Double-masked Study of AR-13324 Ophthalmic Solution in Patients With Glaucoma or Ocular Hypertension: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Double-masked Study of AR-13324 Ophthalmic Solution in Patients With Glaucoma or Ocular Hypertension (NCT02207491), a randomized phase 3 study. The primary outcome is Intraocular Pressure (IOP).

2. Clinical Question

3. Trial Design

This was a Phase 3 randomized, parallel-group, active-controlled study described as double-masked in its title and quadruple-masked in the registry design fields. The official title characterizes it as multi-center and gives a 3-month study period. The record lists enrollment of 411 and status as completed. The study dates are recorded as starting in 2014-07, with primary completion in 2015-03.

The two described treatment groups used different regimens. Participants assigned to AR-13324 Ophthalmic Solution 0.02% received an evening drop in both eyes and placebo in the morning. Participants assigned to Timolol maleate Ophthalmic Solution 0.5% received drops in both eyes in the morning and evening. The registry also lists placebo as an intervention, but does not describe a placebo-only treatment group in the arm descriptions. The exact role of each masking party is not reported in the registry record.

The primary efficacy measure was mean intraocular pressure, with a 3-month timeframe and a Per-Protocol analysis population. That population excluded participants with major protocol violations likely to seriously affect the primary outcome and summarized participants as treated for analysis. The record lists extent of exposure as a secondary outcome. It does not report the randomized allocation ratio, details of how the random sequence was generated or concealed, or the number of participants analyzed for the primary outcome.

4. Participant Flow and Accounting

The registry reports how participants moved through each stage of the study. All counts below are exactly as posted; missing counts are not inferred from other stages.

Before assignment: Prior to enrollment, adult participants were to have a Screening Visit and 2 Qualification Visits to allow for washout of ocular hypotensive medication if needed. The Randomized Population includes all subjects who were randomized to treatment. Baseline variables and demographic characteristics were summarized for this population.

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: Per-Protocol (PP) Population. The PP population includes subjects who did not have major protocol violations likely to seriously affect the primary outcome of the study. The PP population summarizes subjects as treated for purpose of analysis.

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: Randomized Population

6. Primary Endpoint

The registry lists the primary outcome as Intraocular Pressure (IOP), measured over 3 months.

The primary endpoint was mean intraocular pressure (IOP), measured in mmHg, at 3 months. IOP is the pressure within the eye; in this study it was the measure used to assess ocular hypotensive efficacy. The registry describes the endpoint as a mean, a summary of a continuous measurement across the analysis population. A mean allows the groups’ average measured pressure to be compared, while the spread of individual measurements matters for judging how precisely that comparison is estimated.

The stated primary efficacy population was Per-Protocol. It included participants who did not have major protocol violations likely to seriously affect the primary outcome, and it summarized them as treated. This differs conceptually from an analysis that retains all participants according to randomized assignment, although the registry does not report an intention-to-treat analysis for this outcome.

The registry record does not report the numerical mean IOP values, standard deviations, between-group estimate, confidence interval, or test result. It also notes that the primary outcome has several categories or time points and was not reduced to a single comparison. Consequently, the endpoint’s definition is available, but a single numerical efficacy contrast cannot be interpreted from the record.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

What does a mean endpoint represent?

General statistical explanation: A mean is the arithmetic average of the measurements included in an analysis. It can describe the central level of a continuous outcome such as IOP, but it does not show how much measurements vary between participants. A group mean alone is therefore not enough to judge how precisely a treatment contrast is estimated. The registry identifies the endpoint as a mean and the dispersion measure as standard deviation, but it does not report numerical means or standard deviations for the primary efficacy outcome.

The treatment question is ordinarily expressed as a contrast between group means at the defined assessment. The estimate describes the observed difference under the specified analysis, while a confidence interval describes a range of values compatible with the data and the analysis assumptions. A narrower interval indicates greater precision than a wider interval, though precision does not by itself establish clinical importance. In this record, no primary contrast or confidence interval is reported, and the outcome has several categories or time points rather than a single reduced comparison. There is therefore no reported estimate to interpret in those terms.

Why does the analysis population matter?

The registry identifies the Per-Protocol population as the primary efficacy population. It defines that population by excluding participants with major protocol violations likely to seriously affect the primary outcome, and says the analysis summarizes participants as treated. Such an analysis describes outcomes among those meeting the stated protocol criteria under the treatment they received. General statistical caution is that exclusion after randomization can affect comparability if the reasons for exclusion are related to outcomes or differ between groups. The registry does not report the number excluded, their reasons, or a separate analysis retaining participants according to randomized assignment.

Randomization is intended to support a fair comparison by allocating treatment without selecting it according to participants’ expected outcomes. Its value for interpretation depends on the analysis and on how the trial was conducted. The record identifies the study as randomized, but details of sequence generation, allocation concealment, adherence, and the handling of treatment changes are not reported in the registry record. No assumptions about those procedures can be made from the masking label alone.

What can standard deviations and confidence intervals tell a reader?

General statistical explanation: A standard deviation describes the spread of observations around a group mean. It is not the same as the uncertainty around the mean or around a between-group contrast. Precision also depends on how many participants contribute usable measurements and on the analysis method. A confidence interval for a contrast combines the estimate and its uncertainty, giving more information than a significance test alone. Neither the primary outcome standard deviations nor a confidence interval for an IOP contrast are reported in the registry record.

A p-value, if reported, would quantify how incompatible the observed data are with a specified null model under the test’s assumptions; it would not state the probability that a treatment is effective. The registry does not report a primary efficacy p-value or identify the test used. It is therefore not possible to reconstruct or characterize a significance test for the primary outcome.

What does the sample-size planning information mean?

General statistical explanation: A planning calculation describes the sample size that would be required under specified assumptions to detect a chosen effect with a chosen probability of statistical significance. It is not a measure of the probability that a completed study found a real effect, and it is not observed power. The record’s planning assumptions specify a two-sided significance level of 0.05, equal allocation between the two arms, a normal approximation, and effects defined as fractions of an observed effect. These are planning assumptions, not evidence that the trial’s original design used them.

The record says the illustration is based on the observed effect, but it does not report the numerical primary effect in the results available for interpretation. Any such planning values should therefore be read as hypothetical illustrations under stated assumptions rather than as observed trial outcomes or a description of the original design justification. The original sample-size rationale is not reported in the registry record.

Why can multiple outcome assessments complicate interpretation?

General statistical explanation: When an outcome is assessed at multiple time points or in multiple categories, selecting a single result after looking at the data can make nominal uncertainty measures misleading. A prespecified analysis plan can define which comparisons are primary and how multiplicity is handled. The registry states that the primary outcome includes several categories or time points and is not reduced to one comparison, but does not report the statistical plan or a multiplicity adjustment. Thus no single result should be treated as the complete efficacy finding based on this record alone.

The study lists two outcome measures and one analysis. Those registry counts do not supply the missing outcome estimates or establish how analyses were selected. The record’s endpoint description, design details, and adverse-event counts are informative, but they do not replace the missing inferential results for mean IOP.

10. Multiplicity, Missing Data and Analysis Populations

The registry identifies mean IOP as the primary efficacy outcome and states that it has several categories or time points, but it was not reduced to a single comparison. The registry record does not report which time points or categories were designated as primary for inference, whether a particular contrast was prespecified, or whether multiplicity was addressed. When several comparisons are examined, the chance of obtaining an apparently unusual result can increase; methods that control or otherwise account for multiplicity depend on the planned analysis. No such method is reported.

Missing-data procedures are also not reported in the registry record. The record does not say how missing IOP measurements were handled, whether any values were imputed, or how participants without an assessment at the stated timeframe were treated in analysis. Those details matter because the analyzed measurements may not represent all randomized participants if missingness is related to health status, tolerability, or treatment response.

The primary efficacy population is Per-Protocol, defined by the absence of major protocol violations likely to seriously affect the outcome, and described as analyzed as treated. The numbers analyzed and excluded, the criteria’s application by group, and any sensitivity analyses are not reported. The record also does not report an intention-to-treat efficacy estimate. These omissions limit assessment of how robust the primary comparison would be to different population definitions and missing-data assumptions. The registry lists extent of exposure as a secondary outcome, but does not provide enough information to assess its analysis or its relationship to efficacy interpretation.

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 5% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: prostate cancer (0.5%), exacerbation of coronary artery disease (0.5%), hypertension (0.5%), worsening of adenomyosis (0.5%), congestive heart failure (0.5%).

The registry reports serious adverse events for the two treatment groups. In the AR-13324 Ophthalmic Solution 0.02% and placebo group, 203 participants were at risk and 3 were affected; in the timolol group, 208 were at risk and 4 were affected. Deaths were reported as 0 in each group. The registry also reports other, non-serious adverse events: 145 affected participants in the AR-13324 and placebo group and 75 in the timolol group, with 203 and 208 participants at risk, respectively.

These are the registry’s reported counts. They do not establish that treatment caused an event, and the counts alone do not show the event timing, duration, severity, or clinical context. No rates or comparisons are calculated. The registry lists prostate cancer, exacerbation of coronary artery disease, hypertension, worsening of adenomyosis, congestive heart failure, and left upper extremity numbness among the top serious-event terms, each recorded as 0.5%. The record does not provide enough detail in this listing to assign those terms to a treatment group or assess individual cases.

Safety interpretation is also limited by the lack of detailed event narratives and by the 3-month study timeframe. The reported counts should be read as descriptive registry data, not as proof of causation or as a complete account of comparative safety.

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

The registry record documents a randomized, active-controlled study in patients with ocular hypertension or open-angle glaucoma and an elevated IOP. It specifies the treatment regimens, a mean IOP primary outcome, a Per-Protocol analysis population, and a 3-month timeframe. It also reports enrollment and selected adverse-event counts. Those details describe what the study set out to examine and some of the information recorded about participants’ safety.

The record does not report numerical primary IOP results. In particular, it does not provide group means, a defined between-group estimate, a confidence interval, or a primary efficacy p-value. It also notes several outcome categories or time points without reducing them to one comparison. As a result, the registered results do not establish the direction, size, or precision of an efficacy difference. The absence of a reported estimate is not evidence that the groups were the same, and it is not evidence that one regimen was superior.

The safety counts are likewise not a basis for attributing events to treatment or for making a definitive comparative safety judgment. They are descriptive counts recorded for the groups, without the detail needed to assess event context or causal relationships. The registry reports no deaths in either group, but that observation does not answer every safety question or establish safety beyond the study’s timeframe.

More complete interpretation would require outcome estimates and uncertainty measures, details of the analysis plan and multiplicity handling, and information about missing observations and analysis populations. The registry record does not report these details. The appropriate conclusion is therefore about the scope of the evidence recorded: the design and certain safety counts are described, while the principal numerical efficacy findings needed to judge the IOP comparison are not reported.

13. Why This Trial Matters Statistically

This trial is statistically informative as an example of why a clear design description and a complete results record are both needed. The registry identifies randomization, masking, parallel groups, an active comparator, the treatment schedules, a primary outcome, and the analysis population. These features help define the intended comparison. But a design description cannot reveal the observed treatment contrast without outcome estimates.

The primary outcome is a continuous measure summarized as mean IOP, with standard deviation identified as the dispersion measure. For a reader assessing a treatment comparison, the group summaries and an estimate of the contrast are central; uncertainty measures are needed to judge precision. Those numerical primary results are not reported in the registry record. The note that the outcome has several categories or time points also underscores why the selected comparisons and handling of multiplicity matter.

The Per-Protocol definition illustrates another important statistical issue: the population used for analysis shapes the question answered. Excluding major protocol violations may focus attention on participants meeting the study criteria, while also making it important to know who was excluded and how that selection was handled. The registry does not report those details or a parallel intention-to-treat result.

Finally, the safety counts demonstrate the value and limits of descriptive reporting. Counts can identify what the registry records, but without context and detailed analysis they do not establish causes or comparative risks. Taken together, the record allows a reader to understand the trial’s intended structure and some recorded safety information, while also making clear that the main efficacy comparison cannot be interpreted quantitatively from the registered results.

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 interpreting efficacy is that numerical results for mean IOP are not reported in the registry record. Group means, standard deviations, an effect estimate, a confidence interval, and a p-value are absent. The record further notes that the primary outcome has several categories or time points but is not reduced to a single comparison, leaving the specific efficacy contrast unresolved.

The primary analysis uses a Per-Protocol population, defined by excluding participants with major protocol violations likely to seriously affect the outcome, and summarizes participants as treated. The registry does not report the number analyzed, the number excluded, reasons for exclusion, missing-data handling, or sensitivity analyses. It also does not report whether results differ under an analysis based on randomized assignment.

Details of the randomization procedure, allocation concealment, masking roles, adherence, and the statistical analysis plan are not reported in the registry record. The record does not explain whether or how multiplicity was addressed across the outcome categories or time points. These gaps prevent assessment of important assumptions behind any primary efficacy inference.

The safety information is limited to selected counts and serious-event terms. It does not provide event-level timing, duration, severity details, or causal assessments. The study timeframe is 3 months, so the record does not characterize outcomes beyond that period. These limitations concern what can be concluded from the registry record; they do not establish that the unreported analyses or information were absent from other study materials.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: Double-masked Study of AR-13324 Ophthalmic Solution in Patients With Glaucoma or Ocular Hypertension — NCT02207491.
• Registry record last updated 2018-04-13; status last verified 2018-01.
• Results first posted 2018-04-13.
• 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

This completed Phase 3 study was randomized, parallel, quadruple-masked, active-controlled, and described as multi-center. It enrolled 411 patients with ocular hypertension or open-angle glaucoma and elevated IOP. The compared regimens were AR-13324 Ophthalmic Solution 0.02% in the evening with morning placebo, and Timolol maleate Ophthalmic Solution 0.5% twice daily. The study timeframe was 3 months.

The primary efficacy outcome was mean IOP in the Per-Protocol population, described as analyzed as treated. Extent of exposure was listed as a secondary outcome. Numerical primary efficacy estimates and their uncertainty are not reported in the registry record; the record notes multiple outcome categories or time points without a single reduced comparison. Serious and other adverse-event counts and deaths are recorded, but the available safety details do not establish causation or provide a complete comparative assessment.