DE-111 Against Timolol Ophthalmic Solution 0.5%: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for DE-111 Against Timolol Ophthalmic Solution 0.5% (NCT01342094), a registered phase 3 study. The primary outcome is Change From Baseline in Mean Diurnal IOP (Intraocular Pressure) at End of Study.

2. Clinical Question

The brief summary describes a multicenter, randomized, double-masked, parallel-group comparison and says safety was also to be evaluated. However, the record does not state the allocation method, and the arm comparison is flagged as not a like-for-like control comparison. The record also lists triple masking, while the official title refers to a double-masked study. These descriptions do not resolve how assignment or masking operated in practice.

The clinical question is therefore clear at the level of the intended outcome and treatments, but the inferential question cannot be answered from the posted endpoint information. A treatment comparison requires the observed change in each group, or an estimated between-group contrast with an uncertainty measure. Those results are not reported in the registry record. The endpoint description alone cannot show whether the groups differed, how large any difference was, or how precisely it was estimated.

3. Trial Design

This is a completed Phase 3 study of DE-111 ophthalmic solution versus timolol ophthalmic solution 0.5%. The record identifies a parallel model and lists primary open-angle glaucoma and ocular hypertension as the conditions. The enrollment is 166. The recorded start is 2011-05 and primary completion is 2012-09. The sponsor is Santen Pharmaceutical Co., Ltd.

The brief summary describes a multicenter, randomized, double-masked comparison. The official title also says double-masked, whereas the masking field lists triple masking. The record does not explain that difference. More importantly for interpreting a treatment contrast, allocation is not stated, and the listed arms are flagged as not a like-for-like control comparison. The summary's description of randomization therefore does not supply the missing allocation details or resolve the stated concern about comparability. The actual assignment process is not reported in the registry record.

The DE-111 arm description includes DE-111 once daily and placebo twice daily in both eyes. The timolol arm description includes timolol 0.5% twice daily and placebo once daily in both eyes. Thus, the descriptions include placebo dosing alongside each named active treatment. The record lists placebo as an intervention, but does not describe a separate placebo-only arm.

The primary outcome is a continuous measure: change from baseline in mean diurnal intraocular pressure at the end of the study. The stated time points are Week 0 (Baseline) and Week 4 (End of Study). The record identifies one outcome measure and one analysis, but does not report endpoint estimates, variability values, a between-group test, or the analysis population. It also does not report detailed eligibility criteria, the allocation procedure, or the statistical analysis plan. Those gaps limit assessment of how the intended design was implemented and how well the analysis supports a causal comparison.

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: Prior to randomization all participants in the study were receiving Timolol ophthalmic solution 0.5% (one drop at a time, BID).

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.

Population: Subjects who have instilled the investigational drug at least once.

6. Primary Endpoint

The registry lists the primary outcome as Change From Baseline in Mean Diurnal IOP (Intraocular Pressure) at End of Study, measured over Week 0(Baseline) and Week 4(End of Study).

The primary endpoint is change from baseline in mean diurnal intraocular pressure at the end of the study, measured in mmHg. It compares the Week 4 value with the Week 0 baseline value. The record defines mean diurnal pressure as the average of measurements taken at 9:30 before dosing, 11:30, and 17:30. This definition combines several readings across the day into one continuous outcome rather than treating each measurement time as a separate primary endpoint.

A change score expresses how a participant's measured value differs from their own baseline. Comparing change between treatment groups can help distinguish the course of the outcome during the study from differences that were already present at baseline. The endpoint is a mean, so a group-level summary describes average change; it does not show the range of individual responses. The standard deviation, when reported, describes variation among observations and is not itself a measure of uncertainty in the estimated group mean.

Mean diurnal pressure is used in this record to assess the stated pressure-lowering objective. The endpoint definition and measurement schedule do not, by themselves, establish a treatment effect. The registry record does not report the group means, standard deviations, estimated contrast, confidence interval, or p-value for this endpoint. Consequently, the direction, magnitude, and precision of the posted endpoint result are not reported in the registry record.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

What does a mean change represent?

The endpoint is a continuous measure, and the registry record describes it as a mean. In general, a mean summarizes the central level of observed measurements. A change from baseline is a within-person difference between a follow-up value and a baseline value; a group mean change then summarizes those individual changes. It does not imply that every participant changed by the same amount. The record states the endpoint and measurement times, but does not report the group mean changes.

For a continuous outcome, a standard deviation describes how spread out individual observations are around a mean. It is distinct from the standard error, which concerns the precision of an estimated mean or contrast. The endpoint dispersion is identified as standard deviation, but the actual values are not reported in the registry record. Without those values, the observed variability cannot be described from this record.

How should a treatment contrast be read?

A between-group contrast compares the outcome summaries for the treatment groups. Its direction depends on the order in which groups are subtracted and on how the outcome is defined. Because this endpoint is a change in pressure, interpretation also depends on the sign convention used for change. The registry record does not report the numerical contrast or its sign convention. It is therefore not possible to say which group had the greater mean reduction or to quantify a difference.

In general, a confidence interval gives a range of values compatible with the estimate under the statistical model and sampling assumptions. Its width conveys precision: a narrower interval indicates greater precision than a wider interval. A p-value, in general, measures how unusual data at least as inconsistent with a specified null hypothesis would be if that hypothesis and the analysis assumptions held. Neither measure is a measure of clinical importance on its own. The registry record does not report a confidence interval or p-value for the primary endpoint, and the analysis method used for that comparison is not reported in the registry record.

What can be learned from the analysis description?

The registry record lists one outcome measure and one analysis. That count does not reveal the statistical model, covariates, handling of repeated readings, or whether the analysis used change scores or adjusted follow-up values. Those details are not reported in the registry record. The measured mean is based on readings at several times, but the record does not say whether those readings were analyzed only as the defined average or whether other analyses were conducted.

The record's sample-size assumptions describe a planning illustration based on the observed effect, with a two-sided significance level of 0.05, equal allocation, and a normal approximation. The effect to detect is specified as a stated fraction of the observed effect. For outcomes other than time-to-event outcomes, such illustrations are expressed as participants per arm. These are planning assumptions, not evidence that the trial used that design calculation. The registry record does not report the trial's own sample-size justification or its planned effect size. A planning illustration based on an observed effect must not be read as observed power or as a substitute for the result and its uncertainty.

In general, power is a design concept: it concerns the probability that a specified test will reject a null hypothesis under a particular assumed effect and model. It cannot establish whether a result is important, unbiased, or reproducible. Retrospective calculations based on an observed estimate are particularly dependent on that estimate and do not resolve uncertainty in the observed treatment effect. The registry record does not report an original power calculation or design assumptions beyond the planning illustration.

Why does the comparison structure matter?

For a treatment comparison to have a clear interpretation, the assignment process and analysis should support comparability between groups. The summary describes randomization, but allocation is not stated, and the arms are flagged as not a like-for-like control comparison. These descriptions leave uncertainty about how treatment groups were formed and what the comparison can isolate. The arm descriptions identify placebo dosing alongside each active regimen, but do not supply further design detail.

Masking can reduce the influence of expectations on care, measurement, and reporting, depending on who is masked and how. The title calls the study double-masked, while the record lists triple masking. The registry record does not explain who was masked or why the descriptions differ. The labels alone are not enough to assess how masking was implemented or maintained.

In general, over-dispersion occurs when observed variability exceeds what a statistical model assumes. A model that underestimates variability can produce uncertainty estimates that are too narrow. This is a general consideration, not a reported finding about this continuous endpoint. The registry record does not report a model diagnosis or evidence of over-dispersion. More broadly, methods can be judged only when the model, assumptions, outcome estimates, and uncertainty are available; those details are not reported in the registry record.

10. Confidence Intervals for Each Arm

No two-arm comparison is shown for this trial, but each arm's mean can be given with a t-based 95% confidence interval computed from the posted mean, spread and number of participants.

R code and output

arm <- c("DE-111", "Timolol")
n   <- c(82, 84)
m   <- c(-3.2, -1.7)
sp  <- c(2.1, 2.1)
sd  <- sp      # posted standard deviations
for (i in seq_along(n)) {
  se <- sd[i] / sqrt(n[i]); h <- qt(0.975, n[i] - 1) * se
  cat(sprintf("CARM|%s|%d|%.3f|%.3f|%.3f|%.3f\n", arm[i], n[i], m[i], sd[i], m[i] - h, m[i] + h))
}

CARM  DE-111  82  -3.200  2.100  -3.661  -2.739
CARM  Timolol  84  -1.700  2.100  -2.156  -1.244

11. Multiplicity, Missing Data and Analysis Populations

The registry record lists one primary outcome measure and one analysis. It does not report a multiplicity strategy, such as how statistical error would be controlled across multiple endpoints, time points, or analyses. The single listed outcome does not establish that no other analyses were conducted; the analysis plan and any additional analyses are not reported in the registry record.

Missing-data handling is also not reported in the registry record. There is no description of whether participants without a Week 4 measurement were included, excluded, or handled through an imputation or model-based approach. The record does not give the endpoint analysis population, the number with endpoint data, reasons for missingness, or a sensitivity analysis. The adverse-event denominators cannot answer those questions because they describe the safety entries, not the primary endpoint analysis population.

Analysis populations are important because results can depend on who is included and how participants are classified. The registry record does not state whether the primary analysis included participants according to assigned treatment, treatment received, or another rule. Although the brief summary describes randomization, the record does not state the allocation method, and it flags the arms as not a like-for-like control comparison. No further population definition is reported.

These omissions do not show that multiplicity or missing data were mishandled. They mean that the registry record does not give enough information to assess those features of the analysis. The absence of endpoint estimates further prevents checking whether conclusions might depend on analytical choices.

12. 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 posted safety entries list serious adverse events for DE-111 and timolol. For DE-111, 0 serious adverse events are recorded among 82 at risk; for timolol, 0 are recorded among 84 at risk. The record lists 11 other adverse events for DE-111 and 2 for timolol, with the same respective at-risk denominators. These figures are counts as recorded, not an explanation of the events or a complete safety assessment.

The record does not provide serious-event terms; the serious-event terms list is empty. Deaths are recorded as null, so deaths are not reported in the registry record; null should not be interpreted as a reported count of zero. The record also does not give event descriptions, severity grades for the other events, exposure duration, event timing, or an analysis of whether events were considered related to treatment.

Counts alone do not describe the uncertainty around an event rate or establish a causal difference between regimens. The record does not report a statistical comparison of these safety entries. They should therefore be read as descriptive registry counts, separate from the unreported primary endpoint results, and not as a definitive assessment of comparative safety.

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

The registry record establishes that the study was intended to compare DE-111 ophthalmic solution with timolol ophthalmic solution 0.5% in patients with primary open-angle glaucoma or ocular hypertension. It specifies a continuous primary endpoint: change from baseline in mean diurnal intraocular pressure at Week 4, using an average of readings at 9:30 before dosing, 11:30, and 17:30. It also provides dosing descriptions and selected adverse-event counts.

The record does not report the primary endpoint estimates or the statistical comparison. As a result, it cannot show the observed direction or size of a difference, nor how precisely any difference was estimated. It cannot establish that one regimen was superior, equivalent, or similar to the other. The stated objective of testing superiority is a study aim, not an outcome.

The completed status and Phase 3 designation do not fill in the missing outcome results. Nor does the enrollment figure establish how many participants contributed to the primary analysis. The analysis population, missing-data approach, statistical model, and allocation details are not reported in the registry record. The summary describes randomization, but allocation is not stated, and the comparison is flagged as not a like-for-like control comparison.

The safety entries show no serious adverse events recorded for either group and list other adverse-event counts of 11 for DE-111 and 2 for timolol. Deaths are not reported in the registry record. These entries do not provide event-level detail or a statistical comparison and cannot be used to infer a primary endpoint effect.

Accordingly, the record can describe what investigators intended to measure and some reported safety counts, but not the study's primary efficacy result. A conclusion about the comparative outcome would require endpoint estimates and their uncertainty, along with enough information about analysis and group assignment to judge the comparison.

14. Why This Trial Matters Statistically

This study illustrates why a well-defined endpoint is not the same as a reported result. The registry record gives a specific continuous outcome, the time points, and the schedule used to calculate mean diurnal pressure. Those details make the target measurement understandable. But without group results and an estimated contrast, readers cannot assess the observed treatment difference or its precision.

It also highlights the importance of design transparency. A summary describing randomization and masking may appear to answer questions about comparison quality, but the record does not state the allocation method, flags the arms as not a like-for-like control comparison, and uses different masking descriptions across its entries. These gaps limit assessment of whether the groups can be interpreted as a direct treatment comparison.

The safety entries show why denominators and event definitions matter. Counts are meaningful only in relation to the population and observation context to which they apply. The registry record lists at-risk denominators and separate serious and other event counts, but does not provide event terms or deaths. Those data should not be stretched into a broad safety conclusion.

Statistically, the record separates the questions of measurement, estimation, and interpretation. The outcome definition addresses measurement. An estimated between-group contrast would address the observed comparison, while an uncertainty measure would show its precision. Neither is reported. A stated superiority objective and a completed study cannot substitute for those estimates. The distinction is essential when reading registry information: a precise question can coexist with an incomplete account of the evidence needed to answer it.

15. 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 most consequential limitation for statistical interpretation is that the registry record does not report the primary endpoint results. Group changes, standard deviations, a between-group estimate, confidence interval, and p-value are not reported in the registry record. The treatment comparison therefore cannot be evaluated for direction, magnitude, or precision.

Important design and analysis details are also absent. The record does not state the allocation method, despite the summary describing randomization, and it flags the arms as not a like-for-like control comparison. The title describes the study as double-masked, while the masking field lists triple masking; the difference is not explained. The statistical model, analysis population, missing-data approach, and multiplicity strategy are not reported in the registry record.

The endpoint description gives the measurement schedule and definition of the diurnal mean, but does not report how many participants contributed measurements or how variability was handled in the analysis. Enrollment and safety denominators cannot be assumed to describe the endpoint analysis population. Reasons for missing measurements and sensitivity analyses are not reported in the registry record.

The safety information is limited to aggregate counts. Serious-event terms are not listed, deaths are not reported in the registry record, and the other adverse-event entries lack descriptions and contextual details. These limitations do not establish that an analysis was inadequate or that events were absent; they identify what cannot be checked from this record. The sample-size assumptions are described as a planning illustration rather than the trial's own design justification, which is not reported in the registry record.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: DE-111 Against Timolol Ophthalmic Solution 0.5% — NCT01342094.
• Registry record last updated 2015-07-10; status last verified 2015-06.
• Results first posted 2015-05-15.
• 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.

19. Record Summary

NCT01342094 is a completed Phase 3, parallel-model study sponsored by Santen Pharmaceutical Co., Ltd. The recorded start is 2011-05, and primary completion is 2012-09. The enrollment is 166. The conditions are primary open-angle glaucoma and ocular hypertension.

The stated comparison is DE-111 ophthalmic solution versus timolol ophthalmic solution 0.5%, with placebo dosing described alongside each active regimen. The primary endpoint is change from baseline in mean diurnal intraocular pressure at Week 4, calculated from readings at 9:30 before dosing, 11:30, and 17:30. The primary endpoint result is not reported in the registry record.

The summary describes randomization, but allocation is not stated; the comparison is flagged as not a like-for-like control comparison. Masking is described inconsistently in the record. Safety entries list 0 serious adverse events for each group, other adverse-event counts of 11 for DE-111 and 2 for timolol, and deaths are not reported in the registry record.