Safety and Efficacy of Ophthalmic Phentolamine Mesylate in Glaucoma: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Safety and Efficacy of Ophthalmic Phentolamine Mesylate in Glaucoma (NCT03960866), a randomized phase 2 study. The primary outcome is Intraocular Pressure.

2. Clinical Question

3. Trial Design

The registry describes NCT03960866 as a completed, randomized, parallel-group phase 2 study sponsored by Opus Genetics, Inc. Its official title calls it double-masked, while the registry’s masking field lists triple masking. That difference in terminology is present in the record; further information about which roles were masked is not reported in the registry record. The study compared phentolamine mesylate ophthalmic solution 1% with its vehicle.

The registry lists enrollment as 39. The recorded start date is 2019-05-28, and the primary completion date is 2019-09-11. The treatment descriptions specify daily dosing in each eye for 14 days, at or before bedtime. The primary endpoint timeframe is 15 days. These dates and durations describe the registry record; they do not establish the length of each participant’s follow-up beyond the posted endpoint timeframe.

Eligibility included adults with ocular hypertension in both eyes or open-angle glaucoma in one eye and ocular hypertension in the fellow eye, with the condition previously untreated or treated with <=2 ocular hypotensive medications. The record does not report the allocation sequence method, concealment procedures, site count, detailed baseline characteristics, or the analysis population definitions. The registry lists pupil diameter, distance visual acuity, and conjunctival hyperemia as secondary outcomes. It posts a detailed numerical comparison for distance visual acuity; detailed results for the other listed secondary outcomes 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.

Overall Study

Analysis population for the primary outcome, as defined in the registry: Patients underwent a Screening visit where they were included in the trial if they were at least 18 years of age with either OHT in both eyes or OAG in 1 eye with OHT in the fellow eye, which was previously untreated or treated with ≤2 ocular hypotensive medications.

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 Intraocular Pressure, measured over 15 days.

The primary endpoint is change from baseline in mean diurnal intraocular pressure in the study eye, measured at 15 days and expressed in mmHg. The registry reports group means and standard deviations. Negative changes represent reductions from baseline; the posted group means are negative in both treatment groups.

Intraocular pressure is relevant to the study’s stated objective of evaluating whether the intervention lowers pressure in people with open-angle glaucoma or ocular hypertension. Measuring change from baseline describes how the endpoint shifted during the study relative to each group’s starting measurement. Comparing the groups’ mean changes helps assess whether the observed shift differed between assignment to phentolamine mesylate and assignment to vehicle.

A group mean does not describe every participant’s response. The standard deviations indicate variation in individual changes around each group mean, and that variation contributes to uncertainty in the estimated between-group difference. The registry does not report a threshold for a clinically important difference, nor does it provide details about how the diurnal measurements were scheduled or combined. The result therefore describes the posted pressure endpoint and its statistical precision, not the importance of a particular change for an individual.

7. Results Posted in the Registry

• Nyxol Ophthalmic Solution 1%: mean -2.30 versus -2.18 on control; difference -0.12 (95% CI -1.73 to 1.49), standardized effect d = -0.05; z-test p = 0.884.

8. Secondary Efficacy Endpoints

The registry also posts results for secondary outcomes. For each outcome below, the endpoint type, the test applied to the posted summary statistics, the result and its interpretation are given in turn. Secondary endpoints are usually not adjusted for multiple testing, so they support rather than confirm the primary finding.

Distance Visual Acuity

• Endpoint type: Binary: the number of participants with the event, compared as proportions.
• Test: Unadjusted two-proportion z-test, with a Wald 95% confidence interval for the risk difference.
• Result:
  • Nyxol Ophthalmic Solution 1%: 63.2% (12/19) versus 20.0% (4/20) on control; risk difference 43.2 percentage points (95% CI 15.3 to 71.0), risk ratio 3.16 (1.23–8.10); unadjusted two-proportion z-test p = 0.006.
• Interpretation:
  • The 95% confidence interval excludes no difference, so the proportion with the event is statistically higher for Nyxol Ophthalmic Solution 1% than for the control. This is an unadjusted, secondary comparison, so it is suggestive rather than confirmatory.

The registry names pupil diameter, distance visual acuity, and conjunctival hyperemia as secondary outcomes. It posts a detailed comparison for distance visual acuity, while detailed numerical results for pupil diameter and conjunctival hyperemia are not reported in the registry record. This uneven reporting limits assessment of whether the secondary findings form a consistent pattern across the outcomes the study planned to examine.

The posted distance visual acuity comparison has an unadjusted statistical signal. That finding is separate from the primary intraocular pressure comparison and does not make the primary estimate more precise or establish that the outcomes changed together. Because the registry does not report detailed results for the other named secondary outcomes, the overall secondary-outcome pattern cannot be fully evaluated from the record.

Unadjusted secondary results carry less weight when multiple outcomes are considered because testing several outcomes creates more opportunities for a seemingly notable result to occur by chance. The registry does not report a multiplicity adjustment, a prespecified hierarchy for secondary outcomes, or a plan specifying how secondary results would support the primary question. The secondary finding is therefore best treated as a signal requiring cautious interpretation rather than as confirmation of the primary result. No additional conclusion about consistency, mechanism, or clinical importance can be drawn from the incomplete posted outcome details.

Secondary outcomes registered for this trial, for reference (only those above were recalculated):

• Pupil Diameter
• Distance Visual Acuity
• Conjunctival Hyperemia

9. Statistical Interpretation

10. Statistical Methods Explained

What does a difference in means represent?

For a continuous endpoint, the difference in means compares the average change in one group with the average change in the other. The recalculation expresses the contrast as phentolamine mesylate minus vehicle: -2.3 minus -2.18 is reported as a mean difference of -0.12 mmHg. A negative contrast in this direction means the active-group mean change was more negative than the vehicle-group mean change. This is a between-group comparison, distinct from describing whether either group changed from its own baseline.

What does the t-test assess?

The sponsor reports a two-sided t-test for the net mean difference, with p = 0.89. A t-test evaluates whether the observed difference is compatible with a null value of no mean difference under its assumptions. A two-sided test considers departures in either direction. The p-value does not measure the probability that the null hypothesis is true, and it does not quantify the size or clinical importance of a difference.

The recalculated unadjusted p-value is 0.884. It is derived from the posted group summary statistics and is not an adjusted model result. The close agreement with the sponsor’s p-value is consistent with the posted analysis, but the recalculation does not supply unreported details of the sponsor’s statistical plan. Those details, including any covariate adjustment or treatment of missing observations, are not reported in the registry record.

Why do standard deviations matter?

The standard deviation describes the spread of observed changes around a group mean. It is not the uncertainty in the mean itself, and it is not a confidence interval. The active group’s reported standard deviation is 2.986 mmHg and the vehicle group’s is 1.856 mmHg. Differences in spread, group sizes, and the estimated means all contribute to the uncertainty of a comparison.

The recalculation uses a pooled standard deviation of 2.47 mmHg and reports a standardized effect size of -0.049. Standardizing expresses the mean difference relative to the pooled spread, which can help describe the magnitude without the endpoint’s original units. It does not make the result more precise, establish clinical importance, or remove uncertainty. The record does not report the method used to choose or justify a variance assumption for the sponsor’s analysis.

What is the role of the confidence interval?

The recalculated 95% confidence interval is -1.732 to 1.492 mmHg. In general, a confidence interval describes a range of effect estimates compatible with the data and the method used, while reflecting sampling uncertainty. This interval includes zero, the value representing no between-group difference. It also includes differences favoring either direction. Its width is important: the point estimate alone is not a precise description of what the data can distinguish.

The recalculated interval is based on posted summary statistics, and it is explicitly unadjusted. It does not account for any analysis choices that are not available in the registry record. The sponsor’s own result should remain distinct from this recalculation; the sponsor reports no confidence limits for its comparison.

Why do unadjusted secondary tests need caution?

When several outcomes are examined, each unadjusted test is interpreted without accounting for the number of opportunities to observe a low p-value. This can increase the chance that at least one result appears statistically notable by chance. The registry lists multiple secondary outcomes and the posted distance visual acuity comparison has an unadjusted p-value. The record does not report a multiplicity adjustment or a hierarchy governing interpretation across outcomes. Accordingly, that result is exploratory in the context of the primary endpoint and the other secondary outcomes.

What do the planning calculations mean?

The planning illustrations use the observed effect, a two-sided significance level of 0.05, equal allocation between the two arms, and a normal approximation. They show the participants per arm that would be needed under those assumptions to target specified power for the stated fractions of the observed effect. These are hypothetical planning quantities, not a reconstruction of the trial’s design process. The trial’s original sample-size assumptions and justification are not reported in the registry record. The planning values are not observed power and should not be read as evidence that the study had a particular chance of detecting its actual effect.

11. Confidence Intervals and Precision

The recalculated 95% confidence interval for the primary mean difference extends from -1.732 to 1.492 mmHg. It includes zero and spans estimates on both sides of no difference. Thus, the point estimate of -0.12 mmHg should not be read as a precise estimate of the true between-group difference. The interval is compatible with a negative difference as well as a positive one under the recalculation method.

The width reflects uncertainty in an estimate based on the posted group sizes and variation. The primary endpoint groups have reported sample sizes of 18 and 19, and the reported standard deviations are 2.986 and 1.856 mmHg. A small study with variable measurements can yield a broad interval, even when the point estimate is near zero. The interval does not prove that the groups are equivalent: an equivalence conclusion would require an appropriate design and a prespecified margin, neither of which is reported in the registry record.

The sponsor’s analysis gives a p-value of 0.89 but does not post confidence limits. The recalculated interval is therefore useful for illustrating the precision of an unadjusted comparison from the summary statistics, while remaining separate from the sponsor’s reported analysis. Neither result identifies a clinically important threshold; such a threshold is not reported in the registry record. The posted precision supports caution about interpreting the magnitude or direction of the underlying difference.

12. Planning a Similar Trial: Sample Size

This is a planning illustration, not a re-evaluation of the original trial. It asks: if a new study wanted to detect a difference like the one observed, or a smaller one, how large would it need to be? It is deliberately not “observed power” of the finished trial, which is not a meaningful quantity.

The planning figures are participants per arm, not total participants and not total events. They are illustrations based on the observed effect, using a two-sided significance level of 0.05, equal allocation between the two arms, and a normal approximation. The calculations consider 100%, 75%, and 50% of the observed effect. The trial’s own original design assumptions and sample-size justification are not reported in the registry record.

The 80% power column gives the participants per arm estimated to provide an 80% chance of detecting the specified effect under the stated assumptions, if that effect and the calculation assumptions hold. The 90% power column gives the corresponding planning quantity for a 90% target. These are prospective planning concepts: they describe how a study might be sized before data are collected, not what happened in this trial.

For example, the primary-outcome planning values are 6,653 participants per arm for 80% power and 8,906 participants per arm for 90% power when planning for 100% of the observed effect. Planning for 75% of the observed effect gives 11,827 and 15,832 participants per arm, respectively; planning for 50% gives 26,610 and 35,622. Smaller effects require more participants under the same assumptions because they are harder to distinguish from random variation.

These calculations are not observed power. They are highly dependent on the effect used for planning and the stated assumptions; the observed effect in a small trial may itself be imprecise. The values should not be taken as a recommended design or as proof of what the original investigators expected.

13. How the Sample Size Is Derived

Power is the probability that a study of a given size rejects the null hypothesis when a specific true effect exists. It depends on four things: the effect to detect, the variability of the outcome, the significance level (here a two-sided α of 0.05, so z_1−α/2 = 1.960) and the desired power (z_1−β = 0.842 for 80% and 1.282 for 90%).

Formula

n is the number of participants in each arm, Δ is the difference in means to detect and σ is the common standard deviation.

Worked calculation for this trial

1. Observed difference Δ = -0.120; pooled standard deviation σ = 2.470.
2. n = 2 × (1.96 + 0.842)² × 2.470² / -0.120² = 6,652.3, rounded up to 6,653 participants per arm for 80% power.

The smaller-effect rows in the table above repeat the same calculation with the effect multiplied by 0.75 and 0.5 (for ratios, applied to the logarithm of the ratio).

R code

alpha <- 0.05
z_a   <- qnorm(1 - alpha / 2)          # two-sided
delta <- -0.12                      # observed difference in means
sigma <- 2.47028384719536                     # pooled standard deviation
n_per_arm <- function(power, frac = 1) {
  ceiling(round(2 * (z_a + qnorm(power))^2 * sigma^2 / (delta * frac)^2, 6))
}
for (f in c(1, 0.75, 0.5))
  cat(sprintf("%3.0f%% of observed effect: n per arm = %s (80%% power), %s (90%% power)\n", 100 * f,
              format(n_per_arm(0.80, f), big.mark = ","), format(n_per_arm(0.90, f), big.mark = ",")))

# Check against R's built-in function (t-based, so very slightly larger)
cat("power.t.test:", round(power.t.test(delta = delta, sd = sigma, power = 0.80)$n, 1), "\n")

# Simulation: exact two-sample t-test using simulated means and variances
set.seed(3960866)
n    <- n_per_arm(0.80)
reps <- 20000
m_diff <- rnorm(reps, delta, sigma * sqrt(2 / n))             # difference in sample means
s2     <- sigma^2 * rchisq(reps, 2 * (n - 1)) / (2 * (n - 1))   # pooled sample variance
tstat  <- m_diff / sqrt(s2 * 2 / n)
cat(sprintf("Simulated power at n = %s per arm: %.3f (%d replicates)\n", format(n, big.mark = ","), mean(abs(tstat) > qt(0.975, 2 * (n - 1))), reps))

Output from running the code

100% of observed effect: n per arm = 6,653 (80% power), 8,906 (90% power)
 75% of observed effect: n per arm = 11,827 (80% power), 15,832 (90% power)
 50% of observed effect: n per arm = 26,610 (80% power), 35,622 (90% power)
power.t.test: 6653.2 
Simulated power at n = 6,653 per arm: 0.800 (20000 replicates)

The simulation draws many sets of group means and variances at the planned sample size and counts how often the two-sample t-test rejects the null. It should land close to the target power; at very small required sample sizes it can fall below it, because the normal approximation is rough there.

14. Analyses Reported by the Sponsor

The sponsor reports a two-sided t-test with a net mean difference of 0.12 and p = 0.89. The recalculation expresses the contrast in the reverse order, active treatment minus vehicle, and reports -0.12 with p = 0.884. The signs differ because reversing the order of a difference reverses its sign; the magnitude is the same at the displayed precision. The p-values are closely aligned.

The sponsor’s registry result is the reported trial analysis. The recalculation is a simple, unadjusted analysis from the posted summary statistics and is useful as a check on the scale and uncertainty of the comparison. It does not reproduce unavailable analysis details or override the sponsor’s analysis. The registry does not post a confidence interval for the sponsor’s test; the recalculated interval is -1.732 to 1.492 mmHg.

The registry record does not report whether the sponsor’s analysis used adjustments, how missing observations were handled, or which analysis population was used. Because these details are unavailable, similarity between the p-values should not be interpreted as proof that every analysis choice was identical. Both results indicate that the posted primary comparison does not provide a precise estimate of a difference between groups.

15. Multiplicity, Missing Data and Analysis Populations

The registry lists several secondary outcomes alongside the primary intraocular pressure endpoint. A set of analyses across multiple endpoints raises a multiplicity question: if each is tested separately without adjustment, the chance of at least one low p-value arising by chance can increase. This is a general statistical concern, not a claim that the posted secondary finding is false. The record does not report whether the investigators used a multiplicity procedure, a hierarchy of hypotheses, or another approach to control interpretation across endpoints.

The sponsor reports a two-sided primary t-test. However, the full statistical analysis plan, including its prespecified model and rules for handling multiple outcomes, is not reported in the registry record. The posted distance visual acuity test is unadjusted. With no documented adjustment or hierarchy, it should not be treated as if it were an independently confirmatory test.

Missing-data methods and analysis populations are also not reported in the registry record. The available arm sizes differ across posted outcomes, but the record does not explain the reasons for those differences or identify whether the estimates use an intention-to-treat, per-protocol, or other population. The participant flow, exclusions after randomization, and reasons for missing endpoint measurements are not reported in the registry record. Consequently, the extent to which missing observations could affect the comparisons cannot be assessed.

Interim analyses, stopping rules, and any sample-size re-estimation are not reported in the registry record. Nor is the original sample-size justification reported. These omissions do not establish that such procedures were absent; they mean that readers cannot evaluate them from the registry information. The most defensible reading is therefore limited to the posted estimates and their stated or recalculated uncertainty, with secondary findings interpreted cautiously and without assuming unreported analysis procedures.

16. 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 0% reporting threshold.

Most frequent non-serious adverse event terms

The registry reports no serious adverse events in either arm: the serious-event count is 0 among 19 at risk in the phentolamine mesylate group and 0 among 20 at risk in the vehicle group. It also reports 0 deaths in each group. These figures describe the recorded serious adverse event and death counts; they do not establish that no events of any kind occurred.

For other adverse events, the registry reports 5 affected participants among 19 at risk in the active group and 1 among 20 at risk in the vehicle group. These are descriptive counts. The record does not provide detailed event terms for these other events, their severity, timing, duration, or attribution. It also does not report definitions or additional detail about how adverse events were collected.

Zero serious events in the posted groups should be interpreted in light of the study’s size and 15-day primary endpoint timeframe. Such a result cannot rule out uncommon events or characterize safety with precision. The registry lists no top serious adverse-event terms. These results describe what was posted for this trial and do not establish a general safety profile.

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

The primary data describe a mean reduction from baseline in intraocular pressure in both the phentolamine mesylate and vehicle groups at 15 days. The estimated between-group difference is -0.12 mmHg when expressed as active treatment minus vehicle. The recalculated confidence interval is broad and includes no difference, with estimates in either direction. The statistical result therefore does not give a precise estimate of the relative change between groups.

This finding should not be read as proof that the treatments are equivalent, nor as proof that there is no possible difference. The registry does not report an equivalence or noninferiority margin. A non-significant test alone cannot establish equivalence. Likewise, the negative changes within both groups do not establish that the active treatment caused a reduction beyond what was observed with vehicle.

The trial’s 39 enrollment and short treatment and endpoint timeframe constrain what can be learned about precision and longer-term outcomes. The registry does not report the full analysis plan, missing-data handling, detailed baseline characteristics, or a clinically important difference threshold. These gaps make it difficult to judge how well the posted results represent all randomized participants and what magnitude of difference would matter clinically.

A secondary distance visual acuity result has an unadjusted signal, but it does not replace the primary endpoint or resolve its uncertainty. Detailed results for the other named secondary outcomes are not reported in the registry record, and the record does not describe multiplicity control. Overall, the posted data answer a narrow, short-term comparison with limited precision; they do not establish broader effects, durability, or a clinical recommendation.

18. Why This Trial Matters Statistically

This trial illustrates why a comparison between groups matters more than a within-group change when the research question concerns an intervention’s relative effect. Both groups have negative mean changes from baseline, but the primary estimate is the difference between those changes. The posted means are close, and the recalculated interval shows that the estimated contrast remains uncertain.

It also demonstrates the value of reading a point estimate together with its confidence interval. A small point estimate may attract attention, but the interval indicates the range of values compatible with the unadjusted data and method. Here, the interval includes no difference and both possible directions. That context prevents a single estimate or p-value from being mistaken for a precise answer.

The registry’s sponsor analysis and the unadjusted recalculation are similar in magnitude and statistical conclusion, while the recalculation adds an interval based on summary data. Keeping those analyses distinct helps readers assess what is directly reported and what is reconstructed from posted summaries. The result also highlights the limits of secondary-outcome signals when multiplicity procedures and complete outcome details are unavailable.

Finally, the planning illustrations show how sample-size requirements depend on the effect targeted: smaller effects require more participants under the stated assumptions. Those illustrations are not evidence of the trial’s original design rationale and not observed power. Together, these features make the study useful for teaching interpretation of mean differences, uncertainty, and reporting gaps without turning a limited registry result into a stronger conclusion than it supports.

19. 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 primary endpoint comparison is based on small posted analysis groups, and the recalculated confidence interval is broad. This limits precision about the direction and size of the between-group difference. Enrollment is listed as 39, but the registry does not explain the differences between enrollment and the group sizes appearing for the primary endpoint or other outcomes.

The primary timeframe is 15 days, and the treatment descriptions specify 14 days of dosing. The record therefore provides only a short-term endpoint view; longer-term outcomes are not reported in the registry record. The registry also does not report detailed baseline characteristics, so comparability of the groups on clinically relevant features cannot be assessed from the posted information.

Several analysis details are not reported in the registry record: the full statistical analysis plan, analysis population, missing-data handling, allocation concealment, and rationale for the original sample size. No confidence interval is posted for the sponsor’s primary analysis. The interval discussed in the recalculation comes from unadjusted summary statistics and may not reflect unreported model choices.

Secondary reporting is incomplete: detailed numerical results are posted for distance visual acuity, but not for pupil diameter or conjunctival hyperemia. Multiplicity handling and a hierarchy among outcomes are not reported. Safety information is also limited; the registry gives counts but does not provide detailed terms or event descriptions for other adverse events. These limitations restrict conclusions about consistency across outcomes, the influence of missing data, and the breadth of safety characterization.

20. Related Tutorials

21. Related Statistical Calculators

22. Sources

• ClinicalTrials.gov: Safety and Efficacy of Ophthalmic Phentolamine Mesylate in Glaucoma — NCT03960866.
• Registry record last updated 2026-10-30; status last verified 2023-08.
• Results first posted 2023-07-12.
• 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.

23. Record Summary

NCT03960866 is a completed, randomized, parallel-group phase 2 study of phentolamine mesylate ophthalmic solution 1% versus its vehicle in adults with open-angle glaucoma or ocular hypertension. The primary endpoint was change from baseline in mean diurnal intraocular pressure in the study eye at 15 days.

The posted group means were -2.3 mmHg for active treatment and -2.18 mmHg for vehicle. The sponsor reported a net mean difference of 0.12 and p = 0.89. The unadjusted recalculation, expressed active minus vehicle, was -0.12 mmHg, with a 95% confidence interval from -1.732 to 1.492 and p = 0.884. The estimate is not precise enough to determine the direction or magnitude of a between-group difference.

The record includes a secondary distance visual acuity comparison and adverse-event counts, but detailed results for other named secondary outcomes are not reported in the registry record. The short timeframe, limited precision, and unreported analysis details call for cautious interpretation.