Safety and Efficacy of Nyxol (0.75% Phentolamine Ophthalmic Solution) in Subjects With Dim Light Vision Disturbances: 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) in Subjects With Dim Light Vision Disturbances (NCT04638660), a randomized phase 3 study. The primary outcome is Percent of Subjects With 3 Lines mLCVA Improvement in Study Eye.

2. Clinical Question

The endpoint focuses on a threshold improvement rather than the average change in visual acuity. A participant either met the stated improvement threshold compared with baseline or did not. The posted outcome is therefore expressed as a count of participants with the event in each arm, with the arm denominators reported separately.

The study also listed objectives concerning visual performance and safety. Secondary outcomes included improvement in mesopic low-contrast visual acuity, photopic low-contrast visual acuity and mesopic high-contrast visual acuity, as well as changes in mesopic pupil diameter. The primary result addressed in the posted comparison is specifically the three-line mesopic low-contrast acuity outcome at Day 8; it should not be treated as a result for every listed objective or secondary measure.

3. Trial Design

The registry identifies this as a Phase 3, randomized, placebo-controlled, double-masked study with a parallel-group design. It lists quadruple masking. The intervention was phentolamine ophthalmic solution 0.75%, and the comparator was the phentolamine ophthalmic solution vehicle. Both arm descriptions specify one drop in both eyes at or near bedtime, between 8PM and 10PM.

The registry lists enrollment as 144 and the study status as completed. The recorded start date is 2020-12-30, and the primary completion date is 2022-05-19. The posted primary outcome has an 8 days timeframe and refers to improvement at Day 8 compared with baseline. The outcome is defined in the study eye, while the dosing instructions refer to both eyes.

For the primary outcome, the posted arm counts are 9 participants in the phentolamine arm and 2 in the vehicle arm. The corresponding arm denominators in the efficacy results are 70 and 73. The registry record does not explain the relationship between the listed enrollment and the denominators used for this outcome, nor does it report the participant flow or reasons for any difference.

The registry lists five outcome measures and four posted secondary outcomes. The posted results do not include analysis records. Details such as the randomization procedure, the specific masking arrangements, the analysis population, the method used to address missing endpoint data, and the trial's original sample-size justification are not reported in the registry record. The randomized, masked design describes how the study is classified; by itself it does not fill in those unreported operational or analytical details.

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

Reasons for not completing this period:

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 With 3 Lines mLCVA Improvement in Study Eye, measured over 8 days.

The primary endpoint is the percent of subjects with three lines of improvement in study-eye mesopic low-contrast visual acuity at Day 8. The definition requires an improvement of at least 15 ETDRS letters compared with baseline, measured in monocular mesopic low-contrast visual acuity. This is a threshold endpoint: each participant is classified according to whether the specified improvement was reached.

Mesopic vision refers generally to vision under intermediate, dim-light conditions. Low-contrast acuity assesses the ability to identify visual targets with relatively little contrast against their background. These general descriptions help explain why the endpoint is relevant to a trial of dim light vision disturbances; they do not add information about how the test was administered in this study. Testing details beyond the stated endpoint definition are not reported in the registry record.

A threshold endpoint can be summarized as the number of participants reaching the improvement criterion and the number assessed in each arm. It gives a clinically interpretable responder-style summary, but it does not show the full distribution of individual changes. Participants with different amounts of improvement above the threshold are counted alike for this endpoint, and participants who improve without reaching the threshold do not meet its event definition. The posted outcome therefore answers a specific question about reaching the stated level of improvement, not every possible question about visual acuity change.

The primary timeframe is listed as 8 days, and the description specifies Day 8 compared with baseline. The posted primary result should be read in that time-specific context; it does not describe longer-term outcomes.

7. Results Posted in the Registry

• Phentolamine Ophthalmic Solution 0.75%: 12.9% (9/70) versus 2.7% (2/73) on control; risk difference 10.1 percentage points (95% CI 1.4 to 18.8), risk ratio 4.69 (1.05–20.96); unadjusted two-proportion z-test p = 0.023.

8. Statistical Interpretation

9. Statistical Methods Explained

The primary outcome is binary because it records whether each participant reached the defined improvement threshold. For a binary endpoint, each arm can be described by its event count and its denominator. The posted counts are 9 of 70 in the phentolamine arm and 2 of 73 in the vehicle arm. These counts retain information that would be lost if the result were described only through a relative measure or a p-value.

What does the risk difference mean?

The risk difference compares the event proportions by subtracting the vehicle-arm proportion from the phentolamine-arm proportion. The posted estimate is 0.101. It is an absolute-scale contrast: it describes the difference in the probability of meeting the endpoint, rather than how many times larger one arm's event frequency is relative to the other. The 95% confidence interval, 0.014 to 0.188, expresses uncertainty in that absolute contrast. The calculation method for the posted interval is not reported in the registry record.

How do the risk ratio and odds ratio differ?

A risk ratio compares event proportions as a ratio, while an odds ratio compares event odds. Both are relative measures and use one as their null value, indicating no relative difference. The posted risk ratio is 4.693, with a 95% confidence interval from 1.051 to 20.96. The posted odds ratio is 5.238, with a 95% confidence interval from 1.09 to 25.17. These measures can appear numerically different because they use different scales, especially when outcomes are not common. They should not be read as interchangeable with the absolute risk difference.

The relative-effect confidence intervals are broad. This is consistent with limited precision for estimating a relative effect when the endpoint event counts are small. A broad interval allows a range of possible relative magnitudes and cautions against treating the point estimate as a precise measure of how large the contrast is. The interval limits do not eliminate uncertainty merely because the lower limits are above one.

What does the p-value test?

The posted unadjusted p-value is 0.023. In general, a p-value measures how incompatible the observed data, or more extreme data, are with a specified null model, assuming that model and the test assumptions hold. It is not the probability that the null hypothesis is correct, and it does not indicate the probability that the result will replicate. The registry record does not report the test used to obtain this p-value, so its exact calculation and assumptions are not described in the posted record.

The label unadjusted matters: the value is not presented as accounting for multiple comparisons. The registry record lists one primary outcome and four secondary outcomes, but it does not report a multiplicity strategy or secondary-outcome analysis records. If several hypotheses are tested, the chance of at least one small p-value can increase; general approaches to multiplicity include prespecifying a primary hypothesis, adjusting thresholds, or controlling an error rate. Which approach, if any, was used in the trial is not reported in the registry record.

Why can over-dispersion matter?

Over-dispersion is a general concern when observed variability exceeds what a statistical model assumes. For a simple binary outcome, the outcome for each participant is commonly modeled as a Bernoulli event, with variation determined by the event probability. In clustered or repeated-measure settings, outcomes may be more alike within groups or participants than a simple independent model allows. Ignoring that extra dependence can make standard errors too small and confidence intervals too narrow. The posted primary outcome is a participant-level threshold measure, but the registry record does not describe whether any clustering, repeated-measure adjustment, or over-dispersion assessment was relevant to its analysis.

Randomization supports a comparison of assigned groups, while masking can help limit some sources of bias. Neither feature, by itself, establishes that all randomized participants were included in the analysis or that missing endpoint data were handled without bias. The posted results do not identify an intention-to-treat, per-protocol, or other analysis population. The registry record also does not describe covariate adjustment, missing-data methods, model diagnostics, or the primary statistical test. Those omissions limit the level of detail with which the reported estimates can be independently interpreted.

The posted comparison is unadjusted and uses the arm counts and denominators recorded for the endpoint. The effect estimates and confidence intervals are useful descriptions of the observed contrast, but the exact underlying analysis specification is not reported in the registry record. General statistical interpretation should therefore distinguish the numerical result from unreported choices about analysis population, modeling, and multiplicity.

10. Confidence Intervals and Precision

Precision concerns how much uncertainty surrounds an estimate. The risk-difference estimate is 0.101, and its 95% confidence interval extends from 0.014 to 0.188. The interval is entirely above zero, the null value for a risk difference. It nevertheless spans a range of absolute effects, so the point estimate should not be treated as exact. The width reflects uncertainty in the estimate under the method used to construct the interval.

The relative measures are less tightly bounded: the risk ratio is 4.693, with an interval from 1.051 to 20.96, and the odds ratio is 5.238, with an interval from 1.09 to 25.17. Both intervals extend from values close to their null value of one to much larger relative effects. This makes the direction of the estimated relative contrast more constrained than its size. The small event counts are important context for that uncertainty; a few endpoint events can have a substantial influence on estimates based on rare outcomes.

A confidence interval is a method-based range that, across repeated studies conducted under the same assumptions, would capture the target parameter at the stated rate. It is not a guarantee that the true effect lies within this particular interval, and it does not describe the range of individual responses. The confidence level and interval method are not otherwise detailed in the registry record, although the posted results identify these intervals as 95% confidence intervals.

The interval for the absolute effect and the intervals for relative effects answer different questions and should be read on their respective scales. The risk-difference interval gives an absolute contrast; the ratio intervals give relative contrasts. Precision is therefore not summarized by a single universal measure. The estimates support a more cautious interpretation of the magnitude than the point estimates alone might suggest.

11. 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 sample-size table and curve are planning illustrations based on the observed effect, not a report of the trial's original sample-size design. The figures are participants per arm, not total participants or total events. The planning assumptions are a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation. The effect to detect is set to the stated fraction of the observed effect.

The row planning for 100% of the observed effect lists 110 participants per arm for 80% power and 146 participants per arm for 90% power. The row planning for 75% of the observed effect lists 166 participants per arm for 80% power and 221 participants per arm for 90% power. The row planning for 50% of the observed effect lists 306 participants per arm for 80% power and 408 participants per arm for 90% power. The curve provides a visual way to read how the planning requirement changes across effects under those assumptions.

In general, power is the probability of detecting an effect of the specified size under a particular model and design, if that effect is present. The 80% power column gives a planning size intended to reach 80% power under the stated assumptions; the 90% column applies a higher power target. A higher target generally requires more participants when other assumptions remain fixed. Smaller effects are harder to distinguish from random variation and therefore need more participants, as the planning rows illustrate.

These numbers are not observed power. They are illustrative calculations based on the observed effect and the listed assumptions. The trial's own original design assumptions and sample-size justification are not reported in the registry record, so these planning figures should not be taken as the study's prespecified target or as a retrospective assessment of the trial's success.

12. 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, p₀ and p₁ are the control and treatment proportions, and p̄ is their average.

Worked calculation for this trial

1. Control proportion p₀ = 0.027; treatment proportion p₁ = 0.129; average p̄ = 0.078.
2. First term: z_1−α/2 × √[2p̄(1−p̄)] = 1.96 × 0.3792 = 0.7433.
3. Second term: z_1−β × √[p₀(1−p₀) + p₁(1−p₁)] = 0.842 × 0.3724 = 0.3134.
4. n = (0.7433 + 0.3134)² / (0.1012)² = 109.1, rounded up to 110 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
p0 <- 0.0273972602739726                          # control proportion
p1 <- 0.128571428571429                          # treatment proportion
n_per_arm <- function(power, frac = 1) {
  q1 <- p0 + (p1 - p0) * frac               # smaller effect = fraction of the observed difference
  pbar <- (p0 + q1) / 2
  z_b <- qnorm(power)
  ceiling(round((z_a * sqrt(2 * pbar * (1 - pbar)) + z_b * sqrt(p0 * (1 - p0) + q1 * (1 - q1)))^2 / (q1 - p0)^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 (unrounded n per arm)
cat("power.prop.test:", round(power.prop.test(p1 = p0, p2 = p1, power = 0.80)$n, 1), "\n")

# Simulation: how often does the z-test reject at the 80%-power sample size?
set.seed(4638660)
n    <- n_per_arm(0.80)
reps <- 20000
x0 <- rbinom(reps, n, p0); x1 <- rbinom(reps, n, p1)
ph <- (x0 + x1) / (2 * n)
z  <- ((x1 - x0) / n) / sqrt(ph * (1 - ph) * 2 / n)
cat(sprintf("Simulated power at n = %s per arm: %.3f (%d replicates)\n", format(n, big.mark = ","), mean(abs(z) > z_a, na.rm = TRUE), reps))

Output from running the code

100% of observed effect: n per arm = 110 (80% power), 146 (90% power)
 75% of observed effect: n per arm = 166 (80% power), 221 (90% power)
 50% of observed effect: n per arm = 306 (80% power), 408 (90% power)
power.prop.test: 109.1 
Simulated power at n = 110 per arm: 0.842 (20000 replicates)

The simulation draws many pairs of event counts at the planned sample size and counts how often the two-proportion z-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.

13. Multiplicity, Missing Data and Analysis Populations

The registry record lists one primary outcome and four secondary outcomes. The primary outcome is a threshold improvement in study-eye mesopic low-contrast visual acuity at Day 8. Secondary outcomes include the percent of subjects with mesopic low-contrast visual acuity improvement; the percent with photopic low-contrast visual acuity and mesopic high-contrast visual acuity improvement; change from baseline in mesopic pupil diameter; and percent change from baseline in mesopic pupil diameter. The posted results do not include analysis records for these outcomes.

Multiplicity is the general statistical issue that arises when multiple hypotheses or outcomes are analyzed. Testing many outcomes can increase the chance of at least one result appearing statistically notable by chance. A trial may address this by specifying a hierarchy, adjusting significance thresholds, or using another prespecified strategy. The registry record does not report whether any such approach was planned or used. The primary comparison is posted as unadjusted, so the p-value should not be interpreted as adjusted for the other listed outcomes.

The record does not report how missing Day 8 measurements were handled, whether participants were excluded from the endpoint analysis, or which analysis population was used. It therefore does not establish whether the result includes all randomized participants, only participants with available outcome measurements, or another defined group. The arm denominators for the outcome are reported, but the record does not explain participant flow or reasons for any missing observations.

The registry record also does not report an imputation method, sensitivity analysis for missing data, covariate-adjusted analysis, or handling of protocol deviations. These details matter because missingness or exclusions can affect an estimated treatment contrast if they are related to treatment assignment or outcome. Without the analysis plan and population definitions, the posted result can be described as an unadjusted arm comparison, but its robustness to these choices cannot be assessed from the registry record alone.

14. Safety Results

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

Deaths

Other (non-serious) adverse events

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

Most frequent non-serious adverse event terms

The serious adverse event figures show 0 serious adverse events among 71 participants at risk in the phentolamine arm and 0 among 73 participants at risk in the vehicle arm. The death counts are also 0 in each arm. These are the serious-event and death counts posted in the registry record.

The record separately reports 23 participants with other adverse events among 71 at risk in the phentolamine arm, and 2 among 73 at risk in the vehicle arm. The registry record does not provide further detail in these figures about event terms, severity, relatedness, timing, or how events were counted. The serious-event figures should not be conflated with the separately reported other adverse-event counts.

Zero reported serious adverse events does not demonstrate that serious events are impossible or that there is no safety risk. It describes what was reported in the trial groups and within the observation recorded for the study. The safety denominators differ from the efficacy denominators, and the registry record does not explain that difference. These figures are descriptive and do not by themselves establish a comparative safety conclusion.

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

The posted result shows that more participants in the phentolamine arm than in the vehicle arm met the specified three-line improvement threshold at Day 8: 9 of 70 compared with 2 of 73. The unadjusted risk difference is 0.101, and its 95% confidence interval is 0.014 to 0.188. This describes an observed difference for a defined endpoint and time point. It is not a result for every measure of vision or for all outcomes relevant to dim light vision disturbances.

The estimate does not say how much each participant's vision changed, because the primary endpoint classifies participants by whether they reached a threshold. It does not report average visual-acuity change, the distribution of changes below or above the threshold, or how long any improvement lasted. The outcome is specific to the study eye and Day 8. Longer-term outcomes and the results of the listed secondary measures are not reported in the registry record.

The confidence interval indicates uncertainty in the size of the absolute contrast, while the wide relative-effect intervals indicate that the relative magnitude is not precisely pinned down. The unadjusted p-value of 0.023 is one part of the statistical evidence, not a measure of clinical importance or proof of causation. Interpretation also depends on analysis details that are not reported, including the analysis population, handling of missing data, and any multiplicity approach.

The trial is classified as randomized, placebo-controlled, double-masked, and parallel-group, which describes important design features. The registry record does not provide all operational or analysis details needed to assess how those features were implemented or how they affected the posted estimate. The results therefore support a precise description of the observed endpoint comparison, but not conclusions about outcomes that were not measured or reported. No treatment recommendation follows from these statistics alone.

16. Why This Trial Matters Statistically

This trial illustrates why an endpoint definition matters. The primary outcome is not a general measure of visual function; it is the proportion meeting a threshold of at least 15 ETDRS letters, or at least three lines, of improvement in study-eye mesopic low-contrast visual acuity at Day 8. A clear definition makes the event count interpretable, while also setting boundaries on what the outcome can establish.

It also shows why both absolute and relative measures are useful. The risk difference of 0.101 conveys an absolute contrast, while the risk ratio and odds ratio express relative contrasts. The relative estimates have wide confidence intervals, illustrating that a seemingly large point estimate can still be uncertain when event counts are small. Reporting the intervals alongside the point estimates prevents a single number from carrying more certainty than the data support.

The distinction between a posted endpoint result and a full analysis plan is important. The registry record classifies the trial as randomized and masked, but does not report several details that shape interpretation, including the analysis population, missing-data methods, and multiplicity strategy. Those details are not administrative trivia: they help readers understand which participants and hypotheses the estimates represent.

Finally, planning calculations based on an observed effect are not the same as the original design justification. The listed sample-size illustrations make assumptions explicit and show that smaller target effects require more participants under those assumptions. They should not be confused with observed power or with the trial's original plan. Keeping these distinctions clear helps clinical researchers interpret a striking point estimate without losing sight of precision, analysis choices, and the narrow scope of the measured endpoint.

17. 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 is a threshold outcome at Day 8. It captures whether participants reached a specified level of improvement, but does not describe the magnitude of change for each participant or its duration. The registry record does not post the detailed results for the listed secondary visual-acuity and pupil-diameter outcomes, limiting assessment across the broader set of stated objectives.

The primary comparison is unadjusted, and the record does not report the statistical test, interval construction method, analysis population, or handling of missing endpoint data. It also does not report whether the primary hypothesis was protected against multiplicity from other analyses. These omissions constrain independent assessment of the analysis and the robustness of the result.

The observed event counts are limited, and the confidence intervals—especially those for the relative measures—are wide. The point estimates should therefore be interpreted with attention to uncertainty. The registry lists enrollment as 144, while the posted efficacy denominators are 70 and 73; the record does not explain participant flow or the relationship between these figures. Safety denominators are reported separately, without an explanation of their relationship to the efficacy population.

Further trial-specific details, including eligibility criteria, participant characteristics, randomization procedures, masking implementation, protocol deviations, and follow-up beyond the listed primary timeframe, are not reported in the registry record. The safety summary does not give detail about the nature, seriousness classification beyond the listed categories, relatedness, or timing of the other adverse events. These gaps limit the scope of conclusions that can be drawn from the posted results.

18. Related Tutorials

19. Related Statistical Calculators

20. Sources

• ClinicalTrials.gov: Safety and Efficacy of Nyxol (0.75% Phentolamine Ophthalmic Solution) in Subjects With Dim Light Vision Disturbances — NCT04638660.
• Registry record last updated 2026-10-30; status last verified 2023-08.
• Results first posted 2023-08-09.
• 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.

21. Record Summary

The registry record describes a completed Phase 3 randomized, placebo-controlled, double-masked, parallel-group study of phentolamine ophthalmic solution 0.75% versus its vehicle in subjects with dim light vision disturbances. Enrollment is listed as 144. The recorded study start date is 2020-12-30, and primary completion is listed as 2022-05-19.

The primary outcome was the proportion of participants with at least 15 ETDRS letters, or at least three lines, of improvement in study-eye mesopic low-contrast visual acuity at Day 8. The posted counts were 9 of 70 in the phentolamine arm and 2 of 73 in the vehicle arm. The unadjusted risk difference was 0.101, with a 95% confidence interval from 0.014 to 0.188, and the unadjusted p-value was 0.023.

The record lists four secondary outcomes but does not post analysis records for them. It reports 0 serious adverse events and 0 deaths in each arm; other adverse-event counts are reported separately. Details on missing data, analysis populations, multiplicity, and several design and analysis procedures are not reported in the registry record.