Pozelimab and Cemdisiran Combination Therapy in Adult Participants With Paroxysmal Nocturnal Hemoglobinuria Who Switch From Eculizumab Therapy: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Pozelimab and Cemdisiran Combination Therapy in Adult Participants With Paroxysmal Nocturnal Hemoglobinuria Who Switch From Eculizumab Therapy (NCT04888507), a na phase 2 study. The primary outcome is OLTP: Number of Participants With Treatment-emergent Adverse Events (TEAEs).

2. Clinical Question

The clinical question centers on participants changing from eculizumab monotherapy to the combination. The registry describes a safety-focused primary objective and secondary objectives covering markers and clinical consequences of intravascular hemolysis. These include lactate dehydrogenase (LDH) control and stability, breakthrough hemolysis, inhibition of CH50, red blood cell transfusion requirements, hemoglobin levels, fatigue, and health-related quality of life. It also lists objectives concerning drug and protein concentrations, immunogenicity, safety after dose intensification, and longer-term safety and efficacy during an optional open-label extension period.

Because this is a single-group study, it does not directly compare the combination with continued eculizumab or another control treatment. Its design can describe outcomes observed during the study, but cannot isolate the effect of the combination from other explanations through a concurrent randomized comparison. The registry record does not report a comparative treatment-effect estimate for the primary question.

3. Trial Design

This was a Phase 2, single-arm, open-label study of pozelimab and cemdisiran in adult participants with paroxysmal nocturnal hemoglobinuria who switched from eculizumab therapy. The registry lists six participants enrolled and marks the study as completed. The recorded study start date is 2021-07-08, and the primary completion date is 2022-05-05.

There was one treatment group, described as pozelimab plus cemdisiran. Allocation is recorded as not applicable, masking as none, and the model as single group. Accordingly, the design has no randomized control group and no blinded comparison. The combination is the intervention of interest, while participants’ prior eculizumab therapy describes the switch context rather than a concurrent comparator arm.

The primary objective was to evaluate safety and tolerability. Secondary objectives addressed hemolysis-related measures, transfusions, hemoglobin, fatigue and health-related quality of life, drug and protein concentrations, immunogenicity, safety after dose intensification, and an optional open-label extension period. The listed secondary outcome measures include changes in LDH and transfusion-related measures over specified periods. These objectives span different types of outcomes, so they do not all answer the same clinical or statistical question.

The registry record does not report details such as the dosing schedule, eligibility criteria, planned sample-size justification, or the statistical analysis plan. It also does not describe the procedures used to manage the transition from eculizumab. Such details should not be inferred from the study title or objectives. The design and enrollment indicate that the posted findings should be read as descriptive evidence from a small, uncontrolled study, not as a randomized estimate of comparative effectiveness.

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: A total of 7 participants were screened and 6 were enrolled and received study treatment.

Open-Label Treatment (OLTP) (32 Weeks)

Reasons for not completing this period:

Open-Label Extension (OLEP) (52 Weeks)

Analysis population for the primary outcome, as defined in the registry: The safety analysis set included all participants who received any amount of study drug.

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 safety analysis set included all participants who received any amount of study drug.

6. Primary Endpoint

The registry lists the primary outcome as OLTP: Number of Participants With Treatment-emergent Adverse Events (TEAEs), measured over Up to Day 225.

The primary endpoint is the number of participants with treatment-emergent adverse events (TEAEs), with a timeframe of up to Day 225. It is defined as a count of participants with an event, rather than a measure of event severity, duration, or rate. The safety analysis set is described as all participants who received any amount of study drug.

Counting participants with TEAEs is a common way to summarize the occurrence of adverse events in a safety population. It gives a direct account of how many participants experienced at least one event under the endpoint definition. It does not, by itself, describe how many separate events occurred, how often they recurred, or how serious they were. Those questions require additional outcome details.

The endpoint is suited to a study whose primary objective is safety and tolerability, but interpretation depends on the event definitions, ascertainment, observation period, and the population included in the analysis. The timeframe specifies the period covered by this endpoint; it does not establish that every participant had the same amount of observation. The registry record does not report an analyzed primary endpoint result or additional details about event coding and ascertainment. The serious adverse-event summaries should not be treated as a substitute for the TEAE endpoint: they describe a more specific safety category and are reported separately.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The registry classifies the primary outcome as a count of participants with an event. For a binary event outcome, each participant is categorized according to whether the event was recorded under the specified definition and observation period. A count is an absolute summary. A proportion would require a denominator and a clearly defined analysis population; a comparison would additionally require a suitable comparator. The primary outcome definition names the safety analysis set, but the primary endpoint result itself is not reported in the registry record.

What does an open-label, single-group design allow?

In a single-group study, outcomes are observed in participants receiving the intervention without a concurrent control group. This can document events and describe changes over time, but it does not provide a randomized contrast. Random allocation is one method for balancing known and unknown factors between groups; without that comparison, a change after treatment begins cannot automatically be attributed to treatment. The study’s open-label designation means masking is listed as none. In general, knowing the treatment can influence subjective reporting or assessment, although this does not establish that any particular result was biased.

The setting also matters: participants switched from eculizumab therapy. The study therefore addresses a transition context, not a comparison between otherwise equivalent groups assigned to different therapies. The registry record does not report details that would allow the transition process or potential sources of confounding to be assessed.

How should safety counts be read?

A count of participants with at least one event differs from a count of all events. A participant may experience more than one event, and a participant-level count does not reveal recurrence or event duration. Serious adverse events are a defined subset of safety events and should be kept distinct from the broader TEAE endpoint. The record’s serious-event summaries describe participants at risk and participants with serious events, while the primary endpoint is defined as participants with treatment-emergent adverse events. The two summaries answer different questions.

General statistical interpretation also depends on the denominator and observation time. Participants who are followed for different durations may have different opportunities for an event to be observed. The endpoint specifies a timeframe, but the registry record does not report participant-level follow-up or an event-rate analysis. A simple participant count cannot account for differences in time at risk.

What do statistical tests and confidence intervals contribute?

In general, a statistical test evaluates whether data are compatible with a specified null hypothesis under its assumptions; it does not measure clinical importance or prove that an effect is absent. A confidence interval conveys uncertainty around an estimate and can show which effect sizes remain compatible with the data and analysis assumptions. Neither a test result nor an interval can be interpreted without knowing the estimate, method, population, and comparison being analyzed. The registry record reports no analysis records, effect estimates, confidence intervals, or test results for the outcomes described in the objectives.

For event-count data, methods may need to account for the fact that events can occur repeatedly within a participant. General count models can require assumptions about the event distribution; over-dispersion occurs when observed variability is greater than a model’s basic assumptions allow. A participant-level binary endpoint avoids counting repeated events as separate observations, but loses information about recurrence and total event burden. No model choice or adjustment for repeated events is reported in the registry record.

How do the sample-size illustrations differ from trial design evidence?

The registry describes sample-size calculations as planning illustrations based on the observed effect, with a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation. The effect to detect is framed as a stated fraction of the observed effect. For time-to-event outcomes, the described calculations use a total number of events; for other outcomes, they use participants per arm. These are hypothetical planning assumptions, not the study’s observed results and not observed power. The study itself is single-group, so the assumed two-arm allocation does not describe its enrollment design. The registry record does not report the trial’s own sample-size justification, and the illustration values are not reported in the record details.

Because the study enrolled six participants and has no randomized comparator, any future interpretation of estimates would need to emphasize uncertainty and scope. A small sample can yield imprecise estimates, especially for uncommon events, and does not support broad generalization without further evidence. This is a general statistical caution, not a claim about an unreported estimate from this study.

10. Exact Estimates for Each Arm

No two-arm comparison is shown for this trial, but each arm's result can still be summarized with exact interval estimates computed from the posted counts. The Clopper-Pearson interval is exact and conservative; the Wilson interval is a common closer-to-nominal alternative; the Bayesian credible interval uses a uniform Beta(1, 1) prior. For small groups the three can differ noticeably.

R code and output

arm    <- c("Participants With PNH")
n      <- c(6)
events <- c(6)
for (i in seq_along(n)) {
  ci <- binom.test(events[i], n[i])$conf.int          # Clopper-Pearson exact interval
  cr <- qbeta(c(0.025, 0.975), 1 + events[i], 1 + n[i] - events[i])   # Bayesian, uniform Beta(1,1) prior
  wi <- (function(x, n) { p <- x / n; z <- qnorm(0.975); d <- 1 + z^2 / n
    c((p + z^2 / (2 * n) - z * sqrt(p * (1 - p) / n + z^2 / (4 * n^2))) / d, (p + z^2 / (2 * n) + z * sqrt(p * (1 - p) / n + z^2 / (4 * n^2))) / d) })(events[i], n[i])
  cat(sprintf("ARM|%s|%d|%d|%.1f|%.1f|%.1f|%.1f|%.1f|%.1f|%.1f\n", arm[i], n[i], events[i], 100 * events[i] / n[i],
              100 * ci[1], 100 * ci[2], 100 * wi[1], 100 * wi[2], 100 * cr[1], 100 * cr[2]))
}

ARM  Participants With PNH  6  6  100.0  54.1  100.0  61.0  100.0  59.0  99.6

11. Multiplicity, Missing Data and Analysis Populations

The registry lists 58 outcome measures, covering safety and a range of secondary topics, including LDH, transfusions, hemoglobin, fatigue, health-related quality of life, concentrations, and immunogenicity. When a study evaluates many outcomes, the chance of at least one apparently unusual result can increase if each is assessed separately. General approaches to multiplicity include prespecifying a primary comparison, adjusting inference across a family of tests, or clearly labeling secondary and exploratory findings. Which approach was planned for this study is not reported in the registry record.

The record lists zero analysis records. It does not provide a statistical analysis plan, the number or ordering of planned hypothesis tests, multiplicity adjustments, or inferential results. Thus, the presence of many outcome measures should not be mistaken for evidence that each was analyzed or that any result was statistically significant. The objectives and outcome descriptions specify intended areas of assessment, not findings.

Missing-data methods are also not reported in the registry record. There is no description of how missing measurements, withdrawals, incomplete follow-up, or unavailable outcome assessments were handled. This matters because an analysis can depend on whether missingness is rare, related to participant characteristics, or related to outcomes. Without the analysis population and missing-data approach for each outcome, the impact of incomplete data cannot be assessed.

The primary safety population is defined as all participants who received any amount of study drug. The registry does not report analysis populations for the secondary outcomes or clarify whether the same participants contributed to each measure. The extension period is optional, and the record does not explain how participation or follow-up in that period was accounted for in analyses. These omissions limit the ability to judge completeness and consistency across outcomes.

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: haemolysis (20.0%), respiratory tract infection (20.0%), endometrial hyperplasia (16.7%).

The serious adverse-event summaries list one participant with a serious adverse event among six at risk in the OLTP period, and one among five at risk in the OLEP period. No deaths are recorded for either group. These are period-specific descriptions from the registry record. The optional extension and the absence of information about overlap mean that the groups should not be added together or assumed to represent independent sets of participants.

The registry lists haemolysis and respiratory tract infection at 20.0% each, and endometrial hyperplasia at 16.7%, as top serious terms. These percentages describe listed terms; they do not establish causation, and the record does not provide enough detail to reconstruct event timing or participant-level histories. The percentages should be quoted as reported, not converted into counts.

These serious-event summaries are not the primary TEAE result. Serious adverse events represent a particular safety category, whereas the primary endpoint counts participants with treatment-emergent adverse events. The primary endpoint result is not reported in the registry record. The serious-event summaries also do not, by themselves, establish comparative risk: the study has no control group, and the record does not provide an inferential comparison. Interpret them as descriptive safety information within the stated study periods, not as evidence of treatment causation or a comparison with eculizumab.

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

The registry record establishes that this completed Phase 2 study evaluated pozelimab and cemdisiran in adults with paroxysmal nocturnal hemoglobinuria switching from eculizumab. It describes the primary safety objective, a TEAE-count endpoint up to Day 225, and a broad set of secondary objectives. It also records serious adverse-event summaries for the OLTP and OLEP periods, including no deaths in either summary.

Those entries do not establish how often participants experienced any TEAE under the primary endpoint definition, because its result is not reported in the registry record. Nor do the listed serious terms demonstrate that the study drugs caused the events. The registry’s objectives concerning LDH, transfusions, hemoglobin, symptoms, quality of life, concentrations, and immunogenicity should not be read as evidence that favorable or unfavorable changes occurred. Their results are not reported in the registry record.

The study cannot provide a randomized estimate comparing the combination with continued eculizumab or another treatment, because it has one group and no concurrent comparator. The open-label design further means that outcomes were not assessed under masking. These features limit causal interpretation, especially for outcomes involving reporting or judgment. The small enrollment also limits how much can be learned about uncommon events and makes precision a particular concern, although the record does not report a primary endpoint estimate or interval to quantify it.

In general, results from an uncontrolled study can inform description of outcomes in the study setting, but causal conclusions require stronger comparative evidence and a transparent analysis. Here, the available registry information supports a description of the study design and recorded serious-event summaries. It does not establish treatment benefit, lack of benefit, or comparative safety. No treatment recommendation follows from these registry entries.

14. Why This Trial Matters Statistically

Statistically, this trial matters because it concerns a treatment transition in a defined clinical context: adults with paroxysmal nocturnal hemoglobinuria who switch from eculizumab to pozelimab and cemdisiran. The registry’s objectives show that the investigators intended to evaluate more than a single safety count. They include laboratory measures, transfusion outcomes, patient-reported concerns such as fatigue and health-related quality of life, and measures of drug exposure and immunogenicity. These domains illustrate why clinical studies often need multiple outcome definitions and distinct analyses.

The study also highlights the limits of small, single-group evidence. A completed study can still have limited interpretability if its primary endpoint result and analysis methods are not available in the registry record. Without a concurrent comparator, observed outcomes cannot be cleanly separated from changes over time or other features of switching therapy. Without reported estimates and uncertainty measures, readers cannot judge the precision of the results that may have been collected.

Its posted serious-event summaries are useful as descriptive safety information, but they do not resolve those limitations. The record’s planning illustrations also need to be kept separate from the actual study design: assumptions about two-arm allocation do not turn a single-group trial into a comparative one, and planning calculations are not observed power.

The statistical lesson is to distinguish study objectives, outcome definitions, observed results, and causal conclusions. Each has a different evidentiary role. The registry record identifies the questions and some safety summaries, while leaving important analysis details and the primary endpoint result unreported. That distinction is essential when evaluating what a small, uncontrolled study can contribute.

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 most direct limitation is that the primary endpoint result is not reported in the registry record. The record defines the endpoint as the number of participants with TEAEs up to Day 225, but the separate serious adverse-event summaries do not supply that result. Therefore, the primary safety outcome cannot be evaluated from the recorded information.

The study is single-arm and open-label, with allocation recorded as not applicable and masking as none. It has no concurrent control group for estimating comparative effects. Participants were switching from eculizumab, so changes observed during the study could reflect factors other than the combination; the record does not report information that would allow those explanations to be separated. Open-label assessment can also affect reporting or evaluation, particularly for subjective outcomes.

Enrollment was six, limiting the scope of conclusions, especially about uncommon events. The serious adverse-event summaries are reported separately for OLTP and OLEP, and the record does not describe overlap between those groups. Since the extension is optional, the extension summary should not be treated as a direct comparison with the earlier period.

Important statistical details are not reported in the registry record: the analysis plan, sample-size justification, missing-data handling, multiplicity approach, outcome-specific analysis populations, and inferential estimates. The record lists 58 outcome measures but no analysis records. This makes it difficult to assess whether planned analyses were carried out as intended or how uncertainty was quantified. These limitations apply to interpretation of the registry information and do not establish what may be available from other sources.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Pozelimab and Cemdisiran Combination Therapy in Adult Participants With Paroxysmal Nocturnal Hemoglobinuria Who Switch From Eculizumab Therapy — NCT04888507.
• Registry record last updated 2025-08-29; status last verified 2025-08.
• Results first posted 2025-06-25.
• 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

The registry identifies NCT04888507 as a completed Phase 2, single-arm, open-label study of pozelimab and cemdisiran in adults with paroxysmal nocturnal hemoglobinuria switching from eculizumab. Six participants were enrolled. The recorded start date is 2021-07-08, and the primary completion date is 2022-05-05.

The primary objective was safety and tolerability. The primary outcome is the number of participants with treatment-emergent adverse events up to Day 225, in a safety set defined as participants receiving any amount of study drug. Its result is not reported in the registry record. Separate serious adverse-event summaries list one affected participant in OLTP and one in OLEP, with no deaths in either summary.

The registry lists 58 outcome measures and no analysis records. It does not report the primary endpoint analysis, missing-data methods, multiplicity approach, or the trial’s sample-size justification. With no randomized comparator, the record supports descriptive interpretation rather than a causal treatment comparison.