Open-Label Study of Intravitreal ICON-1 in Patients With Choroidal Neovascularization Secondary to Age-related Macular Degeneration (AMD): Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Open-Label Study of Intravitreal ICON-1 in Patients With Choroidal Neovascularization Secondary to Age-related Macular Degeneration (AMD) (NCT03452527), a randomized phase 2 study. The primary outcome is Change in Choroidal Neovascularization (CNV) Over Time.

2. Clinical Question

The study was intended to evaluate the safety and effects of repeated intravitreal ICON-1 at 0.6 mg, used as maintenance therapy or in combination with aflibercept. The central statistical question is therefore about the difference between treatment strategies on a structural eye measure over time, not about a comparison with no treatment.

The registry also lists change in Best Corrected Visual Acuity over time as a secondary outcome. That outcome is clinically distinct from CNV area: visual acuity describes visual function, whereas CNV area describes an anatomic feature. The record does not report numerical findings for either outcome. It notes that the OCT-A changes did not correlate with changes in CNV by FA and that further analysis was not performed. Consequently, the registry entry does not establish how either outcome varied across the randomized strategies.

3. Trial Design

This was a Phase 2, randomized, open-label, multicenter study with a parallel-group model. The registry lists enrollment of 15 and gives the status as terminated. The recorded study start date is 2018-03-26, and the primary completion date is 2019-04-25. The reason for termination is not reported in the registry record.

The two listed strategies were ICON-1 maintenance therapy after initial aflibercept treatment and ICON-1 combination therapy with aflibercept treatment. Both involved intravitreal ICON-1; the distinction was whether ICON-1 was used for maintenance after initial aflibercept or alongside aflibercept treatment. The record does not specify further details of the treatment schedule, allocation procedure, or treatment adherence.

Randomization is intended to make treatment groups comparable, on average, with respect to factors that could affect outcomes. In an open-label study, participants and study staff know which strategy is assigned. That knowledge may influence care or outcome assessment, so the method of outcome assessment matters. The primary outcome description says investigators assessed the OCT-A change; masking of those assessors is not reported in the registry record.

A parallel design assigns participants to a strategy that is followed over the study rather than having each participant receive both strategies in sequence. The registry does not provide the allocation ratio, details of randomization, eligibility criteria, or the statistical rationale for the enrollment target. Those omissions limit how fully the design and its precision can be assessed from the registry entry alone.

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

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: The change in choroidal neovascularization by OCT-A, reported as assessed by the investigators. The changes did not correlate with the change in choroidal neovascularization by FA and therefore further analysis was not performed.

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 Change in Choroidal Neovascularization (CNV) Over Time, measured over Month 9.

The primary outcome is titled Change in Choroidal Neovascularization over time, with the timeframe identified as Month 9. Its description specifies mean change from baseline in CNV area in the study eye. The population description says the change was assessed by investigators using OCT-A. The intended quantity is therefore a change in an anatomic measure between baseline and the specified follow-up, rather than a count of clinical events.

In general, measuring change from baseline can account for where participants began on an outcome scale, while the group mean describes the average change within a treatment strategy. The comparison of those changes can be informative about whether the strategies are associated with different average changes. The record does not report the group estimates, their variability, or a between-strategy estimate, so the magnitude and precision of any difference cannot be evaluated.

The registry entry says OCT-A changes did not correlate with changes in CNV by FA and that further analysis was not performed. This is important context for interpreting the endpoint: the recorded OCT-A measure was not supported by a corresponding FA pattern in the reported description. The record does not give the correlation estimate, FA results, or details of the decision not to proceed with further analysis.

There is also a metadata ambiguity: the outcome is labelled with unit participants and data type number, while its textual description specifies mean change in CNV area. Numerical endpoint results are not reported in the registry record.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The study design and outcome wording give some information about the intended analysis, but the registry record does not describe a statistical analysis plan or report inferential results. The concepts below explain how such data are generally interpreted; they should not be read as a description of analyses confirmed to have been conducted for this study.

What does randomization contribute?

In general, randomization assigns participants to strategies by chance. It is used to reduce systematic differences between groups at the time of assignment, including differences in factors that are measured and factors that are not measured. With small enrollment, chance imbalances can still occur, so randomization does not guarantee that the groups are alike in every relevant respect. The registry says the study was randomized but does not report the allocation method, concealment procedures, or baseline characteristics needed to assess group balance.

What does an average change describe?

The primary endpoint is described as mean change from baseline in CNV area. A mean is an average across the observed participants contributing data. A mean change within a group describes the average direction and magnitude of change for that group; a contrast between group means would describe the difference between the strategies on that measure. Neither quantity is reported in the registry entry. The endpoint's metadata labels it as participants and number, despite the text describing a mean change in an area measure, so the precise form of the registered data display is not entirely clear.

In general, variability matters alongside an average. Participants can have different changes even when their group mean is similar. A standard error or confidence interval can communicate the uncertainty around an estimate; a confidence interval gives a range of values compatible with the data and the method used to construct it. No variability estimate or confidence interval for the primary outcome is reported in the registry record. Without such information, the precision of any observed change cannot be assessed.

What can a significance test tell a reader?

In general, a significance test evaluates how compatible the observed data are with a specified null hypothesis under the assumptions of the test. A p-value is not the probability that a treatment strategy is effective, nor does it describe the size or clinical importance of an effect. Interpretation needs the estimated effect and its uncertainty, as well as knowledge of the analysis choices. The registry record lists no analyses and reports no p-value or test for the primary endpoint. No particular statistical test should therefore be attributed to this trial on the basis of the entry.

Why consider over-dispersion?

In general, over-dispersion refers to variability in data that is greater than a chosen statistical model expects. It can make standard errors too small and confidence intervals too narrow if the model does not account for that extra variability. Whether this issue applies depends on the outcome scale and the analysis model. The primary outcome is described as mean change in CNV area, not as a count outcome, and the registry does not report a model or dispersion estimate. There is no basis in the record to say that over-dispersion was assessed or was a concern in the primary analysis.

How should planning illustrations be read?

In general, a sample-size calculation asks how many participants would be needed under specified assumptions to detect a chosen effect with a chosen error rate and power. It is a planning exercise, not a measure of what a completed study actually achieved. The planning assumptions described for the illustrations use a two-sided significance level of 0.05, equal allocation, and a normal approximation, with the target effect expressed as a fraction of an observed effect. These assumptions are not reported as the trial's own design rationale. The registry does not report a sample-size justification, and a planning illustration must not be interpreted as observed power or as evidence that the study had adequate precision.

The record does not report enough analysis detail to evaluate model selection, handling of repeated measurements, baseline adjustment, outlier procedures, or sensitivity analyses. Those methods can matter for longitudinal outcome data. They are not inferred from the endpoint title or study design.

10. Multiplicity, Missing Data and Analysis Populations

The registry lists a primary outcome of change in CNV over time and a secondary outcome of change in Best Corrected Visual Acuity over time. The primary outcome description identifies Month 9, while the outcome title refers to change over time. The record does not explain whether multiple time points or outcome components were tested, or which comparison was designated for confirmatory inference.

In general, testing several outcomes, time points, or treatment contrasts can increase the chance of finding at least one apparently notable result by chance. Statistical plans may address this through a prespecified testing sequence or an adjustment for multiple comparisons. The registry record does not report a multiplicity strategy. It also lists no analyses, so no adjustment or unadjusted testing should be assumed.

The record does not report how missing outcome measurements were handled, how many participants contributed to each endpoint, or which analysis population was used. It is therefore not possible to determine whether the reported outcome description reflects all randomized participants, participants who completed follow-up, or another population. No imputation method, sensitivity analysis, or reason for missing measurements is reported in the registry record.

The enrollment target's statistical justification and any interim analyses are also not reported in the registry record. The planning assumptions used for sample-size illustrations are not the same as a documented trial-specific design or analysis plan. Together, these omissions prevent a detailed assessment of multiplicity control, missing-data assumptions, and the population underlying any outcome estimate.

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: transient ischemic attach (tia) (14.3%), sepsis (14.3%), metabolic encephalopathy (12.5%), urosepsis (12.5%).

For ICON-1 maintenance therapy, the registry reports serious adverse events for 2 of 7 participants at risk and other adverse events for 6 of 7 at risk; deaths are reported as 0. For ICON-1 combination therapy, it reports serious adverse events for 1 of 8 participants at risk and other adverse events for 8 of 8 at risk; deaths are reported as 0. These are group-specific counts as recorded, not estimates of comparative treatment effect.

The listed serious adverse-event terms and percentages are Transient Ischemic Attach (TIA), 14.3%; Sepsis, 14.3%; Metabolic Encephalopathy, 12.5%; and Urosepsis, 12.5%. The entry does not provide further context for these term-level percentages, such as timing or a comparison adjusted for exposure.

In general, safety counts in a small study can be imprecise and should be interpreted alongside definitions, follow-up duration, and participant exposure. The registry record does not report those details or a statistical comparison of adverse events between strategies. The counts should not be treated as proof of a causal relationship, nor should an absence of reported deaths be taken to establish broader safety.

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

The record documents a randomized study of two ICON-1 treatment strategies in patients with CNV secondary to age-related macular degeneration. It describes a Month 9 primary outcome based on mean change in CNV area assessed by OCT-A and notes that OCT-A changes did not correlate with changes in CNV by FA. It also reports selected adverse-event counts. These details identify the research question and some of the reported safety information.

The record does not report the numerical primary outcome results, a comparison between strategies, or uncertainty around an effect. It therefore cannot establish the direction or magnitude of a difference in CNV area. It likewise does not report numerical findings for the listed secondary visual-acuity outcome. The absence of these results in the registry entry is not evidence that the strategies had the same outcomes.

The study's open-label design and the absence of reported details about outcome-assessor masking are relevant limitations when considering possible assessment influences. The registry does not explain the termination, describe missing outcomes, or identify the analysis population. These gaps make it difficult to determine how the recorded results relate to all participants assigned to a strategy.

In general, a treatment comparison is best understood through an effect estimate, its uncertainty, the analysis population, and the methods used to handle missing measurements and multiple outcomes. Those elements are not reported for the primary endpoint in this record. The reported adverse-event counts are descriptive; they do not resolve the lack of efficacy estimates or establish that one strategy is safer than the other.

Accordingly, the registry entry supports a description of the study design, its intended endpoint, and its stated OCT-A and FA caveat. It does not support a conclusion about the comparative effect of the two strategies on CNV area or visual acuity.

13. Why This Trial Matters Statistically

This study raises a useful statistical issue: an endpoint can be specified in a registry without the numerical information needed to interpret its treatment comparison. Naming mean change in CNV area and a follow-up timeframe tells readers what investigators intended to assess, but not how large the observed changes were, how variable they were, or how precisely the strategies differed.

The record's statement that OCT-A changes did not correlate with FA changes also illustrates why outcome measurement and measurement method matter. Two methods intended to assess CNV change may not produce findings that track together. Without the underlying estimates and methodological details, readers cannot assess the strength of the relationship or decide how much weight to place on either measure.

The small enrollment and terminated status make transparent reporting especially important, but neither fact reveals the reason for termination or the consequences for analysis. A registry record that reports outcome estimates, uncertainty intervals, analysis populations, and missing-data handling would make it easier to distinguish an inconclusive result from an absence of a meaningful difference. Those details are not reported for the primary outcome.

The study also has a secondary visual-acuity outcome and safety reporting, which are not interchangeable with the structural CNV endpoint. Considering outcomes separately helps prevent a structural measure, a functional measure, or adverse-event counts from being treated as substitutes for one another. The record's main statistical lesson is therefore about the limits of inference when design information is available but outcome estimates and analysis details are not.

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.

Several limitations are specific to the information recorded for this study. The registry gives enrollment of 15 and a terminated status, but does not explain the termination or indicate whether it affected planned follow-up. Without that context, readers cannot judge how the status relates to the availability or completeness of outcome data.

The primary outcome description says the investigator-assessed OCT-A changes did not correlate with changes in CNV by FA and that further analysis was not performed. The record does not report the OCT-A or FA estimates, the correlation measure, the number of observations contributing to it, or the reason for the lack of correlation. This leaves the endpoint's evidential basis difficult to evaluate.

The outcome metadata labels the primary measure as participants and number, while the description says mean change in CNV area. The registry does not clarify that difference or provide a numerical outcome display. It also does not report an analysis population, missing-data handling, baseline group characteristics, outcome-assessor masking, or the statistical model.

The open-label design may permit knowledge of assignment to influence care or assessment; the record does not state whether assessors were masked. The allocation method and ratio are not reported. The reason for the enrollment target, any interim analysis, and the rationale for termination are not reported in the registry record. These limitations concern both the conduct details available to readers and the absence of results needed to quantify the primary comparison.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: Open-Label Study of Intravitreal ICON-1 in Patients With Choroidal Neovascularization Secondary to Age-related Macular Degeneration (AMD) — NCT03452527.
• Registry record last updated 2021-04-13; status last verified 2020-11.
• Results first posted 2021-03-15.
• 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

NCT03452527 is a Phase 2 randomized, open-label, multicenter, parallel study of repeated intravitreal ICON-1 for CNV secondary to age-related macular degeneration. The listed strategies are ICON-1 maintenance therapy after initial aflibercept treatment and ICON-1 combination therapy with aflibercept. Enrollment is 15, and the registry status is terminated.

The primary outcome is described as mean change from baseline in CNV area in the study eye at Month 9, assessed by investigators using OCT-A. The record states that OCT-A changes did not correlate with CNV changes by FA and that further analysis was not performed. Numerical primary and secondary outcome results, an inferential comparison, and its uncertainty are not reported in the registry record.

Safety counts are recorded for serious and other adverse events, and deaths are listed as 0 in each strategy group. The record does not explain the study's termination or report a trial-specific statistical analysis plan, missing-data methods, or sample-size justification.