A Phase 2 Study Evaluating the Safety and Efficacy of Netarsudil Ophthalmic Solution in Patients With Corneal Edema Due to Fuchs Corneal Dystrophy: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for A Phase 2 Study Evaluating the Safety and Efficacy of Netarsudil Ophthalmic Solution in Patients With Corneal Edema Due to Fuchs Corneal Dystrophy (NCT04498169), a randomized phase 2 study. The primary outcome is Central Corneal Thickness (CCT).

2. Clinical Question

In practical statistical terms, the trial asks whether the two assigned dosing schedules were associated with different average short-term changes in corneal thickness in the defined analysis population. It does not, by itself, establish how those changes relate to outcomes beyond the measured endpoint or timeframe. The registry record does not report a primary endpoint assessment at the end of the 8 week treatment period.

3. Trial Design

This was a randomized, open-label, parallel-group Phase 2 study sponsored by Aerie Pharmaceuticals. The registry record lists the study as completed, with enrollment of 40. It compared two dosing schedules of Netarsudil Ophthalmic Solution: once daily in the evening and twice daily in the morning and evening. Both regimens used one drop of 0.02% solution in the study eye for an 8 week period. The arm descriptions state up to 20 subjects in each group, and the posted primary outcome groups each contain 20 participants.

Random allocation is intended to make assigned groups comparable, on average, with respect to factors known and unknown at the time of assignment. In an open-label study, participants and study personnel are not masked to the assigned schedule. That may matter for outcomes influenced by expectations or clinical decisions; central corneal thickness measured by ultrasound pachymetry is an objective measurement, although the registry record does not report whether assessors were masked.

The primary outcome is described as mean change from baseline in central corneal thickness, with a timeframe of baseline and 4 weeks, in the Modified Intent-to-Treat Population. The treatment period is described as 8 weeks, so the reported primary measurement timeframe falls before the stated end of treatment. The registry record does not report why that timepoint was selected or provide a primary endpoint assessment at 8 weeks.

The record lists one outcome measure and one reported analysis, with no secondary outcomes posted. Further design details, including the randomization procedure, allocation concealment, the protocol’s sample-size justification, and the original statistical analysis plan, are not reported in the registry record. The trial’s start date was 2020-09-17 and its primary completion date was 2021-08-11.

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: All participants underwent a washout of their pre-study treatment for Fuchs Corneal Dystrophy for a period of 24 hours prior to the baseline visit.

Modified Intent-to-Treat Population

Safety Population

Per-Protocol Population

Study Completion

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: Modified Intent-to-Treat Population

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: 40 participants were randomized; 20 each to the Netarsudil QD and the Netarsudil BID arms. 1 participant discontinued from each arm due to adverse events. 40 participants were included in both the mITT population for the primary endpoint analysis and the safety population for safety analysis. 6 participants were excluded from the per-protocol analysis due to protocol deviations (2 in the Netarsudil QD arm, 4 in the Netarsudil BID arm). There were no Covid-19 related protocol deviations.

6. Primary Endpoint

The registry lists the primary outcome as Central Corneal Thickness (CCT), measured over Baseline & 4 weeks.

Central corneal thickness (CCT) is the thickness of the cornea at its center. In this trial it was measured by ultrasound pachymetry, and the primary endpoint was the mean change from baseline at 4 weeks, expressed in µm. A change score represents the difference between a participant’s measurement at the follow-up timepoint and that participant’s baseline measurement. Negative group means therefore indicate an average decrease from baseline in the posted results.

Using a continuous measurement preserves the size and direction of observed changes rather than reducing each participant’s result to a yes-or-no category. Comparing group means can summarize whether the average change differs between assigned regimens. The endpoint is directly related to the stated study objective of evaluating changes in corneal edema, but the registry record does not report a threshold for a clinically important change or explain how changes in CCT correspond to symptoms or other clinical outcomes.

The posted means are −28.4 µm for once-daily dosing and −20.1 µm for twice-daily dosing. These are group averages, not descriptions of every participant’s response. The reported standard deviations, 35.72 µm and 39.12 µm respectively, describe the spread of individual measurements around each group mean. The primary endpoint timeframe is baseline and 4 weeks; the registry record does not report a primary result at the end of the 8 week treatment period.

7. Results Posted in the Registry

• Twice Daily Netarsudil Ophthalmic Solution: mean -20.10 versus -28.40 on control; difference 8.30 (95% CI -14.92 to 31.52), standardized effect d = 0.22; z-test p = 0.483.

8. Statistical Interpretation

9. Statistical Methods Explained

The registry identifies the primary endpoint as a continuous measure summarized by its mean and standard deviation. The reported outcome is mean change from baseline in central corneal thickness, with a separate group summary for each randomized regimen. A mean describes the average measurement in a group; a standard deviation describes how dispersed individual measurements are around that mean. Neither statistic shows the full distribution of participant-level changes.

What does a within-group test ask?

General statistical explanation: a one-sample t-test compares a group mean with a specified reference value. For a change-from-baseline measure, a common reference is zero change, though the registry record does not state the reference value or test details. This type of test asks whether the group’s mean change differs from its reference. It does not test whether the mean change differs between two independent groups.

The registry reports a one-sample t-test within group for the two listed groups and gives a p-value, but the associated test estimates, confidence intervals, and full reporting details are absent. A single reported p-value alongside the groups does not provide a complete account of how results for each group were tested. The registry record does not report whether the test was one- or two-sided or whether any adjustment was made.

What does the recalculated comparison ask?

The recalculated comparison uses the two posted group means and standard deviations to estimate the unadjusted difference in average change. The contrast is defined as twice-daily minus once-daily. Because the two regimens were assigned to separate groups, this is a comparison of independent group means. The recalculated estimate is 8.3 µm, with a 95% confidence interval from −14.92 to 31.52 µm and an unadjusted p-value of 0.483.

This calculation is based on posted summary statistics rather than participant-level data. It is not adjusted for baseline values or other covariates. The record does not report whether the sponsor’s analysis used adjustment, a different analysis population, or other methods that might account for the flagged discrepancy. Since the discrepancy is true, the sponsor’s own analysis takes precedence; the recalculation is informative as a transparent unadjusted comparison, not as the definitive trial analysis.

How should a p-value be understood?

General statistical explanation: a p-value describes how compatible the observed data are with a specified null model, under the assumptions of the test. It is not the probability that the null hypothesis is true, nor does it measure the clinical importance of an effect. A p-value from a within-group test cannot be used as though it were a test of the difference between regimens. Interpretation also depends on the analysis plan, measurement process, and the extent to which the analysis was prespecified; these details are not reported in the registry record.

What does a confidence interval add?

General statistical explanation: a confidence interval conveys uncertainty around an estimated effect, as well as the direction and range of values compatible with the analysis. It is more informative than a point estimate alone because it shows whether the data are consistent with meaningfully different possible effects. The recalculated interval includes zero and extends in both directions, indicating that the posted summaries do not precisely determine the between-group difference. The interval is not a range containing a fixed proportion of individual participant results.

What assumptions are not documented?

The registry record does not report the original sample-size justification, the statistical analysis plan, the handling of missing outcome measurements, or details of the test assumptions. It also does not report an analysis adjusted for baseline CCT or other covariates. General statistical explanation: analyses of continuous outcomes may rely on assumptions about the distribution of data or model errors. With small groups, unusual observations or departures from assumptions can affect estimates and uncertainty. Participant-level data and analysis details would be needed to assess these issues directly.

The record lists the Modified Intent-to-Treat Population for the endpoint, but does not define membership in that population or explain how participants with missing measurements were handled. The published group counts alone do not establish whether every randomized participant contributed an outcome or how incomplete observations were treated. These omissions limit how fully the analysis can be reproduced or evaluated.

10. Confidence Intervals and Precision

The recalculated unadjusted mean difference is 8.3 µm, defined as twice-daily minus once-daily dosing. Its 95% confidence interval is −14.92 to 31.52 µm. The estimate is accompanied by substantial uncertainty: the interval includes zero, and it extends from a difference favoring a more negative average change in the twice-daily group to a difference in the opposite direction. The posted summaries therefore do not pin down the comparative effect precisely.

General statistical explanation: a confidence interval describes the uncertainty in an estimated quantity under the analysis assumptions. A 95% interval is generated by a procedure designed to cover the true parameter in 95% of repeated samples if its assumptions hold. It is not a statement that there is a 95% probability that this particular interval contains the true difference, and it does not describe the range of individual participant outcomes.

The outcome groups each contain 20 participants. The standard deviations are 35.72 µm for once-daily dosing and 39.12 µm for twice-daily dosing, compared with a mean difference of 8.3 µm. This combination of group size and observed variability contributes to the width of the interval. No recalculated confidence intervals are available for the individual group means in the registry record.

The interval is an unadjusted recalculation from the posted group summaries, not a sponsor-reported interval. Its assumptions and scope differ from the sponsor’s reported within-group test. A discrepancy is flagged, and the sponsor’s own analysis takes precedence. The registry record does not provide the additional analysis details needed to determine why the results differ or whether the sponsor’s analysis produced a direct between-group interval.

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 planning figures are participants per arm, not total events. They are illustrations based on the observed effect, not the original trial’s design calculations. The stated assumptions are a two-sided significance level of 0.05, equal allocation between the two arms, and a normal approximation. The planning exercise sets the effect to detect at the stated fraction of the observed effect. The trial’s own original sample-size assumptions are not reported in the registry record.

The 80% power column gives the planned participants per arm for an analysis with an 80% chance of detecting the assumed effect if that effect is real and the planning assumptions hold. The 90% power column gives the corresponding per-arm figure for a higher chance of detection under those same assumptions. These are planning targets, not descriptions of the trial’s achieved ability to detect an effect.

For planning for 100% of the observed effect, the figures are 320 participants per arm for 80% power and 429 participants per arm for 90% power. For planning for 75% of the observed effect, they are 569 and 761 participants per arm. For planning for 50% of the observed effect, they are 1,279 and 1,713 participants per arm. The pattern reflects a general principle: smaller effects are harder to distinguish from random variation and require more participants to detect at a given power and significance level.

The curve should be read as the relationship between the assumed effect size and the participants required under these planning assumptions; movement toward a smaller assumed effect corresponds to a larger required group size. These figures are not observed power, and they do not establish what the original study was designed to detect. The registry record does not report the trial’s original sample-size rationale.

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, Δ is the difference in means to detect and σ is the common standard deviation.

Worked calculation for this trial

1. Observed difference Δ = 8.300; pooled standard deviation σ = 37.459.
2. n = 2 × (1.96 + 0.842)² × 37.459² / 8.300² = 319.7, rounded up to 320 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 <- 8.3                      # observed difference in means
sigma <- 37.4585958092398                     # 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(4498169)
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 = 320 (80% power), 429 (90% power)
 75% of observed effect: n per arm = 569 (80% power), 761 (90% power)
 50% of observed effect: n per arm = 1,279 (80% power), 1,713 (90% power)
power.t.test: 320.7 
Simulated power at n = 320 per arm: 0.798 (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.

13. Analyses Reported by the Sponsor

The registry’s reported analysis is a one-sample t-test within group. It reports a p-value but does not include a corresponding estimate, confidence interval, or enough detail to reconstruct the test. A within-group test and a direct comparison between dosing regimens answer different questions: the former concerns change within a group relative to a reference, while the latter concerns the difference in mean change between groups.

The recalculated unadjusted comparison uses the posted means and standard deviations and estimates a twice-daily minus once-daily mean difference of 8.3 µm. Its 95% confidence interval is −14.92 to 31.52 µm, and its unadjusted p-value is 0.483. A discrepancy is flagged between this recalculation and the sponsor’s reported analysis. Under that circumstance, the sponsor’s own analysis takes precedence.

The recalculation should therefore not be presented as a correction to the sponsor or as the definitive trial result. It is a separate comparison derived from the posted summary statistics. The registry record does not report enough detail to explain the discrepancy, establish whether the sponsor conducted a direct between-group analysis elsewhere, or determine whether differences in population, model, or other analysis choices account for it.

14. Multiplicity, Missing Data and Analysis Populations

Multiplicity concerns arise when an analysis includes multiple outcomes, comparisons, timepoints, or statistical tests. Repeated testing can increase the chance that at least one result appears unusual by chance. General statistical explanation: plans may address multiplicity by selecting a primary comparison in advance or by adjusting how statistical evidence is evaluated. The registry record does not report a multiplicity strategy.

The record lists one outcome measure and one reported analysis, and it lists no secondary outcomes. The primary endpoint is change in CCT at 4 weeks, while the two assigned regimens create a natural between-group comparison. The posted sponsor analysis is described as a one-sample t-test within group; the record does not clarify whether separate tests were performed for each group, how those tests related to the primary objective, or whether other analyses were planned or conducted. It also does not report interim analyses.

The analysis population is identified as Modified Intent-to-Treat, but its definition is not reported in the registry record. The posted outcome groups each contain 20 participants. The registry does not explain whether that population includes all randomized participants, what eligibility conditions applied to the analysis, or whether any participants were excluded after randomization.

Missing-data handling is also not reported in the registry record. The available summaries do not say how absent 4-week measurements were treated, whether any imputation was used, or whether the analysis accounted for incomplete follow-up. These details matter because the composition of the analyzed population and assumptions about missing measurements can affect both estimates and uncertainty.

The original statistical analysis plan, rules for selecting or prioritizing analyses, and prespecification of the reported test are not reported in the registry record. Without those details, it is not possible to establish whether the posted analysis reflects the planned primary analysis or how any additional testing was handled. These reporting gaps limit interpretation and reproducibility; they do not establish that a particular procedure was or was not used.

15. 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 serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: viral gastroenteritis (5.0%).

The posted safety figures list serious adverse events in zero participants in the once-daily group and one participant in the twice-daily group. The number at risk is 20 in each group. Deaths are listed as zero in both groups. These counts describe the registry’s reported safety information and should not be treated as evidence about the cause of an event.

The record also lists other adverse events in 5 participants in the once-daily group and 7 participants in the twice-daily group. These are distinct from the serious adverse event counts and should not be combined with them. The registry record does not report whether events were judged related to treatment, their duration, severity beyond the serious classification, or the criteria used to collect and classify them.

Viral gastroenteritis is listed among the leading serious-event terms at 5.0%. The registry record does not make the denominator or arm attribution for that term clear in the posted summary. Small safety counts are descriptive and do not provide a precise comparison of risk between regimens. The study’s safety results should be interpreted within the limits of its size, follow-up, and reporting detail.

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

The posted results describe average 4-week changes in central corneal thickness for two randomized dosing groups. The once-daily group mean was −28.4 µm and the twice-daily group mean was −20.1 µm. The recalculated unadjusted difference was 8.3 µm for twice-daily minus once-daily dosing, with a 95% confidence interval from −14.92 to 31.52 µm. This interval spans zero and a range of differences in either direction, so the posted summary statistics do not precisely establish the comparative size or direction of the difference.

The registry also reports a within-group one-sample t-test, but that test is not equivalent to a direct comparison of the two schedules. A discrepancy is flagged between the reported analysis and the recalculation; the sponsor’s own analysis takes precedence. The registry does not supply the estimates and details needed to determine exactly how its reported test relates to the primary comparative question.

These findings do not establish that either regimen is better or worse. They are not a complete account of individual responses, and group means do not indicate how many participants experienced a particular amount of change. The registry record does not report a clinically important threshold for CCT change, participant-level data, or a direct connection between the measured change and symptoms or other outcomes.

The endpoint was measured at 4 weeks even though the treatment period was 8 weeks. The record does not report a primary result at the end of treatment or evidence about whether the observed changes persisted. Nor do these results address outcomes that were not posted as trial endpoints. The safety counts are descriptive; they do not establish causation or provide a precise estimate of comparative safety.

Overall, the record provides short-term group summaries from a small Phase 2 comparison, alongside a sponsor-reported within-group analysis and a separate unadjusted recalculation. The uncertainty, analysis discrepancy, and missing methodological details all limit how firmly the comparative result can be interpreted.

17. Why This Trial Matters Statistically

This trial illustrates why the statistical question must match the study question. When two randomized groups receive different regimens, the direct comparative question concerns the difference between their average changes. A within-group test instead asks whether a group’s change differs from a reference. Those questions are related but not interchangeable, and evidence from one does not automatically establish an answer to the other.

It also illustrates why effect estimates and confidence intervals are important alongside p-values. The recalculated mean difference is 8.3 µm, but its 95% confidence interval, −14.92 to 31.52 µm, is broad and includes zero. A reader can therefore see both the direction of the point estimate and the range of uncertainty, rather than relying on a binary label based on a significance threshold.

The discrepancy between the sponsor’s reported analysis and the unadjusted recalculation makes transparent reporting especially important. A reported test should be accompanied by the estimate it addresses, its uncertainty, the analysis population, and enough methodological detail to understand its relationship to the primary objective. Here, those details are not reported in the registry record, and the sponsor’s own analysis takes precedence over the recalculation.

The planning illustrations show how sample-size requirements depend on the effect one aims to detect, under stated assumptions. Smaller target effects require more participants. They should not be mistaken for the trial’s original design rationale or for an assessment of observed power.

Finally, short follow-up, limited group sizes, and sparse safety counts constrain the scope of inference. These statistical features matter when interpreting any observed group pattern: they shape how precisely it is estimated and which questions the record can answer.

18. 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 outcome groups each contain 20 participants, and the recalculated comparison has a broad confidence interval. This limits precision for the between-group contrast. The registry record does not report the trial’s original sample-size rationale, so the intended detectable effect and the basis for the planned enrollment cannot be assessed from the record.

The primary endpoint timeframe is baseline and 4 weeks, while the dosing period is 8 weeks. A primary result at the end of the treatment period is not reported in the registry record, which limits interpretation of later changes or persistence. The record also does not post secondary outcomes, so the evidence described is confined to the listed CCT endpoint and the reported safety information.

The analysis has a material reporting limitation: the sponsor’s reported one-sample t-test within group does not present the same comparison as the recalculated between-group estimate. A discrepancy is flagged, and the sponsor’s own analysis takes precedence. The registry does not provide sufficient estimates or methodological detail to reconcile the analyses or determine the sponsor’s direct comparative result.

Other relevant details are not reported in the registry record, including the definition of the Modified Intent-to-Treat Population, handling of missing measurements, baseline CCT summaries, assessor masking, and whether the analysis adjusted for baseline or other characteristics. The open-label design also means participants and study personnel knew the assigned regimen, though the primary measurement itself was objective. Safety counts are sparse, and the record does not describe event attribution or classification procedures in detail. These limitations narrow the conclusions that can be drawn from the posted results.

19. Related Tutorials

20. Related Statistical Calculators

21. Sources

• ClinicalTrials.gov: A Phase 2 Study Evaluating the Safety and Efficacy of Netarsudil Ophthalmic Solution in Patients With Corneal Edema Due to Fuchs Corneal Dystrophy — NCT04498169.
• Registry record last updated 2022-09-15; status last verified 2022-08.
• Results first posted 2022-09-01.
• 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.

22. Record Summary

NCT04498169 was a completed randomized, open-label, parallel-group Phase 2 study sponsored by Aerie Pharmaceuticals. It compared once-daily evening dosing with twice-daily morning and evening dosing of Netarsudil 0.02% ophthalmic solution in the study eye for an 8 week period. The registry record lists enrollment of 40 and a primary endpoint of mean change from baseline in CCT by ultrasound pachymetry at 4 weeks in the Modified Intent-to-Treat Population.

The posted mean changes were −28.4 µm for once-daily dosing and −20.1 µm for twice-daily dosing. An unadjusted recalculation gives a between-group difference of 8.3 µm, with a 95% confidence interval of −14.92 to 31.52 µm and p = 0.483. The registry’s reported analysis is a one-sample t-test within group; a discrepancy is flagged, so the sponsor’s own analysis takes precedence. Important details about the analysis plan, missing data, and analysis population are not reported in the registry record.