Safety and Efficacy of Triple Combination Therapy in Patients With Primary Open-Angle Glaucoma or Ocular Hypertension: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Safety and Efficacy of Triple Combination Therapy in Patients With Primary Open-Angle Glaucoma or Ocular Hypertension (NCT01241240), a randomized phase 3 study. The primary outcome is Change From Baseline in Mean Worse Eye Intraocular Pressure (IOP) at Week 12.

2. Clinical Question

IOP is the pressure of fluid inside the eye. For the endpoint, the worse eye was identified using baseline IOP results, and the Week 12 mean worse-eye IOP used measurements at hours 0 and 2. The endpoint description defines a negative change from baseline as improvement. That definition clarifies the sign of a reported change, but it does not establish that either group had a particular change or that the groups differed.

3. Trial Design

The registry record identifies this as a phase 3 randomized, parallel-group trial with triple masking. It was sponsored by Allergan and is listed as completed. The enrollment entry is 192. The study began in 2011-03, and primary completion is listed as 2013-09. These record details describe the trial’s administrative and design features; they do not substitute for outcome data.

The two interventions were bimatoprost/brimonidine tartrate/timolol ophthalmic solution and fixed-combination 0.2% brimonidine tartrate/0.5% timolol ophthalmic solution. Both arm descriptions specify administration to each eye twice daily for 12 weeks. The record’s brief summary frames the comparison as an evaluation of safety and efficacy in people with primary open-angle glaucoma or ocular hypertension.

Random allocation means treatment assignment was determined through a chance-based process rather than chosen solely by participants or investigators. A parallel design means the assigned groups are compared over the trial rather than participants crossing from one assigned treatment to the other. Masking is intended, in general, to reduce the influence of treatment knowledge on trial conduct or assessment. The registry record identifies triple masking but does not report which roles were masked or give further details about how masking was maintained.

The primary outcome concerns change in mean worse-eye IOP from baseline to Week 12. The record also lists secondary outcomes for change from baseline in mean worse-eye IOP and mean worse-eye IOP. It lists 3 outcome measures, but the available record does not provide the corresponding outcome values or a single primary comparison. The trial design therefore establishes what was compared and what was intended to be measured, while leaving the treatment contrast itself unquantified 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

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: Participants from the modified Intent-to-treat (mITT) population, that included all randomized participants who had at least 1 post-baseline IOP measurement, with data available for analysis at the given time-point.

5. Baseline Characteristics

The table reproduces the baseline characteristics posted in the registry, which describe the participants analysed at baseline and help show whether the randomized groups were comparable.

6. Primary Endpoint

The registry lists the primary outcome as Change From Baseline in Mean Worse Eye Intraocular Pressure (IOP) at Week 12, measured over Baseline, Week 12.

The primary endpoint is change from baseline in mean worse-eye intraocular pressure at Week 12, expressed in mmHg. IOP measures fluid pressure inside the eye. The record states that each eye’s IOP was based on the average of 2 measurements, or, if a third measurement was required, the median of the 3 measurements. The worse eye was selected using baseline IOP results. At Week 12, mean worse-eye IOP was the average of measurements taken at hours 0 and 2.

Change from baseline expresses the follow-up measurement relative to the participant’s starting measurement. The endpoint description specifies that a negative change indicates improvement. In general, a change score can make the direction of movement easier to interpret, while using the baseline-defined worse eye gives a consistent basis for identifying the eye evaluated at follow-up. This definition does not show the observed change; no group means, standard deviations, or treatment contrast for the primary endpoint are reported in the registry record.

IOP is used as a measurable trial outcome because it captures a pressure-related feature of the eye. The endpoint is a continuous measure, so statistical summaries commonly describe its average and variability. The registry record identifies the mean as the parameter and standard deviation as the dispersion measure, but it does not report their primary-outcome values.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The primary endpoint is continuous: it measures change in IOP in mmHg, rather than assigning each participant to a category. The registry identifies the parameter as a mean and the dispersion measure as a standard deviation. A mean describes the average value in a group. A standard deviation describes how spread out participant values are around that average. They answer different questions: the mean describes the group’s central level, while the standard deviation describes individual variability.

What would a treatment contrast represent?

In a randomized parallel-group trial, the primary comparison would ordinarily summarize the difference in endpoint values between the assigned groups. For a change-from-baseline endpoint, the comparison needs to make clear whether it is comparing group mean changes or another specified estimand. The registry record does not report a single primary comparison or the group values needed to interpret one. It is therefore not possible to state an estimated treatment difference or its direction.

Randomization supports comparisons between groups by making assignment chance-based. It does not guarantee that every measured characteristic will be identical across groups, nor does it itself provide an outcome estimate. A valid interpretation also depends on what participants were included in the analysis, how missing measurements were handled, and how the endpoint and comparison were defined. The record describes the mITT population, but does not report an analysis method for missing outcome data or a detailed statistical analysis plan.

How should uncertainty be understood?

General statistical explanation: a confidence interval expresses the range of effect values compatible with the data and the method used, subject to its assumptions. A narrower interval indicates greater precision than a wider interval, but does not by itself establish clinical importance. A p-value addresses how unusual the observed data would be under a specified null hypothesis and model; it does not measure the size or importance of an effect. The registry record does not report a primary-outcome confidence interval or p-value, so neither precision nor statistical evidence for a primary contrast can be assessed.

The endpoint is based on repeated IOP measurements. As described in the record, each eye’s value used an average of 2 measurements, or the median of 3 if a third measurement was required. At Week 12, the worse-eye mean used measurements at hours 0 and 2. Averaging repeated readings can represent the measured level across those readings, while a median can reduce the influence of an unusually high or low reading when a third reading is taken. This is a general explanation of these summaries, not evidence about the observed data in this trial.

Why does the worse-eye definition matter?

The record says the worse eye was chosen based on baseline IOP results. Defining the eye at baseline makes the endpoint’s eye selection independent of the Week 12 value. In general, selecting an eye based on follow-up results could make comparisons harder to interpret because the selected eye would depend on the outcome being assessed. The registry gives the baseline rule, but does not report participant-level measurements or how ties, if any, were handled.

The endpoint description also specifies that a negative change from baseline indicates improvement. This defines the sign convention and helps avoid confusing a decrease in pressure with an increase. It does not tell readers whether the observed average change was negative, whether one group changed more than the other, or how variable changes were.

What can be inferred from the sample-size approach?

The record describes a planning illustration based on the observed effect, with a two-sided significance level of 0.05, equal allocation, and a normal approximation. It says the target effect is a stated fraction of the observed effect. Such planning calculations illustrate how a hypothetical future study’s required number of participants per arm might vary with the effect targeted and the assumed analysis. They are not observed power for this completed trial and do not establish that the trial was adequately powered. No numerical planning outputs or design justification are reported in the registry record.

General statistical explanation: over-dispersion occurs when observed variation is greater than a model assumes. If a model underestimates variability, its uncertainty estimates can be too small and its confidence intervals too narrow. This concept matters when selecting models for data that do not follow the model’s variance assumptions. The primary outcome is described as a continuous mean with standard deviation; the registry record does not report that over-dispersion was identified or that a particular adjustment was used.

Interpretation also depends on multiplicity. If several outcomes, time points, or comparisons are tested, the chance of at least one apparently unusual result can increase unless the analysis accounts for those tests. The record notes that the primary outcome has several categories or time points and is not reduced to one comparison. It does not report a multiplicity adjustment or a hierarchy of tests. Accordingly, no adjustment method or confirmatory status should be inferred.

10. Multiplicity, Missing Data and Analysis Populations

The primary outcome is described as having several categories or time points, and the registry record does not reduce it to one comparison. That matters because an endpoint measured at multiple time points or in multiple forms can generate multiple possible comparisons. General statistical explanation: when many hypotheses are tested, interpreting each result as if it were the only test can increase the chance of a false-positive finding. A prespecified testing hierarchy or multiplicity adjustment can address that concern, but the relevant plan is not reported in the registry record.

The record lists 3 outcome measures, including the primary endpoint and secondary outcomes for change from baseline in mean worse-eye IOP and mean worse-eye IOP. It does not report a statistical analysis plan explaining how those measures or time points were prioritized. The number of analyses listed is 0, but that registry entry does not establish whether analyses were performed elsewhere. A multiplicity strategy is not reported in the registry record.

For the primary analysis population, the record specifies the mITT definition: randomized participants with at least 1 post-baseline IOP measurement and data available for analysis at the given time-point. This is more specific than simply using everyone enrolled, because participants without the required post-baseline data would not meet the stated definition. The number included at each time-point and the reasons for unavailable data are not reported in the registry record.

The record does not describe an imputation method, a sensitivity analysis for missing measurements, or assumptions about why data were missing. General statistical explanation: missing-data methods can yield different results depending on assumptions about the relationship between missingness and the unobserved outcome. Without the method and supporting details, it is not possible to assess that sensitivity for this trial. The available record therefore defines an analysis population but does not provide enough information to evaluate missing-data handling or multiplicity control.

11. 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 serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: bradycardia (1.1%), pneumothorax (1.1%), pyomyositis (1.1%), pituitary tumour (1.1%).

The registry lists serious adverse events separately from other adverse events. In the Triple Combination Therapy group, the serious-adverse-event entry lists 3 affected participants among 93 at risk; in the Combigan® group, it lists 0 among 98 at risk. For other adverse events, the corresponding entries are 57 among 93 at risk and 25 among 98 at risk. These are the counts and at-risk group sizes recorded; they are not a comparison adjusted for follow-up time or other factors.

The listed serious-event terms are Bradycardia, Pneumothorax, Pyomyositis, and Pituitary tumour, each reported as 1.1%. The record does not establish from these term entries whether events were related to treatment. A term-level percentage also should not be treated as an overall serious-event percentage or added to another term; the record does not provide enough detail about overlap to do that.

Deaths are not reported in the registry record. The serious and other adverse-event figures describe events recorded for the trial groups, but do not by themselves establish causation, comparative risk over time, or the completeness of event ascertainment. They should be read as descriptive safety information rather than as a standalone determination of treatment safety.

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

The record allows readers to understand the trial’s central comparison: randomized participants with primary open-angle glaucoma or ocular hypertension received either bimatoprost/brimonidine tartrate/timolol ophthalmic solution or fixed-combination brimonidine tartrate/timolol ophthalmic solution. The primary endpoint was change from baseline in mean worse-eye IOP at Week 12. The endpoint definition identifies how measurements were summarized and states that a negative change indicates improvement.

What the record does not establish is the size or direction of the primary treatment contrast. It contains no primary-outcome group means, mean changes, standard deviations, confidence interval, or p-value. It therefore cannot show whether the groups differed, how precisely a difference was estimated, or whether any difference was statistically or clinically important. The missing numerical comparison should not be interpreted as evidence of no difference.

The adverse-event entries give descriptive counts for serious and other events in each group. They do not establish that treatment caused an event, nor do they provide a complete basis for comparing safety across groups. The record does not report deaths, and that absence from the record should not be translated into a claim that no deaths occurred.

General statistical explanation: trial results are most informative when an effect estimate is read together with its uncertainty, analysis population, outcome definition, and missing-data approach. Here, the endpoint and the mITT population are described, but the primary effect estimate, uncertainty, and missing-data methods are not reported in the registry record. Consequently, the record supports a description of what was planned and how the endpoint was defined, along with selected safety counts, but it does not support a conclusion about comparative efficacy.

13. Why This Trial Matters Statistically

This trial illustrates why a clearly defined endpoint and a reported treatment contrast are both necessary for statistical interpretation. The record specifies a continuous IOP outcome, a baseline rule for selecting the worse eye, the Week 12 measurement times, and the sign convention for change. Those details help readers understand what an eventual estimate would mean and how its direction should be read.

At the same time, endpoint detail cannot replace the numerical results. Without group estimates and uncertainty, readers cannot judge the magnitude or precision of the primary comparison. The registry entry notes that the primary outcome has several categories or time points and is not reduced to one comparison. That makes transparent reporting of the intended contrast and any multiplicity approach especially relevant; those details are not reported in the registry record.

The trial also illustrates the distinction between enrollment and the analysis population. The enrollment entry is 192, while the primary endpoint uses an mITT definition requiring post-baseline IOP data available at the relevant time-point. Because the number analyzed and the handling of missing measurements are not reported, enrollment alone does not describe the information contributing to the primary endpoint.

Finally, the record separates serious from other adverse-event counts, which is useful for organizing safety information. These counts remain descriptive without further information on event timing, relatedness, follow-up, and analysis. For clinical researchers and biostatisticians, the main statistical lesson is that design and measurement definitions are important, but interpretable evidence also requires a prespecified comparison, results, uncertainty, and transparent accounting of analyzed and missing data.

14. 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 important limitation of the available registry record is the absence of a single numerical primary-outcome comparison. Group-specific endpoint values, variability estimates, and uncertainty measures are not reported. The record’s note that the primary outcome has several categories or time points and is not reduced to one comparison further limits interpretation: the intended contrast among those possibilities is not identified in the available information.

The primary analysis population is defined as mITT participants with at least 1 post-baseline IOP measurement and data available at the given time-point. However, the number analyzed at each time-point, participant flow, and reasons for missing measurements are not reported in the registry record. The record also does not describe imputation, sensitivity analyses, or assumptions about missingness. It is therefore not possible to evaluate how incomplete data might affect the endpoint comparison.

Although the registry identifies a randomized, triple-masked, parallel design, it does not report which parties were masked, how the allocation sequence was generated or concealed, or a detailed statistical analysis plan. It does not report a multiplicity strategy for the listed outcome measures and time points. These omissions leave uncertainty about the planned analysis and interpretation framework; they do not prove that such procedures were absent from study conduct.

The adverse-event information is limited to listed counts, at-risk group sizes, and selected serious-event terms. Deaths are not reported in the registry record. Details about event timing, duration, relatedness, and completeness are not reported, limiting comparative safety interpretation. The record also provides no numerical sample-size illustration outputs or justification for the trial’s design enrollment. These limitations concern the information available in the registry record and should not be taken as proof that unreported analyses or procedures did not occur.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: Safety and Efficacy of Triple Combination Therapy in Patients With Primary Open-Angle Glaucoma or Ocular Hypertension — NCT01241240.
• Registry record last updated 2014-09-10; status last verified 2014-09.
• Results first posted 2014-09-10.
• 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.

18. Record Summary

NCT01241240 is listed as a completed phase 3 randomized, triple-masked, parallel-group trial sponsored by Allergan. The enrollment entry is 192. The trial compared bimatoprost/brimonidine tartrate/timolol ophthalmic solution with fixed-combination 0.2% brimonidine tartrate/0.5% timolol ophthalmic solution in participants with primary open-angle glaucoma or ocular hypertension. Both arm descriptions specify one drop in each eye, twice daily for 12 weeks.

The primary endpoint was change from baseline in mean worse-eye IOP at Week 12, measured in mmHg. The registry describes how IOP readings and the worse eye were defined and states that a negative change indicates improvement. It defines the mITT population but does not report the analyzed number or a single primary-outcome comparison. Serious and other adverse-event counts are listed by group, while deaths are not reported in the registry record. Consequently, the record describes the trial design and endpoint but does not provide a numerical basis for interpreting comparative primary efficacy.