OPT-302 With Aflibercept in Neovascular Age-related Macular Degeneration (nAMD): Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for OPT-302 With Aflibercept in Neovascular Age-related Macular Degeneration (nAMD) (NCT04757636), a randomized phase 3 study. The primary outcome is Mean Change in Early Treatment Retinopathy Study (ETDRS) Best-corrected Visual Acuity (BCVA) Letters.

2. Clinical Question

3. Trial Design

This was a phase 3, multicentre, randomised, parallel-group study of intravitreal OPT-302 combined with aflibercept compared with aflibercept alone in participants with nAMD. The registry describes the study as double-masked and sham-controlled; the masking field lists quadruple masking. There were three groups: 2.0 mg aflibercept with standard-dosing 2.0 mg OPT-302, 2.0 mg aflibercept with extended-dosing 2.0 mg OPT-302, and 2.0 mg aflibercept with sham. Aflibercept was scheduled at 4-weekly intervals for three treatments and then at 8-weekly intervals in each group. The standard OPT-302 schedule was 4-weekly; in the extended-dosing arm, the schedule changed after three treatments to 8-weekly intervals.

The record lists enrollment of 998, a study start date of 2021-03-12, primary completion on 2025-03-31, and status as terminated. The brief description calls it a 2-year study and says primary efficacy would be determined at Week 52. These record details describe the registered study; the termination status alone does not explain why the study ended. A reason for termination is not reported in the registry record.

The primary efficacy analysis population was the modified Intent-to-Treat set, defined as randomised participants with at least one dose of study medication. Efficacy analyses followed randomised assignment. The primary analysis was described as a mixed model for repeated measures, with least-squares means and standard errors reported for change in ETDRS letter score. The registry record does not report the original sample-size justification or the trial's full statistical analysis plan. The posted results therefore support interpretation of the listed endpoints and analyses, but do not establish all planned analyses or the reasons for any changes to the study.

4. Participant Flow and Accounting

The registry reports how participants moved through each stage of the study. All counts below are exactly as posted; missing counts are not inferred from other stages.

Before assignment: Participants who met all inclusion criteria and none of the exclusion criteria were enrolled in the study. 2 subjects (in the 2.0 mg aflibercept with sham arm) were enrolled, but never treated.

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: Modified Intent-to-Treat (mITT) analysis set - comprised all randomised participants with at least one dose of study medication. Participants were analysed according to the study medication to which they were randomised for all efficacy analyses.

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: Modified Intent-to-Treat (mITT) dataset comprised all randomised participants with at least one dose of study medication. Participants were analysed according to the study medication to which they were randomised for all efficacy analyses. Data from 3 participants at a single site (all randomised to the Aflibercept + Sham arm) were excluded from all analyses based on study site noncompliance with potentially signficant impact to reliability of data.

6. Primary Endpoint

The registry lists the primary outcome as Mean Change in Early Treatment Retinopathy Study (ETDRS) Best-corrected Visual Acuity (BCVA) Letters, measured over Baseline to Week 52.

The primary endpoint measures the mean change in Early Treatment Diabetic Retinopathy Study (ETDRS) best-corrected visual acuity letter score in the study eye from baseline to Week 52. The registry specifies the unit as letters read and the reported statistic as a least-squares mean, with standard error as its measure of dispersion. A positive endpoint value indicates improvement in the letter score from baseline, while a negative value indicates deterioration.

Visual acuity is a direct measure of the visual function being studied in nAMD, and a letter-score change gives a quantitative way to compare average change across the randomised groups. Mean change captures the overall group-level pattern, rather than whether every participant changed in the same direction or by the same amount. The least-squares means come from the stated repeated-measures model and are model-based estimates, not simply raw averages. Their interpretation depends on the model and analysis population described in the registry record.

The primary time point was Week 52, with the endpoint covering baseline to that visit. The registry identifies the analysis as an overall-population mixed model for repeated measures. Further details about the model specification, covariates, handling of missing visits, or assumptions are not reported in the registry record. The endpoint is therefore best read together with the reported group estimates and confidence intervals, while keeping those unreported analytic details in mind.

7. Results Posted in the Registry

• 2.0 mg Aflibercept With Extended Dosing 2.0 mg OPT-302: mean 12.82 versus 13.48 on control; difference -0.66 (95% CI -2.68 to 1.36), standardized effect d = -0.05; z-test p = 0.522.
• 2.0 mg Aflibercept With Sham: mean 13.66 versus 13.48 on control; difference 0.18 (95% CI -1.84 to 2.20), standardized effect d = 0.01; z-test p = 0.861.

8. Secondary Efficacy Endpoints

The registry also posts results for secondary outcomes. For each outcome below, the endpoint type, the test applied to the posted summary statistics, the result and its interpretation are given in turn. Secondary endpoints are usually not adjusted for multiple testing, so they support rather than confirm the primary finding.

Proportion of Participants Gaining 15 or More ETDRS BCVA Letters

• Endpoint type: Binary: the number of participants with the event, compared as proportions.
• Test: Unadjusted two-proportion z-test, with a Wald 95% confidence interval for the risk difference.
• Result:
  • 2.0 mg Aflibercept With Extended Dosing 2.0 mg OPT-302: 52.3% (156/298) versus 54.4% (167/307) on control; risk difference -2.0 percentage points (95% CI -10.0 to 5.9), risk ratio 0.96 (0.83–1.12); unadjusted two-proportion z-test p = 0.614.
  • 2.0 mg Aflibercept With Sham: 53.5% (162/303) versus 54.4% (167/307) on control; risk difference -0.9 percentage points (95% CI -8.8 to 7.0), risk ratio 0.98 (0.85–1.14); unadjusted two-proportion z-test p = 0.817.
• Interpretation:
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between 2.0 mg Aflibercept With Extended Dosing 2.0 mg OPT-302 and the control. The interval gives the range of effects that remain compatible with the data.
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between 2.0 mg Aflibercept With Sham and the control. The interval gives the range of effects that remain compatible with the data.

Proportion of Participants Gaining 10 or More ETDRS BCVA Letters

• Endpoint type: Binary: the number of participants with the event, compared as proportions.
• Test: Unadjusted two-proportion z-test, with a Wald 95% confidence interval for the risk difference.
• Result:
  • 2.0 mg Aflibercept With Extended Dosing 2.0 mg OPT-302: 66.1% (197/298) versus 66.4% (204/307) on control; risk difference -0.3 percentage points (95% CI -7.9 to 7.2), risk ratio 0.99 (0.89–1.11); unadjusted two-proportion z-test p = 0.929.
  • 2.0 mg Aflibercept With Sham: 67.3% (204/303) versus 66.4% (204/307) on control; risk difference 0.9 percentage points (95% CI -6.6 to 8.3), risk ratio 1.01 (0.91–1.13); unadjusted two-proportion z-test p = 0.818.
• Interpretation:
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between 2.0 mg Aflibercept With Extended Dosing 2.0 mg OPT-302 and the control. The interval gives the range of effects that remain compatible with the data.
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between 2.0 mg Aflibercept With Sham and the control. The interval gives the range of effects that remain compatible with the data.

Change in Choroidal Neovascularisation (CNV) Area by Fluorescein Angiography (FA)

• Endpoint type: Continuous: a mean value per participant, compared as a difference in means.
• Test: Unadjusted two-sample z-test for the difference in means, using the posted standard errors.
• Result:
  • 2.0 mg Aflibercept With Extended Dosing 2.0 mg OPT-302: mean -4.92 versus -4.91 on control; difference -0.01 (95% CI -0.47 to 0.45), standardized effect d = -0.00; z-test p = 0.966.
  • 2.0 mg Aflibercept With Sham: mean -4.61 versus -4.91 on control; difference 0.30 (95% CI -0.16 to 0.76), standardized effect d = 0.11; z-test p = 0.200.
• Interpretation:
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between 2.0 mg Aflibercept With Extended Dosing 2.0 mg OPT-302 and the control. The interval gives the range of effects that remain compatible with the data.
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between 2.0 mg Aflibercept With Sham and the control. The interval gives the range of effects that remain compatible with the data.

The posted secondary outcomes cover visual-acuity letter gains, change in choroidal neovascularisation area, and an optical coherence tomography fluid-related outcome. Across these outcomes, the group-level pattern does not present a uniformly distinct separation between the OPT-302 arms and the aflibercept-plus-sham group. The posted analyses include contrasts that are close to zero as well as intervals that span values on both sides of zero. The overall picture is therefore broadly consistent with the primary endpoint's limited precision for distinguishing the groups, rather than establishing a clear, consistent between-group pattern.

Secondary endpoints add different perspectives to the primary visual-acuity measure. Some describe the number of participants reaching a letter-gain threshold, while another assesses anatomical change. Agreement across outcomes can be informative, but these endpoints do not replace the prespecified primary question or prove that changes in one measure correspond to changes in another. The registry record does not report a multiplicity strategy for interpreting the collection of secondary analyses.

Unadjusted secondary results carry less weight because multiple endpoints and contrasts create more opportunities for chance findings when each result is considered separately. In addition, the posted analyses use endpoint-specific denominators and methods, so their uncertainty and populations may not be identical to those for the primary analysis. Secondary results are best treated as supportive or exploratory evidence unless a prespecified testing hierarchy or adjustment is reported. Such a plan is not reported in the registry record.

Secondary outcomes registered for this trial, for reference (only those above were recalculated):

• Proportion of Participants Gaining 15 or More ETDRS BCVA Letters
• Proportion of Participants Gaining 10 or More ETDRS BCVA Letters
• Change in Choroidal Neovascularisation (CNV) Area by Fluorescein Angiography (FA)
• Proportion of Participants With Absence of Both Sub-retinal Fluid and Intra-retinal Cysts by SD-OCT

9. Statistical Interpretation

10. Statistical Methods Explained

The primary outcome is continuous: it is a mean change in ETDRS letter score. The registry reports a least-squares mean and standard error for each group, and says that the primary analysis used a mixed model for repeated measures (MMRM). An MMRM uses measurements across visits to estimate change over time and compare groups, while accounting for the fact that repeated observations from the same participant are related. The registry does not report the specific model terms, covariance structure, or other implementation details, so those aspects cannot be evaluated from the record.

A least-squares mean is a model-based group estimate. It can differ from a raw arithmetic mean because it reflects the fitted model and any included terms. A standard error describes the estimated sampling uncertainty of that group estimate; it is not the spread of individual participants' scores. The primary arm estimates have standard errors of 0.729, 0.728, and 0.728, respectively. These values should be read as uncertainty measures for the estimated means, not as ranges containing individual participant outcomes.

Between-group differences answer a different question from the arm-specific means. A difference is an estimate of how far apart two group results are under a chosen contrast direction. Its confidence interval describes a range of values compatible with the data and analysis under the interval's assumptions. An interval that crosses zero does not identify a clear direction of difference at that confidence level. It does not prove that the groups are identical or that any clinically important effect is absent.

The registry's primary comparisons use MMRM and report least-squares mean differences, 95% confidence intervals, and p-values. The additional recalculations use posted arm estimates and standard errors to produce simple unadjusted comparisons. These recalculations are useful as a transparent check of the summary statistics, but they do not reproduce the repeated-measures model or its assumptions. They may differ from model-based estimates because they do not use the same information or adjustment. In this record, the sponsor's comparison of standard-dosing OPT-302 with sham is reported in the reverse contrast direction from the recalculated sham-versus-standard comparison; the numerical estimates have opposite signs, while describing the same pair of groups.

A p-value measures how unusual data at least as incompatible with a specified null hypothesis would be, if that null hypothesis and the analysis assumptions held. It is not the probability that the null hypothesis is true, and it is not a measure of clinical importance. A large p-value does not establish no difference. For these results, p-values should be considered alongside estimates and confidence intervals, which show the direction and range of uncertainty more directly.

For continuous outcomes, standard errors may sometimes be used to approximate the standard deviation of individual values when reconstructing an unadjusted comparison. Such a reconstruction is only an approximation, particularly when the posted summaries come from a model. The recalculated pooled standard deviation for the primary comparisons is 13.26, and the corresponding standardized estimates are -0.050 for extended dosing versus standard dosing and 0.014 for sham versus standard dosing. These derived effect-size descriptions are not the sponsor's model-based results and are not substitutes for the reported MMRM analyses.

Over-dispersion is a general concern for count or binary data when variability is greater than a model assumes; it can make standard errors too small and confidence intervals too narrow if ignored. The primary endpoint is continuous rather than a count, so the specific over-dispersion issue for counts is not the central feature of its analysis. For the secondary binary outcomes, the registry lists Mantel-Haenszel risk differences in its reported analyses. The record does not include enough detail to assess all assumptions or adjustments used in those analyses.

Multiple comparisons are another general statistical concern. Testing several endpoints or group contrasts raises the chance of at least one apparently unusual result if each test is interpreted in isolation. The registry record lists multiple outcome measures and analyses, but does not report whether a multiplicity adjustment or hierarchical testing plan was used. Consequently, the posted secondary p-values should be treated as unadjusted evidence unless the registry reports otherwise. Analysis-population definitions also matter: the primary endpoint uses a modified Intent-to-Treat set, while the registry's listed secondary arm denominators vary by endpoint. Details of missing-data handling are not reported in the registry record.

11. Confidence Intervals and Precision

The confidence intervals quantify uncertainty around the estimated group differences. For the sponsor-reported primary comparison of standard-dosing OPT-302 with sham, the 95% interval runs from -2.20 to 1.84 letters. For extended-dosing OPT-302 with sham, it runs from -2.86 to 1.18 letters. Both intervals include zero and permit estimates on either side of zero. Thus, the posted results do not pin down a single direction of difference with high precision.

The recalculated contrasts also have intervals that cross zero: -2.679 to 1.359 letters for extended dosing versus standard dosing, and -1.839 to 2.199 letters for sham versus standard dosing. These are unadjusted recalculations from the posted summary statistics, rather than the sponsor's MMRM contrasts. They are useful for illustrating uncertainty in those simple comparisons, but should not be treated as replacements for the reported model-based analysis.

Confidence intervals are not guarantees that the true value lies within the stated range. They describe a procedure's long-run coverage under its assumptions. A wide interval indicates less precision; a narrow interval indicates more precision, all else equal. Whether an interval is sufficiently precise for a substantive question depends on what range of effects would matter, and a threshold for clinical importance is not reported in the registry record.

The arm estimates themselves have standard errors of 0.729, 0.728, and 0.728. Those standard errors describe uncertainty in the estimated group means, whereas the confidence intervals above describe uncertainty in between-group differences. Neither form of precision information captures all possible uncertainty from unreported model choices, missing-data assumptions, or multiplicity procedures.

12. 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 sample-size figures are planning illustrations based on the observed effect, not the trial's own design calculation. For these outcomes, the figures are participants per arm, not total event counts. The stated assumptions are a two-sided significance level of 0.05, equal allocation between the two arms, and a normal approximation. The effect to be detected is set to the listed fraction of the observed effect: 100%, 75%, or 50%. The original trial's sample-size justification and design assumptions are not reported in the registry record.

The 80% power column gives the estimated number of participants per arm for a design with an 80% chance of detecting the assumed effect if that effect is real and the assumptions hold. The 90% power column gives the corresponding per-arm planning number for a higher chance of detection. These are prospective planning quantities, not a measure of the probability that the observed trial result is true or a retrospective score of the trial.

Read across a comparison's rows to see how the planning number changes when the target effect is made smaller relative to the observed effect. A smaller effect is harder to distinguish from random variation, so it requires more participants under the stated assumptions. The resulting figures can become very large when the observed difference is small. They should therefore be read as sensitivity illustrations tied to the observed estimate, rather than as recommendations for a future study or as evidence that the original study was adequately or inadequately sized.

The figures are not observed power. Observed power is not a useful substitute for examining the estimate and its confidence interval after a study is complete. Precision is more directly assessed from the intervals around the reported effects.

13. 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, Δ is the difference in means to detect and σ is the common standard deviation.

Worked calculation for this trial

1. Observed difference Δ = -0.660; pooled standard deviation σ = 13.264.
2. n = 2 × (1.96 + 0.842)² × 13.264² / -0.660² = 6,340.3, rounded up to 6,341 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
delta <- -0.66                      # observed difference in means
sigma <- 13.2641243803125                     # pooled standard deviation
n_per_arm <- function(power, frac = 1) {
  ceiling(round(2 * (z_a + qnorm(power))^2 * sigma^2 / (delta * frac)^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 (t-based, so very slightly larger)
cat("power.t.test:", round(power.t.test(delta = delta, sd = sigma, power = 0.80)$n, 1), "\n")

# Simulation: exact two-sample t-test using simulated means and variances
set.seed(4757636)
n    <- n_per_arm(0.80)
reps <- 20000
m_diff <- rnorm(reps, delta, sigma * sqrt(2 / n))             # difference in sample means
s2     <- sigma^2 * rchisq(reps, 2 * (n - 1)) / (2 * (n - 1))   # pooled sample variance
tstat  <- m_diff / sqrt(s2 * 2 / n)
cat(sprintf("Simulated power at n = %s per arm: %.3f (%d replicates)\n", format(n, big.mark = ","), mean(abs(tstat) > qt(0.975, 2 * (n - 1))), reps))

Output from running the code

100% of observed effect: n per arm = 6,341 (80% power), 8,488 (90% power)
 75% of observed effect: n per arm = 11,272 (80% power), 15,090 (90% power)
 50% of observed effect: n per arm = 25,362 (80% power), 33,952 (90% power)
power.t.test: 6341.2 
Simulated power at n = 6,341 per arm: 0.802 (20000 replicates)

The simulation draws many sets of group means and variances at the planned sample size and counts how often the two-sample t-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.

14. Analyses Reported by the Sponsor

The sponsor-reported primary analyses use MMRM and compare each OPT-302 dosing arm with aflibercept plus sham. The reported standard-dosing versus sham estimate is -0.18 letters, with a 95% confidence interval from -2.20 to 1.84 and p = 0.861. The extended-dosing versus sham estimate is -0.84 letters, with a 95% confidence interval from -2.86 to 1.18 and p = 0.416. These estimates and intervals are the registry's own model-based results.

The recalculations are simple unadjusted comparisons based on the posted arm summaries. They compare extended dosing and sham with the standard-dosing arm, rather than reproducing both sponsor-reported contrasts. For the standard-dosing versus sham pair, the recalculated contrast is expressed in the opposite direction: sham versus standard is 0.18, whereas the sponsor reports standard versus sham as -0.18. The change in sign follows the contrast direction; the underlying pair of groups is the same.

The sponsor's MMRM estimates should be the main reference for the analyses it reports. The recalculations are a transparent supplementary check, not a correction to the sponsor's analysis. Because they do not use the repeated-measures model, their estimates and intervals need not match the model-based results for other contrasts.

15. Multiplicity, Missing Data and Analysis Populations

The registry record lists a primary outcome and several secondary outcomes, with multiple analyses across the study arms. When many outcomes or contrasts are tested, the chance of at least one apparently notable result can rise even if there is no corresponding underlying effect. Statistical methods address this issue through approaches such as adjusting significance thresholds or specifying a hierarchy in which testing proceeds in a prespecified order. Whether such a strategy was used for this trial is not reported in the registry record.

The primary results are presented with confidence intervals and p-values, but the record does not state whether those results were adjusted for other comparisons. The secondary reported analyses also have p-values, and no multiplicity correction is listed. The secondary results should therefore not be read as if each were the only test conducted. A result that looks notable in isolation would require cautious interpretation in the context of the full set of outcomes and any analysis plan, which is not reported.

The primary analysis population is the modified Intent-to-Treat set, defined as randomised participants with at least one dose of study medication. Efficacy analyses were conducted according to randomised study medication. That definition is not identical to including every randomised participant regardless of treatment exposure, and the registry does not give further detail about exclusions or participant flow for the primary analysis.

Missing data can affect longitudinal analyses if participants miss visits or leave the study. An MMRM can use available repeated measurements, but its interpretation depends on assumptions about the process leading to missing observations. The registry record does not report the extent or pattern of missing primary endpoint data, the specific missing-data assumptions, or sensitivity analyses. It is therefore not possible to assess from the record whether missingness may have influenced the estimates.

The secondary outcome denominators vary across endpoints and groups. This may reflect the analysis populations or outcome availability, but the reasons are not reported in the registry record. The record also does not provide enough information to determine whether analyses were prespecified exactly as posted, whether interim analyses took place, or whether any planned analyses were changed.

16. 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: pneumonia (2.1%), atrial fibrillation (1.2%), acute myocardial infarction (1.2%), cholecystitis (0.9%), endophthalmitis (0.9%).

The registry lists serious adverse events among 333 participants at risk in the standard-dosing OPT-302 arm, 330 in the extended-dosing arm, and 330 in the aflibercept-plus-sham arm. The numbers affected were 71, 61, and 68, respectively. Other adverse events were reported for 288, 290, and 282 participants, respectively. Deaths were listed as 9, 12, and 6. These are counts in the posted safety groups; they are not estimates of causal effects of treatment.

The listed serious adverse-event terms include pneumonia at 2.1%, atrial fibrillation at 1.2%, acute myocardial infarction at 1.2%, cholecystitis at 0.9%, endophthalmitis at 0.9%, and cardiac failure at 0.9%. The record excerpt does not provide event-level narratives, timing, severity details beyond the serious-event classification, or adjusted comparisons. A comparison of counts alone does not establish that a study medication caused an event or that groups have equivalent safety profiles. These figures describe what was posted and should be interpreted with the limits of the registry's safety detail in mind.

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

The Week 52 results describe mean change in visual-acuity letter score in the registered analysis population. The group estimates were positive, and the sponsor-reported comparisons with aflibercept plus sham had confidence intervals that included zero. The posted data therefore do not establish a clear between-group difference for those comparisons. The intervals also include estimates in both directions, so they do not establish that the groups are equivalent or that any difference is absent.

The results do not, by themselves, answer why the study was terminated. The registry record lists its status as terminated, but a reason is not reported in the registry record. The posted endpoint results also cannot determine whether all planned analyses were completed or how missing data, multiplicity, or changes to the analysis plan were handled when those details are not reported.

These are trial-level statistical findings, not a basis for individual treatment decisions. They should not be translated into a claim that a treatment works or does not work. The primary outcome is a group mean, and individual participants may have had different outcomes. The confidence intervals describe uncertainty in group contrasts under the analyses' assumptions, not the range of outcomes for individual people.

Interpretation is further bounded by the distinction between sponsor-reported MMRM estimates and unadjusted recalculations from summary statistics. The recalculations are useful for checking the broad scale and direction of simple comparisons, but they do not reproduce the sponsor's model. The registry's reported analysis remains the appropriate reference for the sponsor's stated primary comparisons, while the missing details and terminated status warrant caution about broader conclusions.

18. Why This Trial Matters Statistically

This trial illustrates why an estimated effect should be read together with its uncertainty. The primary arm means are close in magnitude, and the sponsor-reported confidence intervals for the comparisons with sham span zero. Looking only at the point estimates or p-values would omit the range of differences compatible with the posted data. Confidence intervals make the limits of precision visible.

It also demonstrates that a recalculation and a sponsor analysis may address related but not identical questions. The recalculation uses arm-level summaries and a simple unadjusted comparison; the registry reports MMRM contrasts. The analysis method and contrast direction matter when interpreting whether two estimates agree. Clear distinction between these approaches prevents an approximate check from being mistaken for the registered model-based result.

The record also shows why planning illustrations should not be confused with the trial's original design. The listed participant counts are hypothetical planning quantities derived from observed effects under stated assumptions, while the original design justification is not reported. When observed estimates are small, planning figures can become large, emphasizing how difficult it is to design a study around a small target difference with high power.

Finally, the terminated status and the absence of reported details about multiplicity, missing data, and sample-size justification are part of the statistical context. They limit the questions that can be answered from the posted record and show why careful reading involves study design, analysis, precision, and reporting completeness—not just a single endpoint estimate.

19. 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 registry record identifies the study as terminated but does not report a reason. That limits interpretation of the study's conduct and completion. Although the brief description calls it a 2-year study and identifies Week 52 as the primary efficacy time point, the record does not explain how termination affected planned follow-up or analyses.

The original sample-size justification and the assumptions used to plan enrollment are not reported. The planning illustrations based on observed effects are not a substitute for those design details. The record also does not report whether interim analyses were conducted, whether the analysis plan changed, or whether there were deviations from the planned methods.

For the primary outcome, the MMRM is identified, but the record does not give its full specification, including model terms or covariance structure. Details of missing data, missingness patterns, sensitivity analyses, and the handling of participants without Week 52 measurements are not reported. These omissions limit independent assessment of the model's assumptions and robustness.

The posted recalculations are approximate, unadjusted comparisons based on arm summary statistics. They do not recreate the sponsor's longitudinal model and should not be treated as replacements for the sponsor-reported analyses. The registry record also does not report a multiplicity adjustment or testing hierarchy, which constrains interpretation of secondary findings. Finally, safety counts are presented without the detail needed to establish causal attribution or compare risk while accounting for other factors.

20. Related Tutorials

21. Related Statistical Calculators

22. Sources

• ClinicalTrials.gov: OPT-302 With Aflibercept in Neovascular Age-related Macular Degeneration (nAMD) — NCT04757636.
• Registry record last updated 2025-08-05; status last verified 2025-06.
• Results first posted 2025-08-05.
• 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.

23. Record Summary

The registry describes a phase 3, multicentre, randomised, parallel-group, sham-controlled study of OPT-302 with aflibercept in participants with nAMD. It lists enrollment of 998, study start on 2021-03-12, primary completion on 2025-03-31, and status as terminated. The primary endpoint was mean change in ETDRS best-corrected visual acuity letter score from baseline to Week 52 in the modified Intent-to-Treat analysis set, using MMRM.

The posted group estimates were 13.48 letters for standard-dosing OPT-302 with aflibercept, 12.82 for extended-dosing OPT-302 with aflibercept, and 13.66 for aflibercept with sham. The sponsor-reported primary contrasts with sham had 95% confidence intervals that included zero. The registry record does not report the reason for termination, the original sample-size justification, or key details about multiplicity and missing-data handling.