Aflibercept Injection for Proliferative Diabetic Retinopathy: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Aflibercept Injection for Proliferative Diabetic Retinopathy (NCT01805297), a randomized phase 2 study. The primary outcome is Rate of Resolved Post-operative Vitreous Hemorrhage..

2. Clinical Question

The registry describes a study evaluating ocular and systemic safety of intravitreal aflibercept in patients undergoing surgery for proliferative diabetic retinopathy. Its primary endpoint focuses on postoperative vitreous hemorrhage, while the listed secondary outcomes include mean change in visual acuity, need for any additional surgical intervention, and changes in mean central retinal thickness. The posted primary outcome is therefore one part of a broader assessment, not a complete account of all clinical outcomes.

The comparison is between the two recorded surgical strategies, but the comparator description includes preoperative aflibercept as well. Because the registry does not explain whether that wording is intentional or how the strategies differ apart from the intraoperative injection, interpretation should follow the arm descriptions without assuming a different treatment contrast. The record does not provide further detail about eligibility criteria or the precise clinical circumstances that led participants to undergo surgery.

3. Trial Design

This is a randomized, parallel-group Phase 2 trial with no masking recorded. The registry lists the University of Oklahoma as sponsor and the study status as completed. The recorded start is 2013-03, and primary completion is 2014-02. Enrollment is listed as 12.

Participants were assigned to a group titled Vitrectomy With Aflibercept Injection or a group titled Standard Vitrectomy. Each arm lists 6 participants. The first description specifies preoperative and intraoperative intravitreal aflibercept, whereas the second specifies preoperative aflibercept followed by standard of care vitrectomy. This wording means the registry descriptions do not present the comparator as a strategy without preoperative aflibercept. The record does not report further details that resolve this feature of the comparison.

Random allocation can help make treatment groups comparable in expectation, but it cannot guarantee balance in a small study. With no masking recorded, the record does not indicate that participants or study staff were blinded to assignment. It does not report further information about the randomization procedure, allocation concealment, or whether outcome assessment was masked.

The primary outcome is recorded at 24 weeks and concerns postoperative vitreous hemorrhage. The arm results are participant counts. The record also lists three secondary outcomes: mean change in visual acuity, need for any additional surgical intervention, and changes in mean central retinal thickness. Four outcome measures are listed overall, while the analysis count is recorded as 0. The record does not report a detailed statistical analysis plan, a sample-size justification, or interim analyses. These omissions prevent a full assessment of the trial's planned analysis and the role each outcome was intended to play.

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

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 Rate of Resolved Post-operative Vitreous Hemorrhage., measured over 24 weeks.

The primary endpoint is titled Rate of Resolved Post-operative Vitreous Hemorrhage. Its description defines the outcome as the percentage of patients who had no vitreous hemorrhage before or at week 24, with a timeframe of 24 weeks. The unit is participants, and the posted arm results are counts of participants meeting the outcome. In the arm titled Vitrectomy With Aflibercept Injection, the count is 6 of 6; in Standard Vitrectomy, it is 5 of 6.

This endpoint is relevant to the surgical setting because it records whether vitreous hemorrhage was present over the stated period. A binary outcome reduces each participant's status to whether the defined condition was met or not. That can make an outcome straightforward to summarize, but it also discards information about timing, duration, recurrence, and severity unless those details are captured separately. The registry record does not give definitions for those features or further information about how the outcome was assessed.

The title uses the word “rate,” while the description refers to a percentage and the posted results are counts. Those formats should not be conflated: the registry's actual arm entries are participant counts, not a reported rate estimate. No confidence interval or inferential comparison is reported in the registry record. Accordingly, the counts describe the recorded outcome in each arm but do not on their own quantify the precision of the difference between strategies.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

Statistical methods help distinguish what was observed from what can reasonably be inferred. In this record, the primary endpoint is binary: participants either meet the stated condition of no vitreous hemorrhage before or at week 24, or they do not. The registry reports the number meeting the condition in each arm. It does not report a model-based estimate or uncertainty interval for the comparison.

What does a participant count show?

A count is a direct description of how many participants in a group met an outcome definition. It does not, by itself, express uncertainty about the underlying event probability or the contrast between groups. Counts are useful for transparency, particularly when group sizes are small, because readers can see the observed outcome numbers rather than relying only on a summary statistic. Here, the arm entries are 6 of 6 and 5 of 6.

A binary endpoint simplifies a participant's outcome into two categories. This can be appropriate when the clinical question concerns whether a defined event occurred by a specified time. The simplification can also conceal distinctions such as how long an event lasted, when it occurred, or whether it recurred. The registry does not report these features for this endpoint.

What would an interval estimate add?

In general, a confidence interval describes the range of values compatible with the observed data under a specified statistical method. It communicates precision as well as direction and magnitude. A wide interval indicates substantial uncertainty; an interval that excludes a null value may be relevant to a formal test, depending on the method and estimand. No confidence interval is reported for this comparison, so its precision cannot be assessed from an interval estimate in the registry record.

For a binary endpoint, common comparative approaches include estimating a difference in event proportions, a relative measure, or using a test suited to small cell counts. The choice depends on the question, design, and analysis plan. These are general examples, not methods identified as having been used in this trial. The registry record does not report the sponsor's statistical method for this outcome.

Why does small group size matter?

When groups are small, each participant's outcome has substantial influence on the group summary. This can produce unstable estimates and broad uncertainty. It also limits the ability of randomization to ensure close balance in baseline characteristics. These considerations do not invalidate the observed counts; they affect how confidently those counts can be generalized or interpreted as evidence of a treatment contrast.

Statistical significance and clinical importance are different questions. A test addresses compatibility with a statistical null hypothesis under its assumptions. It does not by itself establish clinical relevance, and a non-significant result would not prove equivalence. Conversely, a difference in observed counts is not, by itself, evidence that the underlying strategies differ. No p-value or formal test result is reported.

What is the status of recalculation?

The registry record indicates that values were missing or not estimable for a two-arm comparison of this binary endpoint. Thus, a simple unadjusted recalculation from the posted summary statistics is not available. There is no sponsor analysis reported that could take precedence over such a recalculation. The interpretation should stay with the arm counts and acknowledge that a comparative estimate is unavailable.

How should planning calculations be read?

In general, a sample-size calculation estimates the number of participants needed to detect a specified effect under assumed statistical conditions. It is a planning exercise, not a measure of how much power the completed trial actually achieved. The registry's planning assumptions describe a two-sided significance level of 0.05, equal allocation, and a normal approximation, with the target effect expressed as a fraction of the observed effect. Those assumptions do not amount to the trial's own design justification. The record does not report such a justification. Any planning illustration should therefore be read as conditional on its stated assumptions, not as an observed finding or confirmation of adequate power.

Multiplicity arises when several outcomes or hypotheses are assessed. Considering many tests can increase the chance of at least one apparently unusual result by chance, unless the analysis plan addresses this. The registry lists a primary outcome and three secondary outcomes, but does not report a multiplicity procedure or a hierarchy governing interpretation. The available record consequently does not establish how results across outcomes were meant to be judged together.

Finally, a complete analysis also depends on defining who was analyzed and how missing observations were handled. Neither the analysis population nor a missing-data approach is reported in the registry record. Without these details, readers cannot determine whether all assigned participants contributed to each outcome or how unavailable outcome data were treated.

10. Exact Estimates for Each Arm

No two-arm comparison is shown for this trial, but each arm's result can still be summarized with exact interval estimates computed from the posted counts. The Clopper-Pearson interval is exact and conservative; the Wilson interval is a common closer-to-nominal alternative; the Bayesian credible interval uses a uniform Beta(1, 1) prior. For small groups the three can differ noticeably.

R code and output

arm    <- c("Vitrectomy With Aflibercept Injection", "Standard Vitrectomy")
n      <- c(6, 6)
events <- c(6, 5)
for (i in seq_along(n)) {
  ci <- binom.test(events[i], n[i])$conf.int          # Clopper-Pearson exact interval
  cr <- qbeta(c(0.025, 0.975), 1 + events[i], 1 + n[i] - events[i])   # Bayesian, uniform Beta(1,1) prior
  wi <- (function(x, n) { p <- x / n; z <- qnorm(0.975); d <- 1 + z^2 / n
    c((p + z^2 / (2 * n) - z * sqrt(p * (1 - p) / n + z^2 / (4 * n^2))) / d, (p + z^2 / (2 * n) + z * sqrt(p * (1 - p) / n + z^2 / (4 * n^2))) / d) })(events[i], n[i])
  cat(sprintf("ARM|%s|%d|%d|%.1f|%.1f|%.1f|%.1f|%.1f|%.1f|%.1f\n", arm[i], n[i], events[i], 100 * events[i] / n[i],
              100 * ci[1], 100 * ci[2], 100 * wi[1], 100 * wi[2], 100 * cr[1], 100 * cr[2]))
}

ARM  Vitrectomy With Aflibercept Injection  6  6  100.0  54.1  100.0  61.0  100.0  59.0  99.6
ARM  Standard Vitrectomy  6  5  83.3  35.9  99.6  43.6  97.0  42.1  96.3

11. Multiplicity, Missing Data and Analysis Populations

The registry lists one primary outcome concerning postoperative vitreous hemorrhage and three secondary outcomes: mean change in visual acuity, need for any additional surgical intervention, and changes in mean central retinal thickness. It lists four outcome measures overall. The analysis count is recorded as 0. Results for the secondary outcomes are not reported in the registry record.

Multiplicity is a general concern when several outcomes or comparisons are examined. The chance of finding an apparently notable result by chance can rise when many statistical tests are considered. Researchers may address this with a prespecified hierarchy, adjusted significance thresholds, or another stated strategy. The registry record does not report a multiplicity adjustment, an outcome hierarchy, or a statistical plan that would show how multiple findings were to be interpreted. It is not possible to infer that no adjustment was used from this absence alone.

The record does not report the analysis population, such as whether the primary analysis included all randomized participants or followed another rule. It also does not report how missing outcome data were handled, whether any participants lacked an endpoint assessment, or whether sensitivity analyses were conducted. These details matter because excluding participants or making assumptions about unavailable outcomes can affect an estimate and its uncertainty.

The arm counts provide a direct descriptive summary, but they do not resolve these reporting gaps. Without the analysis population and missing-data approach, the exact basis of the endpoint summary is not fully documented. Without results for the listed secondary outcomes, the primary endpoint cannot be considered alongside the other outcomes named in the registry.

12. 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 non-serious adverse event terms

The registry reports serious adverse events for each arm. In Vitrectomy With Aflibercept Injection, 0 serious adverse events are recorded among 6 participants at risk; in Standard Vitrectomy, 0 are recorded among 6 participants at risk. Deaths are recorded as 0 in both groups. These entries describe the safety data recorded in the registry, not proof that serious events cannot occur.

The record separately reports other adverse events: 6 participants in the aflibercept injection arm and 5 in the Standard Vitrectomy arm are listed as affected, with 6 participants at risk in each group. “Other adverse events” should not be read as equivalent to serious adverse events. The serious-event counts are separately reported as 0 for both arms.

Zero observed serious events is a descriptive result in a small study. It does not establish the absence of risk, particularly when the number of participants observed is limited. The record does not provide event-level details for the other adverse events, their severity, timing, duration, or relationship to treatment. No serious-event terms are listed. The safety figures should therefore be interpreted as registry-reported counts over the study, not as a comprehensive characterization of safety or a basis for comparing risks precisely.

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

The result means that the registry records the defined no-hemorrhage outcome for 6 participants in the Vitrectomy With Aflibercept Injection arm and 5 participants in the Standard Vitrectomy arm at the 24-week endpoint. The recorded group sizes are 6 in each arm. This is a description of what was posted, not a precise estimate of how the strategies compare in a broader population.

The result does not establish that one strategy is superior, equivalent, or safer than the other. The registry does not report a confidence interval, p-value, or sponsor-reported analysis for the primary comparison. The available counts cannot show how much uncertainty surrounds a comparative effect. Nor do they establish that the observed pattern would persist in another group of patients.

The treatment contrast also needs careful interpretation. Both arm descriptions include preoperative aflibercept, and the first additionally describes an intraoperative injection. The registry does not clarify the wording or provide further details about the intended distinction between arms. It would therefore be unwarranted to characterize the trial as a simple comparison of aflibercept against no aflibercept.

The study's stated purpose includes evaluating ocular and systemic safety, but the safety counts are limited to the adverse-event entries reported in the registry. No serious adverse events or deaths are listed in either arm, while other adverse events are recorded. These observations do not establish absence of risk, and the record lacks detailed descriptions of the other adverse events.

Finally, the secondary outcome results are not reported in the registry record, and key analysis details—including the analysis population, missing-data handling, and multiplicity approach—are also not reported. The primary counts should be understood as a narrow piece of evidence from a completed randomized Phase 2 study, with substantial limitations on comparative inference.

14. Why This Trial Matters Statistically

This trial is statistically instructive because it combines random allocation with a very small study and a binary primary outcome. Randomization is valuable for comparative questions, but it does not remove uncertainty from a sparse dataset. The posted counts are easy to understand, yet they do not provide the precision information needed to judge the strength of a between-arm contrast.

The record also illustrates why the written definition and the numerical format of an endpoint matter. The endpoint title refers to a rate, and its description refers to a percentage, while the arm entries are counts of participants. Reading the actual outcome definition and posted values avoids treating a count as though a rate or comparative estimate had been reported.

Another important lesson is that a trial's labels and descriptions must be read together. The comparator is called Standard Vitrectomy, but its description includes preoperative aflibercept. That detail complicates a simple interpretation of the treatment contrast. Statistical comparison is only meaningful when the interventions being compared are clearly characterized.

Finally, registry reporting supports transparency but may not include everything needed for a full statistical appraisal. Here, the analysis count is 0, no comparative inference is reported, and information about the analysis population, missing data, and multiplicity is absent. These limitations show why readers should distinguish posted descriptive results from conclusions that require a specified analysis and uncertainty assessment.

15. 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 primary limitation is the small number of participants in each arm, with 6 listed in each group. With sparse binary outcome data, individual observations can have substantial influence on the reported count. The registry does not provide an interval estimate or formal test to convey uncertainty about the comparison.

The arm descriptions are not fully straightforward as a comparison: both include preoperative intravitreal aflibercept, while the intervention arm also includes an intraoperative injection. The registry does not clarify the intended distinction or provide further detail about delivery of the procedures. This constrains interpretation of what aspect of care the arm comparison represents.

The record does not report eligibility criteria in detail, baseline characteristics, the randomization procedure, allocation concealment, or masking of outcome assessment. Although the study is recorded as randomized and unmasked, the available description does not support a fuller appraisal of possible bias or group comparability.

Important analysis details are also absent. The registry does not report the analysis population, missing-data handling, a statistical plan, a sample-size justification, interim analyses, or a multiplicity strategy. The listed secondary outcomes do not have results in the registry record, limiting assessment beyond the primary endpoint. The record reports other adverse-event counts but does not give event-level details, severity, or timing.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Aflibercept Injection for Proliferative Diabetic Retinopathy — NCT01805297.
• Registry record last updated 2023-12-27; status last verified 2023-12.
• Results first posted 2017-09-13.
• 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.

19. Record Summary

NCT01805297 is a completed randomized Phase 2 parallel-group trial sponsored by the University of Oklahoma. The registry lists enrollment of 12, no masking, and a primary completion date of 2014-02. The study concerns vitrectomy for severe proliferative diabetic retinopathy and describes preoperative aflibercept in both arms, with intraoperative aflibercept also described in the intervention arm.

The primary endpoint is postoperative vitreous hemorrhage at 24 weeks. The posted counts are 6 of 6 in the Vitrectomy With Aflibercept Injection arm and 5 of 6 in Standard Vitrectomy. No comparative estimate or inferential analysis is reported in the registry record. Three secondary outcomes are listed, but their results are not reported. The record also lacks details on the analysis population, missing-data handling, multiplicity, and the intended distinction between the arm regimens.