Study to Assess the Safety and Efficacy of BOL-303242-X Ophthalmic Suspension in Dry Eye Syndrome: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Study to Assess the Safety and Efficacy of BOL-303242-X Ophthalmic Suspension in Dry Eye Syndrome (NCT01163643), a randomized phase 2 study. The primary outcome is Mean Corneal Staining Score.

2. Clinical Question

3. Trial Design

This was a Phase 2, randomized, double-masked, parallel-group, vehicle-controlled, multicenter exploratory study of BOL-303242-X ophthalmic suspension in dry eye syndrome. The registry reports enrollment of 356 participants and a completed status. The study start is recorded as 2010-07 and primary completion as 2011-06. The stated dosing period was 12 weeks.

Six groups are represented in the intervention and outcome records: 0.3% suspension, 1% suspension, 2% suspension, 2% suspension in the morning with vehicle in the afternoon, vehicle in the morning with 2% suspension in the afternoon, and vehicle. The vehicle group is described as receiving vehicle twice daily (BID). This setup allowed the study to examine more than one concentration and to evaluate morning-only and evening-only use of the 2% suspension against a vehicle comparison. The registry describes random allocation, double masking, and a parallel-group model; details of how the randomization sequence was generated or how masking was maintained are not reported in the registry record.

The primary outcome was the mean corneal staining score at 12 weeks. Its posted analysis included randomized participants with Week 12 results and did not impute missing Week 12 data. The outcome group sizes differ from the overall enrollment, and safety denominators also differ from the outcome group sizes. The reasons for these differences, including participant flow by group, are not reported in the registry record. The registry lists two outcome measures but no secondary results are posted. The original sample-size rationale, allocation ratio, and trial-specific statistical analysis plan 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: Randomized participants with Week 12 results were included, with no imputation of missing data at Week 12.

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.

Only the first 6 of 7 groups are shown.

6. Primary Endpoint

The registry lists the primary outcome as Mean Corneal Staining Score, measured over 12 weeks.

The primary endpoint was the mean corneal staining score at 12 weeks. The score was formed by adding grades from five regions of the corneal surface: central, superior, temporal, nasal, and inferior. Each region was graded from 0, meaning none, to 3, meaning severe. The total score could range from 0 to 15, and higher totals indicated worse outcome. This is a continuous measure, so its mean describes the average score in each group, while the standard deviation describes how dispersed individual scores were around that group average.

Corneal staining is used in this study as a way to quantify the extent of staining across specified corneal regions. A score based on several regions captures a broader surface assessment than a grade from one region alone. For the posted comparison, the question is whether the average score at Week 12 differs between each suspension group and vehicle. The score’s direction matters: a higher mean is a worse score, not a better one. Interpretation also depends on the size and uncertainty of the difference, not only on which group has the numerically higher or lower mean. The registry does not report a threshold for a clinically meaningful score difference.

7. Results Posted in the Registry

• 2% BOL-303242-X Ophthalmic Suspension: mean 4.00 versus 3.70 on control; difference 0.30 (95% CI -0.82 to 1.42), standardized effect d = 0.09; z-test p = 0.598.
• 2% BOL-303242-X Ophthalmic Suspension in the Morning: mean 3.90 versus 3.70 on control; difference 0.20 (95% CI -1.31 to 1.71), standardized effect d = 0.06; z-test p = 0.795.
• 2% BOL-303242-X Ophthalmic Suspension PM: mean 3.90 versus 3.70 on control; difference 0.20 (95% CI -1.28 to 1.68), standardized effect d = 0.06; z-test p = 0.791.
• 1% BOL-303242-X Ophthalmic Suspension: mean 4.40 versus 3.70 on control; difference 0.70 (95% CI -0.44 to 1.84), standardized effect d = 0.20; z-test p = 0.231.

8. Statistical Interpretation

9. Statistical Methods Explained

The endpoint is continuous, and the registry reports a mean and standard deviation for each group. A mean gives the group’s average Week 12 corneal staining score. The standard deviation (SD) describes how much scores vary among participants in that group; it is not the uncertainty of the mean itself. The posted SDs range from 3.03 to 3.87 across groups, while the means range from 3.7 to 4.4. The score’s defined range was 0 to 15, with higher values indicating worse outcome.

How are the group comparisons expressed?

Each contrast compares a BOL-303242-X group with vehicle. The mean difference is the treatment-group mean minus the vehicle-group mean. Thus, the reported difference of 0.3 for 2% suspension corresponds to means of 4.0 and 3.7, respectively; positive values indicate a higher average score in the suspension group. Since higher scores indicate worse outcome, the sign of the difference is important. The same interpretation applies to the morning-only, afternoon-only, 1%, and 0.3% comparisons.

The differences are described as recalculated, unadjusted comparisons based on the posted group summary statistics. They are not adjusted for other variables. The registry record lists no analysis results of its own, and the displayed p-values are unadjusted. A p-value summarizes how incompatible the observed data are with a null model of no group difference, under the assumptions of the comparison method. It is not the probability that the null hypothesis is true, nor does it measure the size or clinical importance of a difference. Here, the p-values range from 0.231 to 0.795. They should be considered alongside the estimates and confidence intervals, rather than used as a stand-alone decision rule.

What does a confidence interval communicate?

A confidence interval describes the uncertainty around an estimated difference under the statistical method used. Its endpoints identify a range of values reasonably compatible with the data and model. All five intervals include zero, the value corresponding to no difference between group means. They also extend into positive and negative values, meaning the data are compatible with either direction of difference within the respective ranges. The intervals do not show that the groups are equivalent: equivalence requires a prespecified margin and an analysis designed to assess whether the uncertainty lies within that margin. Such a margin is not reported in the registry record.

The posted intervals and p-values are unadjusted. There are five treatment-versus-vehicle comparisons in the primary results. When several hypotheses are tested, the chance of at least one apparently notable result can differ from that for a single test. Whether and how the original analysis addressed this issue is not reported in the registry record. The recalculated contrasts therefore should not be interpreted as evidence from a multiplicity-adjusted analysis.

How should the standard deviations be understood?

SD describes participant-to-participant spread, whereas the standard error describes uncertainty in an estimated mean. The posted comparisons include standard errors for each group mean; for example, the standard error for vehicle is 0.407. Standard errors are influenced by the spread of scores and the number of participants contributing data. A smaller standard error generally indicates a more precise estimate of the mean, but does not imply that individual participant outcomes were less variable.

The comparisons also report pooled SD values and standardized differences. A pooled SD combines within-group variability into a common scale for describing the contrast. The standardized difference expresses the mean difference relative to this pooled variability, making it a scale-free description of magnitude. These standardized values are small in the posted comparisons, but their interpretation still depends on the study context and does not replace the original score units or its confidence interval. The registry does not report a clinically meaningful threshold for either the raw or standardized difference.

What is known about the analysis population?

The primary-endpoint description says randomized participants with Week 12 results were included and missing Week 12 values were not imputed. This is a results-available analysis population rather than an analysis that fills in missing outcomes. The number of participants in each primary outcome group is reported, but the reasons some randomized participants may not appear in those groups are not stated. Methods for handling missing outcomes beyond the explicit absence of imputation, and any sensitivity analyses, are not reported in the registry record. The overall statistical analysis plan, covariate adjustment, and trial-specific sample-size justification are also not reported in the registry record.

10. Confidence Intervals and Precision

The estimated mean differences are imprecise: each 95% confidence interval is broad and includes zero. For 2% suspension, the estimate is 0.3, with an interval from -0.817 to 1.417. The interval allows for a mean score lower than vehicle as well as a mean score higher than vehicle. The morning-only 2% interval runs from -1.31 to 1.71; the afternoon-only 2% interval runs from -1.282 to 1.682. For 1% suspension, the interval is -0.445 to 1.845, and for 0.3% suspension it is -0.689 to 1.489. In every case, the estimate is a small positive difference, but the range of uncertainty includes both directions.

A confidence interval is not a range containing a known proportion of individual participant scores. It represents uncertainty in the estimated group difference under the method used. These intervals do not show that there is no difference; rather, the data do not pin down the difference closely enough to rule out a range of possibilities. Nor do they establish equivalence, because no equivalence margin is reported and the comparisons were not described as equivalence tests.

The outcome group sizes are 64 for 2% suspension, 35 for morning-only 2%, 33 for afternoon-only 2%, 71 for 1%, 64 for 0.3%, and 67 for vehicle. The relatively smaller outcome groups in the schedule-specific arms correspond to wider intervals than some of the other comparisons, although variability also matters. The registry does not provide confidence intervals for each group mean separately. The reported uncertainty is for the difference against vehicle, and the estimates are unadjusted. No further adjustment for multiple comparisons is reported in the registry record.

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 describe participants per arm for 80% power and participants per arm for 90% power. They are planning illustrations based on each posted observed difference, not the trial’s original design assumptions. The listed assumptions are a two-sided significance level of 0.05, equal allocation between the two arms, and a normal approximation. Each row considers the stated fraction of the observed effect: 100%, 75%, or 50%. All non-time-to-event figures are participants per arm; the event-total convention for time-to-event outcomes does not apply to this continuous endpoint.

The 80% power column gives the illustrative number of participants per arm that would yield an 80% chance of detecting the specified effect under those assumptions, if that effect were the true one. The 90% power column expresses the corresponding planning target for a 90% chance. These are design probabilities conditional on the assumed effect and analysis model, not probabilities that the treatment works or that a result will be significant. They are not observed power.

The illustrations use the observed difference as their starting point. For example, the 2% comparison has figures of 1,857 participants per arm for 80% power and 2,486 for 90% power when planning for 100% of the observed effect. The figures increase when planning for 75% or 50% of that effect. This pattern is expected: a smaller effect is harder to distinguish from random variation, so more participants are needed to reach the same planned power. The smallest observed contrast is not required to define a clinically meaningful target, and the registry does not report an effect-size assumption from the original protocol. These illustrations should therefore be read as conditional scenarios rather than evidence about the study’s original enrollment 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 = 0.300; pooled standard deviation σ = 3.262.
2. n = 2 × (1.96 + 0.842)² × 3.262² / 0.300² = 1,856.4, rounded up to 1,857 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 <- 0.3                      # observed difference in means
sigma <- 3.26237857298756                     # 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(1163643)
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 = 1,857 (80% power), 2,486 (90% power)
 75% of observed effect: n per arm = 3,301 (80% power), 4,419 (90% power)
 50% of observed effect: n per arm = 7,426 (80% power), 9,941 (90% power)
power.t.test: 1857.3 
Simulated power at n = 1,857 per arm: 0.796 (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. Multiplicity, Missing Data and Analysis Populations

Five treatment groups are compared with vehicle for the primary continuous outcome. The posted p-values are unadjusted. The registry record does not report whether the trial’s original analysis controlled the family-wise error rate or used another multiplicity strategy. Because multiple comparisons can affect the interpretation of nominal p-values, the posted unadjusted results should not be treated as if they were adjusted for the full set of contrasts. No secondary results are posted, despite the registry listing two outcome measures.

The primary-endpoint population is described as randomized participants with Week 12 results, with no imputation of missing Week 12 data. This means the posted means and comparisons use available Week 12 observations rather than replacing missing values with estimates. The outcome group counts are 64, 35, 33, 71, 64, and 67 across the five suspension groups and vehicle, respectively. The registry does not explain the reasons for missing Week 12 outcomes, provide group-specific missing-data counts, or describe sensitivity analyses for missing data. The primary analysis population should therefore not be assumed to include every randomized participant.

Whether the original trial used an intention-to-treat population, a per-protocol population, covariate adjustment, or other prespecified analysis choices is not reported in the registry record. Nor are the original statistical analysis plan, a missing-data model, or a multiplicity procedure reported. These gaps matter because the available-case means and unadjusted comparisons answer a narrower question than an analysis incorporating all randomized participants or controlling across multiple tests. The posted results can be interpreted as descriptive group averages and unadjusted contrasts for participants with Week 12 results, while broader inferential claims require methods and details not reported in the registry record.

14. Safety Results

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

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 are participant counts, not rates. The registry reports zero participants with serious adverse events in each group: 67 at risk in the 2% group, 37 in the morning-only 2% group, 34 in the afternoon-only 2% group, 73 in the 1% group, 69 in the 0.3% group, and 71 in the vehicle group. No serious adverse event terms are listed. The deaths field is not reported in the registry record, so it should not be interpreted as a reported zero.

The record also reports participants with other adverse events: 1 in the 2% group, 2 in the morning-only 2% group, 1 in the afternoon-only 2% group, 2 in the 1% group, 3 in the 0.3% group, and 5 in the vehicle group. These counts do not establish that the groups had equal safety, and the registry record does not supply event-level details in the posted summary. Safety denominators differ from the Week 12 outcome group sizes, so they should not be treated as interchangeable populations. The counts are a limited summary of reported adverse-event information, not a complete characterization of risks.

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

The posted primary results show Week 12 mean corneal staining scores from 3.7 in the vehicle group to 4.4 in the 1% suspension group. Each suspension-group mean was numerically higher than the vehicle mean, and higher scores were defined as worse outcomes. The mean differences against vehicle ranged from 0.2 to 0.7. Their confidence intervals all included zero and extended in both directions. These results therefore leave substantial uncertainty about the direction and size of the group differences.

The unadjusted p-values, ranging from 0.231 to 0.795, do not establish a statistically significant difference under the conventional 0.05 threshold. They also do not prove that there is no difference, and the wide confidence intervals do not establish equivalence. The registry does not report a clinically meaningful difference threshold, an equivalence margin, or a multiplicity-adjusted analysis. The results cannot identify a preferred concentration or dosing schedule on the basis of the posted primary outcome alone.

This is a statistical description of the registered outcome data, not medical advice. It does not establish whether BOL-303242-X is beneficial or harmful, and it should not be used to guide an individual treatment decision. The results concern the specified corneal staining score at 12 weeks among randomized participants with Week 12 results, without imputation of missing values. They do not describe unposted outcomes, later outcomes, or participants whose Week 12 results were unavailable. The trial is labeled exploratory, and the registry’s posted results do not provide the full analysis plan or additional secondary outcome findings.

16. Why This Trial Matters Statistically

Statistically, this study is notable for evaluating several concentrations and two schedule-specific versions of the 2% suspension against a common vehicle group. Such a design can address more than one exploratory question in a single trial, but the resulting set of comparisons needs careful interpretation. The registry posts five unadjusted contrasts and does not report a multiplicity procedure. Point estimates and p-values therefore should be read together with their uncertainty, rather than treating any single comparison as a stand-alone verdict.

The primary outcome is continuous and has a defined score range and direction. That makes it possible to describe both group averages and the dispersion of participant scores, while interpreting differences in the original score units. In these results, the mean differences are modest in magnitude relative to the uncertainty intervals, which are broad and include zero. The data consequently illustrate why a point estimate alone is insufficient: its precision determines how narrowly the study can characterize plausible between-group differences.

The available-case endpoint population and lack of imputation are also statistically important. The Week 12 means represent participants with observed Week 12 results, and the record does not explain the missingness or provide sensitivity analyses. This limits assessment of how representative the posted comparisons are of all randomized participants. Finally, the sample-size figures are conditional planning illustrations based on observed effects; they are not a substitute for the unreported original design rationale. Together, these features make the record a useful example of reading exploratory comparisons with attention to endpoint direction, uncertainty, missing observations, and multiplicity.

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 registry reports an exploratory study, but does not provide the original protocol’s sample-size justification, statistical analysis plan, or detailed rationale for the selected outcome analysis. The planning illustrations are based on observed differences and should not be mistaken for the study’s own design targets. The record also does not specify whether the original analysis used covariate adjustment or a multiplicity strategy for the five treatment-versus-vehicle comparisons.

Primary-endpoint results include randomized participants with Week 12 observations, with no imputation for missing Week 12 data. The reasons for missing results and the number missing by group are not reported in the registry record. Without these details or sensitivity analyses, it is not possible to assess from the posted information how missing outcomes may have influenced the group averages. The record does not report a clinically meaningful difference threshold for the corneal staining score.

The posted primary comparisons are unadjusted and all confidence intervals include zero. The uncertainty is substantial, and the results do not demonstrate equivalence or identify a preferred dose or schedule. No secondary outcome results are posted. The record also does not give detailed participant flow or explain the differences between overall enrollment, endpoint counts, and safety denominators. These limitations mean that conclusions should stay focused on the reported Week 12 means and unadjusted contrasts, rather than extending to outcomes or analyses that are not reported in the registry record.

18. Related Tutorials

19. Related Statistical Calculators

20. Sources

• ClinicalTrials.gov: Study to Assess the Safety and Efficacy of BOL-303242-X Ophthalmic Suspension in Dry Eye Syndrome — NCT01163643.
• Registry record last updated 2020-09-25; status last verified 2020-09.
• Results first posted 2020-09-03.
• 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

NCT01163643 is a completed Phase 2 randomized, double-masked, parallel-group, vehicle-controlled, multicenter exploratory study of BOL-303242-X ophthalmic suspension for dry eye syndrome. Enrollment was 356, and the stated dosing period was 12 weeks. The primary outcome was mean corneal staining score at Week 12, on a 0-to-15 scale where higher scores indicated worse outcome.

The registry posts group means and standard deviations and five unadjusted mean-difference comparisons against vehicle. All five confidence intervals include zero. The primary endpoint used randomized participants with Week 12 results and did not impute missing data. No secondary results are posted; details of multiplicity handling, the original sample-size rationale, and the full analysis plan are not reported in the registry record. Serious adverse events were reported for zero participants in each group; death counts are not reported in the registry record.