstructed from the registry information.

10. Multiplicity, Missing Data and Analysis Populations

The registry lists five outcome measures and describes several study objectives, including reversal of mydriasis, return to baseline accommodation, safety, additional benefits, and pharmacokinetic sampling. The primary outcome description also indicates multiple categories or time points, and the posted results do not reduce it to one comparison. No numerical outcome analyses are reported. The registry record does not describe a hierarchy of outcomes, a multiplicity adjustment, or another strategy for controlling the chance of false-positive findings across multiple comparisons.

In general, multiplicity matters when several outcomes, time points, treatment comparisons, or subgroups are tested. If each is assessed separately without adjustment or a prespecified hierarchy, the chance of at least one result appearing noteworthy can increase. This general concern does not establish that the study used or failed to use any particular method. The analysis plan is not reported in the registry record.

The record also does not describe how missing outcome measurements were handled, how many participants had missing primary endpoint data, or whether any imputation or sensitivity analyses were performed. In general, missingness can affect interpretation when the likelihood of an outcome being observed is related to treatment or to the outcome itself. Without information about completeness and the assumptions used to address missingness, the potential influence on the estimates cannot be assessed.

Although enrollment is listed as 368, the registry does not report the analysis population or the group-specific denominators for efficacy outcomes. Enrollment alone does not identify how many participants were included in a particular analysis. The record also does not report whether analyses followed assignment regardless of treatment received, or whether any other population was used. These omissions limit assessment of the relationship between randomization, outcome availability, and the reported safety counts.

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 3% reporting threshold.

Most frequent non-serious adverse event terms

The registry lists zero serious adverse events among 244 participants at risk in the phentolamine ophthalmic solution 0.75% arm, and zero among 124 at risk in the vehicle arm. It also lists zero deaths in each arm. For other adverse events, the registry reports 43 among 244 at risk in the phentolamine arm and zero among 124 at risk in the vehicle arm.

These figures are event counts as recorded, not a complete comparison of safety. The record does not give the terms or descriptions for the other adverse events, their timing, severity, duration, or whether they were considered related to treatment. The list of top serious-event terms is empty, consistent with the reported absence of serious events in these summaries, but it does not provide additional event detail.

In general, a zero count in a study does not show that an event is impossible or that the treatment has no safety risks. The interpretation depends on the amount and duration of follow-up, the population, event definitions, and completeness of reporting. Those details are not reported in the registry record. The arm counts should not be read as adjusted estimates, and the registry does not provide a formal statistical safety comparison or uncertainty intervals.

The reported counts apply to the listed at-risk denominators for these adverse-event summaries. The record does not explain whether the same participants contributed to each category or provide a fuller account of safety monitoring. Accordingly, these figures describe the recorded serious-event, death, and other-event counts, but do not establish a comprehensive safety profile.

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

The registry record establishes that NCT05134974 was a randomized, parallel-arm phase 3 study in healthy subjects comparing phentolamine ophthalmic solution 0.75% with vehicle after pharmacologically induced mydriasis. It also defines a primary endpoint based on return of the study-eye pupil diameter to within 0.2 mm of baseline at 90 minutes. These design details clarify the question the study set out to address.

What the registry record does not establish is the numerical result for that primary endpoint. It does not report the group-specific numbers meeting the threshold, an estimated difference, a confidence interval, or a significance test. The additional listed outcome measures likewise have no numerical analyses in the record. Without those results, the magnitude and precision of any efficacy comparison cannot be described, and absence of a reported result should not be interpreted as evidence of no effect or of equal outcomes.

The record provides adverse-event counts, including zero serious adverse events and zero deaths in both arms, and 43 other adverse events in the phentolamine arm compared with zero in the vehicle arm. Those counts do not by themselves show that a treatment caused an event or that one arm had a greater overall risk. Event descriptions and a formal comparison are not reported in the registry record. They should be interpreted as recorded counts, not as a complete account of safety.

More broadly, a trial result is interpreted through the endpoint definition, analysis population, completeness of follow-up, statistical method, and uncertainty around the estimate. Several of these details are not reported. The registry entry therefore describes the study’s intent and some safety counts, but it does not support a quantitative conclusion about the primary efficacy comparison or a full appraisal of the statistical evidence.

The study’s healthy-subject setting also defines the population represented by its results. In general, findings from healthy participants do not automatically describe findings in other populations. The registry record does not report a broader clinical population, and no conclusions about populations beyond the study description can be drawn from the information available.

13. Why This Trial Matters Statistically

This trial is statistically notable for a focused, threshold-based primary outcome paired with a randomized, vehicle-controlled design. The endpoint asks whether pupil diameter in the study eye returns close to baseline by a specified time. A clear threshold and assessment time help define what counts as meeting the endpoint, while the parallel-arm comparison provides a structure for comparing the active solution with vehicle.

The registry record also illustrates why an endpoint definition is not enough to interpret a trial. To judge a treatment comparison, readers need the observed outcome counts or proportions, the estimated contrast, and an indication of uncertainty. Those primary endpoint results are not reported. Without them, the statistical question remains defined but unanswered by the posted numerical results.

The study includes several objectives and listed outcomes, making transparent reporting of the outcome hierarchy and multiplicity strategy relevant. In general, an explicit plan helps readers understand which comparison was primary and how secondary or repeated comparisons were interpreted. The registry does not report such a strategy or the outcome analyses. This gap limits evaluation of the statistical plan, rather than demonstrating that a particular approach was or was not used.

The record also makes clear that safety counts and efficacy results answer different questions. Serious adverse events and deaths are reported as zero in both arms, while the other-event counts differ. These counts are important to describe, but without event detail, follow-up information, or an analysis, they cannot stand in for a comprehensive safety comparison.

Finally, the record lists sample-size planning illustrations based on the observed effect, but those illustrations are not observed power and do not replace a prospective design justification. The original sample-size rationale is not reported. Taken together, the trial’s design and endpoint are interpretable, while the missing primary results and analysis details constrain what can be concluded statistically.

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 central limitation for interpretation is that the registry record does not report numerical results for the primary endpoint. It gives the endpoint definition and timeframe but no group-specific outcome counts, analysis denominators, estimated treatment contrast, confidence interval, or p-value. The efficacy comparison therefore cannot be quantified or assessed for precision from this record.

The record lists several secondary outcomes and objectives but does not give their numerical results. It does not report how the several categories or time points associated with the primary outcome were handled in analysis, or how multiple outcomes and comparisons were addressed. The statistical analysis plan, including the test or model used, is not reported in the registry record.

Although enrollment is listed as 368, the record does not provide participant flow, arm-specific efficacy denominators, or analysis-population definitions. It does not state how missing data were handled, whether sensitivity analyses were conducted, or whether outcome measurements were complete. These omissions prevent assessment of the effects of missingness, exclusions, or analysis choices on the efficacy findings.

The record describes the study as triple-masked in its masking field, while the official title calls it double-masked. It does not reconcile these descriptions or identify who was masked. Details about allocation concealment, adherence, protocol deviations, and the randomization procedure are also not reported in the registry record.

Safety information is limited to the reported serious-event, death, and other-event counts. Descriptions of the other adverse events, their timing, severity, relatedness, and follow-up duration are not reported. The healthy-subject population and the stated focus on pharmacologically induced mydriasis also define the scope of the study description; the record does not provide results for other populations or clinical settings.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: Safety and Efficacy of Nyxol (0.75% Phentolamine Ophthalmic Solution) to Reverse Pharmacologically-Induced Mydriasis (MIRA-3) — NCT05134974.
• Registry record last updated 2026-10-30; status last verified 2023-08.
• Results first posted 2023-08-01.
• 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

NCT05134974 is a completed randomized, parallel-arm phase 3 study sponsored by Opus Genetics, Inc. The registry lists enrollment as 368 and describes healthy subjects receiving phentolamine ophthalmic solution 0.75% or its vehicle one hour after pharmacologically induced mydriasis. Each arm description specifies two drops in the study eye and one drop in the non-study eye. The registry masking field says triple masking, while the official title says double-masked.

The primary outcome is the percentage of subjects’ study eyes returning to within 0.2 mm of baseline pupil diameter at 90 minutes. Five outcome measures are listed, but no numerical outcome analyses are reported in the registry record. The safety summaries list zero serious adverse events and zero deaths in both arms; other adverse-event counts are 43 in the phentolamine arm and zero in the vehicle arm.

The record does not report the primary efficacy estimate, its uncertainty, the analysis population, missing-data methods, or the statistical analysis plan. It therefore describes the trial design and some safety counts, but does not provide the numerical results needed to interpret the primary efficacy comparison.