Safety and Efficacy Study of Intravitreal Ocriplasmin in Subjects With AMD With Focal Vitreomacular Adhesion: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Safety and Efficacy Study of Intravitreal Ocriplasmin in Subjects With AMD With Focal Vitreomacular Adhesion (NCT00913744), a randomized phase 2 study. The primary outcome is Proportion of Subjects With Focal Vitreomacular Adhesion (VMA) Release by Day 28.

2. Clinical Question

3. Trial Design

This was a randomized, double-masked, parallel-group Phase 2 trial comparing intravitreal ocriplasmin with sham injection in subjects with exudative age-related macular degeneration and focal vitreomacular adhesion. The official title describes it as a multicenter study. The registry record lists the trial status as completed, enrollment as 100, a start date of 2010-01, and primary completion in 2012-12.

Random allocation and double masking are important features for interpreting a comparison between groups. Randomization is intended to make the groups comparable in expectation with respect to factors that could influence the outcome. Masking can reduce the risk that knowledge of assignment affects assessments or other study procedures. The endpoint assessment was performed by a masked Central Reading Center using Optical Coherence Tomography, as described in the record. The registry record does not give details of the randomization sequence, allocation concealment, or how masking was maintained.

The two listed groups were ocriplasmin and sham injection. Arm descriptions contain no further details. The primary efficacy data set was the Full Analysis Set, and the record states that missing data for any reason were imputed using Last Observation Carried Forward. The posted results list 74 subjects for ocriplasmin and 25 for sham. These are the group sizes attached to the endpoint results; the record separately gives overall enrollment as 100.

The registry record does not report the trial's original sample-size justification, planned power, target effect, or design assumptions. It also does not report the protocol's planned analysis methods in detail. Such omissions limit the ability to determine how the posted analysis compares with every planned analysis, beyond the endpoint and method information recorded for the results.

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 Full Analysis Set (FAS) was the primary data set for efficacy analysis. Data that were missing for any reason were imputed using the Last Observation Carried Forward (LOCF) method.

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: Full Analysis Set (FAS): All randomized subjects who have been administered trial medication and for whom data of at least one post-baseline efficacy assessment is available. One subject (ocriplasmin) was not included in the FAS because the subject withdrew consent after receiving study treatment and refused further contact.

6. Primary Endpoint

The registry lists the primary outcome as Proportion of Subjects With Focal Vitreomacular Adhesion (VMA) Release by Day 28, measured over Day 28.

The primary endpoint was the proportion of subjects with focal vitreomacular adhesion release by Day 28. It is a binary outcome: for each subject, the endpoint classifies whether release was observed by the specified assessment time, and the group result expresses the share meeting that definition as a percentage.

The record states that release was determined by a masked Central Reading Center's Optical Coherence Tomography evaluation. Use of a central masked assessment can help make endpoint classification more consistent and limit the influence of treatment knowledge on image interpretation. The endpoint focuses on an anatomical finding, rather than a broad clinical outcome. Its use therefore answers a specific question about whether the adhesion was judged released by the assessment time; it does not by itself describe other outcomes or establish the broader clinical significance of release.

The endpoint's timeframe was Day 28. The primary efficacy analysis used the Full Analysis Set, with missing data imputed by Last Observation Carried Forward for any reason. The registry record does not report further details about the endpoint's operational criteria or the handling of individual assessment situations. It lists one outcome measure and no posted secondary outcome results.

7. Results Posted in the Registry

• Ocriplasmin: 24.3% (18/74) versus 12.0% (3/25) on control; risk difference 12.3 percentage points (95% CI -3.7 to 28.4), risk ratio 2.03 (0.65–6.31); unadjusted two-proportion z-test p = 0.193.

8. Statistical Interpretation

9. Statistical Methods Explained

The primary outcome is binary: each subject either had focal vitreomacular adhesion release by Day 28 or did not, according to the masked Central Reading Center's Optical Coherence Tomography evaluation. The reported group percentages describe the proportion with the event. In a comparison of two binary outcomes, the difference in proportions expresses how far apart the group event rates are on the probability scale. A difference of zero corresponds to equal proportions; a positive difference, when defined as ocriplasmin minus sham, points toward a higher event proportion in the ocriplasmin group.

What does the Fisher Exact analysis do?

The sponsor's reported analysis is identified as Fisher Exact, with the parameter described as a difference in proportions. Fisher's exact test is a method for comparing event counts between two groups in a two-by-two arrangement. General explanation: the method evaluates the observed allocation of events across groups under a no-association model, conditional on the margins of the count table. It is often useful when event counts are limited, because it does not rely on the same large-sample approximation as some other tests. The registry record reports the method but does not describe any further details of its implementation.

The sponsor reports a difference of 12.3 percentage points, a 95% confidence interval from -3.7 to 28.4, and p = 0.262. The confidence interval includes zero, the value representing no difference in proportions. The result is therefore compatible with no difference as well as a range of differences in either direction. A non-small p-value is not proof that the groups are equivalent; equivalence requires a prespecified margin and a suitable design and analysis, which are not reported in the registry record.

How should the recalculation be understood?

The recalculated analysis is an unadjusted recalculation from the posted summary statistics. Its reported p-value is 0.193. It does not incorporate adjustment for other variables or additional information that might have been used in a fuller analysis. The sponsor's analysis remains the registry's reported analysis; the recalculation is a distinct statistical reading of the posted counts and percentages. The registry record does not report a discrepancy between the sponsor result and the recalculation. The methods nonetheless differ, so the p-values need not match exactly.

General explanation: a p-value is calculated with reference to a null hypothesis and a statistical model. It indicates how unusual data at least as incompatible with that null would be if the model and null were true. It is not the probability that the null hypothesis is true, nor the probability that the observed difference arose by chance in an unrestricted sense. The p-value also does not measure the size or clinical importance of an effect. Those questions require attention to the estimated difference, its uncertainty, and the context of the endpoint.

What does the Full Analysis Set and imputation mean?

The record identifies the Full Analysis Set as the primary data set for efficacy analysis. It states that data missing for any reason were imputed using Last Observation Carried Forward. In general, this method uses a subject's last observed value as the value carried forward to a later assessment. Its effect depends on the pattern and timing of missing observations and on whether carrying the last observation forward is a reasonable representation of what would otherwise have been observed. The registry record does not report the number of missing endpoint observations, the reasons for missingness, or sensitivity analyses using alternative approaches.

Because the endpoint is binary and assessed at Day 28, missing-data handling can affect how subjects are classified in the analysis. The record's description does not supply enough detail to evaluate the consequences of the imputation for the reported group proportions. The listed arm sizes and percentages should therefore be understood alongside the stated Full Analysis Set and imputation approach, rather than assumed to be based only on complete Day 28 observations.

Why do confidence intervals matter alongside tests?

General explanation: a confidence interval presents a range of values compatible with the data and the method used, at a stated confidence level. It helps show both the estimated direction and the precision of a group comparison. A wide interval indicates that the data do not pin down the effect closely. If an interval for a difference includes zero, the data do not exclude no difference at that confidence level. The interval does not assign a probability to the true effect being within its specific bounds after the data have been observed.

For this trial, the sponsor reports a 95% interval spanning negative and positive differences. That range communicates substantial uncertainty, even though the point estimate is positive. The recalculation's interval also crosses the null. Reading the interval together with the estimate is more informative than treating a test result as a simple yes-or-no verdict.

What can be inferred from the available analysis record?

The record reports one primary outcome measure and one analysis, and it lists no posted secondary outcomes. It identifies the sponsor's test and the endpoint population and missing-data approach. It does not provide the detailed statistical analysis plan, model covariates, procedures for interim analyses, or multiplicity strategy; these items are not reported in the registry record. Their absence prevents a complete assessment of whether the posted analysis reflects every planned decision.

The listed planning illustrations are separate from the trial's observed analysis. They use the observed effect as a basis for hypothetical planning under stated assumptions. They are not a measure of the probability that this completed trial detected an effect. Sample-size calculations depend on assumptions about the effect to detect and the analysis model; changing those assumptions changes the number of participants required. The registry record does not report whether these illustrative assumptions were used in the original trial design.

10. Confidence Intervals and Precision

The sponsor's estimated difference in proportions is 12.3 percentage points. Its 95% confidence interval extends from -3.7 to 28.4 percentage points. The interval includes zero, meaning that no difference is among the values compatible with the data under this analysis and confidence procedure. It also spans estimates favoring either group. The point estimate alone therefore gives an incomplete account of the result.

Confidence intervals express uncertainty about an estimate. In general, a narrower interval indicates greater precision, while a wider interval leaves more uncertainty about the effect's size. A 95% confidence procedure has a repeated-sampling interpretation: if the same method were applied across many comparable repetitions under its assumptions, 95% of the resulting intervals would cover the fixed underlying parameter. It does not mean that there is a 95% probability that this particular interval contains the true value.

The interval's breadth is consistent with the modest group sizes attached to the endpoint results: 74 in the ocriplasmin group and 25 in the sham group. The endpoint percentages are 24.3% and 12.0%, respectively. The registry record does not report a target precision or a clinically important difference against which the interval could be assessed. Thus, the interval is informative about statistical uncertainty, but the record does not establish which values within it would matter clinically.

The recalculated analysis also has an interval that crosses the null value. The unadjusted recalculation reports p = 0.193, while the sponsor's Fisher Exact analysis reports p = 0.262. These figures arise from different methods and should not be conflated. Both analyses leave uncertainty about the group difference; neither supports interpreting the point estimate as a precise measure of the underlying effect.

11. Planning a Similar Trial: Sample Size

This is a planning illustration, not a re-evaluation of the original trial. It asks: if a new study wanted to detect a difference like the one observed, or a smaller one, how large would it need to be? It is deliberately not “observed power” of the finished trial, which is not a meaningful quantity.

The planning illustrations report participants per arm, not total events. They are based on the observed effect and show hypothetical group sizes for detecting the stated fraction of that effect under the specified assumptions. The displayed effect scenarios are planning for 100% of the observed effect, 75% of the observed effect, and 50% of the observed effect. For each scenario, the figures give participants per arm for 80% power and participants per arm for 90% power.

The planning assumptions are a two-sided significance level of 0.05, equal allocation between the two arms, and a normal approximation. The effect to detect is the stated fraction of the observed effect. These are planning assumptions for the illustrations, not the trial's original design assumptions; the original design assumptions are not reported in the registry record. The record's overall enrollment is 100, while the endpoint results list 74 subjects in the ocriplasmin group and 25 in the sham group.

In plain language, 80% power refers to the chance that a study would produce a statistically significant result under the assumed effect and model, if that effect were the true one. The 90% power column uses a higher target chance of detecting the assumed effect, and therefore requires more participants under the same general setup. The smaller-effect scenarios require more participants because a weaker separation between groups is harder to distinguish from sampling variation. The illustrations are not observed power; they are prospective planning calculations under stated assumptions.

12. How the Sample Size Is Derived

Power is the probability that a study of a given size rejects the null hypothesis when a specific true effect exists. It depends on four things: the effect to detect, the variability of the outcome, the significance level (here a two-sided α of 0.05, so z_1−α/2 = 1.960) and the desired power (z_1−β = 0.842 for 80% and 1.282 for 90%).

Formula

n is the number of participants in each arm, p₀ and p₁ are the control and treatment proportions, and p̄ is their average.

Worked calculation for this trial

1. Control proportion p₀ = 0.120; treatment proportion p₁ = 0.243; average p̄ = 0.182.
2. First term: z_1−α/2 × √[2p̄(1−p̄)] = 1.96 × 0.5452 = 1.0686.
3. Second term: z_1−β × √[p₀(1−p₀) + p₁(1−p₁)] = 0.842 × 0.5382 = 0.4530.
4. n = (1.0686 + 0.4530)² / (0.1232)² = 152.4, rounded up to 153 participants per arm for 80% power.

The smaller-effect rows in the table above repeat the same calculation with the effect multiplied by 0.75 and 0.5 (for ratios, applied to the logarithm of the ratio).

R code

alpha <- 0.05
z_a   <- qnorm(1 - alpha / 2)          # two-sided
p0 <- 0.12                          # control proportion
p1 <- 0.243243243243243                          # treatment proportion
n_per_arm <- function(power, frac = 1) {
  q1 <- p0 + (p1 - p0) * frac               # smaller effect = fraction of the observed difference
  pbar <- (p0 + q1) / 2
  z_b <- qnorm(power)
  ceiling(round((z_a * sqrt(2 * pbar * (1 - pbar)) + z_b * sqrt(p0 * (1 - p0) + q1 * (1 - q1)))^2 / (q1 - p0)^2, 6))
}
for (f in c(1, 0.75, 0.5))
  cat(sprintf("%3.0f%% of observed effect: n per arm = %s (80%% power), %s (90%% power)\n", 100 * f,
              format(n_per_arm(0.80, f), big.mark = ","), format(n_per_arm(0.90, f), big.mark = ",")))

# Check against R's built-in function (unrounded n per arm)
cat("power.prop.test:", round(power.prop.test(p1 = p0, p2 = p1, power = 0.80)$n, 1), "\n")

# Simulation: how often does the z-test reject at the 80%-power sample size?
set.seed(913744)
n    <- n_per_arm(0.80)
reps <- 20000
x0 <- rbinom(reps, n, p0); x1 <- rbinom(reps, n, p1)
ph <- (x0 + x1) / (2 * n)
z  <- ((x1 - x0) / n) / sqrt(ph * (1 - ph) * 2 / n)
cat(sprintf("Simulated power at n = %s per arm: %.3f (%d replicates)\n", format(n, big.mark = ","), mean(abs(z) > z_a, na.rm = TRUE), reps))

Output from running the code

100% of observed effect: n per arm = 153 (80% power), 204 (90% power)
 75% of observed effect: n per arm = 254 (80% power), 339 (90% power)
 50% of observed effect: n per arm = 529 (80% power), 707 (90% power)
power.prop.test: 152.4 
Simulated power at n = 153 per arm: 0.808 (20000 replicates)

The simulation draws many pairs of event counts at the planned sample size and counts how often the two-proportion z-test rejects the null. It should land close to the target power; at very small required sample sizes it can fall below it, because the normal approximation is rough there.

13. Analyses Reported by the Sponsor

The registry record reports the sponsor's comparison as a Fisher Exact analysis of the difference in proportions. The estimate is 12.3 percentage points, with a 95% confidence interval from -3.7 to 28.4 and p = 0.262. This is the reported analysis of the primary endpoint. Its interval includes zero, and the posted result leaves uncertainty about the size and direction of the difference.

The unadjusted recalculation from the posted summary statistics gives p = 0.193. It is not the sponsor's analysis and does not replace it. It uses a separate calculation from the posted group results, while the sponsor reports a Fisher Exact method. Different methods can yield different p-values. The registry record does not identify a discrepancy between the reported analysis and the recalculation; the difference in p-values should be read in light of the distinct methods, rather than as evidence that one result is a correction of the other.

Both readings have the same broad interpretive limitation: the data do not precisely establish the size of a group difference. The sponsor's interval crosses the no-difference value, and the recalculated interval also crosses the null. The sponsor's reported analysis is the primary record result; the recalculation is supplementary statistical context.

14. Multiplicity, Missing Data and Analysis Populations

The registry record lists one outcome measure and one analysis, and it reports no secondary outcome results. It identifies focal vitreomacular adhesion release by Day 28 as the primary endpoint. It does not report a multiplicity strategy, such as how statistical testing would be controlled across multiple endpoints, time points, or analyses. With no secondary results posted, the available record supports interpretation of the single listed primary endpoint, but it does not establish how any broader family of planned comparisons was handled.

The Full Analysis Set was the primary data set for efficacy analysis. The record states that data missing for any reason were imputed with Last Observation Carried Forward. It does not report how many subjects had missing observations, why the observations were missing, or whether missingness differed between groups. It also does not report sensitivity analyses under alternative assumptions about missing data. These omissions matter because the endpoint is classified at Day 28, and the imputation approach can influence how incomplete outcome information contributes to the analysis.

The registry record does not report the detailed statistical analysis plan, including whether covariate adjustment was planned, how other analyses were to be prioritized, or whether interim analyses were planned. These details should not be inferred from the single posted result. The available information identifies the endpoint, analysis population, imputation approach, and sponsor's test, but is not sufficient to reconstruct all protocol-level analysis decisions.

General explanation: multiplicity can arise when several statistical hypotheses are tested, because repeated testing can increase the chance of at least one apparently unusual result under a global no-effect situation. A prespecified strategy can address that issue. Missing-data methods address a different source of uncertainty: the outcome is not observed for some participants, and the analysis must make assumptions about those unobserved values. The registry record does not give enough information to assess either issue beyond the stated LOCF method and the single posted primary analysis.

15. 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: retinal detachment (4.0%), visual acuity reduced (4.0%), cystitis (4.0%), vascular pseudoaneurysm (4.0%), dizziness postural (4.0%).

The registry record lists serious adverse events affecting 18 of 75 at risk in the ocriplasmin group and 2 of 25 at risk in the sham group. These are counts of subjects affected, not counts of every event occurrence. The record separately lists other adverse events affecting 33 of 75 at risk with ocriplasmin and 11 of 25 at risk with sham; these are not the serious adverse event counts.

The listed serious adverse event terms each have a reported frequency of 4.0%: Retinal detachment, Visual acuity reduced, Cystitis, Vascular pseudoaneurysm, Dizziness postural, and Ateriosclerosis. The registry record does not provide further event-level detail in the information available, such as timing, severity beyond the serious classification, or the number of occurrences for each term. Death counts are not reported in the registry record.

These safety figures are descriptive. They should be read in relation to the listed numbers at risk and the trial's recorded follow-up, rather than treated as a complete comparative safety assessment. The registry record does not provide enough detail to attribute individual events to treatment or to assess their clinical course.

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

The primary result describes the proportion of subjects with OCT-assessed focal vitreomacular adhesion release by Day 28. The posted percentages are 24.3% for ocriplasmin and 12.0% for sham. The sponsor reports a difference of 12.3 percentage points, but its 95% confidence interval extends from -3.7 to 28.4. Because this interval includes zero and spans values in both directions, the estimate does not precisely determine the underlying difference.

That interpretation is not the same as concluding that the groups are equivalent, nor is it a claim that one group has a definitively higher outcome rate. The posted analysis leaves a range of possibilities compatible with the data. The recalculated unadjusted p-value is 0.193; the sponsor's Fisher Exact analysis reports p = 0.262. Neither p-value should be treated as the probability that a treatment effect exists or as a measure of clinical importance.

The endpoint is a Day 28 anatomical assessment. It does not establish how subjects felt or functioned, whether changes persisted, or how other clinical outcomes compared. The registry record does not report secondary outcome results. It also does not give a threshold for a clinically important difference, so the statistical estimates cannot be classified against such a threshold from this record alone.

The record identifies a randomized, double-masked comparison, with assessment by a masked Central Reading Center. Those features are relevant to the quality of the comparison, but they do not remove uncertainty from the limited endpoint sample sizes or resolve limitations in what is reported. The Full Analysis Set used LOCF imputation for missing data, and the record does not report the extent or pattern of missingness.

Overall, the posted data provide an estimate of the day-28 endpoint comparison, with substantial uncertainty around its magnitude. They do not establish a precise group difference, equivalence, or a broader clinical conclusion. Interpretation should remain confined to the recorded endpoint, population, assessment time, and analysis information.

17. Why This Trial Matters Statistically

This trial is statistically informative because it illustrates the difference between a point estimate and the uncertainty around that estimate. The observed percentages favor a higher day-28 release proportion in the ocriplasmin group, but the sponsor's confidence interval includes no difference and extends in both directions. A positive point estimate alone cannot resolve whether the underlying difference is close to zero or substantially larger.

The comparison also shows why a p-value should not be read as a verdict. The sponsor's Fisher Exact result is p = 0.262, while the unadjusted recalculation gives p = 0.193. The values differ because the methods differ. Both should be considered alongside the confidence interval and the limited group sizes, rather than used as standalone measures of evidence or importance.

The endpoint and assessment process provide a clear statistical target: a binary Day 28 OCT finding assessed by a masked central reader. At the same time, that target is narrow. It does not represent every aspect of clinical outcome, and the registry record contains no secondary outcome results for broader context. The Full Analysis Set and LOCF approach also underline that the analysis depends on how missing endpoint data were handled.

Finally, the planning illustrations make explicit that sample-size requirements depend on the effect assumed for planning. Smaller assumed effects require more participants to distinguish them from random variation under the stated assumptions. Those illustrations are not the trial's original design rationale. The record does not report the original assumptions, making it impossible to evaluate whether the completed trial was planned around a particular target effect or precision.

18. 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.
• Participant counts were reconstructed from posted percentages and arm sizes, so small rounding differences are possible.

The endpoint results are based on 74 subjects in the ocriplasmin group and 25 in the sham group. The imbalance in the listed group sizes and the limited total number of subjects with the endpoint constrain precision. The sponsor's confidence interval is broad and includes no difference, so the estimated group contrast remains uncertain.

The registry record describes missing data imputation by Last Observation Carried Forward, but it does not state how many Day 28 observations were missing, why they were missing, or whether the pattern varied by group. It does not report sensitivity analyses that could show how robust the result is to other missing-data assumptions. The record also does not give further operational details for determining release beyond the masked central OCT assessment.

Only the primary outcome is posted, and no secondary results are reported. The endpoint concerns an anatomical assessment at Day 28; the record does not provide other outcome results that could clarify the broader clinical context or persistence of the finding. A threshold for a clinically important difference is not reported.

The registry record does not report the original sample-size justification or detailed statistical analysis plan. It also does not report the multiplicity strategy, interim analyses, or further analysis details such as covariate adjustment. Therefore, the planning illustrations cannot be treated as a record of the original design, and the extent to which all prespecified analyses are represented cannot be assessed.

The safety information is also limited in detail. The record lists serious adverse event counts and several event terms, but it does not provide event-level timing or clinical course in the information available. These limitations restrict interpretation to the descriptive figures posted in the registry record.

19. Related Tutorials

20. Related Statistical Calculators

21. Sources

• ClinicalTrials.gov: Safety and Efficacy Study of Intravitreal Ocriplasmin in Subjects With AMD With Focal Vitreomacular Adhesion — NCT00913744.
• Registry record last updated 2014-12-17; status last verified 2014-04.
• Results first posted 2014-05-05.
• 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.

22. Record Summary

The registry record describes a completed randomized, double-masked, parallel-group Phase 2 trial of intravitreal ocriplasmin versus sham injection in subjects with exudative age-related macular degeneration and focal vitreomacular adhesion. Enrollment is listed as 100. The primary endpoint was the proportion with focal vitreomacular adhesion release by Day 28, assessed by a masked Central Reading Center using Optical Coherence Tomography.

The posted results report 24.3% for ocriplasmin and 12.0% for sham. The sponsor's reported difference is 12.3 percentage points, with a 95% confidence interval from -3.7 to 28.4 and p = 0.262 by Fisher Exact analysis. The unadjusted recalculation reports p = 0.193. The interval includes no difference, leaving uncertainty about the size and direction of the comparison.

The Full Analysis Set was used for efficacy, with missing data imputed by Last Observation Carried Forward. No secondary outcome results are posted. The record does not report the original sample-size justification or detailed analysis plan.