Comparing the Safety and Efficacy of BOL-303259-X Ophthalmic Solution With Timolol Maleate Ophthalmic Solution in Subjects With Open-Angle Glaucoma or Ocular Hypertension: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Comparing the Safety and Efficacy of BOL-303259-X Ophthalmic Solution With Timolol Maleate Ophthalmic Solution in Subjects With Open-Angle Glaucoma or Ocular Hypertension (NCT01749930), a randomized phase 3 study. The primary outcome is Mean IOP.

2. Clinical Question

Intraocular pressure, abbreviated IOP, is the measurement named in the primary outcome. The registry describes mean IOP at specified visits and times, while the trial objective frames the comparison in terms of IOP reduction. Numerical estimates of mean IOP or its reduction for either treatment, along with a direct between-group estimate, are not reported in the registry record. Therefore, the record does not establish the size or precision of the observed treatment contrast.

The registry also lists secondary outcomes based on whether IOP is at most 18 mm Hg and whether IOP reduction is at least 25%. These thresholds describe additional questions about pressure levels and response categories; they are not substitutes for the primary mean-based comparison. Numerical results for these secondary outcomes are not reported in the registry record.

3. Trial Design

This was a randomized, multicenter, double-masked, parallel-group Phase 3 study. The registry records enrollment of 420 and a completed status. The recorded start was 2013-01, and primary completion was 2015-05. The sponsor was Bausch & Lomb Incorporated.

During the masked comparison, participants assigned to BOL-303259-X received the ophthalmic solution once daily in the evening and vehicle once daily in the morning. Participants assigned to timolol received timolol maleate ophthalmic solution 0.5% twice daily. Both regimens were administered into the study eye or eyes for 3 months, through Visit 6. The registry describes the study as randomized, but the method used to generate or conceal the allocation sequence is not reported in the registry record.

After Visit 6, the protocol description calls for an open-label safety phase lasting an additional 3 months, during which all participants receive BOL-303259-X once daily. Because this phase is open label and no longer maintains the original masked comparison, its safety observations should be distinguished from the randomized, masked treatment period. The registry lists a separate BOL-303259-X Safety Extension Phase in the adverse-event information.

The registry describes mean IOP measurements at 8 AM, 12 PM, and 4 PM at Visit 4 (Week 2), Visit 5 (Week 6), and Visit 6 (Month 3). It does not identify a single time point as the sole primary comparison in the material recorded for this outcome. The sample-size justification, detailed analysis plan, and operational details of the multicenter conduct 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: Intent-to-treat population with LOCF

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: Intent-to-treat population. Of the 420 subjects randomized, 5 subjects did not receive any instillation of study medication. The safety population consisted of 415 subjects, whereas the ITT population consisted of 414 subjects.

6. Primary Endpoint

The registry lists the primary outcome as Mean IOP, measured over 8 AM, 12 PM, and 4 PM at Visit 4 (Week 2), Visit 5 (Week 6), and Visit 6 (Month 3).

The primary outcome is mean intraocular pressure in the study eye, measured in mm Hg. IOP is the clinical measurement named in the trial’s efficacy objective: the study aims to compare mean IOP reduction after 3 months of treatment. The registry describes the outcome as a least-squares mean, with standard deviation as the dispersion measure, in the intent-to-treat population with LOCF.

Measurements are specified for 8 AM, 12 PM, and 4 PM at Visit 4 (Week 2), Visit 5 (Week 6), and Visit 6 (Month 3). Repeated measurements can describe pressure across different times of day and visits rather than relying on a single recorded value. However, the registry record does not report the numerical means, standard deviations, changes from baseline, or between-treatment contrasts for these measurements. It also does not state which time-specific contrast governs the primary conclusion.

In general, a mean summarizes the average measurement in a group, while a standard deviation describes the spread of individual measurements around that average. A least-squares mean is generally a model-based average, potentially adjusted for factors included in the model. The model and adjustment variables are not reported in the registry record, so the exact meaning of adjustment for this trial cannot be specified beyond the stated least-squares mean designation.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

What does randomization contribute?

In general, randomization assigns participants to treatment groups using a chance-based process. Its statistical purpose is to reduce systematic differences in both measured and unmeasured characteristics at the start of a comparison. This can make a between-group contrast more interpretable as an effect of assignment, provided the trial is analyzed appropriately and follow-up is sufficiently complete. The registry identifies the study as randomized, but the sequence-generation and allocation-concealment methods are not reported in the registry record. Randomization also does not guarantee identical groups on every characteristic, especially in a finite study.

What does double masking mean for interpretation?

In general, masking limits knowledge of assigned treatment among specified groups involved in a study, which may reduce expectation-related influences on assessments or reporting. The registry describes this study as double-masked but does not specify which roles were masked or how masking was maintained. The description applies to the comparative treatment phase; the later safety phase is explicitly open label. Results from that open-label phase need to be interpreted separately because knowledge of treatment can influence reporting and assessment.

How should the least-squares mean be understood?

A least-squares mean is generally a model-based estimate of a group average. Depending on the model, it can represent an average adjusted for specified covariates or other features of the analysis. The registry names least-squares mean as the outcome parameter and standard deviation as the dispersion measure. It does not report the model formula, covariates, covariance structure, or the method used to handle repeated measurements. Consequently, readers cannot determine from the registry record how the reported statistical procedure, if any, accounted for the scheduled visits and times.

Standard deviation describes the spread of measurements around a mean. It is not the same as a confidence interval, which expresses uncertainty about an estimate. A group mean and its standard deviation alone would not fully convey uncertainty in a treatment contrast; interpretation of a comparison generally also requires an estimate of the contrast and an uncertainty measure. Those numerical efficacy results are not reported in the registry record.

What is the non-inferiority strategy?

In general, a non-inferiority trial asks whether the new treatment is no worse than a comparator by more than a prespecified margin. The margin must be defined before interpreting the result, and the direction of the contrast must be clear. The registry states that the primary objective is to demonstrate non-inferiority for mean IOP reduction after 3 months, followed by a superiority assessment if non-inferiority is determined. It does not report the margin, the exact contrast definition, the test procedure, or the result. The objective therefore describes the intended question, not its answer.

For superiority, a statistical analysis generally assesses whether the data are inconsistent with no treatment difference under a specified model and testing procedure. In this trial, superiority is explicitly conditional on the non-inferiority determination. The registry does not report whether that condition was met or provide a superiority estimate, interval, or test result. No conclusion about either objective can be drawn from the stated aim alone.

Why do repeated measurements matter?

The primary outcome schedule includes 8 AM, 12 PM, and 4 PM measurements at Visit 4 (Week 2), Visit 5 (Week 6), and Visit 6 (Month 3). In general, repeated measurements may be correlated because readings from the same participant are related. An analysis that uses multiple observations needs to address that dependence or define which observation or summary is used. The registry describes the measurement schedule but does not report the model or the way repeated readings were combined or compared. It also does not report a single numerical primary contrast that resolves the multiple time-specific measurements.

What does LOCF imply?

The endpoint population is described as intent-to-treat with LOCF. In general, intent-to-treat analysis aims to retain participants in the groups to which they were randomized, regardless of later treatment adherence, subject to the precise analysis definition. LOCF, or last observation carried forward, fills a later missing measurement with that participant’s most recent observed measurement. This can make a dataset appear complete, but it relies on an assumption that the carried-forward value is a reasonable stand-in for the unobserved value. If the underlying measurement changes over time, that assumption may not hold. The registry does not report how many observations were missing, why they were missing, or whether additional missing-data analyses were conducted.

How should the planning assumptions be read?

The registry includes a sample-size planning illustration described as a recalculation from the observed effect, not the trial’s own design. Its stated 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 a stated fraction of the observed effect. These are planning assumptions, not observed trial outcomes and not observed power. The registry record does not report the trial’s own sample-size justification or the numerical outputs of the planning illustration in the registry record recorded for this analysis. For non-time-to-event outcomes, any such planning result is expressed as participants per arm for 80% power or another stated power level, rather than as a count of events; no numerical planning result is reported.

General statistical interpretation also depends on prespecification: which endpoint is primary, how multiple comparisons are controlled, how participants are analyzed, and how missing observations are handled. The registry provides some endpoint and population descriptions, but it does not report the complete analysis plan. The absence of those details limits evaluation of how closely any eventual result would answer the stated objectives.

10. Multiplicity, Missing Data and Analysis Populations

The outcome schedule contains repeated mean IOP measurements at 8 AM, 12 PM, and 4 PM across Visit 4 (Week 2), Visit 5 (Week 6), and Visit 6 (Month 3). The registry also lists two secondary threshold outcomes: IOP at most 18 mm Hg and IOP reduction of at least 25%. It records four outcome measures and four analyses, but does not describe how those analyses relate to the primary objective or how multiplicity is addressed. A detailed statistical analysis plan, including any adjustment or hierarchy beyond the stated conditional superiority objective, is not reported in the registry record.

In general, testing multiple outcomes or time points can increase the chance of obtaining an apparently notable result by chance if each is interpreted independently. A prespecified testing hierarchy or adjustment can help define how evidence is evaluated. The registry’s description that superiority is assessed if non-inferiority is determined gives an order for those objectives, but it does not provide enough detail to establish the complete multiplicity strategy across the repeated measurements and secondary outcomes.

The primary endpoint population is described as intent-to-treat with LOCF. In general, LOCF carries the most recent observed measurement forward to replace a later missing value. This is an imputation assumption, not an observed measurement, and it can affect estimates when measurements would otherwise change over time. The registry record does not report the amount or pattern of missing data, reasons for missingness, adherence information, or sensitivity analyses evaluating the LOCF assumption. It also does not report a separate analysis population definition or the number of participants included in each endpoint analysis. These omissions limit assessment of how missing observations and analysis-population choices may have influenced the results.

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 3% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: fall (0.7%), left shoulder subluxation of acromioclavicular joint (0.4%), scapular fracture (0.4%), coronary artery disease (0.4%), cholelethiasis (0.4%).

During the BOL-303259-X group’s listed period, the registry reports 4 participants with serious adverse events among 279 at risk, and 50 affected by other adverse events among 279 at risk. In the Timolol group, it reports 0 participants with serious adverse events among 136 at risk, and 12 affected by other adverse events among 136 at risk. For the BOL-303259-X Safety Extension Phase, it reports 2 participants with serious adverse events among 384 at risk, and 32 affected by other adverse events among 384 at risk. These are descriptive counts from the registry record, not adjusted comparisons.

The record lists serious-event terms including Fall at 0.7%, left shoulder subluxation of acromioclavicular joint at 0.4%, Scapular fracture at 0.4%, Coronary artery disease at 0.4%, Cholelethiasis at 0.4%, and head injury at 0.4%. The denominator and the method used to select these terms are not reported in the registry record. Death counts are not reported in the registry record.

In general, adverse-event counts do not by themselves establish that treatment caused an event or show whether groups differ statistically. The extension phase is open label and should not be treated as a continuation of the masked randomized comparison. Differences in exposure, follow-up, and ascertainment are not detailed in the registry record, so the counts should be read as reported safety observations rather than as a causal or comparative risk estimate.

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

The registry describes a randomized, double-masked comparison of BOL-303259-X once daily and timolol maleate 0.5% twice daily in participants with open-angle glaucoma or ocular hypertension. Its primary objective concerns non-inferiority in mean IOP reduction after 3 months, with superiority to be assessed if non-inferiority is determined. That design and objective define the question the trial intended to address.

The registry record does not report the numerical primary outcome estimates or the information needed to assess their precision. Without the treatment contrast, confidence interval, non-inferiority margin, and analysis result, the recorded objective cannot be translated into a conclusion about whether the non-inferiority criterion was met. The record likewise does not report numerical results for the secondary threshold outcomes. It is therefore not possible to characterize the magnitude or statistical uncertainty of the efficacy findings from the information recorded.

In general, a statistically interpretable result combines an estimate with an uncertainty measure and a clearly defined analysis. A result may be more or less compatible with a specified criterion depending on both the estimate and its precision. The design features of randomization and masking support the intended comparison, but they do not supply missing outcome values or resolve unreported methods. Nor does an enrollment figure by itself indicate how many participants contributed usable measurements to a particular analysis.

The safety entries have a different scope from the efficacy objective. They report counts of participants affected in the listed groups and selected serious-event terms, but do not provide a causal assessment or a complete comparative safety analysis. The open-label extension also has a different interpretation from the randomized masked phase. These distinctions are important when describing what the record establishes and what remains uncertain.

Accordingly, the trial record supports a description of the design, endpoint schedule, stated analysis population, objectives, and reported adverse-event counts. It does not support a conclusion about the direction, size, or certainty of the primary efficacy contrast. The distinction is between a study designed to test a clinical question and the numerical evidence needed to judge its result; those efficacy results are not reported in the registry record.

13. Why This Trial Matters Statistically

This trial is statistically informative as an example of a non-inferiority question paired with a conditional superiority objective. Such a sequence requires clear definitions of the treatment contrast, non-inferiority margin, and decision criteria. The registry states the intended order of the objectives, but the margin and numerical analysis results are not reported in the registry record. The design description alone cannot show whether the planned evidentiary criteria were satisfied.

The endpoint also illustrates the difference between naming a measure and fully specifying its analysis. Mean IOP is reported as a least-squares mean, with measurements scheduled at multiple times of day and visits. Repeated measurements can be correlated, and the way they are modeled or summarized affects interpretation. The registry record does not report the model details or the numerical contrasts for those scheduled measurements. That makes it difficult to identify exactly which estimate would answer the primary question.

Missing-data handling matters because the endpoint population uses LOCF. In general, an imputed value is not an observed value, and the assumption behind carrying a previous measurement forward can influence conclusions. Without information on missingness patterns or sensitivity analyses, readers cannot judge how robust the analysis is to that assumption. The record also distinguishes the masked comparison from an open-label safety phase, illustrating why study phases with different masking and treatment assignments should not be collapsed into a single comparison.

Finally, the registry separates the stated efficacy aims from the available numerical evidence. It records trial enrollment and safety counts, but not the primary efficacy estimates or their uncertainty. This makes the study useful for understanding how design, endpoint definition, analysis populations, multiplicity, and missing data shape the interpretation of a clinical-trial record, while leaving the central efficacy conclusion unresolved by the information recorded.

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 principal limitation for statistical interpretation is that numerical primary efficacy results are not reported in the registry record. Mean IOP estimates, treatment contrasts, uncertainty intervals, and test results are not available in the registry record recorded for this analysis. The non-inferiority margin is also not reported, so the decision criterion cannot be evaluated. Numerical findings for the listed secondary outcomes are not reported either.

The outcome is described across multiple visits and times of day, but the registry record does not identify a single governing contrast or explain the model used to handle repeated measurements. Although the measure is described as a least-squares mean, adjustment variables and other model details are not reported. This limits clarity about the estimand and how the reported endpoint would map to the trial objective.

The intent-to-treat population with LOCF is specified, but the registry record does not report missing-data counts, reasons for missingness, adherence, or sensitivity analyses. It also does not report endpoint-specific analysis counts. As a result, the extent to which missing observations or the LOCF assumption could affect interpretation cannot be assessed.

The multiplicity strategy is not reported in sufficient detail to determine how the repeated time points, four outcome measures, and four analyses were handled. The registry describes superiority as conditional on non-inferiority, but does not provide the full testing plan. The sample-size justification for the trial is not reported; the separate planning illustration is not a substitute for it.

Safety information is presented as affected counts and selected event terms, without a reported comparative analysis or full details on exposure and event ascertainment. The open-label extension is a distinct phase, and its counts should not be read as a randomized contrast. These limitations do not invalidate the design description, but they restrict conclusions that can be drawn from the registry record.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: Comparing the Safety and Efficacy of BOL-303259-X Ophthalmic Solution With Timolol Maleate Ophthalmic Solution in Subjects With Open-Angle Glaucoma or Ocular Hypertension — NCT01749930.
• Registry record last updated 2018-11-21; status last verified 2018-08.
• Results first posted 2018-11-21.
• 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

NCT01749930 is a completed Phase 3 randomized, multicenter, double-masked, parallel-group study sponsored by Bausch & Lomb Incorporated. The registry records enrollment of 420, a start date of 2013-01, and primary completion in 2015-05. Participants with open-angle glaucoma or ocular hypertension were assigned to BOL-303259-X once daily or timolol maleate 0.5% twice daily during the 3-month masked comparison.

The primary objective was non-inferiority for mean IOP reduction, with superiority described as conditional on non-inferiority. The endpoint schedule includes measurements at 8 AM, 12 PM, and 4 PM across Visit 4 (Week 2), Visit 5 (Week 6), and Visit 6 (Month 3), in an intent-to-treat population with LOCF. An open-label safety phase is described for an additional 3 months with BOL-303259-X once daily.

Numerical primary efficacy estimates, uncertainty intervals, and the non-inferiority margin are not reported in the registry record. The record lists adverse-event counts for the treatment groups and safety extension, but does not provide a comparative causal assessment.