Aqueous Humor Dynamics and Brimonidine: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Aqueous Humor Dynamics and Brimonidine (NCT01144494), a randomized early/phase 1 study. The primary outcome is Seated Day-time IOP 9 am and 11 am, Supine Day-time IOP 9 am and 11 am, and Seated Night-time IOP 9 pm and 11 pm.

2. Clinical Question

In broad terms, the research question is whether the measured intraocular pressure profile across daytime and nighttime conditions differs in the study of brimonidine and artificial tears among people with ocular hypertension. The registry frames the investigation around circadian rhythms of aqueous humor dynamics and describes measurements before and after intervention. The primary outcome is not a single summarized reading: it includes measurements at several times and positions. That breadth could help characterize variation across the day and night, but it also means that an overall treatment effect cannot be inferred from a single value unless the analysis specifies how these measurements are combined or compared.

The registry lists aqueous flow, uveoscleral outflow and outflow facility as secondary outcomes. It does not report the results for those outcomes. Accordingly, the record supports a description of the intended scientific question and measurement schedule, not a conclusion about whether brimonidine changed pressure or aqueous humor dynamics relative to artificial tears.

3. Trial Design

The registry identifies this as a randomized, double-masked, crossover study, with enrollment of 35 and status listed as completed. It lists the phase as EARLY PHASE1 and identifies the University of Nebraska as sponsor. The study dates are recorded as 2010-08-01 for start and 2011-10-01 for primary completion. The brief summary describes the investigation as single-center and investigator-masked; the registry’s design fields separately list double masking. The exact procedures used to maintain masking are not reported in the registry record.

In a crossover design, participants receive more than one intervention in an assigned sequence, and outcomes can be compared within the same participant. As a general statistical matter, using participants as their own comparison can account for stable individual characteristics. That design also makes the timing and sequence of interventions important: treatment effects may be mixed with period effects, order effects or carryover if the prior intervention influences later measurements. The sequence assignments, period structure, washout procedures and methods for handling such effects are not reported in the registry record. The design label alone does not establish how those issues were addressed.

The interventions listed are brimonidine and artificial tears. Arm descriptions call these an intraocular pressure-lowering drug and lubricated eye drops, respectively. The summary describes brimonidine for six weeks and an assessment before and after intervention. Detailed treatment schedules, adherence assessments, exact treatment-period durations for each arm and the full crossover sequence are not reported in the registry record.

The primary outcome lists seated daytime and supine daytime intraocular pressure at 9 am and 11 am, and seated nighttime intraocular pressure at 9 pm and 11 pm. Daytime measurements were made by pneumatonometer according to the outcome description. The record lists five outcome measures and three secondary outcomes, but does not provide the analysis plan or outcome values. It also notes that some consented patients did not participate, without specifying the number or reasons in detail. Thus the recorded enrollment should not be treated as the denominator for every measurement or analysis.

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: 2 subjects consented and then dropped out prior to assignment.

Overall Study

Analysis population for the primary outcome, as defined in the registry: some patients were consented but did not participate due to various reasons

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: Intraocular pressure, episcleral venous pressure, and aqueous flow were calculated using data from 29 participants. However, tonography/outflow facility data on 2 participants were not reliable, therefore uveosleral outflow and outflow facility analysis were performed on 27 participants.

6. Primary Endpoint

The registry lists the primary outcome as Seated Day-time IOP 9 am and 11 am, Supine Day-time IOP 9 am and 11 am, and Seated Night-time IOP 9 pm and 11 pm, measured over 6 weeks.

The primary endpoint comprises intraocular pressure measurements in mmHg under different conditions: seated during the day, supine during the day, and seated at night. The listed measurement times are 9 am and 11 am for the daytime conditions, and 9 pm and 11 pm for the nighttime condition. The daytime measurements were made by pneumatonometer. The registry identifies the endpoint summary as a mean with standard error and gives a timeframe of six weeks.

Intraocular pressure is the direct pressure outcome named in the registry’s condition and primary outcome. Measuring it at different times and positions is relevant to the study’s stated interest in circadian rhythms of aqueous humor dynamics: a set of readings can describe pressure across varying conditions rather than relying on one isolated measurement. That rationale is general; the record does not state a specific biological or clinical threshold for interpreting a change.

The multiple conditions and times are important to interpretation. Each reading could answer a somewhat different question, and the registry does not specify whether a single value, a pattern across times, or a comparison of several values was intended as the main inferential target. No means, standard errors, treatment contrasts or confidence intervals are reported in the registry record. The actual endpoint results and their precision therefore cannot be interpreted from the posted record.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The registry identifies randomization, double masking and a crossover model. These design labels describe important features, but they do not reveal the detailed statistical methods used. The analysis plan, model specification, handling of repeated measurements and approach to incomplete data are not reported in the registry record. The explanations below describe general statistical principles rather than asserting that a particular method was used in this study.

What does a crossover design imply?

In a crossover study, participants receive different interventions in an assigned order, and outcomes may be compared within each participant. A within-participant comparison can reduce the influence of characteristics that remain stable over the study, because each person can serve as their own comparison. For that benefit to be interpreted appropriately, analysis needs to account for the structure of the repeated observations and the periods in which treatments were received.

Order and period can matter. Participants may differ because of time, measurement conditions or changes that occur during the study, quite apart from the intervention. Carryover is another general concern: an earlier treatment could influence measurements during a later period. A washout period can be one way a protocol addresses this concern, but the presence, duration and use of any washout are not reported in the registry record. The treatment sequences and any method for accounting for sequence, period or carryover are also not reported. The word “crossover” alone does not indicate which model or adjustment was used.

How should a mean and standard error be read?

The primary outcome is described as a mean with standard error. A mean summarizes the central level of a continuous measurement across observations. A standard error describes the statistical uncertainty in an estimated mean, rather than the spread of individual measurements. It generally becomes smaller when an estimate is more precise, but its interpretation depends on the data and analysis that produced it. The registry does not provide the means or standard errors, so neither the typical measured pressure nor the precision of that estimate can be evaluated.

A standard error is not a substitute for a treatment-effect estimate. For a comparison, readers would need an explicitly defined contrast, such as a difference between interventions, together with an uncertainty measure. In a crossover study, that contrast should reflect the paired or repeated nature of the observations as appropriate. No contrast, confidence interval or inferential test is reported in the registry record.

Why do repeated times and conditions matter?

The endpoint includes measurements across daytime and nighttime and in seated and supine positions. These readings are not automatically interchangeable. A statistical analysis might treat each time-condition combination as a separate outcome, or it might specify a combined measure or repeated-measures model. Each approach answers a different question and can have different uncertainty. The registry does not state which strategy was used. There is also no reported result by time or position from which a reader could assess whether the pattern was consistent.

When outcomes are measured repeatedly, observations from the same participant tend to be related. General statistical methods account for this dependence rather than treating every reading as independent. Ignoring such correlation can lead to incorrect estimates of uncertainty. The data structure, correlation assumptions and any repeated-measures method are not reported in the registry record, so the appropriateness of a particular analysis cannot be assessed.

What do the planning assumptions mean?

The record describes planning calculations using a two-sided significance level of 0.05, equal allocation between arms and a normal approximation. It says that the effect to detect is expressed as a fraction of the observed effect. These are planning assumptions, not evidence about the observed trial result and not a report of the trial’s own design justification. The registry does not report the sample-size justification, or numerical planning estimates in the information available for interpretation.

Planning calculations ask what study size could be needed under assumptions about the effect and analysis. They are not “observed power,” and they do not establish whether the completed study detected an effect. If the underlying observed effect is unavailable, a reader cannot assess the relevance of an illustration based on a fraction of that effect. Any sample-size illustration should therefore be read as a hypothetical planning exercise, not a finding about brimonidine or artificial tears.

More generally, over-dispersion occurs when observed variability is greater than assumed by a statistical model. If a model assumes less variability than the data contain, uncertainty can be understated and statistical evidence can appear stronger than warranted. This is a general caution, not a claim about this study: the registry does not report a model or variability diagnostics from which over-dispersion could be assessed.

10. Multiplicity, Missing Data and Analysis Populations

The primary endpoint includes multiple measurement conditions and clock times, and the registry also lists secondary outcomes for aqueous flow, uveoscleral outflow and outflow facility. Considering several outcomes or comparisons can raise multiplicity concerns. In general, the more inferential tests made, the greater the chance that at least one result may appear notable by chance alone. Researchers may address this by prespecifying a primary contrast, controlling an error rate, using a hierarchical testing strategy or treating secondary results as exploratory. Which, if any, approach was used is not reported in the registry record.

The record’s primary outcome title specifies several readings but does not identify a single numerical contrast or explain how those readings were handled together. No multiplicity adjustment, statistical analysis plan or interim analysis information is reported in the registry record. It would be inappropriate to assume that every measurement was tested separately, or that a particular correction was applied.

Missing data are also relevant. The primary-outcome description says some patients were consented but did not participate for various reasons. It does not give the number, reasons, timing or outcome-data availability for those patients. The number included in each treatment-period analysis is not reported. The registry does not describe imputation, complete-case analysis or sensitivity analyses for missing observations.

The analysis population is not specified. The record does not state whether the primary analysis included everyone randomized, only those who completed both treatment periods, or another defined group. In a crossover study, incomplete participation can leave only one period or one intervention observed for some participants, which affects the possible within-person comparison. Without the population definition and missing-data methods, the impact of incomplete participation cannot be assessed.

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 0% reporting threshold.

Most frequent non-serious adverse event terms

The registry lists serious adverse-event information for the two intervention groups. For the intraocular pressure-lowering drug group, 33 were listed as at risk and 0 as affected by a serious adverse event. For the artificial-tears group, 33 were listed as at risk and 0 as affected by a serious adverse event. These are the serious-event counts recorded for the groups; they do not establish that no events of any kind occurred.

For other, non-serious adverse events, the intraocular pressure-lowering drug group lists 0 affected among 33 at risk, while the artificial-tears group lists 4 affected among 33 at risk. The record does not describe these events in the available information, so their type, severity beyond the registry category, timing and relationship to treatment cannot be assessed. Counts alone also do not establish that an intervention caused an event.

Death counts are not reported in the registry record. The safety figures should be interpreted alongside the study’s design and the completeness of reporting; they are not a statistical comparison of risk. No comparative estimate or uncertainty interval for adverse events is reported. The record therefore supports a description of the posted counts, not a definitive conclusion about relative safety.

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

The registry record establishes that a randomized, double-masked crossover study of brimonidine and artificial tears was completed, and it describes a primary outcome focused on intraocular pressure at several times and positions. It also lists secondary measures related to aqueous humor dynamics. These details clarify the study’s intended scope and the kinds of measurements collected.

However, the record does not report the primary outcome measurements, treatment comparisons, standard errors, confidence intervals or p-values. It therefore cannot show whether pressure differed between the interventions, the size or direction of a possible difference, or the precision of an estimate. The same limitation applies to the listed secondary outcomes: their names are present, but numerical results are not reported. No treatment conclusion follows from the study title, design or endpoint description alone.

General statistical interpretation depends on both the estimate and its uncertainty. A confidence interval can show which effect sizes remain compatible with the data and analysis assumptions; a point estimate without uncertainty can be difficult to interpret, and neither is available. Lack of a reported result should not be confused with evidence of no effect or with evidence of equivalence. Equivalence requires a defined margin and an analysis capable of assessing it, neither of which is reported in the registry record.

The posted adverse-event counts are limited safety information, not a complete account of tolerability or a causal comparison. They do not replace the missing efficacy results. Likewise, any planning calculations are hypothetical design aids and cannot stand in for the outcomes of the completed trial. They are not observed power or evidence that a treatment effect was present.

The defensible conclusion is therefore narrow: the registry describes the design, interventions and intended outcome schedule, but does not provide enough outcome or analysis information to evaluate the comparative effect of brimonidine and artificial tears. Further interpretation would require results and methods not reported in the registry record.

13. Why This Trial Matters Statistically

This study is statistically interesting because its question concerns variation in intraocular pressure over different times of day and body positions, rather than a single reading. Such measurements can raise questions about how repeated observations should be summarized and compared. A prespecified analysis is particularly important when an endpoint includes several conditions and clock times, because separate comparisons and an overall profile answer different questions.

The crossover design also illustrates a useful analytical tradeoff. Comparing interventions within participants can account for stable differences between people, but the interpretation relies on treatment sequence, period and potential carryover being handled appropriately. The registry identifies the design but does not report the sequence, washout arrangements or analysis methods. This makes the design concept visible while leaving important details needed for statistical evaluation unavailable.

The record also demonstrates the difference between registering a study and reporting interpretable results. It identifies enrollment, interventions, outcomes and safety counts, but gives no primary outcome estimates or statistical analyses. Without results and uncertainty measures, readers cannot distinguish a potentially meaningful pattern from random variation or evaluate consistency across measurement conditions.

Finally, the safety entries show why event counts need context: affected counts are reported alongside at-risk counts, while event descriptions and comparative uncertainty are absent. Those entries can be read descriptively but should not be elevated into a broad claim about safety. For researchers, the central lesson is that design labels and outcome definitions are necessary but not sufficient for assessing evidence; numerical estimates, transparent analysis methods and clear accounting of missing observations are also needed.

14. Limitations

• The posted summary statistics are the only data these results rest on; patient-level data, full protocols and statistical analysis plans are not available.
• Recalculated results are simple, unadjusted calculations from posted summaries. They do not replace the sponsor's prespecified analysis.

The most direct limitation is the absence of numerical primary-outcome results. Although the endpoint specifies means and standard errors, neither is reported in the registry record. No treatment effect, confidence interval, p-value or statistical analysis is listed, and the record reports zero analyses. This prevents assessment of both the estimated effect and its precision.

The primary outcome comprises several times and positions, but the record does not identify a single principal contrast or explain how the readings were combined. The multiplicity approach is not reported. Without this information, readers cannot determine which comparison was intended to carry the primary inference or whether results across conditions were consistent.

Important crossover details are also absent. The registry does not report treatment order, period structure, washout arrangements, or the analysis used to account for sequence, period or carryover. These omissions limit assessment of whether the design’s within-participant comparisons were protected from time-related or residual treatment effects.

The record notes that some consented patients did not participate for various reasons, but does not report the number, reasons, data availability or handling of missing measurements. It also does not define the analysis population. Enrollment of 35 should therefore not be interpreted as the number contributing to every outcome or comparison.

Additional limitations include the absence of numerical results for the listed secondary outcomes and limited detail about adverse events. The record identifies the study as single-center in its brief summary, which may constrain how readily findings would generalize if results were available. Because the outcome results are not reported, the practical importance and reproducibility of any potential effect cannot be evaluated.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: Aqueous Humor Dynamics and Brimonidine — NCT01144494.
• Registry record last updated 2023-11-28; status last verified 2023-11.
• Results first posted 2019-04-24.
• 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

NCT01144494 is a completed randomized, double-masked crossover study sponsored by the University of Nebraska. The registry lists EARLY PHASE1, enrollment of 35, a start date of 2010-08-01 and primary completion on 2011-10-01. Its stated subject is circadian rhythms of aqueous humor dynamics in people with ocular hypertension, comparing brimonidine with artificial tears.

The primary outcome describes intraocular pressure measurements in mmHg at daytime and nighttime times and positions, with a six-week timeframe and mean with standard error as the summary. Secondary outcomes include aqueous flow, uveoscleral outflow and outflow facility. The record reports no statistical analyses and does not provide numerical primary or secondary outcome results. It lists serious adverse-event counts of 0 affected in each group, other adverse events of 0 in the intraocular pressure-lowering drug group and 4 in the artificial-tears group, and does not report death counts.