Comparing Safety and Efficacy of Combigan® and Lumigan® With Lumigan® Alone in Glaucoma or Ocular Hypertension Subjects Treated With Xalatan®: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Comparing Safety and Efficacy of Combigan® and Lumigan® With Lumigan® Alone in Glaucoma or Ocular Hypertension Subjects Treated With Xalatan® (NCT01170884), a randomized phase 4 study. The primary outcome is Mean Diurnal Intraocular Pressure (IOP) at Week 12.

2. Clinical Question

The registry frames the comparison around adding the fixed combination to Lumigan in subjects treated with Xalatan, versus Lumigan alone. The primary endpoint is a continuous measurement of pressure inside the eye, summarized as a mean and standard deviation for each arm. The posted comparison reports the difference in mean pressure, with an interval estimate and an unadjusted p-value.

This is a question about the measured Week 12 outcome in the trial population, not a complete assessment of every possible benefit or harm. The registry record includes one posted outcome measure and adverse-event counts. It does not report broader clinical outcomes, detailed participant characteristics, or a full account of treatment changes and follow-up.

3. Trial Design

This was a randomized, single-masked, parallel-group Phase 4 study sponsored by Allergan. The registry lists the study as completed, with enrollment of 121. The recorded start was 2009-12 and the primary completion was 2010-09. The registry describes two treatment arms: Combigan® plus Lumigan®, and Lumigan® alone with Gen Teal® Mild eyedrops used for masking purposes.

The primary outcome was assessed at Week 12 in the study eye. The registry defines the primary population as Intent-to-Treat: all subjects randomized to study medication. The posted arm summaries report 59 subjects for Combigan® plus Lumigan® and 62 for Lumigan®. Those arm counts are the denominators reported alongside the primary outcome and adverse-event summaries.

Random allocation indicates that assignment was by chance, but the method used to generate the allocation sequence, conceal assignments, and implement randomization is not reported in the registry record. The masking designation is single; which people were masked and how masking was maintained beyond the comparator's masking-purpose drops are not reported in the registry record. The protocol's planned allocation ratio, eligibility details, and treatment adherence procedures are also not reported in the registry record.

The registry record reports one outcome measure and no posted analysis entries. It identifies the primary endpoint, time point, summary measure, and analysis population, but a fuller statistical analysis plan is not reported in the registry record. In particular, the original trial design assumptions, how the sample size was chosen, and whether or when interim analyses were planned are not reported. These omissions limit what can be concluded about the prespecified analysis and the design rationale.

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 (ITT) included all subjects who were randomized to study medication.

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 Mean Diurnal Intraocular Pressure (IOP) at Week 12, measured over Week 12.

The primary endpoint was mean diurnal intraocular pressure (IOP) at Week 12, measured in millimeters of mercury (mm Hg). IOP is pressure from fluid inside the eye. The registry defines the diurnal value as the average of the study-eye measurements taken at 8 AM, 10 AM, and 4 PM. Each arm is summarized by its mean and standard deviation.

Averaging measurements across the specified times gives a summary of pressure across those daily measurement occasions rather than a result from just one time point. IOP is used as a measurable clinical outcome in studies of glaucoma and ocular hypertension. This endpoint therefore lets the study compare the groups on a continuous pressure measure at the specified follow-up time.

The registry reports mean IOP of 15.4 mm Hg for Combigan® plus Lumigan® and 19.2 mm Hg for Lumigan® alone. The corresponding standard deviations are 2.34 and 3.42. The posted comparison expresses the difference as the Lumigan®-alone mean minus the combination-arm mean. These are group summaries; they do not describe every participant's measurement or the pattern of measurements across all visits.

The endpoint alone does not establish the clinical importance of a difference or describe outcomes not measured in the registry record. Further details about measurement procedures, handling of readings that could not be obtained, or other endpoints are not reported in the registry record.

7. Results Posted in the Registry

• Lumigan®: mean 19.20 versus 15.40 on control; difference 3.80 (95% CI 2.76 to 4.84), standardized effect d = 1.29; z-test p = <0.001.

8. Statistical Interpretation

9. Statistical Methods Explained

The primary outcome is continuous, so the registry summarizes each arm using a mean and standard deviation. A mean represents the arithmetic average of the recorded measurements. The standard deviation describes how spread out individual measurements are around that average. These statistics answer different questions: the mean describes the group’s central level, while the standard deviation describes within-arm variability.

What does the mean difference represent?

The posted comparison defines the difference as the Lumigan® mean minus the Combigan® plus Lumigan® mean. With this ordering, a positive estimate means the Lumigan®-alone arm has the higher reported mean. The estimate is 3.8 mm Hg. Direction matters when reading any difference: reversing the order would reverse the sign, even though the underlying two group means would be unchanged.

A difference between group means is an estimate of the contrast in the study population, based on the observed measurements. It is not a statement that every participant in one arm had a higher or lower value than every participant in the other. Individual measurements can vary around their arm means, as reflected by the standard deviations of 2.34 and 3.42.

What does the confidence interval add?

A confidence interval conveys the statistical precision of an estimated effect, under the method's assumptions. The posted 95% confidence interval for the mean difference runs from 2.76 to 4.84 mm Hg. A narrower interval indicates greater precision than a wider interval on the same scale. The interval does not show the range of individual IOP measurements, nor does it guarantee that the true effect lies within its limits. Its interpretation depends on the statistical model and analysis procedures used.

The interval does not include zero. In general, zero represents no difference for a difference measure. This feature aligns with the reported unadjusted p-value of <0.001, but the two summaries are not measures of clinical importance. Neither establishes how meaningful the observed difference is to patients or whether it persists beyond the reported time point.

How should the p-value be understood?

A p-value evaluates how compatible the data are with a specified null hypothesis under the test's assumptions. The unadjusted p-value is <0.001. It is not the chance that the result arose “by chance,” the probability that the treatments are equivalent, or the probability that the null hypothesis is correct. It also does not quantify the magnitude of a difference. The registry record does not report the full test specification, so details such as the exact model and any covariate adjustment are not reported in the registry record.

The term unadjusted indicates that the posted p-value is not described as adjusted for multiplicity. The registry reports one outcome measure and no posted analysis entries, but does not report a statistical plan explaining whether other planned hypotheses or analyses were considered. No adjustment procedure should be inferred from the result alone.

Why do allocation and masking matter?

Randomization is intended, in general, to reduce systematic differences between groups at assignment. It does not ensure that groups will be identical in every observed or unobserved characteristic, especially in a study of limited size. The registry identifies random allocation but does not report the sequence-generation or allocation-concealment procedures. Single masking can reduce some forms of bias, depending on who is masked and how. Those details are not reported in the registry record; the comparator description does say that Gen Teal® Mild was used for masking purposes.

These design features provide context for interpreting an arm comparison, but they do not replace information about conduct, adherence, missing measurements, or analysis. The registry record does not provide sufficient detail to assess all of those elements.

What can the arm summaries establish?

The reported means, standard deviations, confidence interval, and p-value describe the posted primary result. The ITT population is defined as all randomized subjects, which is a population definition, not a complete account of the data included in the calculation. The record does not state whether every randomized subject had a Week 12 measurement, how missing readings were treated, or whether any subjects were excluded from the endpoint analysis. Those details matter because missingness or exclusions can affect how representative an estimate is of the randomized population.

For continuous outcomes, interpretation can also depend on distributional assumptions and on whether the analysis accounts for baseline values or repeated measurements. The registry does not report these modeling details. The displayed group summaries remain informative as descriptive results, but the underlying estimation and testing choices cannot be fully evaluated from the registry record.

10. Confidence Intervals and Precision

The posted mean difference is 3.8 mm Hg, with a 95% confidence interval from 2.76 to 4.84 mm Hg. The interval gives a range of effect sizes compatible with the data under the analysis assumptions and conveys uncertainty in the estimated contrast. It is an interval for the difference between arm means, not a range intended to contain most participants' measurements.

The interval's endpoints are above zero. For a difference defined as Lumigan® alone minus Combigan® plus Lumigan®, zero would represent equal means. The interval therefore indicates that the estimated contrast is positive across its reported limits. That statistical feature is distinct from deciding whether any particular value in the interval is important in clinical practice; the registry does not provide a threshold for clinical importance.

Precision depends on the amount and variability of the information used in the analysis, as well as the analysis method. The arm standard deviations are 2.34 and 3.42, and the posted arm counts are 59 and 62. The record does not report enough detail about missing measurements or the exact estimation procedure to reconstruct the precision calculation independently. It also does not report a prespecified target difference against which to judge whether the interval is sufficiently precise.

The confidence interval should be considered together with the point estimate, the unadjusted p-value, and the limitations of the record. It does not account automatically for multiple testing, unreported analysis choices, or bias from missing data. The registry record does not report whether any such adjustments or sensitivity analyses were conducted.

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 are participants per arm, not total event counts. They are illustrations based on the observed mean difference, rather than the trial's original sample-size calculation. The registry record does not report the assumptions used for the trial's own design or sample-size justification.

The planning calculation assumes a two-sided significance level of 0.05, equal allocation between the two arms, and a normal approximation. Each planning row considers detecting a stated fraction of the observed effect. For 100% of the observed effect, the illustration gives 10 participants per arm for 80% power and 13 participants per arm for 90% power. For 75% of the observed effect, it gives 17 participants per arm for 80% power and 23 participants per arm for 90% power. For 50% of the observed effect, it gives 38 participants per arm for 80% power and 51 participants per arm for 90% power.

In plain terms, 80% power is the assumed probability of detecting an effect of the specified size at the stated significance level if that effect is present and the planning assumptions hold. The 90% power column uses a higher target probability under those assumptions. Smaller effects require more participants to detect with the same power, as reflected in the increasing planning figures across the rows. These values are not observed power; they are planning illustrations using the observed effect and stated assumptions.

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 = 3.800; pooled standard deviation σ = 2.944.
2. n = 2 × (1.96 + 0.842)² × 2.944² / 3.800² = 9.4, rounded up to 10 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 <- 3.8                      # observed difference in means
sigma <- 2.94353757329139                     # 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(1170884)
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 = 10 (80% power), 13 (90% power)
 75% of observed effect: n per arm = 17 (80% power), 23 (90% power)
 50% of observed effect: n per arm = 38 (80% power), 51 (90% power)
power.t.test: 10.5 
Simulated power at n = 10 per arm: 0.775 (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

The registry record reports one outcome measure, the primary endpoint of mean diurnal IOP at Week 12, and zero posted analysis entries. It lists no secondary results. This does not establish that no other outcomes or analyses were considered during the study; the protocol and full statistical analysis plan are not reported in the registry record.

Multiplicity arises when several outcomes, time points, subgroups, or statistical tests are evaluated. In general, the more tests considered, the greater the chance that at least one result appears statistically unusual under a null model. The posted comparison is identified as unadjusted, and the registry record does not report whether any multiplicity adjustment was planned or applied. The unadjusted p-value should therefore be interpreted as the reported test result, without assuming a correction for other analyses.

The endpoint population is defined as ITT and includes all subjects randomized to study medication. This identifies the intended analysis population, but does not specify how missing outcome measurements were handled. The registry record does not report the amount or reasons for missing Week 12 data, whether the endpoint analysis included everyone randomized, or whether imputation, a complete-case approach, or another method was used. It also does not report sensitivity analyses examining missing-data assumptions.

Missingness can affect interpretation if the availability of a measurement is related to the outcome or differs in meaningful ways between groups. In general, an ITT label alone does not show that all randomized participants contributed a measured value to every analysis. Without details on measurement availability and handling, the robustness of the estimate to missing data cannot be assessed from the registry record.

The record also does not report subgroup analyses, covariate adjustments, or interim analyses. Their presence or absence should not be inferred from the primary result. These reporting gaps constrain assessment of the full analysis strategy and the potential role of multiplicity.

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 summaries report zero events in the Combigan® plus Lumigan® arm among 59 at risk and zero in the Lumigan® arm among 62 at risk. These are the serious-event counts recorded in the registry, not proof that no serious event occurred outside the recorded follow-up or reporting framework. The registry lists no serious adverse-event terms.

For other adverse events, the record reports 10 affected subjects among 59 at risk in the Combigan® plus Lumigan® arm and 1 among 62 at risk in the Lumigan® arm. The registry does not provide event terms, severity, timing, recurrence, or an account of how events were judged related to study treatment. The counts therefore cannot identify which events occurred or characterize their clinical importance.

Deaths are not reported in the registry record. Adverse-event counts are descriptive safety information and should not be interpreted as a complete comparison of risk without details on collection, follow-up, and event definitions. They also do not establish why the observed counts differ between arms.

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

The posted primary result describes mean diurnal IOP at Week 12 in two randomized arms. The combination arm's reported mean was 15.4 mm Hg, while the Lumigan®-alone arm's mean was 19.2 mm Hg. The reported difference, defined as Lumigan® alone minus the combination, was 3.8 mm Hg, with a 95% confidence interval of 2.76 to 4.84 mm Hg and an unadjusted p-value of <0.001. These statistics describe the measured endpoint and its estimated between-arm contrast.

The result does not establish an effect on outcomes beyond the endpoint and time point recorded. The registry does not report longer-term IOP results, other clinical outcomes, or a threshold for interpreting the clinical importance of a difference. It does not show how results varied across participant characteristics or how individual measurements changed over time. The group means do not predict the result for any one person.

Nor does the result establish that the comparison is free from limitations related to missing measurements, measurement procedures, adherence, or analysis choices. Although the registry defines an ITT population, it does not report how missing Week 12 observations were handled. Details of the statistical model, baseline adjustment, and multiplicity strategy are also not reported in the registry record.

The safety information is likewise bounded. The record lists no serious adverse events in either arm and reports other adverse events in both arms, but does not give event terms or fuller clinical detail. These counts do not provide a complete assessment of safety or explain the observed difference in counts.

Accordingly, the findings support a precise description of the registry's posted group summaries and comparison for this endpoint. They should not be expanded into claims about treatment effects outside the measured outcome, population, and follow-up represented in the record.

16. Why This Trial Matters Statistically

This trial illustrates how a continuous endpoint can be reported through several complementary statistics. The arm means describe the measured pressure level, standard deviations describe variation among measurements, and the mean difference summarizes the contrast. The confidence interval adds information about precision, while the p-value addresses compatibility with a null model under the test assumptions. None of these measures substitutes for the others.

It also shows why the direction of a contrast must be stated. The posted estimate is defined as Lumigan® alone minus Combigan® plus Lumigan®, so the positive value corresponds to the higher reported mean in the Lumigan®-alone arm. Without the ordering, a reader could misread the sign even while correctly copying the magnitude.

The case highlights the difference between a registry's ITT population definition and a complete description of the analysis. The record defines who belongs to the intended population, but does not explain missing Week 12 data or the model used to calculate the comparison. Those details matter for judging whether an estimate represents all randomized subjects as intended and whether the reported uncertainty captures the relevant sources of variation.

Finally, the registry contains both efficacy-endpoint summaries and limited safety counts, while leaving important context unreported. Reading the IOP result alongside the adverse-event information reinforces that a single statistically precise outcome is not a complete account of clinical outcomes. The planning illustrations also demonstrate that design calculations depend on assumptions and target effect size; they cannot be treated as evidence of what the completed study was powered to detect.

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 record provides limited detail for evaluating how the study was conducted and analyzed. It identifies randomization and single masking but does not report sequence generation, allocation concealment, or which people were masked. The use of Gen Teal® Mild for masking purposes is described for the Lumigan® arm, but masking success is not reported.

The endpoint is defined by the average of readings at 8 AM, 10 AM, and 4 PM at Week 12. Further details about measurement procedures, assessor masking, repeated readings, and handling of readings that could not be obtained are not reported in the registry record. Baseline IOP summaries and the statistical treatment of baseline values are also not reported.

Although the record defines the analysis population as ITT, the handling and amount of missing Week 12 data are not reported. The analysis model, covariate adjustments, and any sensitivity analyses are not reported. The record contains no posted analysis entries and no posted secondary results, so the full planned analysis strategy cannot be assessed.

The adverse-event information is limited to counts. Serious-event terms are absent, other event terms are not reported, and deaths are not reported in the registry record. Details such as event timing, severity, follow-up duration for safety, and attribution are not available in the posted record.

Lastly, the trial's original sample-size assumptions, target effect, and any interim-analysis plans are not reported. The displayed planning illustrations use the observed effect under specified assumptions and do not reconstruct the trial's original design rationale. These gaps limit assessment of the study beyond the posted endpoint summaries and adverse-event counts.

18. Related Tutorials

19. Related Statistical Calculators

20. Sources

• ClinicalTrials.gov: Comparing Safety and Efficacy of Combigan® and Lumigan® With Lumigan® Alone in Glaucoma or Ocular Hypertension Subjects Treated With Xalatan® — NCT01170884.
• Registry record last updated 2019-04-24; status last verified 2019-04.
• Results first posted 2012-01-12.
• 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

The registry describes a completed randomized, single-masked, parallel-group Phase 4 study sponsored by Allergan, with enrollment of 121. It compared Combigan® plus Lumigan® with Lumigan® alone in people with glaucoma or ocular hypertension treated with Xalatan®. Gen Teal® Mild was used in the Lumigan® arm for masking purposes.

The primary endpoint was mean diurnal IOP in the study eye at Week 12, defined as the average of readings at 8 AM, 10 AM, and 4 PM. The reported means were 15.4 mm Hg and 19.2 mm Hg, respectively. The comparison was 3.8 mm Hg in the direction Lumigan® alone minus the combination, with a 95% confidence interval of 2.76 to 4.84 mm Hg and an unadjusted p-value of <0.001.

The registry reports zero serious adverse events in each arm and other adverse events in both arms. Event terms and important analysis details, including missing-data handling, are not reported in the registry record.