Safety and Efficacy of ENV515 Travoprost Extended Release (XR) in Patients With Bilateral Ocular Hypertension or Primary Open Angle Glaucoma: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Safety and Efficacy of ENV515 Travoprost Extended Release (XR) in Patients With Bilateral Ocular Hypertension or Primary Open Angle Glaucoma (NCT02371746), a non-randomized phase 2 study. The primary outcome is Summary of Change From Baseline Average Intraocular Pressure Diurnal Measurement by Treatment Group Population (Cohort 1).

2. Clinical Question

The clinical question is narrower than the broad study title: the named primary outcome concerns Cohort 1 and a pressure average taken at specified times of day. It is not a single reported endpoint spanning every cohort. The record says that later protocol amendments changed the study to safety-only for Cohorts 2 and 3, so the diurnal measurements used for the primary endpoint were no longer collected in those cohorts.

The study description includes multiple ENV515 implant regimens and follow-up schedules. As a result, cohort and treatment-group context matters when interpreting any outcomes. A comparison between groups in a non-randomized study can reflect differences in how participants entered or were assigned to groups, as well as differences in treatment. The registry record does not report an adjusted estimate or a detailed analysis plan that would clarify how such differences were handled.

Accordingly, the record identifies the question and outcome definition but does not provide the numerical result needed to assess the observed change, its precision, or the extent to which group differences might be attributable to treatment rather than other factors.

3. Trial Design

This was a Phase 2a, multicenter, three-stage, open-label, prospective study with active-comparator control described in its official title. The registry records non-randomized allocation, no masking, and a parallel model. Enrollment was 41. The sponsor was Envisia Therapeutics, and the study status is completed.

The registry describes three cohorts with differing implant schedules. Cohort 1 received ENV515-1 and ENV515-3 implants in the study eye for 28 days. Cohort 2 received two ENV515-3 implants in the study eye for 12 months, with optional extensions of 6 months and 3 months, for a stated total of 21 months. Cohort 3 received one or two ENV515-3-2 implants in the study eye, with an optional 6-month extension and an additional 6-month extension, for a stated total of 24 months. These are different regimens and observation periods, not interchangeable versions of one uniform treatment schedule.

The listed start date is 2015-01-01, and the primary completion date is 2019-02-13. The record gives the trial phase and overall enrollment but does not report cohort-specific enrollment in the registry record described for this analysis. Nor does it report a detailed account of how participants were allocated among treatment groups or how the active comparator was used in each cohort.

Non-randomized allocation is important for interpretation. Random assignment is one way to reduce systematic baseline differences between groups; because this study was not randomized, the record does not support assuming that its groups were comparable on all relevant characteristics. Open-label conduct also means the study was not masked, although the registry record does not describe the practical consequences of that feature for each outcome assessment.

The primary endpoint is identified for Cohort 1 only. The registry states that a later amendment changed Cohorts 2 and 3 to safety-only follow-up, with 8AM intraocular pressure collected as a safety assessment rather than the earlier diurnal measurement. This change limits the scope of the efficacy-style endpoint: its stated measure should not be generalized to all cohorts or follow-up periods.

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.

Only the first 6 of 7 groups are shown.

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: Safety Population

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: Safety Population

Only the first 6 of 8 groups are shown.

6. Primary Endpoint

The registry lists the primary outcome as Summary of Change From Baseline Average Intraocular Pressure Diurnal Measurement by Treatment Group Population (Cohort 1), measured over Baseline and Day 25.

The primary endpoint is the summary of change from baseline in average diurnal intraocular pressure for treatment groups in Cohort 1. It is a continuous measure reported in mm Hg, with the parameter described as the mean and dispersion described as the standard deviation. The stated timeframe is baseline and Day 25.

Average diurnal intraocular pressure is defined as the average of measurements at 8AM, 10AM, and 4PM. Measuring at multiple specified times describes pressure across parts of the day rather than relying on a single time-point reading. In general, a continuous change measure can retain information about the magnitude and direction of a measured difference; its interpretation depends on the baseline and follow-up summaries and on how much observations vary between participants.

The registry record describes the endpoint but does not report the mean change, group-specific baseline or Day 25 values, standard deviations, confidence intervals, or a test result. Therefore, the size, direction, and precision of the observed change are not reported in the registry record. A definition of an endpoint is not itself evidence of what the measured result was.

The registry also notes that, after a protocol amendment, diurnal measurements were no longer collected for Cohorts 2 and 3. Those cohorts had 8AM intraocular pressure collected as a safety assessment only. Their measurements should not be treated as observations of the same primary endpoint defined for Cohort 1, since the time-of-day measurement scheme and stated purpose differ.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The outcome is continuous: it is a measured quantity, rather than a count of events or a time until an event. The registry identifies the parameter as a mean and the dispersion measure as a standard deviation. The mean describes the center of a set of measurements; the standard deviation describes how spread out individual measurements are around that center. They answer different questions, and neither alone gives the uncertainty of a group comparison.

What does a change score represent?

A change score compares a follow-up measurement with a baseline measurement for the same outcome. In general, analyzing change can describe how measurements shift over time, while reporting only a follow-up value may leave baseline context less visible. Interpretation requires knowing how the score was calculated and whether data from the same participants were available at both time points. The registry identifies change from baseline and the two time points but does not report the numerical change estimates or details of the calculation beyond the endpoint description.

The primary endpoint uses an average of intraocular-pressure readings at 8AM, 10AM, and 4PM. Averaging repeated measurements within a day can represent a prespecified summary across those measurement times. It also means that this endpoint is not identical to a single reading at one time. The later safety-only measurements in Cohorts 2 and 3 were collected at 8AM, so they do not provide the same diurnal average described for Cohort 1.

How should a mean and standard deviation be read?

A mean is a summary of the central tendency of measured values, while a standard deviation conveys the spread of those values. Neither tells the reader whether an estimate is precise enough to distinguish among a range of plausible effects. Precision is often conveyed through a confidence interval or standard error, but those are not reported for the primary endpoint in the registry record. A standard deviation should not be mistaken for a confidence interval: the former describes variation among observations, whereas the latter describes uncertainty in an estimated quantity under an analysis model.

For a comparison of group means, the statistical result depends on the actual group summaries and the analysis used. The registry entries identify only the outcome type and its summary measures. They do not report an inferential test, a model, covariate adjustment, or a confidence interval. No new comparison can be reconstructed from the endpoint description alone.

Why does allocation matter?

Randomization is a design method that assigns participants by chance and can help balance measured and unmeasured characteristics across groups in expectation. This trial's allocation is recorded as non-randomized. Consequently, a difference between groups may be influenced by how groups came to differ before treatment, or by other factors associated with group assignment. Statistical adjustment can sometimes address measured differences, but it cannot automatically remove unmeasured confounding. Whether adjustment was used and which variables were considered are not reported in the registry record.

The study is described as open-label and masking is recorded as none. In general, knowledge of treatment assignment can influence some aspects of care, reporting, or assessment, depending on the outcome and procedures. The endpoint is a measured pressure quantity, but the registry entries do not describe whether outcome assessors were independent or how measurement procedures were standardized. Those details are not reported in the registry record and should not be presumed.

What do the planning assumptions mean?

Sample-size planning asks how many participants per arm might be needed under stated assumptions to detect an effect at a chosen significance level and power. The assumptions specified for the planning illustration include a two-sided significance level of 0.05, equal allocation between two arms, a normal approximation, and an effect defined as a stated fraction of the observed effect. Such calculations are conditional on those assumptions and on the effect used as a planning reference. They are not observed power, and they do not demonstrate that a trial has found an effect.

The record says these illustrations are based on the observed effect, but the numerical primary endpoint estimate is not reported in the endpoint details. No planning count should therefore be inferred from the assumptions alone. A planning calculation is also not evidence that the original study was designed using those assumptions: the registry does not report the trial's own sample-size justification. It does not report the assumptions used for the trial's design, and those should not be guessed.

How should adverse-event counts be interpreted?

The safety entries give group-specific numbers at risk and numbers affected for serious and other adverse events. These are descriptive summaries. A count of participants with an event is distinct from a count of all event episodes, and the registry entries do not specify recurrent-event handling or exposure-adjusted rates. Group follow-up schedules differ, so raw counts alone do not account for time under observation. The record does not report a comparative statistical analysis of adverse events.

General statistical interpretation also distinguishes association from causation. An event recorded during a study is not, by that fact alone, established to have been caused by treatment. The listed safety counts do not supply causal attribution, and the record does not report a formal causal assessment in the registry record. Small group counts can also make estimates unstable; broad conclusions should not be drawn from a few observations.

10. Multiplicity, Missing Data and Analysis Populations

The registry identifies one primary outcome measure and one analysis in its summary, but it does not report a multiplicity-control strategy. Multiplicity arises when multiple outcomes, time points, groups, or analyses are tested: the chance of at least one apparently unusual result can increase as the number of tests grows. Procedures such as prespecifying a primary comparison or adjusting significance thresholds can address particular multiplicity concerns, but the registry record does not say whether any such approach was used. The number of listed analyses alone does not establish the full set of analyses performed.

The study includes multiple cohorts, treatment groups, and observation schedules. The stated primary endpoint is for Cohort 1 at baseline and Day 25. The record says that a later amendment changed Cohorts 2 and 3 to safety-only follow-up, with 8AM pressure collected for safety assessment. The registry entries do not report how the amendment affected any analysis plan beyond that description, nor do they report whether endpoints or analyses were changed in other ways.

Missing-data methods are not reported in the registry record. The endpoint description does not explain how incomplete baseline or follow-up pressure measurements were handled, whether participants with partial measurement times contributed to the daily average, or whether any imputation was used. Those details matter because an analysis based only on complete observations can differ from one using an explicit model or imputation procedure when missingness is related to participant characteristics or outcomes.

The primary population is described as the safety population. The registry entries do not define that population further or explain how it relates to all enrolled participants for the endpoint analysis. An intention-to-treat population, a per-protocol population, or other analysis population should not be assumed. The record also does not report a detailed statistical analysis plan, assumptions about outcome distributions, or a missing-data sensitivity analysis. These omissions limit assessment of the robustness and reproducibility of the primary endpoint analysis.

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 serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: corneal edema (11.1%), cervical spinal stenosis (11.1%), paget's disease of the right nipple (11.1%), spinal cord compression (11.1%), cystocele (11.1%).

The registry lists serious adverse-event figures separately for each group, alongside the number at risk. Cohort 1 - Group 1 lists 7 at risk and 0 affected by serious adverse events; Cohort 1 - Group 2 lists 10 and 1; Cohort 2 - Group 3 lists 2 and 0; Cohort 1 - Group 4 lists 2 and 0; Cohort 2 lists 5 and 0; Cohort 3 - Group 1 lists 6 and 0; and Cohort 3 - Group 2 lists 9 and 4. The listed death count is 0 for every group.

For other adverse events, the corresponding at-risk and affected counts are 7 and 4 for Cohort 1 - Group 1; 10 and 7 for Cohort 1 - Group 2; 2 and 2 for Cohort 2 - Group 3; 2 and 2 for Cohort 1 - Group 4; 5 and 5 for Cohort 2; 6 and 6 for Cohort 3 - Group 1; and 9 and 9 for Cohort 3 - Group 2. These are group-level descriptive figures. They should not be combined into a comparative treatment effect without an analysis that accounts for design, follow-up, and group differences.

The registry also lists serious-event terms with percentages, including corneal edema and several other terms. The entries do not establish that any event was caused by treatment. No adjusted or exposure-time-based safety comparison is reported in the registry record, so these counts describe reported events rather than comparative risks.

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

The registry record establishes that a prospective, open-label, non-randomized Phase 2a study evaluated ENV515 travoprost extended-release implants in people with bilateral ocular hypertension or early primary open-angle glaucoma. It specifies a primary continuous outcome for Cohort 1: change from baseline in average diurnal intraocular pressure at Day 25. It also documents distinct implant regimens, follow-up schedules, a later safety-only amendment for Cohorts 2 and 3, and group-level adverse-event counts.

Those details do not reveal the primary endpoint result. The registry entries described for the outcome do not include the mean change, standard deviation values, confidence interval, or statistical test. It is therefore not possible to state the direction or magnitude of the measured change, or how precisely it was estimated. The endpoint's definition cannot substitute for its observed values.

Nor does the design support reading the groups as randomized, like-for-like controls. Allocation was non-randomized, masking was absent, and the cohorts followed different regimens. Comparisons may be affected by differences between groups or follow-up, and the registry entries do not report an adjusted analysis that resolves those concerns. The official title's active-comparator description does not change the allocation method.

The safety counts show that adverse events were recorded in the groups, with serious-event counts varying across groups and no deaths listed. These observations do not establish treatment causation or provide a complete comparative safety assessment. Event counts should be understood in the context of the group denominators and different schedules, and not as a definitive estimate of relative risk.

In general, statistical evidence can inform how compatible observed data are with specified assumptions; it does not by itself determine clinical importance or a treatment decision. Here, key numerical outcome estimates and methods needed to assess statistical uncertainty are not reported in the registry record. No medical conclusion about benefit or lack of benefit follows from the endpoint definition or descriptive safety counts alone.

13. Why This Trial Matters Statistically

This trial illustrates why the registry's design details and analysis population matter alongside an outcome label. The primary endpoint is a mean change in a continuous measure, but the registry entries do not report its estimate or uncertainty. A precisely defined endpoint is useful for understanding what investigators intended to measure; without its numerical results, it cannot answer whether or how the measured outcome changed.

The non-randomized allocation is a central statistical feature. Group differences in this design are not automatically attributable to the intervention because assignment was not random. That limitation applies even when a study is described as active-comparator-controlled. The record's warning that arms are not a like-for-like control comparison is important context for interpreting any unadjusted group contrast.

The cohort structure adds another lesson: outcomes and follow-up should be interpreted in the cohort and measurement context in which they were collected. Cohort 1's diurnal measure combines readings at specified times of day; Cohorts 2 and 3 changed to safety-only assessment, with 8AM pressure. Treating these measures as identical would obscure the protocol amendment and the difference in outcome purpose.

Finally, the safety listing shows why descriptive adverse-event counts require care. Group denominators and follow-up schedules differ, and event attribution is not established by recording an event during a trial. A statistical reading should separate what is reported—the counts and terms—from what would require a comparative analysis, causal attribution, or a fuller account of exposure and missing data. The record is informative about study structure, while leaving substantial uncertainty about the primary endpoint result.

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 the numerical primary endpoint results are not reported in the registry record. Without group means, variability estimates, confidence intervals, or a test result, the magnitude, direction, and precision of the Cohort 1 change cannot be assessed.

Allocation was non-randomized, and the registry explicitly cautions that arms are not a like-for-like control comparison. The record does not report baseline balance, a detailed allocation process, or an adjusted analysis. Differences between groups could therefore reflect factors other than treatment, and the registry entries do not show how those factors were addressed.

The study was open-label, with no masking. The registry entries do not describe assessor masking, measurement standardization, or safeguards against knowledge of treatment assignment influencing any aspect of assessment. These details are not reported in the registry record.

The cohorts used differing implant regimens and follow-up schedules. In addition, the protocol was amended so that Cohorts 2 and 3 no longer had diurnal measurements and instead collected 8AM pressure as a safety assessment. This makes it important not to generalize Cohort 1's defined primary endpoint across all cohorts.

The record does not report missing-data procedures, endpoint-specific analysis populations beyond identifying the safety population, a detailed statistical analysis plan, or multiplicity handling. It also does not give exposure-adjusted safety estimates or establish causal attribution for listed events. These gaps limit assessment of robustness and comparative safety. The group-level safety counts should be treated as descriptive, not as a substitute for an appropriately specified comparative analysis.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: Safety and Efficacy of ENV515 Travoprost Extended Release (XR) in Patients With Bilateral Ocular Hypertension or Primary Open Angle Glaucoma — NCT02371746.
• Registry record last updated 2019-10-17; status last verified 2019-09.
• Results first posted 2019-10-17.
• 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

NCT02371746 is a completed Phase 2a, multicenter, prospective, open-label, non-randomized study of ENV515 travoprost extended-release implants. Its official title describes active-comparator control, while the registry records that the arms are not a like-for-like control comparison. Enrollment was 41; the listed start date is 2015-01-01 and the primary completion date is 2019-02-13.

The primary outcome is Cohort 1 change from baseline in average diurnal intraocular pressure, measured in mm Hg at baseline and Day 25. The registry defines the average using readings at 8AM, 10AM, and 4PM, but the numerical endpoint result is not reported in the registry record. Cohorts 2 and 3 changed to safety-only assessment after an amendment.

Group-specific serious and other adverse-event counts are listed, with no deaths recorded in any group. The record does not report a detailed statistical analysis plan, missing-data methods, or an adjusted comparison. These design and reporting limitations constrain interpretation of both endpoint comparisons and safety counts.