An Open-label Study to Assess the Long-term Safety, Tolerability, and Efficacy of KarXT in Adult Patients With Schizophrenia (EMERGENT-5): Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for An Open-label Study to Assess the Long-term Safety, Tolerability, and Efficacy of KarXT in Adult Patients With Schizophrenia (EMERGENT-5) (NCT04820309), a na phase 3 study. The primary outcome is Number of Participants With Treatment Emergent Adverse Events (TEAEs).

2. Clinical Question

3. Trial Design

This was a Phase 3, multicenter, outpatient, open-label study of KarXT in de novo subjects with DSM-5 schizophrenia. The registry lists the study as completed, with an enrollment of 566. Its design is single-group, and allocation is recorded as not applicable. There was no masking and no concurrent control group. Consequently, the design supports description of participant outcomes during treatment but does not provide a randomized or controlled estimate of treatment effect.

The brief description characterizes the study as 56 weeks long and states that participants would receive KarXT for up to 52 weeks. The registry gives the primary endpoint timeframe as from consent through the end of the study, approximately 400 days. The study start date is 2021-06-02, and the primary completion date is 2024-05-24. These dates describe the study record; they do not establish that each participant had the same duration of exposure or observation.

KarXT was the intervention, described as a fixed combination of xanomeline 125 mg and trospium chloride 30 mg twice daily. The primary objective concerned long-term safety and tolerability. Secondary objectives concerned long-term efficacy and pharmacokinetics. Listed secondary clinical measures include changes from baseline in PANSS total, positive, negative, and Marder Factor negative scores, change in CGI-S score, and the percentage of participants with a 30% or greater reduction in PANSS total score at Week 52.

The registry record does not report the detailed visit schedule, participant flow, adherence, rules for treatment interruption, or the complete analysis protocol. Those details should not be inferred from the study duration or the endpoint timeframes alone.

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.

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: Safety Population

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.

6. Primary Endpoint

The registry lists the primary outcome as Number of Participants With Treatment Emergent Adverse Events (TEAEs), measured over From time of consent to end of study (approximately 400 days).

The primary endpoint is the number of participants with treatment-emergent adverse events, reported for the Safety Population. An event qualifies as treatment-emergent when its onset is on or after the first dose of KarXT. The registry definition also describes an adverse event as a symptom, physical sign, syndrome, or disease that emerges during the study or worsens from baseline, regardless of whether it is suspected to be caused by the study drug. The definition references the National Cancer Institute Common Terminology Criteria for Adverse Events, version 5.0.

A participant count is a straightforward safety summary: it records how many people experienced at least one qualifying event during the stated observation period. This type of endpoint is useful for describing how frequently participants encountered events while under observation. It does not, by itself, establish that the intervention caused an event. Events can have different clinical importance, and a count of participants does not describe how many repeated events each person experienced, how long events lasted, or their severity unless those features are reported separately.

The timeframe runs from consent to the end of the study, approximately 400 days. The registry record names the primary endpoint, but does not report a distinct overall primary-endpoint result in the available outcome details. The adverse-event summary separately reports serious and other adverse-event counts. Those categories should not be combined into a new total without a clearly reported definition and result.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

What does a participant count represent?

The primary endpoint is a count of participants who experienced at least one treatment-emergent adverse event. This is different from a count of all event episodes: if one participant experiences several events, a participant-level endpoint ordinarily counts that person once, while an event-level endpoint could count each episode. The registry describes the endpoint in terms of participants. It does not report an overall result for that endpoint in the outcome details, so the adverse-event categories should not be substituted for a total without an explicit registry result.

For a participant-level event outcome, the count is usually interpreted alongside the number of participants at risk and the period during which they were observed. Here, the adverse-event summary gives 566 at risk for the reported categories. Follow-up is described as approximately 400 days from consent to study end, but individual follow-up may vary; the registry record does not report participant-level observation time. A count alone does not indicate when events occurred, how long they lasted, or whether participants experienced recurrent events.

Why does the single-group design matter?

In a controlled trial, a comparison between groups can help distinguish an outcome observed under treatment from outcomes that might also occur without that treatment. General statistical principle: random assignment can make groups comparable on average at the outset, while masking can reduce some forms of measurement or reporting bias. Neither a concurrent comparator nor masking is reported for this study. It is single-group and open-label, so its outcome counts describe the observed group rather than a contrast attributable to treatment assignment.

General statistical principle: a confidence interval expresses the range of estimates compatible with the data under a specified method and assumptions. It communicates precision, not certainty that the true value lies within a particular interval. The registry record does not report confidence intervals for the listed results. It also does not report p-values or adjusted estimates. Without those quantities and a defined comparison, the strength and precision of any inferential claim cannot be assessed from the record.

How should adverse-event categories be read?

The safety summary distinguishes participants with serious adverse events from participants with other adverse events. Seriousness and severity are not interchangeable concepts: seriousness generally classifies events by regulatory or clinical consequences, while severity describes intensity. The registry identifies serious-event terms and percentages, but does not provide detailed event-level descriptions, severity grades, exposure-adjusted rates, or an account of whether the same participant contributed to multiple terms. The reported term percentages are descriptive entries, not evidence of a causal relationship.

General statistical principle: event data can be analyzed at the participant level, the event level, or as time to first event. These approaches answer different questions. Participant-level summaries focus on whether a person had an event; event-level analyses can account for repeated episodes; time-to-event methods incorporate when an event first occurs and can address unequal follow-up under appropriate assumptions. The registry record does not report that a time-to-event analysis or a repeated-event model was used. The endpoint definition and summary counts alone do not establish such methods.

Some count models must account for over-dispersion, meaning that variability exceeds what a simple model assumes. General statistical principle: over-dispersion can make standard errors too small if ignored. This concern applies to certain event-count models, particularly when repeated event numbers are modeled. It should not be presumed to apply to a participant-level yes-or-no outcome, and the registry does not report a model, dispersion estimate, or over-dispersion adjustment for this study.

What do the planning illustrations mean?

The accompanying planning illustrations are not observed trial results. They use an observed effect as a reference and specify a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation. Their effect targets are stated fractions of that observed effect. For non-time-to-event outcomes, the illustrations are expressed as participants per arm; time-to-event illustrations use total events. These are hypothetical planning quantities under stated assumptions, not the study’s actual enrollment requirements, observed power, or evidence that the single-group trial tested a two-arm contrast.

The study itself is recorded as single-group, so an equal-allocation, two-arm planning scenario does not describe its design. The registry record does not report the trial’s sample-size justification or whether the trial was designed around these planning assumptions. Sample-size illustrations cannot resolve the absence of a comparator or replace estimates and uncertainty measures from an analysis.

Which analysis methods were actually used?

The registry record does not report the statistical analysis plan, inferential tests, covariate adjustments, interim analyses, or methods for repeated measures. It also does not report estimates or uncertainty intervals for the listed efficacy outcomes. The endpoint definitions describe what was intended to be measured; they do not reveal which statistical procedures were ultimately applied. Any interpretation of a particular model, adjustment, or hypothesis test would therefore go beyond the registry record.

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("KarXT")
n      <- c(566)
events <- c(466)
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  KarXT  566  466  82.3  78.9  85.4  79.0  85.3  79.0  85.3

11. Multiplicity, Missing Data and Analysis Populations

The registry lists 22 outcome measures, including safety outcomes and multiple symptom measures. Several outcomes address related but distinct constructs: PANSS total, positive, negative, and Marder Factor negative scores, along with CGI-S and a PANSS response threshold. When many outcomes are assessed, the chance of at least one apparently notable result can increase if each is tested separately without an appropriate plan. General statistical principle: multiplicity procedures or a prespecified hierarchy can help control how confirmatory claims are made across multiple tests.

The registry record does not report a multiplicity strategy, a hierarchy of outcomes, or which outcomes were intended as confirmatory versus exploratory. It also has no analysis entries, so there are no posted estimates or tests from which to assess how the listed outcomes were handled. Listing an endpoint does not establish that it was analyzed or that a statistically significant result was found.

The primary endpoint specifies the Safety Population, but the record does not describe the full analysis populations or provide a participant flow accounting for included and excluded participants. It does not report the amount or pattern of missing data, reasons for missingness, or methods used to address missing observations. These details matter because missingness can affect interpretation, especially for Week 52 outcomes if participants do not all contribute measurements at that time.

General statistical principle: complete-case analyses use participants with observed data for a given outcome, while imputation methods replace or model missing values under assumptions. Neither approach, nor any sensitivity analysis, is reported in the registry record. The number enrolled should not be assumed to equal the number analyzed for every outcome. Without analysis-population counts and missing-data methods, the completeness and potential selection effects of the reported outcomes cannot be evaluated.

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: schizophrenia (1.8%), psychotic disorder (0.7%), abdominal pain (0.4%), vomiting (0.4%), death (0.4%).

The safety summary records 41 participants with serious adverse events and 356 with other adverse events, each among 566 at risk. It also records 2 deaths. These entries describe events observed during the study; they do not establish that KarXT caused them. Because there is no control group, the counts cannot be compared with outcomes that would have occurred under another treatment or without study treatment.

The listed serious-event terms are schizophrenia, 1.8%; psychotic disorder, 0.7%; abdominal pain, 0.4%; vomiting, 0.4%; death, 0.4%; and dizziness, 0.4%. These percentages should be understood as the registry’s descriptive entries. The record does not explain whether participants could be represented under multiple terms, how terms were selected for listing, or whether every serious event is represented in this list.

Serious events are not the same as all treatment-emergent adverse events, and the count for other adverse events should not be treated as an overall primary-endpoint count. The registry record does not provide event-level timing, duration, severity grades, or a distinct overall result for the primary endpoint. Without those details and a comparison group, the safety figures are useful as descriptive observations but cannot quantify comparative risk or determine causation.

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

The study provides a description of safety observations during treatment with KarXT in a single group of adults with schizophrenia. Its registry record identifies a Phase 3, open-label, multicenter outpatient study, an enrollment of 566, and a primary safety objective. It also reports serious and other adverse-event counts, selected serious-event terms, and 2 deaths. Those observations can inform understanding of what was recorded during the study, but they are not a controlled comparison.

The design does not show what would have happened to similar participants under a different treatment or without KarXT. An event that occurs after treatment begins is treatment-emergent by the stated timing definition, but that timing alone does not demonstrate that treatment caused it. A single-group study also cannot reliably distinguish treatment-associated changes from changes related to the condition, background care, time, or other influences.

The registry lists symptom outcomes and a response threshold at Week 52, but does not report their numerical results or statistical analyses. It therefore does not support conclusions about the magnitude or precision of changes in PANSS or CGI-S scores. Nor does the record supply confidence intervals, p-values, or an analysis of change relative to a comparator. The planned efficacy objectives and listed measures should not be mistaken for reported efficacy findings.

Likewise, the safety counts should not be interpreted as comparative rates or as proof that the treatment is safe or unsafe. The registry record does not report a distinct overall primary-endpoint count in the outcome details, full participant-level follow-up, or event-level context. These gaps limit the precision and scope of interpretation.

Statistically, the appropriate conclusion is narrow: the record describes outcomes observed in the enrolled single group and identifies important information that is not reported. It does not establish a causal treatment effect or comparative benefit-risk profile. Any broader conclusion would require analyses and context not reported in the registry record.

14. Why This Trial Matters Statistically

This trial is statistically informative as an example of the difference between a safety description and a treatment-effect comparison. The study enrolled 566 participants and followed an open-label, single-group design. Such a design can document adverse events and clinical measurements during exposure, but without a comparator it cannot isolate the contribution of treatment from other influences. Recognizing that distinction helps prevent descriptive counts from being read as causal estimates.

The record also illustrates why outcome definitions and analyzed results are separate pieces of information. It defines treatment-emergent adverse events and identifies the Safety Population for the primary endpoint. It lists additional symptom outcomes, but the registry record does not report numerical analyses for them. A registered outcome can clarify what investigators intended to measure, yet it does not by itself establish that results were analyzed, how missing observations were handled, or how uncertainty was quantified.

Multiplicity and missing-data reporting matter because several related outcomes are listed and follow-up includes a Week 52 assessment. Without a stated testing strategy, analysis populations, or missing-data methods, readers cannot determine how robust any eventual set of findings would be. These are not merely technical details: they influence how confidently descriptive or inferential results can be interpreted.

Finally, the planning illustrations use hypothetical two-arm assumptions, while the actual study is single-group. Separating planning scenarios from observed trial evidence avoids treating a hypothetical sample-size calculation as trial performance or evidence of efficacy. Taken together, the record is most useful for understanding the study’s design, safety definitions, reported event counts, and limits on inference.

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 main limitation is the single-group, open-label design. There is no concurrent control group, and allocation is not applicable. Consequently, observed events and any within-group changes cannot be interpreted as differences caused by treatment. Knowledge of treatment assignment may also affect event reporting or outcome assessment. The registry record does not describe masking procedures because masking is listed as none.

Although the primary endpoint is defined, the registry record does not report a distinct overall result for the number of participants with treatment-emergent adverse events. The adverse-event summary separates serious events and other adverse events, but does not provide a complete event-level account or explain how those categories relate to the primary endpoint. The record also does not report event duration, timing, severity grades, or whether people could contribute to several listed serious-event terms.

The registry describes a 56-week study and KarXT dosing for up to 52 weeks, with a primary endpoint timeframe of approximately 400 days from consent to study end. It does not report the distribution of participant follow-up, exposure duration, adherence, or reasons for discontinuation. These omissions limit interpretation of raw counts when observation time may differ across participants.

For the listed Week 52 efficacy measures, numerical estimates, uncertainty intervals, and analysis results are not reported in the registry record. The analysis plan, multiplicity approach, analysis-population details, participant flow, and missing-data methods are also not reported. The record therefore does not allow evaluation of the precision, completeness, or potential bias of efficacy estimates. These limitations are specific to the information recorded for this study and should be kept in view when reading its descriptive safety findings.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: An Open-label Study to Assess the Long-term Safety, Tolerability, and Efficacy of KarXT in Adult Patients With Schizophrenia (EMERGENT-5) — NCT04820309.
• Registry record last updated 2025-09-17; status last verified 2025-09.
• Results first posted 2025-09-17.
• 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

NCT04820309 is a completed Phase 3, multicenter, outpatient, open-label, single-group study of KarXT in adults with DSM-5 schizophrenia. The registry lists an enrollment of 566, a start date of 2021-06-02, and a primary completion date of 2024-05-24. KarXT was described as xanomeline 125 mg and trospium chloride 30 mg twice daily, for up to 52 weeks within a study described as 56 weeks long.

The primary objective was long-term safety and tolerability. The primary endpoint was the number of participants with treatment-emergent adverse events, with a timeframe from consent to study end of approximately 400 days. The safety summary reports 41 participants with serious adverse events, 356 with other adverse events, and 2 deaths among 566 at risk. The registry lists secondary symptom outcomes and pharmacokinetics objectives, but does not report their numerical analyses. With no comparator group and no analysis entries, the record supports descriptive interpretation rather than a causal or comparative estimate.