ESBA1008 Microvolume Study: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for ESBA1008 Microvolume Study (NCT01849692), a randomized phase 2 study. The primary outcome is Percentage of Responders Based on CSFT and BCVA Outcomes at Day 14 and Day 28.

2. Clinical Question

The trial addressed whether participants with exudative age-related macular degeneration met a combined visual-function and retinal-morphology response after treatment with ESBA1008 delivered by microvolume injection or infusion. The registry describes a prospective, randomized, single-masked study with a parallel design and two stages.

The primary outcome combines change in best-corrected visual acuity (BCVA) with change in central subfield thickness (CSFT). A responder needed at least a 4-letter BCVA gain at Day 14, a 4-letter gain at Day 28, an 80-micron CSFT decrease at Day 14, or an 80-micron decrease at Day 28, meeting at least 3 of those 4 criteria. This definition describes the trial’s measurement rule; without the reported group results, it cannot establish how often participants met that rule.

3. Trial Design

The registry classifies NCT01849692 as a Phase 2 randomized, single-masked, parallel study. It describes the study as prospective and two-staged. Enrollment was 107, the status is completed, the study start is recorded as 2013-06, and primary completion is recorded as 2015-01. Alcon Research is the sponsor.

Four ESBA1008 regimens were assigned to cohorts. Cohort 1 received an intravitreal injection of ESBA1008 1.2 mg/10 μL on Day 0, followed by an injection of ESBA1008 6 mg/50 μL on Day 28. Cohort 2 received an intravitreal infusion of ESBA1008 1 mg/8.3 μL on Day 0, followed by the Day 28 injection of 6 mg/50 μL. Cohort 3 received an injection of ESBA1008 0.6 mg/10 μL on Day 0 and the Day 28 injection of 6 mg/50 μL. Cohort 4 received an infusion of ESBA1008 0.5 mg/8.3 μL on Day 0 and the same Day 28 ESBA1008 injection.

In each of cohorts 1 through 4, the comparator was ranibizumab 0.5 mg in 50 μL, administered by intravitreal injection on Day 0 and Day 28. The registry lists cohort-specific serious and other adverse-event groups, with separate comparator entries for the stages. It does not report the allocation procedure, the identity of the masked party, or further details about how participants were assigned within cohorts. Those design details should not be inferred from the labels randomized and single-masked.

The registry also lists secondary outcomes for change from baseline in BCVA and CSFT by cohort. It reports nine outcome measures but no analyses. The study’s stated objective was to evaluate retinal function and morphology after ESBA1008 microvolume delivery; the available record does not provide results for those measures.

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: Of the 107 enrolled, 55 subjects were exited as screen failures prior to randomization. This reporting group includes all randomized participants (52).

Only the first 6 of 8 groups are shown.

Overall Study

Analysis population for the primary outcome, as defined in the registry: This analysis population includes all subjects who were randomized, received the initial injection or infusion, and had a baseline value and at least 1 postbaseline measurement for the period up to Day 28 for the primary efficacy variables (BCVA and/or CSFT). Here, "n" is the number of subjects in each arm group.

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: This analysis population includes all subjects who were randomized, received the initial injection or infusion, and had a baseline value and at least 1 postbaseline measurement for the period up to Day 28 for the primary efficacy variables (BCVA and/or CSFT). Here, "n" is the number of subjects in each cohort for each arm group, respectively.

6. Primary Endpoint

The registry lists the primary outcome as Percentage of Responders Based on CSFT and BCVA Outcomes at Day 14 and Day 28, measured over Baseline, Day 14, Day 28.

The primary endpoint is the percentage of participants classified as responders using BCVA and CSFT measurements at Day 14 and Day 28, relative to baseline. BCVA was measured by the number of letters read on the ETDRS chart, which has a possible 70 letters. CSFT is the central subfield thickness measurement. One eye, designated the study eye, contributed to the analysis.

A participant qualified as a responder by meeting at least 3 of 4 criteria: a BCVA gain of at least 4 letters at Day 14; a BCVA gain of at least 4 letters at Day 28; a CSFT decrease of at least 80 microns at Day 14; and a CSFT decrease of at least 80 microns at Day 28. The endpoint therefore requires improvement across multiple specified measurements and time points; it is not a measure of change in only one variable.

General interpretation: a composite endpoint can represent more than one dimension of a condition in a single classification. Its meaning depends on the component criteria and the rule for combining them. The registry lists a 90% confidence interval as the measure of dispersion, but does not report a responder percentage or its interval. The rationale for selecting these thresholds and this combination is not reported in the registry record.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The registry describes the outcome and some design features, but it does not report the statistical analysis methods or primary outcome results. The explanations below distinguish the stated measurement rule from general statistical concepts; they do not describe analyses that can be confirmed as having been conducted in this study.

What kind of endpoint is being measured?

The primary outcome is binary at the participant level: each participant either meets the responder rule or does not. The reported measure is a percentage of participants with an event, where the event is meeting that response definition. The underlying response combines four criteria concerning BCVA and CSFT at Day 14 and Day 28. The participant must satisfy at least 3 of the 4 criteria.

General explanation: converting continuous measurements such as letter change or thickness change into threshold criteria makes the outcome easier to express as a responder proportion. It also discards some detail: participants just on opposite sides of a threshold may be classified differently even when their measured values are close. The cutoff-based endpoint should therefore be interpreted alongside the actual measurement changes when those are reported. The record lists secondary outcomes for changes in BCVA and CSFT by cohort, but does not report their results.

What does the confidence interval contribute?

The registry specifies a 90% confidence interval for the primary outcome. General explanation: an interval communicates uncertainty around an estimated responder percentage. It is not a guarantee about the result for an individual participant, and it does not by itself state whether a treatment difference is important. Interpretation normally requires the estimate, interval, comparison being made, and analysis method. No estimate or interval is reported in the registry record, so none of those features can be assessed for this endpoint.

The registry does not name the method used to calculate the interval, specify a model, or report a test for comparing groups. It would be inappropriate to assume a particular test or model from the binary form of the outcome alone. It is also not reported in the registry record whether estimates were adjusted for baseline values or other factors.

Why can over-dispersion matter?

General explanation: when data vary more than a statistical model expects, uncertainty estimates from that model can be too small. For a binary outcome, variation between clusters or groups can sometimes make observations less independent than a simple model assumes. An analysis may need to account for such structure when it is present. The registry does not report a model, a dispersion assessment, or any correction for over-dispersion, so no conclusion about those choices is possible for this study.

How should repeated time points and multiple outcomes be considered?

The response definition uses measurements at Day 14 and Day 28, and the record separately lists secondary BCVA and CSFT outcomes for each cohort. General explanation: examining multiple times, outcomes, or treatment groups creates multiple opportunities to observe an apparently notable result. Statistical planning may address this through a prespecified testing sequence or an adjustment, depending on the intended questions. The registry record does not report whether multiplicity was addressed, which comparisons were prespecified, or how the primary and secondary outcomes were ordered for inference.

Repeated measurements on the same participant may also be related. The composite rule treats the specified criteria as components of one classification, but the analysis method for estimating and comparing responder percentages is not reported. The record does not provide the component-level counts needed to understand which criteria were commonly met or how they contributed to the composite.

What can sample-size planning illustrate?

The planning illustration is described as using a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation. Its target effect is a stated fraction of the observed effect. The record says that non-time-to-event planning quantities are participants per arm, while time-to-event quantities are total events. These are planning assumptions, not observed trial outcomes or observed power. The registry record does not report the trial’s own sample-size justification, the effect used in its original planning, or the assumptions behind that design decision. The planning illustration cannot replace those missing design details.

General explanation: a sample-size calculation asks what amount of information would be needed to detect a chosen effect under stated assumptions. Its result depends on the outcome, target effect, error rate, allocation, and analysis method. It does not establish that a study was adequately powered for every endpoint, and an observed result should not be characterized as having a particular power after the fact. No calculation output or trial-specific justification is reported in the registry record.

What analysis details remain unknown?

The registry gives the primary analysis population in broad terms: randomized subjects who received the initial injection or infusion, had a baseline value, and had at least one postbaseline measurement through Day 28 for the primary efficacy variables, BCVA and/or CSFT. However, it does not report the statistical model, method for missing observations, handling of participants who discontinued, treatment of protocol deviations, or whether analyses followed randomized assignment. It also does not explain how the analysis population was implemented for the composite when a participant had an incomplete component measurement. These omissions limit reproducibility and prevent detailed assessment of the analysis.

10. Multiplicity, Missing Data and Analysis Populations

The registry lists one composite primary outcome and secondary outcomes for change from baseline in BCVA and CSFT in each of the four cohorts. It reports nine outcome measures and zero analyses. The record does not state whether a multiplicity procedure was used, whether a hierarchy of hypotheses was set, or which pairwise comparisons were intended to support confirmatory conclusions. The number of outcome measures alone does not reveal how many statistical tests were planned or how their error rates were handled.

The stated analysis population includes randomized subjects who received the initial injection or infusion, had a baseline value, and had at least one postbaseline measurement through Day 28 for BCVA and/or CSFT. This is an eligibility description for the primary efficacy analysis, not a full account of how missing data were treated. The registry does not report the number excluded from that population, reasons for missing measurements, the method used for incomplete records, or sensitivity analyses. It also does not state whether participants were analyzed according to randomized assignment or according to treatment received.

For the composite, a missing value for one of the four criteria could affect whether a participant qualifies as a responder. The registry record does not report how incomplete components were handled. It does not describe imputation, assumptions about missingness, or a rule for classifying participants whose response status could not be determined. These details are necessary for understanding possible bias in the responder percentage.

General explanation: multiplicity and missing data are related to interpretation because both can affect the reliability of estimates and statistical conclusions. Without the prespecified analysis plan and missing-data procedures, the endpoint definition is not enough to reproduce or fully evaluate an analysis. No such procedures are reported in the registry record.

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 serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: pubis fracture (16.7%), fall (10.0%), pneumonia (10.0%), orthostatic hypotension (0.9%).

The registry lists serious adverse events and other adverse events by group. In Stage 1 ESBA 1.2 mg INJ, 0 of 10 participants at risk were affected by a serious event, and 6 of 10 were affected by other events. For Stage 1 ESBA 1 mg INF, the corresponding counts are 0 of 10 and 4 of 10. For Stage 1 LUCENTIS 0.5 mg INJ, they are 1 of 6 and 6 of 6.

In Stage 2 ESBA 0.6 mg INJ, 1 of 10 participants at risk were affected by a serious event and 6 of 10 by other events. In Stage 2 ESBA 0.5 mg INF, the counts are 0 of 10 and 7 of 10. For Stage 2 LUCENTIS 0.5 mg INJ, they are 0 of 6 and 4 of 6. The pretreatment group lists 1 of 107 affected by a serious event and 3 of 107 by other events. Death counts are not reported in the registry record.

The record also lists serious-event terms with percentages: Pubis fracture, 16.7%; Fall, 10.0%; Pneumonia, 10.0%; and Orthostatic hypotension, 0.9%. The denominator and details of the calculation for these term percentages are not reported in the registry record. The counts describe participants affected, not necessarily the number of event episodes. The categories should not be assumed to be mutually exclusive. Group counts are descriptive and, without comparable follow-up details or uncertainty estimates, do not establish treatment-related differences.

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

The record establishes what the investigators intended to measure: a responder classification based on visual acuity and retinal thickness changes at Day 14 and Day 28. It also describes four ESBA1008 dose-and-delivery regimens, ranibizumab comparator groups, a randomized single-masked design, and the broad eligibility conditions for the primary efficacy population. These are useful details for understanding the question the trial was designed to address.

The registry record does not report how many participants met the primary responder definition in any group. It therefore does not establish the observed response percentage, the size or direction of any group difference, or the precision of an estimate. The definition of an endpoint is not itself evidence that the endpoint improved, and the absence of reported results cannot be interpreted as a finding of no difference.

The adverse-event counts provide descriptive information about affected participants in the listed groups. They do not, without fuller context and analysis, establish that ESBA1008 or ranibizumab caused or prevented a particular event. The groups have different listed at-risk counts, and the registry does not give the observation details or comparative safety analyses needed to make a causal interpretation.

General explanation: a trial result is best understood by considering the estimated effect, its uncertainty, the analysis population, the outcome definition, and how the study handled missing data and multiple comparisons. Here, important elements of that evaluation are not reported in the registry record. No medical conclusion about the comparative effects of these treatments follows from the endpoint definition or the available counts alone.

13. Why This Trial Matters Statistically

This study is statistically informative as an example of a multi-component endpoint in a randomized clinical trial. A participant was classified as a responder using both BCVA and CSFT criteria at two postbaseline time points. That rule makes the outcome interpretable as a proportion, but a reader needs the component results and the prespecified analysis to understand what drives the classification and how confidently groups can be compared.

The two-stage design and four ESBA1008 dose-and-delivery regimens also illustrate why transparent reporting of comparisons matters. The record identifies the arms and the ranibizumab comparator, but does not report the planned comparison structure or statistical analysis. Without that information, it is difficult to assess how the primary question relates to the several cohorts and secondary outcomes.

The record is also a useful reminder that design labels and endpoint definitions do not replace results. Randomization and masking are important design features, but interpretation still requires outcome estimates, uncertainty intervals, and clear reporting of analysis populations and missing-data methods. The registry lists a 90% confidence interval for the primary outcome, yet no interval or responder estimate is reported.

Finally, the adverse-event counts show why descriptive safety data need context. Counts by group can help characterize what was recorded, but differences in group size and missing information about follow-up and analysis limit comparisons. Statistical conclusions depend not just on the existence of a count or a defined endpoint, but on how completely the results and methods are reported.

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 registry record does not report primary endpoint results. It provides neither responder counts nor percentages or confidence intervals, despite specifying the outcome and its 90% confidence interval. The record reports zero analyses, so no comparative efficacy estimate can be evaluated.

The analysis population description is incomplete for assessing selection and missing-data effects. It specifies that participants were randomized, received the initial injection or infusion, and had a baseline and at least one postbaseline measurement through Day 28 for BCVA and/or CSFT. It does not report how many participants met those conditions, how incomplete composite components were handled, or what happened to participants without follow-up measurements.

The statistical analysis plan is not reported in the registry record. The test or model, covariate adjustment, comparison sequence, multiplicity handling, and interval calculation method are unspecified. The record also does not provide a trial-specific sample-size justification. These omissions prevent assessment of whether the analysis followed a prespecified plan and how much precision was expected.

For safety, event counts are listed by group, but the record does not provide the event observation period, event-level detail, statistical comparisons, or uncertainty intervals. The basis for the listed serious-event term percentages is not reported. These limits mean the adverse-event counts should be read descriptively, not as stand-alone evidence of between-group differences or causation.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: ESBA1008 Microvolume Study — NCT01849692.
• Registry record last updated 2016-03-24; status last verified 2016-01.
• Results first posted 2016-02-25.
• 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

NCT01849692, titled ESBA1008 Microvolume Study, is a completed Phase 2 randomized, single-masked, parallel study sponsored by Alcon Research. The registry records enrollment of 107, a start date of 2013-06, and primary completion in 2015-01. Its population was subjects with exudative age-related macular degeneration.

The trial evaluated four ESBA1008 microvolume injection or infusion regimens, with a Day 28 ESBA1008 injection, and ranibizumab comparator groups in both stages. The primary endpoint was the percentage of responders based on BCVA and CSFT outcomes at Day 14 and Day 28. A responder had to meet at least 3 of 4 specified improvement criteria.

The registry lists secondary BCVA and CSFT outcomes and group-level adverse-event counts. It does not report primary endpoint estimates, confidence intervals, or analyses. Detailed statistical methods, multiplicity procedures, and missing-data handling are not reported in the registry record.