Phase III Study Assessing the Efficacy and Safety of Pegcetacoplan in Patients With C3 Glomerulopathy or Immune-Complex Membranoproliferative Glomerulonephritis: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Phase III Study Assessing the Efficacy and Safety of Pegcetacoplan in Patients With C3 Glomerulopathy or Immune-Complex Membranoproliferative Glomerulonephritis (NCT05067127), a randomized phase 3 study. The primary outcome is Randomized Controlled Period: Change From Baseline in Log-Transformed Urine Protein-to-Creatinine Ratio (uPCR) at Week 26.

2. Clinical Question

This question uses proteinuria as the measured clinical marker rather than a direct count of kidney failure events. The registry also lists other kidney-related outcomes, including a composite renal endpoint, a reduction in uPCR, biopsy findings, estimated glomerular filtration rate, and serum measures. These can provide related but distinct information: a urine protein measure describes protein loss, while biopsy and blood measures address other aspects of disease. The primary endpoint therefore represents a particular, prespecified measurement of change, not a complete account of every aspect of kidney health.

3. Trial Design

The registry describes NCT05067127 as a Phase 3 randomized, placebo-controlled, double-blinded, multicenter study, and records masking as triple. Its parallel design assigns participants to pegcetacoplan or placebo during the randomized controlled period. The trial status is completed. The recorded start date is 2021-11-12, and the primary completion date is 2024-06-26.

The registry reports enrollment of 124. For the primary endpoint, the pegcetacoplan group has a reported n of 63 and the placebo group has a reported n of 61. The primary analysis population is the ITT set, described as all randomized subjects. The registry does not report the randomization ratio, sequence-generation procedure, or the precise definition of the triple-masking roles in the record summarized for this analysis.

The pegcetacoplan group received twice-weekly subcutaneous infusions. For adults or adolescents >50kg, the listed dose was 20mL (1080 mg); the record also lists weight-based doses of 10mL (540mg), 12mL (648mg), or 15mL (810mg). The placebo group received twice-weekly subcutaneous infusions of 10mL, 12mL, 15mL, or 20mL. Further details of dose selection or dose changes are not reported in the registry record.

The primary endpoint timeframe is baseline (Day -70 to Day 1) to Week 26. Baseline uPCR was defined using an average of first-morning spot urine samples. The record specifies at least 6 of the 9 planned samples and describes how the average was derived when fewer than 6 or more than 9 samples were collected. The principal contrast is based on the equal-weighted average over Weeks 24, 25, and 26. The registry record does not report a sample-size justification or other details of the trial's design calculations.

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 (10 weeks), 26-week randomized controlled period (RCP), followed by a 26-week open-label period (OLP) and follow-up period (8 weeks). Subjects were randomized to receive pegcetacoplan or placebo in a ratio of 1:1 in RCP. A total of 124 subjects were enrolled in this study.

Randomized Controlled Period (26 weeks)

Reasons for not completing this period:

Open-Label Period (26 weeks)

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: The ITT analysis set included all randomized subjects.

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 randomized subjects.

6. Primary Endpoint

The registry lists the primary outcome as Randomized Controlled Period: Change From Baseline in Log-Transformed Urine Protein-to-Creatinine Ratio (uPCR) at Week 26, measured over Baseline (Day -70 to Day 1) to Week 26.

The primary endpoint is change from baseline in log-transformed urine protein-to-creatinine ratio (uPCR) at Week 26, reported in log (uPCR). uPCR is a measure of urinary protein relative to creatinine; the log transformation places the analysis on a transformed scale. The endpoint is continuous, so its reported group summaries are least-squares means rather than event counts or proportions.

Baseline was defined from first-morning spot urine samples collected between the start of screening and Day 1, inclusive. The average used at least 6 of the 9 planned samples where available. Samples from Day -2, Day -1, and before dosing on Day 1 could contribute. If fewer than 6 or more than 9 samples were collected, the record says the average of all collected samples was used. Repeated samples contribute to the baseline measure and can help characterize a participant's starting level rather than relying on a single urine collection.

The treatment contrast is an equal-weighted average over Weeks 24, 25, and 26. A change below zero indicates a decline on the log-transformed scale from baseline; a more negative group mean therefore represents a larger downward change on that scale. The endpoint was used to compare the groups' average changes, not to directly report the percentage of participants meeting a threshold or to establish a change in kidney function. The clinical importance of a given log-scale difference is not established by the statistical result alone.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The primary analysis reports least-squares means and a difference in least-squares means. A least-squares mean is a model-based estimate of a group average, not necessarily the raw arithmetic mean of every observed value. The registry identifies the primary analysis method as MMRM, commonly expanded as a mixed model for repeated measures. In general, a repeated-measures model analyzes observations collected at multiple visits while accounting for the fact that measurements from the same participant are related. The posted record does not provide the full model specification, including all covariates, covariance structure, or estimation details.

The primary endpoint is log-transformed uPCR, measured at baseline and follow-up visits. The reported treatment contrast uses an equal-weighted average over Weeks 24, 25, and 26. Equal weighting means that each of those stated visits contributes the same weight to the contrast, as described in the registry. The least-squares mean change for each group describes the model-based average change, while the difference between groups estimates the contrast of interest. A negative contrast indicates a lower estimated change in the pegcetacoplan group relative to placebo on this scale.

A 95% confidence interval describes a range of estimates compatible with the observed data under the statistical model and its assumptions. It is not a guarantee that the true effect falls within that particular interval, and it does not address sources of bias that the model cannot capture. The interval's position relative to zero is relevant for a difference: an interval excluding zero indicates that the estimate is inconsistent with a zero difference at the corresponding conventional two-sided significance level, under the stated method. The p-value gives a related measure of compatibility with a null hypothesis, rather than a measure of effect size or clinical relevance.

How are binary outcomes compared?

Some secondary outcomes are percentages of participants meeting a defined criterion. For example, the registry records percentages for the composite renal endpoint, a reduction of at least 50% in uPCR, and a decrease in C3c staining. A risk difference compares the event proportions between groups and is expressed on an absolute scale. The recalculated risk differences and confidence intervals are simple unadjusted calculations from the posted counts and denominators. They do not replace the sponsor's reported model-based analyses. The record also reports logistic analyses as odds ratios. An odds ratio compares the odds of the event between groups, which is a different scale from a risk difference; the two measures should not be read as if they were identical.

The unadjusted p-values attached to recalculated binary comparisons are based on the available group summaries and do not account for a larger family of outcomes. They should not be interpreted as proof that the results are independent of the primary endpoint or of other secondary outcomes. For the binary outcomes, the registry also reports logistic odds ratios with 95% confidence intervals and p-values. Those are the sponsor's reported analyses and may use a different statistical approach from the simple unadjusted recalculations.

Why does over-dispersion matter?

Over-dispersion is a general concern for count or binary data when observed variability is greater than a model assumes. When a model understates variability, standard errors can be too small and confidence intervals can be too narrow. This is a general statistical consideration, not a finding reported for this trial. The primary endpoint is continuous and its listed analysis is MMRM; the registry record does not identify an over-dispersion adjustment for that endpoint. The binary endpoints are not evidence, on their own, that over-dispersion was present.

What do planning illustrations mean?

Planning illustrations use the observed effect as a reference and show participants per arm for 80% power or participants per arm for 90% power under stated assumptions. The record describes these as planning illustrations, not as the trial's own design calculation. The assumptions include a two-sided significance level of 0.05, equal allocation between arms, and a normal approximation; the effect to detect is a stated fraction of the observed effect. In general, using a smaller target effect than the observed effect leads to a larger planning requirement, all else equal. These illustrations are not observed power and do not establish the probability that the trial detected a true effect. They also do not establish that the original trial was planned using those assumptions.

Sample-size illustrations depend on assumptions about the effect to detect, variability, allocation, and analysis. Their estimates should not be treated as guarantees for a future study. The registry record does not report the original sample-size justification, the assumptions used to choose the enrollment target, or whether any interim analyses were planned or conducted.

10. Analyses Reported by the Sponsor

The sponsor-reported primary analysis uses MMRM and gives a difference in least-squares means of -1.143, with a 95% confidence interval from -1.436 to -0.85 and p < 0.001. The posted group estimates are -1.114 for pegcetacoplan and 0.029 for placebo. The sponsor's reported contrast is the primary inferential result; the group estimates are not substitutes for that contrast.

The registry record does not flag a discrepancy between the posted primary result and a recalculation. The primary endpoint is not accompanied in the record by a separate simple recalculation of the treatment contrast. For secondary binary outcomes, recalculated risk differences and unadjusted p-values are simple calculations from the posted summary statistics. The sponsor's analyses for those outcomes are reported as logistic odds ratios, so the estimates are on different scales and need not match the recalculated risk differences.

In general, if a recalculation conflicts with a sponsor-reported analysis, the sponsor's own analysis takes precedence for describing the trial's reported result. A simple recalculation can help readers understand the posted group data, but it does not reproduce a full model that may account for additional analysis features. The registry record does not provide enough model detail to independently recreate every reported analysis.

11. Multiplicity, Missing Data and Analysis Populations

The primary endpoint is clearly identified in the registry record, while a range of secondary outcomes is also listed. Testing multiple outcomes creates a multiplicity question: the more hypotheses assessed, the greater the chance that at least one result appears statistically notable by chance alone. Adjustment procedures can control that risk, but the registry record does not report whether a multiplicity strategy was prespecified, which outcomes were included in any testing hierarchy, or whether secondary p-values were adjusted. As a result, unadjusted secondary p-values should not be interpreted as if each were the sole confirmatory test.

The primary analysis population is the ITT set, defined as all randomized subjects. This supports an interpretation based on randomized assignment, but the registry record does not provide a detailed account of the analysis population for every secondary endpoint, or of exclusions and missing observations for each measure. The primary baseline derivation does describe how the average was determined when fewer than 6 or more than 9 urine samples were collected. That rule addresses baseline sample availability; it does not, on its own, describe missing follow-up data.

MMRM is often used with repeated observations, and in general it can use available outcome measurements under assumptions about the missing-data process. The record does not state the assumptions used for missingness, the extent or reasons for missing follow-up data, or sensitivity analyses addressing departures from those assumptions. The handling of missing values for the binary secondary outcomes is also not reported in the registry record. These details matter because results can depend on which observations are included and on how missing outcomes are treated.

Other statistical-plan details are not reported in the registry record, including the full MMRM specification, whether any interim analyses were planned or conducted, and the original sample-size justification. The planning illustrations based on observed effects are not evidence about the trial's design process or missing-data handling. These omissions do not change the estimates as posted, but they limit independent assessment of how robust the inferences are to analysis choices.

12. Safety Results

The registry reports serious adverse events as affected participants divided by participants at risk.

Deaths

Other (non-serious) adverse events

Participants with at least one non-serious event at or above the registry's 5% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: acute kidney injury (3.3%), vomiting (1.8%), pyrexia (1.8%), gastroenteritis (1.8%), herpes zoster meningoencephalitis (1.8%).

During the randomized controlled period, the registry reports serious adverse events in 6 participants at risk in the pegcetacoplan group and 6 participants at risk in the placebo group. It reports 1 death in the pegcetacoplan group and 0 in the placebo group. Other adverse events were reported for 53 participants at risk in the pegcetacoplan group and 56 in the placebo group. These are descriptive counts; they do not by themselves establish that treatment caused an event or that risks were equivalent.

The registry also reports open-label period groups: pegcetacoplan to pegcetacoplan and placebo to pegcetacoplan. In those groups, serious adverse events were reported for 6 and 4 participants, respectively, and deaths were reported as 0 in each group. Because these observations are from the open-label period and involve different treatment histories, they should not be combined with or treated as a randomized comparison against the placebo group from the randomized controlled period.

The registry lists acute kidney injury at 3.3% among the top serious adverse event terms and lists vomiting, pyrexia, gastroenteritis, herpes zoster meningoencephalitis, and shunt infection at 1.8% each. The record excerpt does not supply further detail on event timing, duration, severity, relatedness assessments, or participant-level overlap. Safety counts are therefore best read as descriptive registry summaries, not as complete causal comparisons.

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

The primary statistical result is a difference between randomized groups in change from baseline in log-transformed uPCR, estimated over Weeks 24, 25, and 26. The posted least-squares mean change was -1.114 for pegcetacoplan and 0.029 for placebo, with a reported group difference of -1.143 and a 95% confidence interval from -1.436 to -0.85. The direction and interval indicate a lower estimated change on the log-uPCR scale in the pegcetacoplan group during the randomized controlled period.

This result does not, by itself, establish what a particular participant will experience. A group average can coexist with variation in individual responses. Nor does the log-scale contrast directly state a percentage reduction in urine protein, a probability of avoiding kidney failure, or the duration of any change. Those interpretations would require additional information and, for some outcomes, a different analysis.

The result also does not establish that every secondary measure changed in the same way. The registry's secondary outcomes include different types of measurements and thresholds; not all detailed numerical results are available in the record used for this analysis. Secondary findings should be interpreted in light of multiplicity and any unreported analysis-plan choices. The primary result is specific to its endpoint definition, study population, and observation period.

Statistical evidence and clinical importance are related but distinct. A small p-value indicates that the observed data would be unusual under a specified null model; it does not measure the size of a meaningful clinical change. The confidence interval shows the precision of the estimated contrast under the model, but it does not address every possible source of bias or uncertainty. Clinical interpretation also depends on how changes in uPCR relate to outcomes that matter to patients, and that relationship is not established by this statistical result alone.

Finally, the randomized comparison is distinct from observations during the later open-label period. The primary result does not establish longer-term effects, effects outside the trial population, or comparative outcomes after the randomized controlled period. It is a finding about the endpoint and timeframe defined in the registry record, not a general claim about all aspects of safety or efficacy.

14. Why This Trial Matters Statistically

This trial matters statistically because it uses a randomized, placebo-controlled, masked design to compare a continuous renal marker between groups. Random allocation can support a causal interpretation of a between-group difference when the analysis and follow-up preserve the comparison, while masking can reduce some forms of expectation or assessment bias. Those design features strengthen interpretation, although they do not remove uncertainty from missing data, model assumptions, or measurement choices.

The primary analysis also illustrates why the estimand and scale matter. The endpoint is not simply a single urine value: it uses an average baseline derived from repeated first-morning samples, follows change through Week 26, transforms uPCR, and estimates a contrast averaged over Weeks 24, 25, and 26. Each choice defines what the reported effect means. A reader interpreting the estimate should keep the scale and averaging period in view rather than translating it into a broader statement about kidney outcomes.

The registry reports both a model-based continuous endpoint and other outcomes that use thresholds, biopsy findings, and laboratory measures. Agreement in direction among available outcomes can provide context, but each outcome carries its own measurement and inferential limitations. Multiplicity is important because numerous outcomes can create opportunities for chance findings; the registry record does not describe an adjustment strategy. This makes the distinction between the primary result and secondary evidence especially important.

Finally, the comparison shows how statistical precision and clinical interpretation differ. The primary confidence interval excludes zero, while the effect remains expressed on a transformed scale with no direct clinical threshold posted in the record. The result can therefore be described precisely as a model-based group contrast without overstating what it establishes about individual outcomes, durability, or the totality of safety and benefit.

15. Limitations

• The posted summary statistics are the only data these results rest on; patient-level data, full protocols and statistical analysis plans are not available.
• Recalculated results are simple, unadjusted calculations from posted summaries. They do not replace the sponsor's prespecified analysis.

The registry record gives the primary endpoint definition and main result but does not provide the full MMRM specification. Covariates, covariance structure, detailed estimation choices, and diagnostic checks are not reported in the registry record. Independent reproduction of the model-based result is therefore limited, even though the principal estimate and interval are posted.

Missing-data information is incomplete. The baseline sample rule is described, but the amount and reasons for missing follow-up uPCR measurements, assumptions about missingness, and sensitivity analyses are not reported in the registry record. The detailed analysis population and missing-data handling for each secondary outcome are also not reported. These omissions limit assessment of how sensitive the estimates might be to unavailable measurements.

The record does not report the multiplicity procedure, if any, used across the primary and secondary outcomes. This matters most when interpreting the secondary p-values as confirmatory evidence. The full numerical results for every listed secondary outcome are not included in the record details used for this analysis, so the overall secondary-outcome pattern cannot be completely assessed.

The primary endpoint is a transformed biomarker measure and is summarized through an average over the stated late visits. The statistical estimate does not directly provide a clinical threshold interpretation, long-term outcome, or individual-level response pattern. The registry also records an open-label period, but it is not a continuation of the randomized placebo comparison in the same form; its observations should be interpreted separately.

Lastly, the registry record does not report the original sample-size justification, interim-analysis plan, or complete statistical analysis plan. These limitations do not invalidate the posted results, but they constrain evaluation of prespecification, robustness, and the extent to which secondary findings should be considered confirmatory.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Phase III Study Assessing the Efficacy and Safety of Pegcetacoplan in Patients With C3 Glomerulopathy or Immune-Complex Membranoproliferative Glomerulonephritis — NCT05067127.
• Registry record last updated 2026-01-29; status last verified 2025-08.
• Results first posted 2025-08-06.
• 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.

19. Record Summary

NCT05067127 is a completed Phase 3 randomized, placebo-controlled, triple-masked, parallel-group study of pegcetacoplan in patients with C3 glomerulopathy or immune-complex membranoproliferative glomerulonephritis. The registry reports enrollment of 124 and defines the primary analysis population as all randomized subjects.

The primary endpoint was change from baseline in log-transformed uPCR through Week 26, with the group contrast based on an equal-weighted average over Weeks 24, 25, and 26. The reported difference in least-squares means was -1.143 (95% confidence interval, -1.436 to -0.85; p < 0.001), indicating a lower estimated change on this scale in the pegcetacoplan group than in the placebo group.

Secondary outcomes cover renal, biopsy, and laboratory measures. The registry reports descriptive safety counts for randomized and open-label periods. Details of multiplicity adjustment, missing follow-up data, the full primary model specification, and the original sample-size justification are not reported in the registry record.