Comparison of Combigan Two Times Daily (BID) Versus Simbrinza Three Times Daily (TID): Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Comparison of Combigan Two Times Daily (BID) Versus Simbrinza Three Times Daily (TID) (NCT02167035), a randomized phase 4 study. The primary outcome is Intraocular Pressure.

2. Clinical Question

The central comparison is between two medication regimens in a population already being treated with latanoprost. The registry describes a pilot study intended to assess which treatment, if either, is superior in lowering intraocular pressure. That statement describes the study question; it does not establish that either regimen lowered pressure more than the other. Numerical results for the primary endpoint are not reported in the registry record.

The endpoint schedule includes measurements on Day 0, Day 30, and Day 90, with readings planned at 08:00, 10:00, and 16:00 on each of those days. Since the endpoint spans multiple times and visits, an interpretation requires attention to which measurement or comparison is being considered. A single overall treatment contrast cannot be inferred from the study description alone.

3. Trial Design

This is a Phase 4 randomized, single-masked, parallel-group pilot study. The registry lists an enrollment of 43 and a completed status. The study start is recorded as 2014-08 and primary completion as 2018-03. The sponsor is Cornerstone Health Care, PA.

Participants were assigned to one of two medication groups: Combigan twice daily or Simbrinza three times daily. The listed doses are Combigan 0.2%/0.5%, one drop BID, and Simbrinza 1/0.2%, one drop TID. The study population is described as subjects currently treated with latanoprost for open-angle glaucoma or ocular hypertension. Details about how latanoprost use was handled during the study are not reported in the registry record.

Randomization is intended to create groups that are comparable, on average, with respect to both measured and unmeasured characteristics. In a pilot study, however, chance imbalances can remain, and the registry enrollment is modest. Randomization does not by itself establish that the treatment groups were balanced or that other aspects of trial conduct prevented bias.

The record identifies the trial as single-masked but does not report who was masked. The method used to generate the random sequence, allocation concealment, visit procedures beyond the endpoint description, and any protocol deviations are not reported in the registry record. The parallel design means the listed groups are separate treatment groups rather than participants crossing over between regimens. The record does not report a detailed schedule of treatment duration or a rationale for choosing the pilot design.

The stated primary endpoint population includes enrolled participants randomized to masked study medication who attended Visits 1, 2, and 3 at minimum. This is a modified intent-to-treat definition rather than an analysis definition that necessarily includes every randomized participant. The record does not provide the number of participants included in that population or the numbers excluded from it.

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: Primary endpoint analysis was conducted on the modified intent-to-treat (mITT) population, which consisted of all enrolled subjects randomized to masked study medication and who attended Visits 1,2,and 3 (minimally).

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: Analysis was conducted on the Safety Population (N=43) for Subject Demographics.

6. Primary Endpoint

The registry lists the primary outcome as Intraocular Pressure, measured over Day 0 (08:00, 10:00 16:00), Day 30 (08:00, 10:00, 16:00), Day 90 (08:00, 10:00,16:00).

The primary endpoint is intraocular pressure (IOP), reported as a mean with standard deviation and measured in mmHg. IOP is the pressure inside the eye; it is used in this trial as the outcome for comparing the two treatment regimens in people with open-angle glaucoma or ocular hypertension. The registry describes the study objective as assessing which treatment, if either, is superior in lowering IOP. That objective should not be mistaken for a reported finding: numerical results for the primary endpoint are not reported in the registry record.

Measurements were scheduled on Day 0, Day 30, and Day 90 at 08:00, 10:00, and 16:00. The description specifies Goldmann applanation tonometry, with both eyes tested and the right eye preceding the left. Two readings were to be taken consecutively for each eye. When they were within 2mmHg or less of each other, their mean was to be reported for that time point; when they were more than 2mmHg apart, a third reading was to be taken and the middle reading reported. The description says the same operator and tonometer were preferable at each visit.

Repeated measurements across times and visits can characterize IOP at different points in the day and over follow-up. The registry does not identify one of these measurements as the sole primary comparison or state how measurements across times were combined. Those details are not reported in the registry record.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The registry identifies a continuous primary outcome reported as a mean with standard deviation. It also describes the measurement procedure and multiple scheduled times. The record does not report the statistical analysis used to compare groups, so the concepts below explain how such data are generally interpreted rather than describing an analysis confirmed for this trial.

What does a mean describe?

For a continuous measure, the mean represents the arithmetic average of observed values in a defined group and at a defined time. Here, the endpoint is IOP in mmHg. A mean needs a clear population and measurement occasion to be interpretable: a group mean at a particular visit and time is different from a mean that pools or averages observations across visits or times. The record specifies scheduled measurements but does not report which summaries were calculated.

The standard deviation describes how dispersed individual observations are around a group mean. It is not the uncertainty of the mean itself, and it is not a treatment-effect estimate. A larger standard deviation indicates more variation among the observed values. To judge the precision of a group comparison, readers would need the treatment contrast and an uncertainty measure, such as a confidence interval; these are not reported in the registry record.

Why do repeated measurements matter?

IOP was scheduled at several times of day on Day 0, Day 30, and Day 90. Repeated observations from the same participant are generally related: readings from one person are not independent in the way readings from different people might be. Statistical methods for repeated measures account for this dependence and can use the pattern of observations over time. Treating every reading as independent can understate uncertainty because it ignores the within-person relationship.

There are different possible questions in a repeated-measures study. An analysis might compare groups at a particular visit and time, assess change from baseline, estimate an average contrast across visits, or test whether the pattern over time differs between groups. These approaches target different estimands and may produce different estimates. The registry record does not report which approach, time point, or contrast was designated for the primary analysis. No analysis method should be assumed from the measurement schedule alone.

What do randomization and masking contribute?

Random assignment is designed to reduce systematic differences between treatment groups at the start of a study. It supports a causal comparison when the assignment is implemented as intended and when subsequent analysis and follow-up are appropriately handled. In a relatively small pilot study, randomization does not guarantee that every prognostic characteristic will be balanced by chance.

Masking can reduce the influence of expectations on behavior, outcome assessment, or reporting. The record calls the study single-masked but does not say which people were masked or how masking was maintained. The IOP procedure is described using a tonometer and a reading rule, but the record does not establish whether the operator was masked to treatment assignment. The method of random-sequence generation and allocation concealment is also not reported in the registry record.

How should statistical significance be read?

In general, a p-value is calculated relative to a statistical model and a specified null hypothesis. It is not the probability that a treatment works, and it does not measure the size or clinical importance of a difference. A confidence interval gives a range of estimates compatible with the data and model at its stated confidence level. Both measures depend on the selected endpoint, analysis population, and assumptions. Neither p-values nor confidence intervals for IOP are reported in the registry record.

The record describes a sample-size planning framework using a two-sided significance level of 0.05, equal allocation, and a normal approximation. It says the effect to detect is a stated fraction of the observed effect. Such planning quantities are illustrations under assumptions, not observed treatment effects and not evidence of achieved power. The specific calculated planning values are not reported in the registry record. The record does not report the trial's own sample-size justification, so the planning framework should not be treated as the original design rationale.

What does over-dispersion mean in general?

Over-dispersion occurs when observed variability is greater than a statistical model expects. It is especially relevant to count outcomes, where a simple model may assume a particular relationship between the mean and variance. If that assumption is violated, standard errors and tests may be misleading unless the analysis accounts for the extra variability. The primary outcome in this study is continuous IOP, and the registry does not report a count-outcome analysis or an over-dispersion assessment. This general concept does not imply that over-dispersion was present in this trial.

For a continuous endpoint, relevant model checks might include whether residual patterns are compatible with the chosen model and whether influential observations affect conclusions. The registry does not report a model, diagnostic checks, adjustment variables, or sensitivity analyses. Without those details and the outcome estimates, the statistical properties of the primary comparison cannot be assessed from the registry record.

10. Multiplicity, Missing Data and Analysis Populations

The primary endpoint is scheduled at multiple visits and times of day: Day 0, Day 30, and Day 90, with readings at 08:00, 10:00, and 16:00. The record also lists an Ocular Symptom and Tolerability Questionaire as a secondary outcome and states that there are 2 outcome measures. When several endpoints or time-specific comparisons are examined, the chance of at least one apparently notable result can increase. A prespecified testing strategy can control or otherwise address this multiplicity. The registry record does not report a multiplicity adjustment or testing hierarchy.

The record does not report numerical primary-outcome results or specify which time point or combination of time points formed the primary comparison. It also does not report results for the secondary questionnaire. Whether all planned outcomes and time-specific analyses were reported cannot be determined from the registry record.

Missing-data handling is also not reported. The endpoint population is described as enrolled subjects randomized to masked study medication who attended Visits 1, 2, and 3 at minimum. The record does not give the number analyzed, the number missing measurements at each visit or time, reasons for missingness, or the method used to handle incomplete observations. Missing measurements can affect estimates if participants with observed data differ systematically from those without observed data; the direction and extent of any such effect depend on the pattern and reasons for missingness.

The record does not report whether analyses used all available observations, imputation, or another approach, and it does not describe sensitivity analyses for missing data. Those analysis details are not reported in the registry record. The defined modified intent-to-treat population should therefore not be assumed to include every randomized participant or to resolve potential missing-data concerns.

11. Safety Results

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

Deaths

Other (non-serious) adverse events

Participants with at least one non-serious event at or above the registry's 0% reporting threshold.

Most frequent non-serious adverse event terms

The registry lists serious adverse event counts for each group. In the Combigan BID group, 0 participants were affected among 21 at risk; in the Simbrinza TID group, 0 were affected among 22 at risk. The record lists 0 deaths in each group. These figures describe the counts recorded during the study and do not establish that serious events are impossible or that the treatments have identical safety profiles.

For other adverse events, the record lists 3 affected participants among 21 at risk in the Combigan BID group and 3 among 22 at risk in the Simbrinza TID group. The category is labeled as other adverse events; the record does not identify the event terms, severity, timing, duration, or whether events were considered related to treatment. It also does not report a comparative statistical analysis of adverse events.

Adverse-event counts are usually interpreted alongside the number followed, the duration and completeness of observation, event definitions, and participant-level details. Equal affected-participant counts do not mean the event types or clinical courses were the same. These registry counts are descriptive and do not, on their own, establish equivalence or a difference in safety.

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

The record supports a limited description of the study: a randomized, single-masked, parallel-group pilot comparison of Combigan BID and Simbrinza TID in subjects currently treated with latanoprost for open-angle glaucoma or ocular hypertension. It identifies IOP as the primary endpoint, measured at scheduled times on Day 0, Day 30, and Day 90, and lists tolerability as a secondary objective.

It does not report numerical IOP results. Without group means, variability, treatment contrasts, or uncertainty estimates, the size and direction of any difference cannot be established from the registry record. Nor can the record support a conclusion about whether either regimen was superior for lowering IOP. The study objective is not itself evidence that the objective was achieved.

The adverse-event counts describe what the registry lists: no serious adverse events or deaths in either group, and 3 participants affected by other adverse events in each group. Those counts do not demonstrate equal safety. The record does not give event descriptions or enough detail to judge their clinical importance or compare their patterns.

In general, a statistically detectable difference and a clinically important difference are distinct ideas. Statistical interpretation depends on the estimate, uncertainty, analysis choices, and data quality; clinical importance depends on the meaning of the outcome in context. Since the primary estimates and their precision are not reported in the registry record, neither kind of conclusion can be drawn from the stated study design alone.

The registry also does not report the sample-size justification, detailed analysis plan, missing-data method, or multiplicity strategy. These omissions limit assessment of how the trial was designed to answer its question and how robust an analysis would be. The record describes a completed pilot study, but completion status does not supply the missing outcome evidence.

13. Why This Trial Matters Statistically

This trial raises several statistical issues that are common in clinical comparisons. First, it measures a continuous outcome repeatedly across visits and times of day. A meaningful treatment comparison depends on defining the target contrast: a particular time point, change from baseline, or an overall pattern across observations. The registry lists the measurement schedule but does not report the primary contrast or numerical results. This makes clear why the endpoint definition and analysis plan matter as much as the name of the outcome.

Second, the study is identified as a pilot and lists enrollment of 43. Pilot studies can offer information about feasibility and measurement procedures, but the label does not establish precision or determine whether an estimate is conclusive. Precision depends on the observed variability, the analyzed sample, and the analysis. The registry does not report the IOP summaries or the number included in the primary endpoint population.

Third, this is a comparison of two regimens with different dosing frequencies, in a population described as currently treated with latanoprost. The question is not only whether measurements differ, but how a clearly specified outcome and time point represent the comparison. The registry's multiple scheduled measurements and secondary tolerability objective also raise the need to distinguish primary from secondary analyses and to specify how multiple comparisons are handled.

Finally, the posted safety counts illustrate the limits of descriptive event data. A count alone does not show the nature, timing, or severity of events, and it cannot establish equivalence. Careful interpretation requires estimates, uncertainty, and transparent definitions. Because these details and the primary numerical outcome results are not reported in the registry record, the study question can be described, but its comparative result cannot be quantified from this record.

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 main limitation for interpreting this trial is that numerical primary-outcome results are not reported in the registry record. There are no posted IOP group means, standard deviations, treatment contrasts, confidence intervals, or p-values in the record. Thus, the comparative result and its precision cannot be assessed.

The endpoint schedule includes several visits and times of day, but the registry does not identify the specific primary contrast or explain how repeated measurements were combined. The operator and tonometer were preferably to remain the same at each visit, but the record does not state whether this was achieved. It also does not report whether endpoint assessors were masked.

The record describes a modified intent-to-treat population requiring attendance at Visits 1, 2, and 3 at minimum, but does not report the population size, exclusions, visit-specific completion, or missing-data handling. The method of random-sequence generation and allocation concealment is not reported. The single-masking description does not identify who was masked. The sample-size justification, analysis plan, multiplicity strategy, and sensitivity analyses are also not reported in the registry record.

The safety information is limited to counts of participants affected. Event terms and clinical details are not reported, and the registry provides no comparative safety analysis. Although the study is marked completed, that status does not address these information gaps. The description of participants as currently treated with latanoprost does not provide full details of concomitant treatment during follow-up.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: Comparison of Combigan Two Times Daily (BID) Versus Simbrinza Three Times Daily (TID) — NCT02167035.
• Registry record last updated 2018-10-24; status last verified 2018-10.
• Results first posted 2018-10-24.
• 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

NCT02167035 is a completed Phase 4 randomized, single-masked, parallel-group pilot study sponsored by Cornerstone Health Care, PA. The registry records an enrollment of 43, a start of 2014-08, and primary completion in 2018-03.

The trial compared Combigan 0.2%/0.5%, one drop BID, with Simbrinza 1/0.2%, one drop TID, in subjects currently treated with latanoprost for open-angle glaucoma or ocular hypertension. The primary endpoint was mean IOP in mmHg, scheduled at multiple times on Day 0, Day 30, and Day 90. The endpoint population was defined as enrolled, randomized participants who attended Visits 1, 2, and 3 at minimum.

The registry lists an Ocular Symptom and Tolerability Questionaire as a secondary outcome. It records no serious adverse events or deaths in either group and lists 3 participants with other adverse events in each group. Numerical primary IOP results and key analysis details are not reported in the registry record.