An Extension Study to Assess Long-term Safety, Tolerability, and Efficacy of KarXT in Adult Patients With Schizophrenia (EMERGENT-4): Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for An Extension Study to Assess Long-term Safety, Tolerability, and Efficacy of KarXT in Adult Patients With Schizophrenia (EMERGENT-4) (NCT04659174), 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 extension study. Its registered title identifies it as EMERGENT-4. Participants had DSM-5 schizophrenia and had completed the treatment period of one of the earlier Phase 3 studies, KAR-007 or KAR-009. The study was completed, with enrollment listed as 152.

The planned extension lasted 53 weeks, with KarXT administered for up to 52 weeks. The regimen was a fixed combination of xanomeline 125 mg and trospium chloride 30 mg twice daily. Treatment was given regardless of treatment assignment in the preceding acute study. Allocation is recorded as not applicable, masking as none, and the model as single group. These features mean the extension was not designed as a blinded randomized comparison of KarXT against a concurrent control.

The registry record lists the study start as 2021-02-01 and primary completion as 2023-10-03. Its primary objective concerned long-term safety and tolerability; the secondary objectives concerned efficacy and monitoring trough concentrations. The registered outcomes include adverse-event counts and changes in symptom and severity measures. Numerical results for those secondary efficacy outcomes are not reported in the registry record.

The safety results use the labels KarXT Arm A and KarXT Arm B. The record does not explain how participants were assigned to these labels or what distinguishes them. Because all participants received KarXT and there was no concurrent randomized control group, the arm labels do not establish a like-for-like treatment comparison.

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: All treated participants

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 first dose to end of study (Up to approximately 53 weeks).

The primary endpoint is the number of participants with treatment-emergent adverse events, assessed from the first dose of KarXT to the end of study, up to approximately 53 weeks. A treatment-emergent event is defined by onset on or after the first dose. The registry definition of an adverse event includes a symptom, physical sign, syndrome, or disease that emerges during the study or, if already present at baseline, worsens during the study. The definition applies regardless of suspected cause and refers to the National Cancer Institute Common Terminology Criteria for Adverse Events, version 5.0.

The endpoint population is all treated participants. Counting participants with at least one event gives a straightforward measure of how many experienced an event during the observation period. It does not, by itself, describe how many events each participant experienced, how long events lasted, or whether an event was considered related to treatment. The registry record does not report a numerical result for this primary endpoint.

General statistical context: Safety endpoints commonly use participant counts to describe the frequency of observed events during follow-up. Interpretation depends on the observation period and on which participants were included. A count does not establish cause: events occurring after treatment begins may have other explanations, and the registry definition explicitly does not require suspected causality.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

What does an open-label extension show?

This study is described as an open-label extension: participants received the study treatment with no masking, after completing the treatment period of an earlier study. The registered plan states that all participants would receive KarXT irrespective of treatment assignment in the preceding acute study. As a result, the extension addresses questions about observations during continued treatment, rather than estimating a randomized contrast against a concurrent untreated or alternative-treatment group.

General statistical context: Randomization helps make treatment groups comparable at the start of a trial, on average, for measured and unmeasured characteristics. An extension that enrolls people who completed earlier trials has a different role. Its participants are selected from those who reached the extension, and its results describe that study population and follow-up. Such observations can be informative about longer-term experience, but they do not by themselves isolate the causal effect of treatment.

What does a participant count represent?

The primary endpoint is a count of participants with treatment-emergent adverse events. A participant-level count is distinct from a count of all individual events: someone with multiple events can still contribute as a participant with an event. The registry defines the event window as beginning on or after the first dose and ending at study completion. The outcome population is listed as all treated participants.

General statistical context: Participant counts are often paired with a denominator to convey how many people were observed in a particular group. The denominator and time period matter. If follow-up duration differs across participants, a simple count does not express the amount of time each person was observed. Analyses based on event rates or time to first event can address different questions, but the registry record does not report such an analysis for the primary endpoint.

How should the serious-event counts be read?

The registry record gives serious adverse-event counts and numbers at risk for KarXT Arm A and KarXT Arm B. These figures describe events recorded in the two labelled groups. They are not a randomized comparison: the study is listed as single group, with allocation not applicable and no masking. The record does not explain the distinction between the two arm labels, so their respective counts should not be interpreted as a treatment-versus-control result.

General statistical context: A difference between two observed counts can arise from chance, differing follow-up, or differences in the people observed, among other factors. A comparative analysis needs a clearly defined contrast and methods suited to the design. Merely placing group counts side by side does not supply that analysis. No adjusted estimates, uncertainty intervals, or inferential tests for these safety counts are reported in the registry record.

What is the role of uncertainty?

An estimate is more informative when its precision is also described. Confidence intervals are one way to show a range of values compatible with the observed data under a statistical model. They help distinguish a precise estimate from one that remains uncertain. The registry record does not report confidence intervals for the serious-event counts or for the primary endpoint. The posted information therefore does not establish how precisely the event experience has been estimated.

General statistical context: In some count data, variability is greater than a simple statistical model expects; this is called over-dispersion. A model that ignores over-dispersion can give uncertainty estimates that are too narrow. Whether over-dispersion is relevant depends on the data structure and the analysis. The registry record does not report a model for the primary count endpoint, so it is not possible to assess whether this issue was evaluated.

What analyses are documented?

The record identifies the endpoint, its time frame, and the treated population, and lists secondary outcomes. It does not report a detailed statistical analysis plan, the estimator used for the primary endpoint, a method for handling repeated or multiple events, covariate adjustment, or a hypothesis test for the reported serious-event counts. Those methods are not reported in the registry record. No recalculated estimates are presented in the available results, so there is no recalculation to compare with a sponsor analysis.

The registry also includes a general sample-size-planning description based on an observed effect, with a two-sided significance level of 0.05, equal allocation, and a normal approximation. That description is a planning illustration and is not the design rationale for this single-group extension. No numerical sample-size illustration is reported in the information available for these results. A planning calculation should not be confused with observed power, which is not reported in the registry record.

Why does the analysis population matter?

The primary endpoint specifies all treated participants as its population. This clarifies that the endpoint is intended to describe participants who received treatment, rather than only participants meeting a separate efficacy-analysis definition. The record does not report further details about exclusions, evaluability requirements, or how participants with incomplete follow-up were handled. Those details affect how completely the reported outcomes represent the enrolled population.

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 Arm A", "KarXT Arm B")
n      <- c(68, 84)
events <- c(36, 45)
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 Arm A  68  36  52.9  40.4  65.2  41.2  64.3  41.2  64.4
ARM  KarXT Arm B  84  45  53.6  42.4  64.5  43.0  63.8  43.0  63.9

11. Multiplicity, Missing Data and Analysis Populations

The registry lists several secondary outcomes in addition to the primary safety endpoint. They include serious adverse events, treatment-emergent adverse events leading to study-drug discontinuation, changes in PANSS total, positive, negative, and Negative Marder Factor scores, change in CGI-S score, and PANSS response defined using a reduction threshold. These outcomes address different aspects of safety and symptom change.

When a study assesses multiple outcomes, the chance of at least one apparently notable finding can increase if each is tested separately without an adjustment or a prespecified hierarchy. Whether and how to control that issue depends on the study objectives and analysis plan. A multiplicity strategy, such as a testing hierarchy or adjustment, is not reported in the registry record. Numerical efficacy results and associated tests are also not reported, so the effect of any multiplicity approach cannot be evaluated.

Missing-data handling is not reported in the registry record. The record does not specify how incomplete outcome measurements, missed visits, withdrawal, or varying follow-up were treated in efficacy analyses. The listed primary safety population is all treated participants, but details about the availability of safety follow-up and the treatment of incomplete safety records are not reported.

The registry record also does not report a detailed analysis population for the secondary outcomes, an imputation method, a sensitivity analysis, or an approach to participants who discontinued treatment before the planned end of follow-up. These omissions limit assessment of whether the reported and unreported outcomes would represent everyone enrolled or only participants with particular observed measurements. The absence of these methodological details does not determine the direction of any potential bias; it means the reader cannot evaluate its size from the record.

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 (2.9%), fall (1.5%), anxiety (1.5%), hallucination (1.5%), death (1.2%).

The serious adverse-event counts are 5 among 68 at risk in KarXT Arm A and 3 among 84 at risk in KarXT Arm B. The registry also records deaths of 0 in KarXT Arm A and 1 in KarXT Arm B. These are descriptive safety figures in an open-label extension, not a randomized comparison. The record does not clarify the distinction between the arm labels, and it does not report an adjusted comparison or uncertainty interval for the counts.

Serious adverse events are not interchangeable with all treatment-emergent adverse events. The primary endpoint is broader, counting participants with treatment-emergent adverse events from first dose through the end of study, whether or not an event is serious. A numerical result for that endpoint is not reported in the registry record. The listed serious-event terms and percentages provide additional descriptive detail, but do not establish causation or comparative risk.

General statistical context: An adverse event recorded during treatment is not, by that timing alone, proof that treatment caused it. The registry definition includes events regardless of suspected cause. Interpretation also depends on duration of observation and completeness of follow-up, for which further details are not reported in the registry record.

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

The record documents a completed open-label extension intended to follow adults with schizophrenia during continued KarXT treatment. It reports serious adverse-event counts in the two KarXT-labelled groups and lists serious-event terms. Those observations describe what was recorded among participants under follow-up in this study; they do not establish that KarXT caused or prevented any event.

The study design does not include a concurrent randomized control group. Participants received KarXT regardless of their prior assignment in an earlier acute study, and the record does not explain the distinction between Arm A and Arm B. Therefore, the group labels do not support a controlled estimate of a treatment effect. The reported counts should not be interpreted as evidence that one group had a better or worse outcome than the other.

The study registered a primary endpoint based on participants with treatment-emergent adverse events and secondary efficacy measures based on PANSS and CGI-S. Numerical results for those endpoints are not reported in the registry record. As a result, the posted information cannot characterize the overall frequency of treatment-emergent adverse events, the size or precision of symptom changes, or the proportion meeting the listed response definition.

The event counts also do not describe event duration, recurrence, severity beyond the serious-event classification, or treatment attribution. Further information about follow-up completeness, missing data, statistical comparisons, and uncertainty is not reported in the registry record. These limits matter when considering how broadly the observations apply beyond people who entered this extension after completing an earlier study.

In general, a safety extension can add descriptive information about events occurring over longer follow-up. It is not a substitute for a controlled comparison when the question is whether treatment changes the probability of an outcome. The registry results support a limited description of recorded serious events, not a conclusion about comparative safety or efficacy.

14. Why This Trial Matters Statistically

This study is statistically notable because it addresses a different question from a conventional randomized treatment comparison. It follows participants who completed an earlier study and receive open-label KarXT, with a primary objective of assessing long-term safety and tolerability. The registry records a planned follow-up of 53 weeks and treatment for up to 52 weeks, extending observation beyond an acute study period.

Longer follow-up can be relevant when the outcomes of interest include events that may emerge or accumulate during continued treatment. Participant counts and serious-event terms provide a descriptive view of what was recorded in this extension. They are not, however, a causal comparison. The open-label, single-group design, lack of a concurrent randomized control, and unexplained Arm A and Arm B labels constrain interpretation of group-specific counts.

The record also illustrates the distinction between registered outcomes and results available for interpretation. It lists several efficacy outcomes, but numerical results for those outcomes are not reported in the registry record. Likewise, a numerical result for the primary treatment-emergent adverse-event endpoint is not reported. Clear reporting of estimates, denominators, uncertainty, missing-data handling, and analysis populations would be needed to assess those questions more fully.

For biostatisticians and clinical researchers, the central issue is matching the claim to the design and the data actually reported. The serious-event counts can inform a descriptive account of observed events, while the absence of a controlled contrast and detailed statistical results limits estimation of comparative effects. The extension contributes follow-up context, but its posted results do not settle the listed efficacy questions.

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 important design limitation for causal interpretation is the absence of a concurrent randomized control group. The study is open-label, allocation is listed as not applicable, and all participants received KarXT regardless of treatment assignment in the preceding acute study. Consequently, the serious-event counts cannot isolate an effect of treatment from other explanations.

The safety results use KarXT Arm A and KarXT Arm B labels, but the registry record does not explain what distinguishes those groups. They should not be assumed to represent randomized treatment arms or treated as a like-for-like comparison. The record does not report comparative estimates or uncertainty intervals for the serious-event counts.

The primary endpoint is defined, but its numerical result is not reported in the registry record. Numerical results for the listed efficacy outcomes are also not reported. The record does not provide detailed information about missing data, follow-up completeness, discontinuation handling, or analysis methods for these outcomes. This limits assessment of the precision and representativeness of the observations.

Participants entered after completing an earlier Phase 3 study. The registry record therefore describes an extension population rather than all people who might begin treatment in another setting. The extent to which entry or continuation into the extension selected participants with particular characteristics is not reported in the registry record. Likewise, attribution of the recorded events to treatment is not established by the endpoint definition, which includes events regardless of suspected cause.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: An Extension Study to Assess Long-term Safety, Tolerability, and Efficacy of KarXT in Adult Patients With Schizophrenia (EMERGENT-4) — NCT04659174.
• Registry record last updated 2024-10-28; status last verified 2024-10.
• Results first posted 2024-10-28.
• 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

NCT04659174, EMERGENT-4, is a completed Phase 3, multicenter, outpatient, open-label extension study in adults with DSM-5 schizophrenia who had completed the treatment period of KAR-007 or KAR-009. The registered enrollment is 152. The study began on 2021-02-01 and reached primary completion on 2023-10-03.

Participants received KarXT, a fixed combination of xanomeline 125 mg and trospium chloride 30 mg twice daily, for up to 52 weeks. The primary objective was long-term safety and tolerability; efficacy and trough concentrations were secondary objectives. Serious adverse-event counts are reported for KarXT Arm A and KarXT Arm B, but numerical results for the primary treatment-emergent adverse-event endpoint and listed efficacy outcomes are not reported in the registry record.