Safety, Tolerability, and Efficacy of Anti-Spike (S) SARS-CoV-2 Monoclonal Antibodies for the Treatment of Ambulatory Adult and Pediatric Patients With COVID-19: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Safety, Tolerability, and Efficacy of Anti-Spike (S) SARS-CoV-2 Monoclonal Antibodies for the Treatment of Ambulatory Adult and Pediatric Patients With COVID-19 (NCT04425629), a na phase 3 study. The primary outcome is Number of Participants With Treatment-emergent Serious Adverse Events (SAEs) - [Ph1, Ph2, Ph3 Cohort 1 - Cohort 3].

2. Clinical Question

The trial title describes a master protocol assessing safety, tolerability and efficacy. Its objectives vary by phase and cohort rather than representing a single uniform comparison. Phase 1 and Phase 2 objectives include virologic outcomes; the adult Phase 3 objective concerns COVID-19-related hospitalization or all-cause death. The pediatric cohort focuses on safety, tolerability and serum concentrations over time, while the pregnant cohort focuses on safety and tolerability.

Thus, the central statistical question depends on which cohort and endpoint are being considered. The posted primary safety endpoint is a participant count, whereas efficacy objectives concern clinical events or viral load. Those distinct aims should not be treated as interchangeable evidence. The registry record does not report an efficacy effect estimate or the statistical uncertainty around one.

3. Trial Design

This is a Phase 3 master protocol that also includes Phase 1 and Phase 2 participants. The registry lists enrollment as 10078, start date as 2020-06-16, primary completion date as 2022-01-21, and status as terminated. Regeneron Pharmaceuticals is listed as the sponsor. COVID-19 is the registered condition.

The record describes the overall study model as single group and allocation as not applicable. Masking is listed as none. Although placebo and active-treatment arms are present in the posted safety data, the registry explicitly warns that this is not a randomized comparison and that the arms are not a like-for-like control comparison. Arm counts can therefore be read as reported group descriptions, not as proof that groups were made comparable through random allocation.

Study aims differ by phase. Phase 1 evaluates safety and tolerability and virologic efficacy. Phase 2 includes virologic efficacy objectives. In Phase 3 cohort 1, adults not pregnant at randomization were assessed for clinical efficacy, with the stated objective concerning COVID-19-related hospitalizations or all-cause death. Cohort 2 comprises participants under 18 years and has safety, tolerability and serum-concentration objectives. Cohort 3 comprises participants pregnant at randomization and has safety and tolerability objectives.

The registered intervention is casirivimab plus imdevimab. The arm descriptions include 2.4 g and 8.0 g intravenous regimens in earlier phases and 1.2 g, 2.4 g and 8.0 g intravenous regimens in adult Phase 3. The pediatric description specifies a low dose or body-weight equivalent for those under 18 years. These protocol features provide context for interpreting the safety counts, but do not establish exchangeability across treatment groups or cohorts.

The registry record does not report the full operational details needed to reconstruct enrollment decisions, treatment assignment procedures, or the complete statistical plan. Any conclusions should be limited to the outcomes and design information recorded for this protocol.

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: 10065 were randomized, 135 randomized but not treated

Only the first 6 of 19 groups are shown.

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: Analysis populations were prespecified in the SAP. Pooled analyses were performed for symptomatic adult participants randomized in Phase 1, 2, or 3 (cohort 1) on or before 2/24/21 to placebo, R10933+R10987 1.2 g, 2.4 g, or 8.0 g IV. No phase 1 or 2 participants were randomized to R10933+R10987 1.2 g IV. Asymptomatic adult participants randomized to the asymptomatic cohort of phase 2, symptomatic pediatric / pregnant participants randomized in phase 3 to cohort 2 or 3 were analyzed separately

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.

Only the first 6 of 20 groups are shown.

6. Primary Endpoint

The registry lists the primary outcome as Number of Participants With Treatment-emergent Serious Adverse Events (SAEs) - [Ph1, Ph2, Ph3 Cohort 1 - Cohort 3], measured over Through Day 29.

The registered primary endpoint is the number of participants with treatment-emergent serious adverse events through Day 29. It is a count of participants who experienced at least one event meeting the serious-adverse-event definition, rather than a measure of the total number of event episodes. The record identifies the endpoint as a participant count and specifies the observation window as through Day 29.

Safety endpoints of this kind are used to describe serious events occurring after treatment begins and to support monitoring of potential harms. A count is straightforward to interpret as a number of participants with an event. It does not, by itself, indicate how likely an event is in a group or establish that treatment caused it. For that assessment, the count needs context about the number of participants at risk, how participants entered each arm, the event definitions, follow-up and analysis procedures.

The registry labels this endpoint primary for Phase 1 and Phase 3 cohorts 2 and 3, and secondary for Phase 2 and Phase 3 cohort 1. That distinction matters: the endpoint does not serve the same registered role in every cohort. The record also describes clinical and virologic objectives, but those are different outcomes from the serious-adverse-event count.

Endpoint definitions, ascertainment and analysis details beyond the posted description are not reported in the registry record. The posted counts should therefore be read as descriptive safety information, not as a complete estimate of treatment effect.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The primary safety outcome is binary at the participant level: a participant either had at least one treatment-emergent serious adverse event during the stated window or did not. The registry presents counts of participants with events and counts at risk by group. Such data can be described with event counts, and, when appropriate information is available, with proportions and comparative effect estimates. The record does not post a comparative effect estimate or uncertainty interval for this endpoint.

What does a participant count capture?

A participant count records whether each person experienced at least one qualifying event. It does not count repeated episodes as separate participants. This distinction matters when a person can experience more than one event: the number of participants affected and the total number of event episodes are different quantities. The registered endpoint is explicitly a count of participants.

For a comparative analysis, investigators commonly consider the event frequency in each group and estimate a contrast between groups. A confidence interval can show the range of values compatible with the data and the analysis assumptions, helping readers judge precision. A p-value addresses compatibility with a specified null hypothesis under a statistical model; it does not measure clinical importance. These are general statistical concepts. The registry record does not report a treatment-effect estimate, confidence interval or p-value for the safety endpoint.

Why does the study structure matter?

Random allocation, when used and properly implemented, can balance measured and unmeasured baseline characteristics on average. Here, allocation is listed as not applicable, the model as single group, and masking as none. The record cautions that the arms are not a like-for-like control comparison. As a result, differences in observed counts may reflect differences in participant characteristics, cohort composition, follow-up or other factors as well as any treatment-related effect. The posted arm counts should be read descriptively rather than as an unbiased causal estimate.

Pooling can also change what a summary represents. The registry states that analysis populations were prespecified in the SAP and describes pooled analyses for symptomatic adult participants randomized in Phase 1, 2 or 3 cohort 1 on or before 2/24/21 to placebo, 1.2 g, 2.4 g or 8.0 g. It also states that no Phase 1 or Phase 2 participants were randomized to 1.2 g. Those details define a particular analysis population; they do not establish that all listed safety counts belong to the same pooled population. Full analysis-set definitions and the statistical procedures are not reported in the registry record.

What do the planning illustrations mean?

The registry’s sample-size assumptions describe a planning illustration based on an observed effect, not the trial’s own design. The stated assumptions are a two-sided significance level of 0.05, equal allocation between the two arms, a normal approximation, and an effect to detect defined as a stated fraction of the observed effect. For time-to-event illustrations, the total number of events is used; other illustrations are expressed as participants per arm.

These are hypothetical planning calculations. They describe what a future study might require under stated assumptions; they are not observed trial outcomes and are not observed power. The illustration depends on the effect used as its starting point and on the model assumptions. The registry record does not report a sample-size justification from the original protocol, nor does it report enough detail to treat these illustrations as the study’s prospective design calculation.

What cannot be concluded from the posted methods?

For binary outcomes, analysts may use methods that account for the chosen comparison design, baseline covariates and event frequency. If event data are sparse, some conventional approximations may be unreliable; exact or other suitable methods may be considered in general. Those possibilities are methodological context, not a description of what this trial used. The particular model, covariate adjustment, handling of repeated events, missing-data procedures and inferential test are not reported in the registry record.

Likewise, the record does not report an analysis of over-dispersion. Over-dispersion is a general concern when observed variability exceeds what a statistical model assumes; it is more relevant to certain count models than to a participant-level yes-or-no endpoint. No claim about such a model or diagnostic can be made for this study from the registry information.

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("Combined Phases 1, 2, & 3 Cohort 1 Symptomatic (Pl", "Combined Phases 1, 2, & 3 Cohort 1 Symptomatic (2.", "Combined Phases 1, 2, & 3 Cohort 1 Symptomatic (8.", "Phase 2 Asymptomatic (Placebo)", "Phase 2 Asymptomatic (2.4g IV)", "Phase 2 Asymptomatic (8.0g IV)")
n      <- c(2609, 2614, 1272, 74, 72, 73)
events <- c(97, 31, 19, 0, 0, 0)
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  Combined Phases 1, 2, & 3 Cohort 1 Symptomatic (Pl  2609  97  3.7  3.0  4.5  3.1  4.5  3.1  4.5
ARM  Combined Phases 1, 2, & 3 Cohort 1 Symptomatic (2.  2614  31  1.2  0.8  1.7  0.8  1.7  0.8  1.7
ARM  Combined Phases 1, 2, & 3 Cohort 1 Symptomatic (8.  1272  19  1.5  0.9  2.3  1.0  2.3  1.0  2.3
ARM  Phase 2 Asymptomatic (Placebo)  74  0  0.0  0.0  4.9  0.0  4.9  0.0  4.8
ARM  Phase 2 Asymptomatic (2.4g IV)  72  0  0.0  0.0  5.0  -0.0  5.1  0.0  4.9
ARM  Phase 2 Asymptomatic (8.0g IV)  73  0  0.0  0.0  4.9  0.0  5.0  0.0  4.9

11. Multiplicity, Missing Data and Analysis Populations

The protocol spans phases, cohorts, doses and many outcomes. The registry lists 91 outcome measures and 8 analyses. When many outcomes or comparisons are examined, the chance of obtaining apparently notable results by chance can increase. Statistical plans sometimes address this through a hierarchy of endpoints, adjustment procedures, or a distinction between confirmatory and exploratory analyses. The registry record does not report a multiplicity-adjustment procedure or explain how the many outcomes and analyses were prioritized.

The primary endpoint description identifies treatment-emergent serious adverse events as primary for Phase 1 and Phase 3 cohorts 2 and 3, and secondary for Phase 2 and Phase 3 cohort 1. The record separately describes clinical efficacy objectives for adults in Phase 3. That endpoint-role information is useful, but it is not a complete testing hierarchy. Whether outcomes were tested formally, and whether any adjustment was used, is not reported in the registry record.

The record says analysis populations were prespecified in the SAP and describes a pooled population of symptomatic adults randomized in Phase 1, 2 or 3 cohort 1 on or before 2/24/21. It specifies the listed treatment groups and notes that no Phase 1 or Phase 2 participants were randomized to 1.2 g. The complete population definitions, exclusions and analysis-set rules are not reported in the registry record.

Missing-data handling is not reported in the registry record. That includes whether missing outcome observations were excluded, imputed, treated as not having an event, or addressed through sensitivity analyses. Interim analyses and any associated decision rules are also not reported. Without these details, readers cannot assess how missing observations or repeated looks at the data may have influenced inferential results. The descriptive event counts remain interpretable as posted, but they do not resolve these methodological uncertainties.

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: pre-eclampsia (7.0%), nausea (4.5%), vomiting (4.5%), craniosynostosis (2.9%), foetal malformation (2.9%).

The serious-adverse-event figures are participant counts, with a corresponding number at risk for each posted group. For adult Phase 3, the placebo group reports 103 participants with an event among 2347 at risk; the 1.2 g group reports 39 among 2130, the 2.4 g group 52 among 3157, and the 8.0 g group 19 among 1012. These figures describe what was recorded in each group, not randomized contrasts.

The groups vary in size and belong to a protocol that includes different phases and cohorts. The registry explicitly states that allocation is not applicable and cautions that the arms are not like-for-like controls. Consequently, counts should not be used alone to rank doses or estimate a causal safety effect. The record does not report a comparative model, confidence interval or adjustment for participant differences.

Serious-event counts also differ from counts of all adverse events. The posted outcome concerns participants with at least one treatment-emergent serious adverse event. Deaths are listed separately. The registry’s top serious terms include pre-eclampsia, nausea, vomiting, craniosynostosis, foetal malformation and neonatal hyperbilirubinaemia, with percentages attached to those terms. The denominator and calculation method for those percentages are not reported in the registry record.

Small groups, including the pregnant placebo group with 2 at risk, make raw counts especially limited as comparative evidence. Zero recorded events in a group does not establish absence of risk. These data are best read as descriptive safety reporting within the registry record.

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

The registry establishes that this was a broad master protocol with safety, tolerability, virologic and clinical objectives across several phases and patient cohorts. It records serious-adverse-event counts through Day 29 for placebo and active-treatment arms, along with group sizes at risk and separate death counts. These observations describe events recorded in the listed groups.

The record does not establish that casirivimab plus imdevimab caused a higher or lower rate of serious adverse events, deaths, hospitalization or symptom resolution. Allocation is listed as not applicable, masking as none, and the study model as single group; the registry cautions that arms are not like-for-like controls. Therefore, raw differences between group counts cannot be attributed to treatment without a suitable design and analysis that address group comparability.

Nor do the safety counts answer the registered efficacy questions. The adult Phase 3 objective includes COVID-19-related hospitalization or all-cause death, and the secondary outcomes include symptom resolution and hospitalization-or-death measures. The registry record does not report comparative efficacy estimates for these outcomes. It also does not report the associated uncertainty or formal testing results. No conclusion about efficacy should be drawn from the adverse-event counts.

The posted data also do not establish the frequency of every possible adverse event across all participants, because the available record presents selected outcome summaries and the full ascertainment and missing-data methods are not reported. A serious event occurring after treatment is not automatically caused by treatment. Clinical context, a clear event definition and appropriate comparative evidence are needed to assess causality.

In short, the posted results are useful for seeing which serious events were recorded and in which groups. They are not sufficient to determine comparative safety or efficacy. Any broader conclusion would require evidence and analytic details not reported in the registry record.

14. Why This Trial Matters Statistically

This study illustrates a recurring challenge in clinical-trial interpretation: a single protocol can contain multiple phases, populations, doses and scientific aims. A safety count from an adult cohort cannot automatically answer a question about pediatric participants or pregnancy, and a virologic objective is not interchangeable with a clinical endpoint. Keeping the cohort and endpoint attached to each result is essential.

It also shows why design labels matter. Placebo arms appear in the registry, but allocation is recorded as not applicable and the record warns against treating the arms as like-for-like controls. The presence of a placebo group alone does not establish randomization or eliminate selection differences. A numerical contrast between groups is not necessarily a treatment effect.

Safety counts are informative as descriptions, yet they require careful interpretation. Counts depend on the number of people observed and the population being studied. Small groups can yield sparse events, while larger groups can record more events simply because more participants were observed. Formal estimates of comparative risk and their uncertainty would require an appropriate design and analysis; those are not reported for the posted safety outcome.

The protocol also makes the distinction between a registered objective and a reported result important. The registry states clinical and virologic aims and lists many outcomes, but comparative efficacy estimates are not reported in the registry record. A study’s purpose cannot substitute for its results. Readers should separate what was planned, what was measured, and what the record actually reports.

Finally, the record notes prespecified analysis populations while leaving important details of multiplicity, missing data and statistical procedures unreported. This makes transparent reporting of analysis methods central to judging precision and reliability. The trial is statistically instructive not because the posted counts settle causal questions, but because they demonstrate how design, endpoint, population and analysis determine what a result can support.

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 labels the study as single group, lists allocation as not applicable and reports no masking. It also warns that the arms are not a like-for-like control comparison. This limits interpretation of between-arm differences as causal effects, even though placebo and treatment arms appear in the posted safety data.

The master protocol includes different phases and clinically distinct cohorts. The adult, pediatric and pregnant populations do not represent a single interchangeable group, and their objectives differ. Posted counts from one cohort should not be generalized to another. The record does not provide enough detail to assess whether group differences in baseline characteristics, follow-up or outcome ascertainment could explain observed count patterns.

The status is terminated, but the reason for termination is not reported in the registry record. The record lists enrollment as 10078, yet that figure does not identify how many participants contributed to each endpoint or analysis population. Endpoint-specific denominators are shown for the posted safety groups, but complete participant flow and reasons for missing observations are not reported.

Comparative efficacy results, confidence intervals, p-values and the analysis model are not reported in the registry record. Multiplicity procedures, missing-data methods, interim analyses and detailed outcome definitions are also not reported. Although analysis populations were prespecified in the SAP, their complete criteria are not available in the registry record.

Some cohorts have limited posted group sizes, including the pregnant placebo group with 2 at risk. Sparse counts are inherently imprecise as descriptions of underlying event frequency and cannot support a robust comparison on their own. The serious-term percentages are reported without their denominator or calculation method. These limitations counsel against overinterpreting any single count or percentage.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Safety, Tolerability, and Efficacy of Anti-Spike (S) SARS-CoV-2 Monoclonal Antibodies for the Treatment of Ambulatory Adult and Pediatric Patients With COVID-19 — NCT04425629.
• Registry record last updated 2023-12-21; status last verified 2023-12.
• Results first posted 2023-12-21.
• 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

NCT04425629 is a Phase 3 master protocol sponsored by Regeneron Pharmaceuticals, with Phase 1 and Phase 2 components. It studies casirivimab plus imdevimab in ambulatory patients with COVID-19 across adult, pediatric and pregnant cohorts. The registry lists enrollment as 10078, a start date of 2020-06-16, a primary completion date of 2022-01-21, and status as terminated.

The registered primary endpoint is the number of participants with treatment-emergent serious adverse events through Day 29, primary for Phase 1 and Phase 3 cohorts 2 and 3 and secondary for Phase 2 and Phase 3 cohort 1. The record posts serious-adverse-event counts and deaths by group. Allocation is listed as not applicable, masking as none, and the model as single group; the registry cautions that arms are not like-for-like controls.

The protocol lists virologic and clinical efficacy objectives, but comparative efficacy results and their statistical uncertainty are not reported in the registry record. The posted safety counts therefore support descriptive reading, not a causal comparison or a conclusion about efficacy.