Clobetasol Propionate Ophthalmic Nanoemulsion 0.05% for the Treatment of Inflammation and Pain Associated With Cataract Surgery (CLOSE-1): Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Clobetasol Propionate Ophthalmic Nanoemulsion 0.05% for the Treatment of Inflammation and Pain Associated With Cataract Surgery (CLOSE-1) (NCT04246801), a randomized phase 3 study. The primary outcome is Anterior Chamber Cell Grade.

2. Clinical Question

3. Trial Design

This was a Phase 3, multicenter, randomized, double-masked, parallel-group trial comparing clobetasol propionate ophthalmic nanoemulsion 0.05% with placebo after routine unilateral cataract surgery. The registry lists the trial as completed and identifies Salvat as the sponsor. The record gives a start date of 2020-06-10 and a primary completion date of 2021-05-19.

The study summary describes random assignment in a 2:1 ratio among eligible participants who had postoperative inflammation on the first day after surgery. It states that 140 participants were planned for clobetasol and 70 for placebo, with screening across 20 centers in the US. The registry enrollment field, however, reports 250. These are different record entries: the enrollment field and the summary's planned enrollment are not the same figure.

The summary describes six visits: screening, baseline 24 hours after surgery, Day 3, Day 8, Day 15, and Day 29. The intervention descriptions specify one drop four times a day, and the summary describes treatment for 14 days. Posted primary-outcome denominators are 139 for clobetasol and 67 for placebo; the safety at-risk counts are 140 and 71. These denominators relate to different reported results and should not be treated as interchangeable.

The registry does not report the original sample-size justification, the detailed randomization procedure, or the statistical analysis plan. The posted results therefore support a description of the design and reported comparisons, but not a reconstruction of unreported design decisions.

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: Patients with at least 5 cells in anterior chamber on the first day after surgery (at Visit 1)

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: FAS Population with anterior chamber cell grade assessment at Day 8

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: Safety Population

6. Primary Endpoint

The registry lists the primary outcome as Anterior Chamber Cell Grade, measured over Day 8.

The primary endpoint is the proportion of participants with an anterior chamber cell grade of “0” at Day 8. The registry defines grade “0” as absence of cells and identifies the analysis population as the FAS population with an anterior chamber cell assessment at Day 8. The posted arm counts are participants meeting that endpoint among participants with the relevant assessment.

Anterior chamber cells are a measure of inflammation inside the front part of the eye. In general, an endpoint based on a prespecified clinical assessment gives a trial a concrete outcome to compare between randomized groups. A grade of zero represents the stated absence of cells; it does not, by itself, summarize all inflammatory features, pain, visual function, or safety.

The Day 8 assessment is one time point within the visit schedule described in the record. Results at other visits for this endpoint are not reported in the registry record. The record also does not describe the grading procedure, assessor training, or any threshold beyond the stated grade of “0.” Interpretation should therefore stay focused on the posted Day 8 measure and its defined assessment population.

7. Results Posted in the Registry

• Clobetasol Propionate: 48.2% (67/139) versus 26.9% (18/67) on control; risk difference 21.3 percentage points (95% CI 7.9 to 34.8), risk ratio 1.79 (1.17–2.76); unadjusted two-proportion z-test p = 0.004.

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.

Pain Visual Analogue Scale (VAS) Score

• 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:
  • Clobetasol Propionate: 60.6% (83/137) versus 28.8% (19/66) on control; risk difference 31.8 percentage points (95% CI 18.1 to 45.4), risk ratio 2.10 (1.41–3.15); unadjusted two-proportion z-test p = <0.001.
• Interpretation:
  • The 95% confidence interval excludes no difference, so the proportion with the event is statistically higher for Clobetasol Propionate than for the control. This is an unadjusted, secondary comparison, so it is suggestive rather than confirmatory.

The registry posts one secondary outcome, Pain Visual Analogue Scale (VAS) Score, assessed at Day 8. Its reported comparison has a positive risk difference, so the proportion meeting the recorded status was higher in the clobetasol group than in the placebo group. This direction is consistent with the primary comparison, which also has a higher proportion meeting its defined endpoint in the clobetasol group.

The secondary result is related to, but not interchangeable with, the primary result. The primary outcome is explicitly defined as absence of anterior chamber cells. The registry does not describe the secondary VAS status counted, such as a response threshold or category. Without that definition, the meaning of the secondary count cannot be interpreted as a particular change in pain or level of improvement. The record also does not report results for additional secondary time points.

The secondary comparison is unadjusted, and no secondary analyses are listed as reported analyses. The registry does not report whether this outcome was part of a prespecified testing sequence or whether adjustment for testing multiple outcomes was planned. When multiple outcomes are examined, the chance of obtaining a nominally small p-value can increase; in general, multiplicity procedures address that issue by controlling the interpretation of a family of tests. Without a reported plan, the secondary p-value should carry less weight than a result interpreted under a clearly documented testing strategy.

The consistent direction across the posted primary and secondary comparisons can be noted as a pattern in the record, but it does not remove the uncertainty about the secondary endpoint definition or multiplicity. It also does not establish that the secondary result independently confirms the primary result. The outcomes differ in what is measured, and the registry provides less interpretive detail for the secondary measure.

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

• Pain Visual Analogue Scale (VAS) Score

9. Statistical Interpretation

10. Statistical Methods Explained

The primary and secondary posted outcomes are binary participant counts: the registry reports how many participants met a recorded outcome status and how many participants were assessed in each group. For the primary outcome, the status is explicitly defined as anterior chamber cell grade “0” at Day 8. The secondary outcome is titled Pain Visual Analogue Scale (VAS) Score, but the registry does not define the status counted in the comparison. That limits interpretation of the secondary measure.

What does a risk difference describe?

In general, a risk difference subtracts the proportion meeting an outcome in one group from the proportion in the other. It measures the absolute separation on the probability scale. A positive risk difference in the posted comparisons corresponds to a higher proportion meeting the recorded status in the clobetasol group than in the placebo group. The primary risk difference is 0.213; the secondary risk difference is 0.318. These comparisons use the posted arm counts and are unadjusted.

In general, an absolute difference is tied to the outcome and its definition. It does not say whether the outcome captures every dimension of the condition being studied. Here, the primary outcome is absence of anterior chamber cells at Day 8, not a composite measure of all symptoms or clinical outcomes. For the secondary measure, the counted status is not defined in the registry record, so its meaning is less specific.

How do relative measures differ?

A risk ratio compares the group proportions as a ratio, while an odds ratio compares their odds. Both put the contrast on a relative scale rather than reporting an absolute difference. The registry posts both measures for the primary result, with intervals. They are alternative summaries of the same binary data, not separate findings. Because odds and probabilities are different quantities, an odds ratio should not be read as though it were a risk ratio or an absolute percentage-point difference.

Measures can look more or less dramatic depending on the scale used. For clinical interpretation, the outcome definition and the group proportions remain essential context. The risk difference is often useful for understanding the absolute separation, whereas relative measures describe proportional contrasts. None of these scales alone resolves concerns about missing assessments, outcome selection, or how a response was defined.

What does a p-value say?

In general, a p-value describes how incompatible the observed data are with a specified null hypothesis under a particular statistical model. Smaller p-values indicate greater incompatibility under that model; they are not the probability that the null hypothesis is true, nor the probability that chance alone caused the result. The posted p-values are unadjusted, and the detailed testing procedures are not reported in the registry record. The primary unadjusted p-value is 0.004; the secondary unadjusted p-value is <0.001.

A p-value also does not describe the size or precision of an effect. The risk difference and its interval provide complementary information about magnitude and uncertainty. For a full interpretation, those estimates need to be considered alongside the endpoint definition, analysis population, assessment time, and possible multiplicity.

What is not known about the analysis?

The primary population is described as the FAS population with a Day 8 assessment. The registry does not report the definition of FAS, analysis model, covariates, handling of missing outcome data, or whether any sensitivity analyses were planned. It does not report a statistical analysis plan or details of the interval method. No secondary analyses are listed as reported analyses. These omissions mean that the posted counts and unadjusted contrasts can be described, but the precise procedures behind the estimates cannot be independently reconstructed from the registry record.

In general, randomization is intended to make group comparisons less vulnerable to systematic differences at assignment, and masking can reduce some sources of bias in care or assessment. Those design features do not guarantee that every later measurement is complete or that analysis choices cannot affect interpretation. The record supports noting that the study was randomized and double-masked, but further operational details are not reported.

11. Confidence Intervals and Precision

For the primary risk difference, the posted estimate is 0.213 and its interval runs from 0.079 to 0.348. For the secondary risk difference, the estimate is 0.318 and the interval runs from 0.181 to 0.454. The posted intervals for the primary relative measures are 1.166 to 2.761 for the risk ratio and 1.343 to 4.777 for the odds ratio. These ranges communicate uncertainty around estimates; they are not guarantees that the true value lies within a particular range.

In general, an interval is more informative than a point estimate alone because it displays a range of values compatible with the data under a specified method. A narrower interval indicates greater precision under that method, while a wider interval indicates more uncertainty. Precision depends on factors such as the amount of outcome information and the analysis procedure. The registry does not report the confidence level or the method used to construct these intervals, so those details cannot be assessed from the record.

The primary interval remains above zero, and the posted relative-measure intervals remain above one. Those are different reference points for the different effect scales. This does not resolve the unreported interval method or change the need to interpret the results within their endpoint definitions. The observed assessment denominators are 139 and 67 for the primary comparison, and 137 and 66 for the secondary comparison. The record does not explain why denominators differ across outcomes.

Precision is distinct from clinical importance. The registry does not provide a threshold for a clinically important difference, so the intervals cannot establish whether values within their ranges would be considered important in practice. They describe statistical uncertainty in the posted comparisons, not the full uncertainty arising from unreported analysis details, endpoint definition, or missing-data handling.

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 events. Both posted outcomes are participant-count outcomes rather than time-to-event outcomes. In general, a power column gives the number of participants per arm in a hypothetical design intended to have the stated probability of detecting the chosen effect under the listed assumptions, if the assumptions hold. The 80% and 90% columns represent those two target probabilities, not results measured in the completed trial.

The planning assumptions are a two-sided significance level of 0.05, equal allocation between the two arms, and a normal approximation. The effect to detect is set as the stated fraction of the observed effect. For the primary outcome, planning for 100% of the observed effect gives 80 participants per arm for 80% power and 107 for 90% power; planning for 75% gives 139 and 185; planning for 50% gives 300 and 402. For the secondary outcome, the corresponding figures are 38 and 50 for 100%, 66 and 88 for 75%, and 144 and 192 for 50%.

These are planning illustrations based on the observed comparisons, not the trial's original design calculations. The registry summary describes planned 2:1 allocation, whereas these illustrations assume equal allocation. Smaller effects require more participants under the same planning framework because they are harder to distinguish from sampling variation. This is not observed power: it does not describe the probability that the completed trial detected its effect, and it should not be used to judge the result as successful or unsuccessful.

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

Worked calculation for this trial

1. Control proportion p₀ = 0.269; treatment proportion p₁ = 0.482; average p̄ = 0.375.
2. First term: z_1−α/2 × √[2p̄(1−p̄)] = 1.96 × 0.6848 = 1.3421.
3. Second term: z_1−β × √[p₀(1−p₀) + p₁(1−p₁)] = 0.842 × 0.6679 = 0.5622.
4. n = (1.3421 + 0.5622)² / (0.2134)² = 79.7, rounded up to 80 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 <- 0.26865671641791                          # control proportion
p1 <- 0.482014388489209                          # 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(4246801)
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 = 80 (80% power), 107 (90% power)
 75% of observed effect: n per arm = 139 (80% power), 185 (90% power)
 50% of observed effect: n per arm = 300 (80% power), 402 (90% power)
power.prop.test: 79.7 
Simulated power at n = 80 per arm: 0.802 (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.

14. Multiplicity, Missing Data and Analysis Populations

Multiplicity concerns arise when a study evaluates more than one outcome, time point, subgroup, or statistical contrast. In general, repeated testing can make nominal p-values appear more compelling than they would be under a prespecified strategy that accounts for the family of tests. The registry lists a primary anterior chamber cell endpoint at Day 8 and one secondary outcome, Pain Visual Analogue Scale (VAS) Score, also at Day 8. It reports no secondary analyses as reported analyses.

The registry record does not report a multiplicity plan, hierarchy of outcomes, gatekeeping procedure, or adjusted p-values. It is therefore not possible to determine from the record whether the secondary outcome was intended as confirmatory or exploratory, or how the sponsor planned to handle testing across outcomes or time points. The posted p-values are identified as unadjusted and should be read accordingly.

Missing-data handling is also not reported. The primary endpoint applies to the FAS population with a Day 8 assessment, but the record does not define FAS or state how participants without a Day 8 assessment were handled. The primary endpoint denominators differ from the safety at-risk counts, and the secondary denominators differ from the primary assessment denominators. The record does not explain these differences, so they should not be attributed to a particular cause.

Other analysis populations, rules for incomplete observations, imputation methods, sensitivity analyses, and protocol deviations are not reported in the registry record. These gaps matter because observed-case comparisons can be affected if outcome availability differs between groups or relates to the outcome. They do not establish that such problems occurred; they mean the posted results cannot answer how those possibilities were assessed.

The record also does not report the original sample-size justification or the analysis plan. The separate planning illustrations are based on observed effects and specified assumptions; they do not recover the trial's original planning rationale. Consequently, the primary result can be described using its posted estimates and uncertainty, but claims about prespecification, missing-data robustness, or confirmatory interpretation are not supported by the registry record.

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 2% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: cystoid macular oedema (0.7%).

For serious adverse events, the posted at-risk counts are 140 in the clobetasol group and 71 in the placebo group. The record reports 1 participant affected in the clobetasol group and 0 in the placebo group. The posted other adverse-event counts are 1 and 5, respectively. No deaths are reported in either group. The registry lists cystoid macular oedema as a top serious term at 0.7%.

These are counts, not adjusted comparisons of risk. The at-risk counts for safety are not the same as the primary endpoint assessment denominators, and the record does not provide enough detail to reconcile them. The counts are small, so they describe what was recorded in this trial but do not, by themselves, establish comparative safety or rule out uncommon events. The registry does not report adverse-event definitions, collection procedures, severity breakdowns beyond the serious-event listing, or a statistical comparison of safety outcomes.

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

The registry record shows that, among participants with a Day 8 primary assessment, a larger proportion in the clobetasol group had an anterior chamber cell grade of “0” than in the placebo group. The posted unadjusted risk difference is 0.213, with an interval from 0.079 to 0.348, and the unadjusted p-value is 0.004. This is a statistical description of the recorded endpoint in the analyzed assessment population.

The result does not establish that every participant experienced the same outcome, nor does it describe all aspects of postoperative inflammation, pain, or recovery. A Day 8 measure is one point in the registry's visit schedule. It does not by itself show how outcomes developed at other visits, and the record does not report primary endpoint results at other time points.

The secondary pain VAS comparison points in the same direction, but the registry does not define the counted secondary status. That missing definition limits what can be concluded about the clinical meaning of the secondary result. The absence of a reported multiplicity plan and missing-data procedure also limits how strongly the posted unadjusted results can be interpreted.

The adverse-event counts are descriptive. They do not establish that one group is safer, and they cannot rule out events that are uncommon or not captured in the registry results. Likewise, a statistically separated group comparison does not by itself establish the size of a clinically important benefit; the record does not give a threshold for clinical importance.

Overall, the posted statistics describe differences between randomized groups for the outcomes and assessments reported. They should not be generalized beyond those defined measures, time points, and populations without additional evidence. The registry record alone does not support medical advice or a complete judgment of treatment benefit and risk.

17. Why This Trial Matters Statistically

This trial is statistically informative because it reports a binary primary outcome with arm-specific participant counts, an unadjusted absolute difference, relative measures, intervals, and a p-value. Seeing the group proportions alongside the risk difference helps distinguish the observed magnitude from a significance test. The Day 8 endpoint is also explicitly defined as absence of anterior chamber cells, which keeps the primary comparison tied to a stated clinical measure.

The record illustrates why endpoint definitions matter. The primary outcome has a clear grade threshold, while the secondary pain VAS result is posted as participant counts without a definition of the counted status. The two outcomes have a similar direction in the reported comparisons, but their statistical and clinical meanings cannot be treated as identical. An incomplete definition can limit interpretation even when a p-value is small.

It also demonstrates the importance of reading denominators in context. Primary assessment, secondary assessment, and safety at-risk counts are different. The registry does not explain those differences, and the enrollment field does not match the summary's planned enrollment. Noticing such record-level distinctions prevents conflating planned recruitment, outcome assessment, and safety populations.

Finally, the trial record does not report its detailed statistical plan, multiplicity handling, or missing-data methods. These omissions matter to how confidently readers can characterize the inferential framework. The posted results support a careful description of the measured group differences, while leaving important questions about the original design rationale and analysis procedures unanswered.

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 registry contains different enrollment figures: its enrollment field reports 250, while the study summary says 210 participants were planned and describes planned groups of 140 and 70. The posted primary outcome denominators are 139 and 67, while safety at-risk counts are 140 and 71. These figures refer to different record entries and analysis contexts; the record does not reconcile them.

The primary endpoint is reported for Day 8, and results for this endpoint at other scheduled visits are not reported in the registry record. The secondary outcome is also listed at Day 8, but the counted VAS status is not defined. This makes the clinical interpretation of the secondary comparison less specific than that of the primary outcome.

The registry does not report a detailed statistical analysis plan, the original sample-size justification, multiplicity procedures, interval methods, or missing-data handling. It also does not define the FAS population beyond specifying that the primary assessment includes participants with a Day 8 evaluation. These omissions limit assessment of prespecification and robustness.

Safety information is presented as event counts and at-risk counts, without a detailed comparison or enough reporting to assess collection and classification procedures. The available record supports describing those counts, not drawing broad conclusions about uncommon adverse events or comparative safety. These limitations are features of the available registry reporting; they do not show that a particular bias or analysis problem occurred.

19. Related Tutorials

20. Related Statistical Calculators

21. Sources

• ClinicalTrials.gov: Clobetasol Propionate Ophthalmic Nanoemulsion 0.05% for the Treatment of Inflammation and Pain Associated With Cataract Surgery (CLOSE-1) — NCT04246801.
• Registry record last updated 2022-12-22; status last verified 2022-11.
• Results first posted 2022-12-22.
• 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

The registry describes a completed Phase 3, randomized, double-masked, parallel-group comparison of clobetasol propionate ophthalmic nanoemulsion 0.05% with placebo after routine unilateral cataract surgery. The primary endpoint is the proportion with anterior chamber cell grade “0” at Day 8 among the FAS population with an assessment. The posted unadjusted comparison reports a higher proportion meeting this endpoint in the clobetasol group, with a risk difference of 0.213 and p-value of 0.004.

A Day 8 pain VAS outcome is also posted, but the registry does not define its counted status. Serious and other adverse-event counts are reported descriptively. The original sample-size rationale, multiplicity plan, missing-data methods, and detailed analysis procedures are not reported in the registry record.