A Study to Assess Efficacy and Safety of KarXT in Acutely Psychotic Hospitalized Adult Patients With Schizophrenia (EMERGENT-3): Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for A Study to Assess Efficacy and Safety of KarXT in Acutely Psychotic Hospitalized Adult Patients With Schizophrenia (EMERGENT-3) (NCT04738123), a randomized phase 3 study. The primary outcome is Change From Baseline in Positive and Negative Syndrome Scale (PANSS) Total Score at Week 5.

2. Clinical Question

3. Trial Design

EMERGENT-3 was a Phase 3, randomized, parallel-group, placebo-controlled, multicenter inpatient study in adults with acute psychosis and DSM-5 schizophrenia. The registry record lists the study as completed. Enrollment was 256. The recorded start date is 2021-04-06, and primary completion is recorded as 2022-11-29.

The active group received KarXT, a fixed combination of xanomeline and trospium chloride, and the comparator group received placebo. The brief study description gives the active combination as xanomeline 125 mg and trospium chloride 30 mg twice daily. The official title describes the study as double-blind, while the registry masking classification is triple. The record does not explain the distinction between those descriptions, so neither should be used to infer further masking procedures.

The primary outcome was change from baseline in PANSS total score at Week 5. The primary outcome population is described as participants who were randomized, received at least one dose, had a baseline PANSS assessment, and had at least one post-baseline PANSS assessment. The group sizes shown for the primary outcome are 114 for KarXT and 120 for placebo. These are outcome-analysis counts, not the registry’s overall enrollment figure. The safety denominators are reported separately.

The secondary objectives included assessment of symptoms and disease severity, safety and tolerability, and pharmacokinetics. The registry lists 33 secondary outcomes. The treatment assignment and placebo comparison make the trial suitable for a randomized group contrast, but the registry record does not report the detailed randomization procedure, treatment adherence, or the statistical model used for the primary analysis.

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 participants who were randomized, received at least 1 dose of study drug, had a baseline PANSS assessment, and had at least 1 post-baseline PANSS assessment

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 Change From Baseline in Positive and Negative Syndrome Scale (PANSS) Total Score at Week 5, measured over From baseline up to Week 5.

The primary endpoint was change from baseline in PANSS total score at Week 5. PANSS is a symptom-severity scale used in schizophrenia research. It includes positive symptoms, negative symptoms, and general psychopathology; each of its 30 items is rated from 1 to 7. The total score ranges from 30 to 210, with higher scores indicating more severe symptoms. The registry record defines baseline as the PANSS score at screening.

A change score expresses how the measured score at follow-up differs from the baseline measurement. In this trial, negative change values indicate reductions in PANSS total score. The endpoint is clinically interpretable as a measure of symptom-score change over the study period, while the randomized placebo comparison helps distinguish the average change in the active group from change observed in the comparator group.

The registry reports least-squares mean changes of -20.6 for KarXT and -12.2 for placebo. The estimated mean difference for KarXT relative to placebo is -8.4, with a 95% confidence interval from -12.75 to -4.054. The reported endpoint uses a continuous score and summarizes group averages; it does not mean that every participant changed by the group average, nor does it show the distribution of individual responses.

7. Results Posted in the Registry

• KarXT: mean -20.60 versus -12.20 on control; difference -8.40 (95% CI -12.75 to -4.05), standardized effect d = -0.50; z-test p = <0.001.

8. Secondary Efficacy Endpoints

The registry also posts results for secondary outcomes. For each outcome below, the endpoint type, the test applied to the posted summary statistics, the result and its interpretation are given in turn. Secondary endpoints are usually not adjusted for multiple testing, so they support rather than confirm the primary finding.

Change From Baseline in Positive and Negative Syndrome Scale (PANSS) Positive Score at Week 5

• Endpoint type: Continuous: a mean value per participant, compared as a difference in means.
• Test: Unadjusted two-sample z-test for the difference in means, using the posted standard errors.
• Result:
  • KarXT: mean -7.10 versus -3.60 on control; difference -3.50 (95% CI -4.87 to -2.13), standardized effect d = -0.65; z-test p = <0.001.
• Interpretation:
  • The 95% confidence interval excludes no difference, so the mean is statistically lower for KarXT than for the control. This is an unadjusted, secondary comparison, so it is suggestive rather than confirmatory.

Change From Baseline in Positive and Negative Syndrome Scale (PANSS) Negative Score at Week 5

• Endpoint type: Continuous: a mean value per participant, compared as a difference in means.
• Test: Unadjusted two-sample z-test for the difference in means, using the posted standard errors.
• Result:
  • KarXT: mean -2.70 versus -1.80 on control; difference -0.90 (95% CI -2.03 to 0.23), standardized effect d = -0.20; z-test p = 0.119.
• Interpretation:
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between KarXT and the control. The interval gives the range of effects that remain compatible with the data.

Positive and Negative Syndrome Scale (PANSS) Negative Marder Factor Score Change From Baseline at Week 5

• Endpoint type: Continuous: a mean value per participant, compared as a difference in means.
• Test: Unadjusted two-sample z-test for the difference in means, using the posted standard errors.
• Result:
  • KarXT: mean -3.50 versus -2.70 on control; difference -0.80 (95% CI -2.13 to 0.53), standardized effect d = -0.15; z-test p = 0.238.
• Interpretation:
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between KarXT and the control. The interval gives the range of effects that remain compatible with the data.

The registry lists secondary outcomes covering PANSS positive and negative symptoms, a negative Marder factor score, clinical global severity, a threshold reduction in PANSS total score, adverse events, cholinergic symptoms, and a Simpson-Angus Scale change. Numerical results are posted for selected continuous outcomes, while the registry lists 33 secondary outcomes overall. The breadth of these outcomes means they address different aspects of symptoms and safety rather than repeating the primary total-score question exactly.

The posted secondary pattern is not uniform. The positive-symptom result has an unadjusted p-value below 0.001, while the negative-symptom and negative Marder factor comparisons have intervals that include zero. This pattern is broadly compatible with the primary result showing a group difference in total PANSS change, but the primary score combines several symptom domains and does not require every component to show a separately clear contrast. A total-score result should not be taken as proof of a difference in every subscale.

Secondary results carry less weight when their multiplicity handling is unclear. When many outcomes are examined, the chance of finding at least one apparently strong result by chance can rise. Formal procedures can control that risk, but the registry record does not report whether or how such procedures were used. The posted secondary p-values are unadjusted, so they should be treated as exploratory evidence rather than as a set of independent confirmatory findings.

The registry record also does not provide analysis-level details for the secondary outcomes. Without a reported analysis plan, hierarchy, or adjustment method, the relative priority of these outcomes cannot be determined from the record alone. Their results can inform the overall pattern, but they do not supersede the prespecified primary question as described in the study record.

Secondary outcomes registered for this trial, for reference (only those above were recalculated):

• Change From Baseline in Positive and Negative Syndrome Scale (PANSS) Positive Score at Week 5
• Change From Baseline in Positive and Negative Syndrome Scale (PANSS) Negative Score at Week 5
• Positive and Negative Syndrome Scale (PANSS) Negative Marder Factor Score Change From Baseline at Week 5
• Clinical Global Impression-Severity (CGI-S) Score Change From Baseline at Week 5
• Number of Participants Who Achieve >=30% Reduction in Positive and Negative Symptoms Scale (PANSS) Total Score From Baseline to Week 5
• Number of Participants Experiencing Adverse Events (AEs)
• Number of Participants Experiencing Cholinergic Symptom Adverse Event
• Change From Baseline in Simpson-Angus Scale Total Score (SAS)

9. Statistical Interpretation

10. Statistical Methods Explained

The primary outcome is a continuous measure, and the registry reports least-squares mean changes for each group. A least-squares mean is a model-based group average. The registry record does not describe the model or identify which covariates, if any, were included. Consequently, the reported values can be described as least-squares means, but the exact adjustment behind them cannot be reconstructed from the record.

The KarXT and placebo estimates are -20.6 and -12.2, respectively. The reported mean difference is -8.4, with a 95% confidence interval from -12.75 to -4.054. The direction follows the score definition: lower PANSS values indicate less severe symptoms, and the negative difference corresponds to a larger average reduction for KarXT. The associated p-value is unadjusted and reported as <0.001.

What does a mean difference represent?

A mean difference puts the group contrast back on the original outcome scale. Here, the unit is a PANSS score point. It answers how far apart the estimated group averages are, rather than how much participants vary from one another. A mean difference is often easier to interpret clinically than a standardized effect because it retains the scale’s units. Its interpretation still depends on the meaning and measurement properties of the PANSS score.

How should a standard error be understood?

The registry reports standard errors of 1.584 for the KarXT estimate and 1.552 for placebo. A standard error reflects the uncertainty of an estimated mean under the analysis, rather than the variation among individual participants. A small standard error relative to the estimate indicates that the mean is estimated with greater precision, but it does not imply that individual outcomes are tightly clustered. Standard errors should not be mistaken for standard deviations.

What does the confidence interval add?

A confidence interval expresses the range of values compatible with the observed data and the statistical procedure, under the model’s assumptions. The interval from -12.75 to -4.054 gives a range for the primary group difference. Since the whole interval is below zero, the result is consistent with a larger mean reduction in the KarXT group. The interval is not a range containing a fixed proportion of individual participants, and it is not a guarantee that the true effect lies within its limits.

What does the p-value say?

The unadjusted p-value of <0.001 summarizes how incompatible the observed comparison is with a null hypothesis of no group difference, conditional on the statistical procedure and its assumptions. It does not measure effect size or clinical importance. It also does not express the chance that the null hypothesis is true. Because it is unadjusted, it does not account for the possibility of multiple outcome comparisons.

Why can over-dispersion matter?

Over-dispersion is a general concern when the variability in observed data exceeds what a model’s assumed distribution allows. If a model understates variability, its standard errors can be too small and its intervals too narrow. The primary endpoint is continuous, and the registry reports least-squares means and standard errors; it does not report a model specification or an assessment of over-dispersion. The record therefore does not establish whether this issue was assessed or relevant to the analysis.

What can be inferred from standardized effect estimates?

The posted comparison includes a standardized effect estimate of -0.495. Standardization expresses a difference relative to an estimated measure of variability, allowing scale-free comparison in some settings. The record marks the pooled standard deviation used for this estimate as approximate. A standardized value does not replace the raw-score difference, and it does not establish clinical importance. Its interpretation depends on the variability estimate and on the population and outcome from which it was derived.

Which analysis details remain unknown?

The registry record does not report the primary model specification, covariates, assumptions, missing-data method, or whether an interim analysis was conducted. It also does not report a detailed statistical analysis plan. The outcome population is described by its dosing and assessment requirements, but the record does not explain how participants who lacked post-baseline measurements were handled or how any missing values were treated. These gaps limit independent evaluation of the analysis, even though the group estimates and comparison interval are posted.

11. Confidence Intervals and Precision

The primary comparison is estimated as -8.4 PANSS points for KarXT relative to placebo. Its 95% confidence interval extends from -12.75 to -4.054. The interval gives a range of plausible values for the group difference under the analysis procedure and its assumptions. It lies entirely below zero, so the reported data are inconsistent with a zero difference at the corresponding confidence level under those assumptions.

The interval also conveys uncertainty about the magnitude. It does not identify a single known effect, and its endpoints should not be treated as guaranteed bounds on the true difference. A confidence interval is about the estimated group contrast, not the range of changes among individual participants. Individual responses may vary substantially even when an average contrast is estimated with reasonable precision.

The standard errors for the group estimates are 1.584 for KarXT and 1.552 for placebo. These describe uncertainty in the estimated least-squares means. They are not measures of participant-to-participant spread. The registry record does not report arm-specific confidence intervals or the detailed model used to obtain the least-squares means and comparison interval.

The reported p-value is unadjusted and is <0.001. It supports a statistical difference under the analysis assumptions, but it does not resolve questions about practical importance, generalizability, missing data, or multiplicity. Precision should therefore be read together with the endpoint definition and the limits of the registry record, not as a complete assessment of the result.

12. Planning a Similar Trial: Sample Size

This is a planning illustration, not a re-evaluation of the original trial. It asks: if a new study wanted to detect a difference like the one observed, or a smaller one, how large would it need to be? It is deliberately not “observed power” of the finished trial, which is not a meaningful quantity.

The planning figures are participants per arm, not total trial enrollment and not total events. They are illustrations based on the observed primary effect, using a two-sided significance level of 0.05, equal allocation between the two arms, and a normal approximation. The effect to detect is set to the stated fraction of the observed effect. The registry record does not report the original trial’s design assumptions or sample-size justification, so these figures should not be read as the trial’s planned enrollment target.

For planning around 100% of the observed effect, the illustration gives 64 participants per arm for 80% power and 86 participants per arm for 90% power. For planning around 75% of the observed effect, it gives 114 participants per arm for 80% power and 153 participants per arm for 90% power. For planning around 50% of the observed effect, it gives 256 participants per arm for 80% power and 343 participants per arm for 90% power.

Power is the probability, under the specified assumptions and a particular true effect, that a study would meet its chosen statistical significance criterion. The 80% and 90% columns describe different planning targets: the higher target generally requires more participants for a given effect. Smaller effects are harder to distinguish from random variation, so planning for smaller effects requires more participants. These are planning illustrations, not observed power.

13. How the Sample Size Is Derived

Power is the probability that a study of a given size rejects the null hypothesis when a specific true effect exists. It depends on four things: the effect to detect, the variability of the outcome, the significance level (here a two-sided α of 0.05, so z_1−α/2 = 1.960) and the desired power (z_1−β = 0.842 for 80% and 1.282 for 90%).

Formula

n is the number of participants in each arm, Δ is the difference in means to detect and σ is the common standard deviation.

Worked calculation for this trial

1. Observed difference Δ = -8.400; pooled standard deviation σ = 16.958.
2. n = 2 × (1.96 + 0.842)² × 16.958² / -8.400² = 64.0, rounded up to 64 participants per arm for 80% power.

The smaller-effect rows in the table above repeat the same calculation with the effect multiplied by 0.75 and 0.5 (for ratios, applied to the logarithm of the ratio).

R code

alpha <- 0.05
z_a   <- qnorm(1 - alpha / 2)          # two-sided
delta <- -8.4                      # observed difference in means
sigma <- 16.9581066607461                     # pooled standard deviation
n_per_arm <- function(power, frac = 1) {
  ceiling(round(2 * (z_a + qnorm(power))^2 * sigma^2 / (delta * frac)^2, 6))
}
for (f in c(1, 0.75, 0.5))
  cat(sprintf("%3.0f%% of observed effect: n per arm = %s (80%% power), %s (90%% power)\n", 100 * f,
              format(n_per_arm(0.80, f), big.mark = ","), format(n_per_arm(0.90, f), big.mark = ",")))

# Check against R's built-in function (t-based, so very slightly larger)
cat("power.t.test:", round(power.t.test(delta = delta, sd = sigma, power = 0.80)$n, 1), "\n")

# Simulation: exact two-sample t-test using simulated means and variances
set.seed(4738123)
n    <- n_per_arm(0.80)
reps <- 20000
m_diff <- rnorm(reps, delta, sigma * sqrt(2 / n))             # difference in sample means
s2     <- sigma^2 * rchisq(reps, 2 * (n - 1)) / (2 * (n - 1))   # pooled sample variance
tstat  <- m_diff / sqrt(s2 * 2 / n)
cat(sprintf("Simulated power at n = %s per arm: %.3f (%d replicates)\n", format(n, big.mark = ","), mean(abs(tstat) > qt(0.975, 2 * (n - 1))), reps))

Output from running the code

100% of observed effect: n per arm = 64 (80% power), 86 (90% power)
 75% of observed effect: n per arm = 114 (80% power), 153 (90% power)
 50% of observed effect: n per arm = 256 (80% power), 343 (90% power)
power.t.test: 65 
Simulated power at n = 64 per arm: 0.795 (20000 replicates)

The simulation draws many sets of group means and variances at the planned sample size and counts how often the two-sample t-test rejects the null. It should land close to the target power; at very small required sample sizes it can fall below it, because the normal approximation is rough there.

14. Multiplicity, Missing Data and Analysis Populations

Multiplicity arises when statistical tests are conducted for several outcomes, time points, subgroups, or other comparisons. With more opportunities to test, the probability of at least one apparently unusual result can increase even when there is no true effect. Methods such as hierarchical testing or adjustments to significance thresholds can address this issue, but the registry record does not report a multiplicity strategy. The secondary comparison p-values are identified as unadjusted.

The registry lists 33 secondary outcomes and 34 outcome measures overall. It reports no analysis records. That absence means the registry record does not establish which secondary outcomes were formally prioritized, whether outcomes were tested in a prespecified sequence, or whether any correction for multiple comparisons was applied. The lack of a reported adjustment does not prove that no adjustment was used outside the registry record; it means the record does not document one.

The primary analysis population is defined as randomized participants who received at least one dose, had a baseline PANSS assessment, and had at least one post-baseline PANSS assessment. This definition is not identical to simply including everyone randomized. The record does not report the numbers excluded from this outcome population or the reasons for any exclusions. It also does not describe a missing-data method, imputation, sensitivity analysis, or assumptions about data missingness.

These omissions matter because incomplete follow-up can affect estimated changes, particularly if the likelihood of missing measurement is related to symptoms or treatment. The registry record also does not give the primary statistical model, covariate adjustments, or interim-analysis information. Those details are not reported in the registry record, so the posted estimates can be interpreted as reported but cannot be fully reproduced or audited from the record alone.

15. 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: gastrooesophageal reflux disease (0.8%).

The serious adverse event figures use safety denominators of 125 for KarXT and 128 for placebo. The registry reports 1 participant with a serious adverse event in the KarXT group and 0 in the placebo group. Deaths are reported as 0 in each group. The most frequent serious adverse event term listed is gastrooesophageal reflux disease, reported as 0.8%.

These figures are counts and a reported percentage, not a comparative statistical analysis. The registry record does not provide a confidence interval or a formal test for the serious adverse event comparison. A count of 0 in one group does not establish that the underlying risk is zero, and the counts alone do not quantify the uncertainty in the difference between groups.

The record separately reports other adverse-event counts of 69 for KarXT and 36 for placebo. These should not be confused with the serious adverse event counts. Safety observations need to be interpreted in the context of the recorded definitions, observation period, and reporting practices; those details are not fully described in the registry record.

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

The primary result describes an average difference in PANSS total-score change between randomized groups over the period from baseline through Week 5. The posted estimate favors a larger reduction in the KarXT group, and the confidence interval does not include zero. This is evidence about the group comparison in the study population and under the analysis used; it is not a guarantee about an individual participant’s outcome.

The study concerned hospitalized adults with acute psychosis and DSM-5 schizophrenia. The primary outcome population also required receipt of at least one dose and both baseline and post-baseline PANSS assessments. Results therefore should not automatically be generalized to people outside this setting or to those who do not meet the outcome-population criteria. The record does not establish the result in other clinical populations.

The endpoint was measured at Week 5. It does not establish the durability of the observed difference or address longer-term changes. The outcome is a symptom scale, not a direct measure of every aspect of functioning, quality of life, or service use. Although the study also assessed safety and other outcomes, the registry results do not provide a complete account of all possible benefits and harms.

Statistical evidence of a difference and clinical importance are related but distinct questions. The raw-score estimate and interval describe the size and precision of the average contrast. The registry record does not provide a threshold for interpreting a clinically important PANSS change, so the statistical result alone cannot determine whether the magnitude is important to each participant.

These findings should be read as a report of trial results, not as medical advice or a recommendation about treatment. The registry record leaves important analysis details unreported, including missing-data procedures, the statistical model, and multiplicity handling. Those limits do not erase the posted comparison, but they constrain how completely its reliability and broader implications can be assessed.

17. Why This Trial Matters Statistically

This trial illustrates why the outcome definition and the direction of a scale matter. PANSS total score includes positive symptoms, negative symptoms, and general psychopathology, and higher scores indicate more severe symptoms. The negative changes in both groups therefore represent average reductions, while the group difference describes how those average changes compare. Reading the sign without the scale definition could lead to the wrong interpretation.

It also demonstrates the value of reporting a confidence interval alongside a p-value. The p-value conveys evidence against a null comparison under the analysis assumptions, while the interval communicates both direction and a range of effect magnitudes compatible with the data. The primary interval lies below zero, but its range still matters; statistical significance does not turn an estimated effect into a known fixed quantity.

The secondary outcomes show why multiple testing and outcome hierarchy matter. A trial may assess multiple symptom domains and safety measures, and the apparent strength of individual results can vary. Without a documented multiplicity strategy, secondary p-values should not be treated as equally confirmatory or independent evidence.

Finally, the record highlights the distinction between enrollment and an outcome-analysis population. The primary endpoint population has stated dosing and assessment requirements, while safety denominators are reported separately. Clear reporting of these populations, model details, and missing-data methods is essential for readers assessing how the posted estimates were obtained and to whom they may apply.

18. 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 population was narrowly defined as hospitalized adults with acute psychosis and DSM-5 schizophrenia. That setting may not represent people with schizophrenia treated in other circumstances. The primary outcome was measured through Week 5, so the result does not address persistence of the group difference or longer-term outcomes.

The registry reports least-squares mean changes and a comparison interval but does not describe the statistical model, its covariates, or its assumptions. It does not report missing-data procedures or sensitivity analyses. Because the primary analysis population required a post-baseline PANSS assessment, the record does not show how missing follow-up data affected inclusion or estimates.

The registry lists many secondary outcomes, while the posted secondary p-values are unadjusted and no multiplicity strategy is described. This limits the strength of conclusions drawn from secondary comparisons. The record also does not report the original sample-size justification or trial design assumptions, so the planning illustrations should not be mistaken for the study’s original design calculations.

The trial is described as double-blind in its official title, while the registry masking classification is triple. The record does not explain this difference. The group estimates also summarize averages and do not describe individual response distributions. Safety counts are reported, but the registry record does not provide comparative confidence intervals for those counts or enough detail to fully assess the adverse-event observation and reporting procedures.

19. Related Tutorials

20. Related Statistical Calculators

21. Sources

• ClinicalTrials.gov: A Study to Assess Efficacy and Safety of KarXT in Acutely Psychotic Hospitalized Adult Patients With Schizophrenia (EMERGENT-3) — NCT04738123.
• Registry record last updated 2024-12-09; status last verified 2024-12.
• Results first posted 2024-12-09.
• 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.

22. Record Summary

EMERGENT-3 was a completed Phase 3 randomized, parallel-group, placebo-controlled, multicenter inpatient study of KarXT in adults with acute psychosis and DSM-5 schizophrenia. Enrollment was 256. The primary endpoint was change from baseline in PANSS total score at Week 5.

The registry reports least-squares mean changes of -20.6 for KarXT and -12.2 for placebo, with a mean difference of -8.4 and a 95% confidence interval from -12.75 to -4.054. The unadjusted p-value is <0.001. The primary outcome population required randomization, at least one dose, a baseline PANSS assessment, and at least one post-baseline assessment.

Important analysis details, including the primary model, missing-data procedures, and multiplicity strategy, are not reported in the registry record. The results describe a Week 5 group comparison and should be interpreted within the recorded population and those reporting limits.