A Study to Compare the Efficacy and Safety of Intravitreal APL-2 Therapy With Sham Injections in Patients With Geographic Atrophy (GA) Secondary to Age-Related Macular Degeneration: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for A Study to Compare the Efficacy and Safety of Intravitreal APL-2 Therapy With Sham Injections in Patients With Geographic Atrophy (GA) Secondary to Age-Related Macular Degeneration (NCT03525613), a randomized phase 3 study. The primary outcome is Least Squares (LS) Mean Change From Baseline in Total Area of GA Lesions in the Study Eye at Month 12.

2. Clinical Question

The clinical question is about the change in lesion area, not a direct measure of visual function. The registry also lists secondary measures of lesion area at Month 24 and measures related to retinal sensitivity, reading performance, and visual acuity. Those outcomes can add context, but they address different aspects of the disease and should not be treated as interchangeable with the primary endpoint.

3. Trial Design

NCT03525613 was a Phase 3, randomized, parallel-group study with quadruple masking and sham control. The registry describes the study as multicenter and 24 months in duration. Enrollment was 637. The study status is completed; the registry lists a start date of 2018-08-31 and a primary completion date of 2021-06-28.

The active regimens were intravitreal APL-2, identified in the official title as pegcetacoplan: 15 mg in 0.1 mL given monthly or every other month. Sham procedures followed matching monthly or every-other-month schedules. The primary outcome results use three analysis groups: Pegcetacoplan Monthly, Pegcetacoplan EOM, and Sham Pooled. Thus the posted comparisons are for each active schedule against pooled sham rather than separate sham-schedule comparisons.

The primary endpoint was assessed at Month 12, while the study and several listed outcomes extended through Month 24. The primary analysis population was the modified intent-to-treat set, defined in the registry as assigned participants who received at least one injection and had baseline and at least one post-baseline study-eye lesion-area value assessed by FAF. More detailed eligibility and analysis-population specifications are not reported in the registry record.

The registry lists seven outcome measures and fourteen analyses. The trial's original sample-size justification, allocation details beyond randomization, and the complete statistical analysis plan are not reported in the registry record. The planning illustrations associated with the posted results are separate from the trial's original design assumptions.

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: This study consisted of a screening period (up to 30 days), a randomization visit on Day 1, and a treatment period (up to 24 months). Subjects were randomized in a 2:2:1:1 ratio on Day 1 to receive treatment with pegcetacoplan monthly, pegcetacoplan every other month (EOM), sham injection monthly or sham injection EOM, respectively. A total of 637 subjects were enrolled in this study.

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: The modified intent-to-treat (mITT) analysis set included all subjects assigned to treatment who received at least 1 injection of pegcetacoplan or sham and had baseline and at least 1 post-baseline value of GA lesion area in the study eye as assessed by FAF. Subjects with a baseline and at least 1 post-baseline value of the outcome at a scheduled visit by Month 12 were included in the analysis.

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: The intent-to-treat (ITT) analysis set included all subjects assigned to treatment.

6. Primary Endpoint

The registry lists the primary outcome as Least Squares (LS) Mean Change From Baseline in Total Area of GA Lesions in the Study Eye at Month 12, measured over Baseline (screening) and Month 12.

The primary endpoint is the least-squares mean change from baseline in total area of GA lesions in the study eye at Month 12, measured in mm^2. Baseline was defined as the last available, non-missing observation before the first study-drug administration. Lesion area was assessed by a quantified central reading center using FAF images.

GA lesion area is a structural measure of the affected retinal area. A change score describes how that measured area changed from baseline to the specified follow-up, while a between-group contrast asks whether the average change differed between a pegcetacoplan schedule and pooled sham. In this record, a negative difference for an active arm relative to sham indicates a smaller reported mean change than in the pooled sham group; it does not by itself establish the clinical importance of that difference.

The registry says the least-squares mean was estimated with a mixed-effects model for repeated measures (MMRM). Such model-based means allow an analysis to account for repeated measurements over follow-up rather than treating each visit as an unrelated result. This endpoint is used to assess structural lesion-area change; it is not itself a measure of reading ability, visual acuity, or a person's overall experience. The clinical meaning of a difference depends on the endpoint's interpretation and the precision of the estimate, not only on whether a statistical test crosses a threshold.

7. Results Posted in the Registry

• Pegcetacoplan Monthly: mean 1.56 versus 1.97 on control; difference -0.41 (95% CI -0.64 to -0.18), standardized effect d = -0.35; z-test p = <0.001.
• Pegcetacoplan EOM: mean 1.65 versus 1.97 on control; difference -0.32 (95% CI -0.54 to -0.09), standardized effect d = -0.27; z-test p = 0.006.

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.

LS Mean Change From Baseline in Total Area of GA Lesions in the Study Eye at Month 24

• 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:
  • Pegcetacoplan Monthly: mean 3.12 versus 4.03 on control; difference -0.90 (95% CI -1.30 to -0.50), standardized effect d = -0.44; z-test p = <0.001.
  • Pegcetacoplan EOM: mean 3.28 versus 4.03 on control; difference -0.74 (95% CI -1.13 to -0.36), standardized effect d = -0.37; z-test p = <0.001.
• Interpretation:
  • The 95% confidence interval excludes no difference, so the mean is statistically lower for Pegcetacoplan Monthly than for the control. This is an unadjusted, secondary comparison, so it is suggestive rather than confirmatory.
  • The 95% confidence interval excludes no difference, so the mean is statistically lower for Pegcetacoplan EOM than for the control. This is an unadjusted, secondary comparison, so it is suggestive rather than confirmatory.

LS Mean Change From Baseline in Mean Threshold Sensitivity of All Points of the Study Eye at Month 24

• 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:
  • Pegcetacoplan Monthly: mean -3.32 versus -2.95 on control; difference -0.36 (95% CI -1.08 to 0.35), standardized effect d = -0.10; z-test p = 0.320.
  • Pegcetacoplan EOM: mean -3.06 versus -2.95 on control; difference -0.11 (95% CI -0.73 to 0.51), standardized effect d = -0.04; z-test p = 0.729.
• Interpretation:
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between Pegcetacoplan Monthly 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 Pegcetacoplan EOM and the control. The interval gives the range of effects that remain compatible with the data.

LS Mean Change From Baseline in Monocular Maximum Reading Speed of the Study Eye at Month 24

• 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:
  • Pegcetacoplan Monthly: mean -22.45 versus -16.21 on control; difference -6.24 (95% CI -15.78 to 3.31), standardized effect d = -0.14; z-test p = 0.201.
  • Pegcetacoplan EOM: mean -17.53 versus -16.21 on control; difference -1.32 (95% CI -11.19 to 8.55), standardized effect d = -0.03; z-test p = 0.793.
• Interpretation:
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between Pegcetacoplan Monthly 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 Pegcetacoplan EOM and the control. The interval gives the range of effects that remain compatible with the data.

The secondary outcomes broaden the assessment beyond the Month 12 primary lesion-area endpoint. The registry lists Month 24 lesion area, retinal sensitivity, reading speed, reading independence, and normal-luminance best-corrected visual acuity among the secondary measures. These outcomes concern different dimensions and time points; a result on a structural measure does not necessarily imply a corresponding result on functional measures.

The posted Month 24 lesion-area comparisons follow the same general direction as the primary lesion-area comparisons: the reported contrasts against pooled sham are negative for both pegcetacoplan schedules. By contrast, the unadjusted comparisons for the posted retinal sensitivity and reading-speed measures have confidence intervals that include zero. Taken together, the available secondary results do not form a uniform pattern across structural and functional outcomes. They are contextual evidence, not a single combined endpoint.

Secondary tests generally carry less weight than a prespecified primary test when many outcomes or comparisons are examined. Testing multiple outcomes increases the chance that some results will appear statistically notable by chance. The registry record does not report a multiplicity adjustment or a full hierarchy for interpreting secondary tests. The recalculated secondary p-values are unadjusted, and the posted information does not include sponsor-reported analyses for every listed secondary outcome. Thus, isolated secondary findings should be read cautiously, without treating them as confirmatory evidence equivalent to the primary MMRM analysis.

These distinctions are important for interpretation: the primary outcome addresses lesion-area change at Month 12, while secondary measures can provide complementary information about longer-term lesion area and visual function. The registry record does not report a prespecified method for combining these different outcomes into one overall conclusion.

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

• LS Mean Change From Baseline in Total Area of GA Lesions in the Study Eye at Month 24
• Mean Change in Total Area of GA Lesions in the Study Eye Through Month 24
• LS Mean Change From Baseline in Mean Threshold Sensitivity of All Points of the Study Eye at Month 24
• LS Mean Change From Baseline in Monocular Maximum Reading Speed of the Study Eye at Month 24
• LS Mean Change From Baseline in Mean Functional Reading Independence (FRI) Index Score at Month 24
• LS Mean Change From Baseline in Normal-Luminance Best-Corrected Visual Acuity (NL-BCVA) Score of the Study Eye at Month 24

9. Statistical Interpretation

10. Statistical Methods Explained

What is a least-squares mean? A least-squares mean is a model-based estimate of a group mean. It is often used when an analysis accounts for covariates, repeated observations, or other features of the data. It should not automatically be read as the ordinary arithmetic average of all observed values. The registry states that the primary endpoint used an MMRM, but the full model specification, including its covariates and covariance structure, is not reported in the registry record.

Why use a repeated-measures model? General explanation: participants may have outcome assessments at multiple visits, and those measurements from the same participant are related. An MMRM can model the pattern of repeated measurements and estimate group differences over time. Its estimates depend on the chosen model and the available data. The registry identifies the model used but does not report the complete assumptions, diagnostics, or handling of missing visits.

What does the reported difference mean? The LS mean difference is the estimated group contrast, expressed in the endpoint's units. A negative contrast means the estimated change in the active group is lower than the estimated change in pooled sham. The contrast is not a percentage, and it is not a direct estimate of the probability that an individual will have a particular outcome. The reported 95% confidence interval describes uncertainty around the model-based contrast under the analysis assumptions.

What is the role of a standard error? A standard error describes the estimated sampling uncertainty of an estimate. It is not the same as the standard deviation, which describes variability among observations. The arm summaries list standard errors for the least-squares mean estimates. The unadjusted recalculations use approximate standard deviations inferred from those standard errors; those approximations are not the trial's participant-level variability estimates.

How do the recalculations differ from the sponsor analysis? General explanation: a simple comparison of arm summary values cannot reproduce a model that uses repeated observations and the trial's analysis structure. The recalculated mean differences and confidence intervals are therefore approximate, unadjusted summaries. The reported sponsor analyses use the MMRM and give their own LS mean differences, confidence intervals, and p-values. Since the registry record flags a discrepancy, the sponsor's own analysis takes precedence. The recalculated p-values are unadjusted and should not be substituted for the reported model-based tests.

How should p-values be read? A p-value describes how compatible the observed data are with a specified null hypothesis, assuming the model and test conditions. A small p-value is not the probability that the null hypothesis is true, and it does not quantify the size or clinical value of an effect. The sponsor-reported p-values belong to the MMRM comparisons. The registry does not report whether these primary comparisons were adjusted for multiple testing, or the full testing hierarchy.

What do the planning illustrations represent? General explanation: a planning calculation estimates the sample size that would be needed to detect a specified effect under stated assumptions. The posted illustrations use the observed effect, and also consider smaller fractions of that effect. They are not a reconstruction of the trial's original sample-size planning. The assumptions listed are a two-sided significance level of 0.05, equal allocation between the two arms, and a normal approximation; the target effect is the stated fraction of the observed effect. Continuous-outcome values are participants per arm.

In these illustrations, the planning rows for 100% of the observed effect, 75% of the observed effect, and 50% of the observed effect show how required group size changes when the target effect changes. The columns for 80% and 90% power refer to the probability of detecting the specified effect under the assumed model if that effect is present. They are planning quantities, not a description of the trial's achieved result. Smaller effects require more participants under the same assumptions. These figures are not observed power.

What is not specified? The original sample-size assumptions, complete protocol statistical plan, interim analyses, multiplicity procedure, model details beyond the named MMRM, and full missing-data strategy are not reported in the registry record. These omissions matter because model choices, repeated testing, and incomplete outcome data can affect estimates and the strength of statistical conclusions. General statistical explanations above describe concepts; they do not establish which unreported procedures were used in this trial.

11. Confidence Intervals and Precision

Precision concerns how narrowly the data estimate a quantity. A confidence interval gives a range of values compatible with the observed data and the model at the stated confidence level; it is not a guarantee that the true value lies within that particular interval. The interval's width reflects uncertainty from the data and analysis, while the point estimate gives the central reported contrast.

For the primary Month 12 comparisons, the sponsor-reported 95% confidence intervals are -0.640 to -0.183 mm^2 for monthly pegcetacoplan versus pooled sham and -0.542 to -0.094 mm^2 for every-other-month pegcetacoplan versus pooled sham. Both intervals are entirely below zero, consistent with negative model-based differences. The interval endpoints also indicate that the estimates are not exact; the data are compatible with a range of contrast magnitudes under the analysis model.

The unadjusted recalculated intervals are not identical to the sponsor-reported intervals. They use approximate variability reconstructed from arm summaries and do not reproduce the MMRM. The reported MMRM intervals therefore provide the relevant precision estimates for the sponsor's primary analysis, especially because the registry record flags a discrepancy.

Confidence intervals do not measure clinical importance, account automatically for multiple comparisons, or remove uncertainty caused by model assumptions or missing data. For secondary measures, an interval that includes zero indicates that the posted unadjusted comparison is compatible with no group difference as well as with differences in either direction. The width of such intervals is also relevant: a broad interval can leave substantial uncertainty even when the point estimate is not zero. Precision should be considered together with outcome relevance, study design, and the prespecified analysis plan, whose full details are not reported in the registry record.

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 planning figures for these continuous outcomes are participants per arm, not a total across arms and not a count of events. The stated 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 set to the listed fraction of the observed effect. The original trial design assumptions are not reported in the registry record.

The 80% power column describes the planning group size associated with an 80% chance of detecting the specified effect under those assumptions, if that effect is present. The 90% power column gives the corresponding group size for a 90% chance. These are conventional planning targets, not guarantees about the result of a future study. Read each row as a separate scenario: the figures for 100% of the observed effect use the observed effect as the target, while the 75% and 50% rows use smaller target effects. For example, the primary monthly comparison lists 130 participants per arm for 80% power at 100% of the observed effect and 231 participants per arm for 80% power at 75% of the observed effect.

Smaller target effects require more participants under the same planning assumptions. The figures are illustrations based on the observed effect, not a statement of what the trial originally planned. They are not observed power.

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 = -0.411; pooled standard deviation σ = 1.182.
2. n = 2 × (1.96 + 0.842)² × 1.182² / -0.411² = 129.6, rounded up to 130 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 <- -0.4113                      # observed difference in means
sigma <- 1.18167160931735                     # 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(3525613)
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 = 130 (80% power), 174 (90% power)
 75% of observed effect: n per arm = 231 (80% power), 309 (90% power)
 50% of observed effect: n per arm = 519 (80% power), 694 (90% power)
power.t.test: 130.5 
Simulated power at n = 130 per arm: 0.793 (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's primary analyses are the MMRM comparisons reported in the registry. For monthly pegcetacoplan versus pooled sham, the sponsor reports an LS mean difference of -0.411 mm^2, a 95% confidence interval from -0.640 to -0.183, and p < 0.001. For every-other-month pegcetacoplan versus pooled sham, the reported difference is -0.318 mm^2, a 95% confidence interval from -0.542 to -0.094, and p = 0.005.

The recalculated estimates use the posted arm-level summaries and an approximate conversion of standard errors to variability. They are unadjusted comparisons and do not reproduce the MMRM. The recalculated differences are -0.411 mm^2 and -0.318 mm^2, respectively; their intervals and p-values also differ from the sponsor's reported model-based results.

The record flags a discrepancy between recalculations and the sponsor analysis. The sponsor's own analysis takes precedence for interpretation of the trial's reported primary comparisons. The recalculations can serve as a rough check on direction and scale, but not as a replacement for the MMRM, its reported confidence intervals, or its p-values. The registry does not give further details explaining the discrepancy.

15. Multiplicity, Missing Data and Analysis Populations

Multiplicity arises when an analysis tests more than one outcome, treatment comparison, time point, or subgroup. Each additional test creates another opportunity for a result to appear unusual by chance. Statistical procedures can control this risk by specifying an order for tests or adjusting significance thresholds, but the registry record does not report a multiplicity procedure for the primary comparisons or secondary outcomes. It also does not report a full testing hierarchy. Accordingly, the posted p-values should be understood as the reported tests, not assumed to have a particular adjustment.

The record describes the primary analysis population as the modified intent-to-treat set: participants assigned to treatment who received at least one injection and had baseline and at least one post-baseline study-eye GA lesion-area value assessed by FAF. This definition indicates that the primary analysis was not described as including every randomized participant regardless of treatment receipt or outcome availability. Further details of the population definition are not reported in the registry record.

Missing outcome data can affect an estimate if participants with unavailable assessments differ from those whose assessments are observed. General explanation: repeated-measures models can use available observations without requiring every participant to have a complete series, but the validity of the resulting estimates depends on assumptions about why data are missing and on the model specification. The registry identifies an MMRM for the primary endpoint but does not report its missing-data assumptions, sensitivity analyses, imputation strategy, or the extent and reasons for missing assessments.

The registry also does not report whether interim analyses were conducted, whether any stopping rules were used, or the complete protocol-level statistical analysis plan. These details can affect how tests and confidence intervals should be interpreted. Their absence from the registry record does not establish that a procedure was or was not used; it means the procedure is not reported in the registry record.

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 (5.6%), atrial fibrillation (3.3%), covid-19 (3.3%), covid-19 pneumonia (1.9%), cardiac failure congestive (1.4%).

The serious adverse event listings give affected counts and the corresponding numbers at risk separately for study-eye, fellow-eye, and non-ocular categories. For ocular study-eye serious events, the counts were 5 of 213 for Pegcetacoplan Monthly, 4 of 212 for Pegcetacoplan EOM, and 1 of 211 for Sham Pooled. For ocular fellow-eye serious events, the counts were 1 of 213, 0 of 212, and 2 of 211, respectively. These are registry counts within the listed categories; they should not be added across categories.

For non-ocular serious events, the registry reports 77 of 213 for Pegcetacoplan Monthly, 56 of 212 for Pegcetacoplan EOM, and 55 of 211 for Sham Pooled. Death counts in those non-ocular groups were 20, 9, and 8, respectively. The ocular group listings report zero deaths. The registry also lists serious-event terms including pneumonia, atrial fibrillation, COVID-19, COVID-19 pneumonia, congestive cardiac failure, and endophthalmitis.

These descriptive counts are not, by themselves, a causal comparison or a complete safety assessment. The listed groups and event categories should be read as recorded, without combining them into a single total. The registry record does not provide enough information in these figures to assess timing, exposure-adjusted rates, or the clinical circumstances of individual events.

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

The primary result is an estimate of average change in study-eye GA lesion area at Month 12. The sponsor-reported MMRM contrasts are negative for both pegcetacoplan schedules relative to pooled sham, and their 95% confidence intervals lie below zero. This describes the direction and statistical precision of the reported group comparisons under the specified model.

That finding does not mean every participant had the same change, and it does not establish an individual outcome. A group-average structural measure is not identical to a person's visual function or daily experience. The registry's secondary outcomes cover several other measures, and the available secondary comparisons do not all show the same pattern. Nor does a statistically significant result by itself establish that a difference is large enough to matter clinically; a clinical-importance threshold is not reported in the registry record.

The results also do not establish that the treatment caused every observed difference independently of the study's analysis assumptions. Randomization and masking are features of the design, while the reported estimates still depend on the analysis population, model, outcome data available, and handling of repeated measurements. Important details—including the complete statistical analysis plan, multiplicity procedure, and missing-data strategy—are not reported in the registry record.

Safety counts should be interpreted separately from the primary efficacy endpoint. They describe reported events in specified categories, but the counts alone do not establish whether an event was caused by treatment. Overall, the registry results support a careful statement about the measured endpoint and its uncertainty, not a blanket conclusion about all aspects of benefit, harm, or an individual's likely experience.

18. Why This Trial Matters Statistically

This trial illustrates why the endpoint, analysis model, and comparison need to be read together. The primary measure is a model-based change in lesion area, not a direct functional outcome. The MMRM uses repeated measurements, so its reported LS mean differences and confidence intervals are the relevant sponsor estimates for the primary comparison rather than simple arithmetic contrasts reconstructed from summary values.

The record also makes visible a common distinction in clinical-trial interpretation: the size and direction of an estimate, its uncertainty, and its p-value answer related but different questions. A small p-value does not communicate the clinical importance of a difference, while a confidence interval conveys a range of values compatible with the model and data. The registry's paired active comparisons also emphasize that each dosing schedule is compared against pooled sham, rather than implying a direct comparison between active schedules.

Finally, the secondary outcomes and safety listings show why one endpoint cannot stand in for a complete evaluation. Structural lesion area, visual-function measures, and adverse-event categories carry different meanings. Multiplicity and missing-data details affect the weight that can be placed on the collection of results, yet those procedures are not reported in the registry record. Reading the trial statistically therefore means separating what the posted analyses estimate from what the record does not establish.

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 does not report the complete statistical analysis plan, the original sample-size justification, or the full MMRM specification. The basis for model covariates, within-participant covariance, diagnostic checks, and sensitivity analyses is therefore not available in the record. The primary population definition is also incomplete beyond its stated treatment-receipt and outcome-assessment criteria.

The record does not report a multiplicity strategy for the primary comparisons and secondary outcomes. This is relevant because the registry lists multiple outcomes and analyses, and unadjusted tests do not account for the full testing context. The record also does not describe the amount, timing, or reasons for missing outcome assessments, or the assumptions and sensitivity analyses used to address missing data.

The recalculated estimates are unadjusted approximations from posted summary statistics; they are not equivalent to the sponsor's MMRM. The record flags a discrepancy, so the sponsor's own analysis takes precedence. For secondary outcomes, sponsor-reported analysis details are not available for all measures in the information recorded.

Safety listings are descriptive counts by category and do not, on their own, establish causation or provide exposure-adjusted comparisons. The record does not give the context needed to interpret individual events. The posted outcomes also measure distinct structural and functional concepts, so their estimates should not be combined into a single measure of overall clinical effect.

20. Related Tutorials

21. Related Statistical Calculators

22. Sources

• ClinicalTrials.gov: A Study to Compare the Efficacy and Safety of Intravitreal APL-2 Therapy With Sham Injections in Patients With Geographic Atrophy (GA) Secondary to Age-Related Macular Degeneration — NCT03525613.
• Registry record last updated 2023-07-06; status last verified 2023-06.
• Results first posted 2023-07-06.
• 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

NCT03525613 is a completed Phase 3, randomized, parallel, quadruple-masked, sham-controlled study of intravitreal pegcetacoplan for GA secondary to AMD. The registry lists monthly and every-other-month pegcetacoplan schedules and pooled sham comparisons.

The primary outcome is LS mean change from baseline in study-eye GA lesion area at Month 12, assessed from FAF images with an MMRM. The sponsor-reported comparisons favor a smaller mean lesion-area change relative to pooled sham for both schedules, with the registry reporting 95% confidence intervals below zero. Because the record flags a discrepancy, the sponsor's own analysis takes precedence over the unadjusted recalculations.

Secondary outcomes and adverse-event counts provide additional context, but multiplicity handling, full missing-data methods, and several protocol-level statistical details are not reported in the registry record.