AVE0005 (VEGF Trap) in Patients With Recurrent Symptomatic Malignant Ascites: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for AVE0005 (VEGF Trap) in Patients With Recurrent Symptomatic Malignant Ascites (NCT00396591), a non-randomized phase 2 study. The primary outcome is Percentage of Participants With a Repeat Paracentesis Response (RPR).

2. Clinical Question

3. Trial Design

NCT00396591 is a phase 2, multicenter, open-label, single-arm study of intravenous aflibercept in advanced ovarian cancer with recurrent symptomatic malignant ascites. The registry record lists a planned enrollment of 16 and describes participants as receiving treatment every 2 weeks until a criterion for discontinuation was met. The study is marked completed. Its recorded start is 2006-10, and its primary completion is 2008-11.

The design was non-randomized, with no masking and a single-group model. Accordingly, the primary comparison was between paracentesis timing during treatment and each participant’s pre-registration pattern, rather than between independently assigned treatment and control groups. That within-person reference can describe whether the measured interval changed from baseline, but it does not supply the protection against confounding that random assignment and a concurrent control may provide.

The primary objective was to compare time between paracenteses before and after aflibercept administration. Secondary objectives included further assessment of efficacy and safety. The exploratory objectives concerned pharmacokinetics, immunogenicity, and health-related quality of life. Other listed outcomes include time to repeat paracentesis, 60-day frequency of paracentesis, progression-free survival, overall survival, anti-drug antibody response, and adverse events.

The registry record does not report the detailed protocol, treatment-discontinuation criteria, recruitment flow, analysis population, or statistical analysis plan. It also does not report a concurrent control group or an allocation procedure beyond identifying the study as non-randomized and single-group.

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:

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 Percentage of Participants With a Repeat Paracentesis Response (RPR), measured over up to 2 years post-registration.

The primary endpoint was the percentage of participants with a repeat paracentesis response (RPR), assessed up to 2 years post-registration. RPR was defined as a time to repeat paracentesis at least a two-fold increase over the average duration of the two intervals between the three most recent paracenteses before study registration. The endpoint therefore turns a change in a continuous time interval into a yes-or-no response classification, then expresses the number meeting that definition as a percentage of the total participants.

This type of endpoint is intended to make a clinically recognizable pattern of change interpretable as a responder proportion. It also makes the definition dependent on the choice of baseline reference and the threshold used to classify response. A participant just below the threshold and one with little change are both classified as not meeting the endpoint, while those meeting it may have different magnitudes of change. As a general statistical point, a proportion is easier to interpret when its numerator, denominator, and uncertainty interval are reported together.

The registry record does not report the observed percentage, response count, denominator used in the result, or 95% confidence interval. Thus the endpoint definition is available, but the primary outcome estimate and its precision are not reported in the registry record.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

What does the response definition capture?

The primary endpoint classifies each participant according to whether the time to repeat paracentesis increased by at least a two-fold amount relative to a baseline interval. The baseline was the average duration of the two intervals between the three most recent paracenteses before registration. The resulting endpoint is a proportion: participants who satisfy the rule form the numerator, and the total participants in the endpoint analysis form the denominator. The registry record states this percentage-based definition but does not report the observed numerator, denominator, or response percentage.

As a general statistical point, reducing a continuous measurement to a binary response can simplify communication, but it also discards information about the size of changes within each category. The definition makes the threshold explicit; it does not reveal how close participants were to the threshold, or how the intervals varied across participants. The record does not provide those distributions.

How should a confidence interval be understood?

The endpoint description specifies a 95% confidence interval as the dispersion measure. In general, a confidence interval represents uncertainty in an estimate under the assumptions of the method used to calculate it. It is not a range containing a fixed proportion of individual participant outcomes, and it does not by itself remove limitations in the study design. For a response percentage, the interval’s width depends on factors including the observed response proportion and the amount of outcome information available. The observed interval is not reported in the registry record, so its width and the precision of the estimate cannot be assessed.

The record does not state the confidence-interval calculation method, whether any adjustment was used, or which analysis population posted the estimate. Those details are not reported in the registry record and should not be inferred from the endpoint’s stated dispersion measure.

What can a single-group before-and-after comparison establish?

The trial used each participant’s pre-registration paracentesis pattern as the reference and administered aflibercept in a single group. This can organize a descriptive comparison of intervals before and after treatment. In general, a participant serving as their own reference can control for characteristics that remain stable within that person, but it does not control for changes that occur over time or for other factors that may differ between the pre-treatment and treatment periods. A concurrent randomized comparison would address a different question by comparing outcomes across assigned groups; this study is not described as randomized or controlled in that way.

The endpoint’s baseline is based on recent prior intervals, not a separately randomized comparison period. The registry record does not report whether the baseline data were collected in a standardized way, how incomplete intervals were handled, or whether participants had complete follow-up for the endpoint. Those matters are not reported in the registry record.

What does the planning illustration mean?

The record describes sample-size calculations as planning illustrations based on an observed effect, using a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation; the effect to detect is stated as a fraction of the observed effect. For time-to-event calculations, the stated quantity is the total number of events; for other calculations, it is participants per arm. These are planning assumptions, not results from the single-group study design itself. In particular, a planning illustration is not observed power and cannot substitute for a reported endpoint estimate or its uncertainty.

The record does not report the numerical effect used in those illustrations or a numerical sample-size result in the registry record for this account. No planning quantity can therefore be interpreted as an observed outcome or as a justification for the study’s enrollment. The study’s listed enrollment is 16, but the registry record does not report a sample-size justification.

Why does dispersion matter?

As a general concept, over-dispersion occurs when outcome variability exceeds what a statistical model assumes. If a model underestimates variability, uncertainty intervals may be too narrow and inferential tests may be too optimistic. This is relevant to count or rate outcomes when participant-to-participant variation is greater than a simple model expects. The registry record lists outcomes such as 60-day frequency of paracentesis, but it does not report the statistical model used for that outcome or whether over-dispersion was assessed. No claim about the presence or handling of over-dispersion can be made from the registry record.

More broadly, an analysis method must match the outcome, follow-up, and missingness structure. The record identifies several outcome types, including response percentage, time-to-event outcomes, and adverse-event counts, but does not provide the detailed analysis methods for them. The method, assumptions, and analysis population for each outcome are not reported in the registry record.

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("Aflibercept")
n      <- c(16)
events <- c(10)
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  Aflibercept  16  10  62.5  35.4  84.8  38.6  81.5  38.3  81.6

11. Multiplicity, Missing Data and Analysis Populations

The registry record describes one primary endpoint and lists secondary outcomes including time to repeat paracentesis, 60-day frequency of paracentesis, progression-free survival, overall survival, anti-drug antibody response, and adverse events. Exploratory objectives also concerned pharmacokinetics, immunogenicity, and health-related quality of life. The record does not report how the primary, secondary, and exploratory outcomes were organized into a formal testing hierarchy, or whether any adjustment for multiple statistical tests was planned.

As a general statistical issue, examining multiple outcomes can increase the chance that at least one result appears notable by chance when each is tested separately. A prespecified hierarchy or multiplicity adjustment can help define how such evidence should be interpreted. Whether either approach was used is not reported in the registry record. The record lists no analysis records, and it does not provide outcome-specific estimates or inferential results for the primary endpoint.

Missing-data rules and analysis populations are also not reported in the registry record. The record does not state how missing paracentesis measurements, incomplete follow-up, treatment discontinuation, or withdrawals were handled. It does not identify whether analyses used all registered participants, participants with evaluable endpoint data, or another population definition. Those omissions limit assessment of how the response proportion was constructed and whether participants with different amounts of follow-up contributed comparably.

These are reporting gaps, not proof that a particular method was or was not used. The record does not give enough information to infer the handling of multiplicity, missing data, or analysis populations.

12. 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 5% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: intestinal obstruction (31.2%), vomiting (25.0%), disease progression (25.0%), nausea (12.5%), anaemia (6.2%).

For the Aflibercept group, the registry record reports serious adverse events in 15 of 16 participants and other adverse events in 16 of 16 participants. The serious-event terms with listed percentages are intestinal obstruction (31.2%), vomiting (25.0%), disease progression (25.0%), nausea (12.5%), anaemia (6.2%), and tachyarrhythmia (6.2%). These percentages describe the reported terms; they should not be added together, since the record does not establish that the categories are mutually exclusive.

These are safety observations within a single treatment group, not comparative estimates against another group. The figures do not by themselves establish that aflibercept caused a particular event. The registry record does not report the event-level timing, duration, severity distribution beyond the serious-event classification, recurrence, or attribution details needed for a fuller account. The deaths field is null, so a death count is not reported in the registry record. The listed safety figures should therefore be read as descriptive event reporting, not as evidence of comparative risk.

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

The study record contributes a clearly stated primary response definition for a single-group evaluation of aflibercept in advanced ovarian cancer with recurrent symptomatic malignant ascites. It specifies that response meant an at least two-fold increase in time to repeat paracentesis relative to a defined pre-registration baseline, and identifies an assessment timeframe of up to 2 years post-registration. These details clarify what the investigators intended to measure.

However, the registry record does not report the primary response percentage, the number of participants meeting the criterion, or its 95% confidence interval. It is therefore not possible to judge from this record how frequently the defined response occurred or how precisely it was estimated. That lack of a reported primary result should not be interpreted as either evidence for or evidence against a response.

The single-group design also limits what any before-and-after difference could establish. Without randomization and a concurrent control group, a change from the participants’ prior paracentesis pattern cannot be isolated from other changes over time. The record’s design description supports interpretation as a within-person historical comparison, not a controlled estimate of a treatment effect.

The safety figures are descriptive reports for the treated group. They do not provide a comparative estimate of risk or establish causation. The registry record does not report a detailed analysis plan, handling of missing data, analysis populations, or multiplicity procedures. Those limits matter when assessing both outcome estimates and uncertainty.

In general, statistical interpretation depends on the outcome definition, the estimate, its uncertainty, the analysis methods, and the design generating the data. Here, the endpoint and design are described, but the primary estimate and key analysis details are not reported in the registry record. Conclusions should remain confined to those recorded features and the reported safety figures.

14. Why This Trial Matters Statistically

This trial is statistically notable for using a pre-treatment history as the comparator in a single-group study. The primary question was not framed as a randomized comparison between treatment and control; instead, the response definition compared treatment-period paracentesis timing with each participant’s recent baseline pattern. This makes the construction of the baseline measure central to interpretation. The registry record defines that measure as the average duration of two intervals before registration, but does not report the observed response results.

The endpoint also illustrates a common trade-off in clinical outcome design. A threshold such as an at least two-fold increase creates a binary response that can be communicated as a percentage, while reducing the detail available from the underlying time intervals. A response percentage is most informative alongside its numerator, denominator, and confidence interval; those primary results are not reported in the registry record.

The case also shows why design and reporting must be considered together. A before-and-after comparison can describe change relative to prior experience, but it cannot provide the same causal contrast as a randomized concurrent comparison. Even a precise estimate would not remove that design limitation. Conversely, the absence of a reported estimate means the record does not permit an assessment of precision in the first place.

Finally, the study lists several secondary and exploratory outcomes, while the analysis details and multiplicity approach are not reported in the registry record. This limits interpretation of any set of outcome findings. The statistical importance lies in separating a well-defined measurement question from evidence about the size, certainty, and causal meaning of a result.

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.

Several limitations specific to this trial affect interpretation. It was an open-label, non-randomized, single-group study, with no concurrent control group. The primary endpoint relied on a historical within-participant baseline. As a general design consideration, such a comparison can be affected by changes over time and by differences between the pre-registration and treatment periods. The registry record does not report methods intended to address those concerns.

The primary endpoint’s observed result is not reported in the registry record. Neither the response count nor the percentage and 95% confidence interval are available in the registry record. This prevents evaluation of the endpoint’s magnitude and precision. The record also does not report distributions of paracentesis intervals or additional summaries that would show how individual patterns related to the threshold-based response definition.

The registry record does not report the detailed statistical analysis plan, the analysis population, missing-data handling, or multiplicity procedures. It also does not report the sample-size justification. These omissions make it difficult to assess whether the intended analyses were prespecified, how incomplete follow-up was treated, or how multiple outcomes were interpreted.

Safety reporting is limited to the group-level affected-participant figures and selected serious-event term percentages. Detailed timing, event duration, attribution, and comparative safety information are not reported in the registry record. The design cannot support a direct comparison of event rates with an alternative treatment or control group.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: AVE0005 (VEGF Trap) in Patients With Recurrent Symptomatic Malignant Ascites — NCT00396591.
• Registry record last updated 2013-01-10; status last verified 2011-07.
• Results first posted 2013-01-10.
• 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

NCT00396591 is a completed phase 2, multicenter, open-label, single-group study of intravenous aflibercept every 2 weeks in advanced ovarian cancer with recurrent symptomatic malignant ascites. The registry record lists enrollment of 16, a start of 2006-10, and primary completion in 2008-11.

The primary endpoint was the percentage of participants with a repeat paracentesis response, defined as an at least two-fold increase in time to repeat paracentesis relative to the average of two pre-registration intervals. The assessment timeframe was up to 2 years post-registration. The registry record does not report the observed primary response percentage or its confidence interval.

For the Aflibercept group, serious adverse events were reported in 15 of 16 participants and other adverse events in 16 of 16 participants. The study had no randomized or concurrent control group. Detailed statistical methods, analysis populations, missing-data handling, and multiplicity procedures are not reported in the registry record.