Staccato Loxapine in Agitated Patients With Bipolar Disorder: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Staccato Loxapine in Agitated Patients With Bipolar Disorder (NCT00721955), a randomized phase 3 study. The primary outcome is Change in PANSS Excited Component (PEC) Score From Baseline Following Dose #1 of Staccato Loxapine, Compared With Placebo.

2. Clinical Question

The primary measure focuses on five PANSS items associated with agitation: poor impulse control, tension, hostility, uncooperativeness, and excitement. Each item is scored from 1 to 7, and their sum ranges from 5 to 35. Eligibility criteria selected participants with elevated scores on this measure and at least one item.

The registry also reports two secondary outcomes: Clinical Global Impression-Improvement (CGI-I) score following dose #1 and CGI-I responders. They address global clinical assessment rather than the five-item agitation measure. The available record gives arm-level results for these secondary outcomes, but does not report how responder status was defined. Accordingly, they provide related outcome information, not a replacement for the primary comparison.

3. Trial Design

This was a phase 3, randomized, quadruple-masked, parallel-group study comparing inhaled loxapine with inhaled placebo in bipolar I disorder with acute agitation. The registry identifies the sponsor as Alexza Pharmaceuticals, Inc. It records enrollment of 314 and a completed study. The recorded start was 2008-07, and primary completion was 2008-10.

There were three assigned groups: inhaled placebo, inhaled loxapine 5 mg, and inhaled loxapine 10 mg. Each arm description says the assigned inhalation could be repeated after 2 hours, up to 2 repeats. The primary endpoint, however, is explicitly the change after dose #1 and is assessed at baseline and 2 hours. The record does not establish whether or how later doses were used in the analysis of other outcomes.

Randomization supports comparisons between assigned groups, while masking is intended in general to reduce the influence of treatment knowledge on participant behavior, care, and outcome assessment. The registry labels masking as quadruple but does not identify the masked roles in the record. The parallel model means participants were assigned to a group rather than crossing between study treatments.

The primary analysis population is listed as ITT Population with LOCF. The record does not report further detail about the intention-to-treat definition, the handling of protocol deviations, or the amount and pattern of missing outcome data. It also does not report the original sample-size justification, planned allocation ratio, or statistical analysis plan. Those omissions limit how fully the study's design assumptions and analysis decisions can be assessed from the registry record 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: ITT Population with LOCF

5. Baseline Characteristics

The table reproduces the baseline characteristics posted in the registry, which describe the participants analysed at baseline and help show whether the randomized groups were comparable.

Population: Safety Population

6. Primary Endpoint

The registry lists the primary outcome as Change in PANSS Excited Component (PEC) Score From Baseline Following Dose #1 of Staccato Loxapine, Compared With Placebo, measured over Baseline and 2 hours.

The primary endpoint is change in PANSS Excited Component (PEC) score from baseline to 2 hours following dose #1. The measure sums five PANSS items associated with agitation: poor impulse control, tension, hostility, uncooperativeness, and excitement. Each item has a score from 1 to 7, so the total ranges from 5 to 35. The registry states that participants were eligible with a PEC score of at least 14 and a score of at least 4 on at least one item.

As a continuous outcome, the analysis summarizes the average change in each group, along with standard deviations. A negative change indicates that the follow-up score was lower than baseline. The endpoint is used to quantify the short-term change in a defined set of agitation-related symptoms, and the placebo comparison helps distinguish observed change in the active-dose groups from change in the comparator group.

The measure and assessment time are specific: it is not a general measure of long-term functioning, nor does this endpoint by itself summarize all clinical outcomes or safety. The registry does not report a threshold for what amount of PEC change would be clinically important. The primary analysis population is identified as ITT Population with LOCF, but further details about the implementation of LOCF are not reported in the registry record.

7. Results Posted in the Registry

• Inhaled Loxapine 5 mg: mean -8.10 versus -4.90 on control; difference -3.20 (95% CI -4.51 to -1.89), standardized effect d = -0.66; z-test p = <0.001.
• Inhaled Loxapine 10 mg: mean -9.00 versus -4.90 on control; difference -4.10 (95% CI -5.38 to -2.82), standardized effect d = -0.87; 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.

Clinical Global Impression-Improvement (CGI-I) Score Following Dose #1 of Staccato Loxapine, Compared With Placebo

• 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 deviations.
• Result:
  • Inhaled Loxapine 5 mg: mean 2.10 versus 3.00 on control; difference -0.90 (95% CI -1.18 to -0.62), standardized effect d = -0.86; z-test p = <0.001.
  • Inhaled Loxapine 10 mg: mean 1.90 versus 3.00 on control; difference -1.10 (95% CI -1.39 to -0.81), standardized effect d = -1.03; z-test p = <0.001.
• Interpretation:
  • The 95% confidence interval excludes no difference, so the mean is statistically lower for Inhaled Loxapine 5 mg than for the control. This is an unadjusted, secondary comparison, so it is suggestive rather than confirmatory.
  • The 95% confidence interval excludes no difference, so the mean is statistically lower for Inhaled Loxapine 10 mg than for the control. This is an unadjusted, secondary comparison, so it is suggestive rather than confirmatory.

CGI-I Responders

• Endpoint type: Binary: the number of participants with the event, compared as proportions.
• Test: Unadjusted two-proportion z-test, with a Wald 95% confidence interval for the risk difference.
• Result:
  • Inhaled Loxapine 5 mg: 66.3% (69/104) versus 27.6% (29/105) on control; risk difference 38.7 percentage points (95% CI 26.3 to 51.2), risk ratio 2.40 (1.71–3.37); unadjusted two-proportion z-test p = <0.001.
  • Inhaled Loxapine 10 mg: 74.3% (78/105) versus 27.6% (29/105) on control; risk difference 46.7 percentage points (95% CI 34.7 to 58.6), risk ratio 2.69 (1.93–3.74); unadjusted two-proportion z-test p = <0.001.
• Interpretation:
  • The 95% confidence interval excludes no difference, so the proportion with the event is statistically higher for Inhaled Loxapine 5 mg than for the control. This is an unadjusted, secondary comparison, so it is suggestive rather than confirmatory.
  • The 95% confidence interval excludes no difference, so the proportion with the event is statistically higher for Inhaled Loxapine 10 mg than for the control. This is an unadjusted, secondary comparison, so it is suggestive rather than confirmatory.

The secondary outcomes follow a pattern consistent in direction with the primary endpoint: both active-dose groups have numerically lower CGI-I mean scores than placebo, and the posted responder counts are higher in the active-dose groups. The registry also reports unadjusted comparisons for the continuous CGI-I score and participant counts for CGI-I responders. These outcomes offer a broader view alongside the primary agitation-scale change, but their distinct measurement and analysis mean they should not be treated as duplicate measures of the same quantity.

The sponsor reports ANCOVA results for the continuous CGI-I score, with p < 0.001 for each active-dose comparison versus placebo. No sponsor analysis is listed for CGI-I responders. The registry does not report a definition of responder status, nor does it give a multiplicity adjustment for the secondary comparisons. Therefore, the secondary results add supportive context but should not carry the same inferential weight as a prespecified primary endpoint interpreted under a known analysis plan.

General explanation: testing multiple endpoints and multiple dose comparisons increases the opportunity to observe apparently strong results by chance if each test is considered in isolation. A multiplicity procedure can control that risk, but its use and details are not reported for these secondary outcomes. Their unadjusted significance should consequently be read as exploratory evidence rather than as a definitive set of independently confirmed findings. The overall alignment across the primary and secondary measures is noteworthy descriptively, but the registry does not provide enough detail to establish how the endpoint hierarchy or testing sequence was planned.

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

• Clinical Global Impression-Improvement (CGI-I) Score Following Dose #1 of Staccato Loxapine, Compared With Placebo
• CGI-I Responders

9. Statistical Interpretation

10. Statistical Methods Explained

What does a mean change represent?

The primary measure is continuous, and the registry reports the mean change in each group. A mean combines participants' changes into one average; it does not show the full distribution, the number who improved, or whether responses varied substantially. The standard deviation describes spread among the observed values. In the primary outcome, the reported standard deviations are 4.77 for placebo, 4.9 for 5 mg, and 4.67 for 10 mg. These describe individual-level variation, not uncertainty in the group mean.

General explanation: a change score compares a follow-up measurement with baseline for each participant, then summarizes those changes. A negative group mean means the average follow-up score was below the average baseline score under the reported calculation. It does not imply that every participant had a negative change.

How should the mean differences be read?

The recalculated mean difference compares each active-dose group mean with the placebo group mean. The estimates are -3.2 for 5 mg versus placebo and -4.1 for 10 mg versus placebo. The negative direction follows from the active-dose means being lower than the placebo mean. These are simple, unadjusted recalculations from posted summary statistics. They do not reproduce the sponsor's ANCOVA model.

General explanation: an unadjusted comparison uses the group summaries without accounting for covariates. ANCOVA, in general, estimates a group contrast while accounting for covariate information in a model. The registry identifies ANCOVA as the sponsor's method but does not report the covariates, model specification, or adjusted estimates. Therefore, the two approaches should not be treated as if they produce identical estimates by design.

What do the p-values say?

The recalculated unadjusted p-values are <0.001 for both active-dose comparisons. The sponsor reports ANCOVA p-values of < 0.001 for each comparison and labels both as superiority. A p-value quantifies, under a specified statistical model and null hypothesis, how incompatible the observed data are with that null. General explanation: a small p-value is not the probability that the null hypothesis is true, and it does not measure the size or clinical importance of an effect. The registry does not give enough information to reconstruct the sponsor's ANCOVA analysis.

What do confidence intervals contribute?

The recalculated intervals are -4.511 to -1.889 for 5 mg versus placebo and -5.377 to -2.823 for 10 mg versus placebo. A confidence interval gives a range of effect estimates compatible with the data and the method used, while conveying precision: narrower intervals indicate more precision than wider intervals under the same method. These recalculated intervals do not include zero. The confidence level is not reported in the registry record, and the sponsor's adjusted confidence intervals are not reported either.

General explanation: an interval is not a range in which every participant's outcome is expected to fall. It concerns uncertainty around an estimated group contrast. It also does not account for unreported design choices or missing-data assumptions simply by being calculated.

Why does dispersion matter?

Variation among participant outcomes affects how precisely a group average and between-group contrast can be estimated. The reported standard deviations show that individual change scores vary around each group's mean. General explanation: greater dispersion, all else equal, can make it harder to distinguish a given mean difference from random variation. When data are counts or rates with more variability than a simple model expects, over-dispersion can also make conventional standard errors too small; that is a general issue, not a feature established for this continuous primary endpoint.

The posted summaries do not show outcome distributions, outliers, or subgroup patterns. A mean and standard deviation cannot reveal whether the score changes were approximately symmetric or whether a small number of values strongly influenced the mean. The record does not report diagnostic checks or alternative analyses.

What is the role of the analysis population?

The primary outcome is listed for the ITT Population with LOCF. In general, an intention-to-treat analysis seeks to retain participants in their randomized groups, while LOCF carries a participant's last recorded outcome forward when a later measurement is missing. The registry does not provide enough detail to confirm the precise implementation, the number of missing values, or whether sensitivity analyses were performed. LOCF can rely on assumptions about how an outcome would have behaved after the last observed value; those assumptions cannot be evaluated from the reported summaries alone.

The comparisons are placebo-controlled and randomized, which provides a framework for estimating differences between assigned groups. Interpretation still depends on the conduct of the study, endpoint measurement, missing data, and analysis decisions. The original statistical plan, including any prespecified covariates or multiplicity procedures, is not reported in the registry record.

11. Confidence Intervals and Precision

The recalculated mean difference for inhaled loxapine 5 mg versus placebo is -3.2, with a confidence interval from -4.511 to -1.889. For inhaled loxapine 10 mg versus placebo, the estimate is -4.1, with a confidence interval from -5.377 to -2.823. Both intervals lie on the negative side of zero, consistent with the negative direction of the estimated differences. These are unadjusted recalculations, not intervals from the sponsor's ANCOVA.

Precision is about the uncertainty around an estimate, not whether an estimate is important. The intervals provide a range of values compatible with the data and calculation method, but the confidence level is not reported in the registry record. Their width reflects uncertainty from the observed sample and the calculation assumptions; it does not cover all possible sources of bias or uncertainty about the analysis plan.

The registry reports arm-level standard deviations of 4.77 for placebo, 4.9 for 5 mg, and 4.67 for 10 mg, with analysis sample sizes of 105, 104, and 105. These summaries help characterize the information behind the recalculated intervals, but they do not show individual outcomes or missingness. The sponsor reports ANCOVA p-values but not adjusted effect estimates or adjusted confidence intervals, so the precision of the sponsor's adjusted contrasts cannot be assessed from its reported statistics.

A confidence interval should not be read as a range for individual treatment responses or as proof that the true effect must be inside that particular realized interval. It also does not by itself establish clinical importance. The registry does not report a threshold for meaningful PEC change, which leaves the practical interpretation of the estimated differences unresolved by these statistical summaries alone.

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 for 80% power and participants per arm for 90% power. They are not total event counts: the posted outcomes are continuous or participant-count outcomes, not time-to-event outcomes. The figures are planning illustrations based on the observed effect, not a report of the trial's original sample-size calculation.

The listed assumptions for these illustrations are a two-sided significance level of 0.05, equal allocation between the two arms, a normal approximation, and an effect to detect set to the stated fraction of the observed effect. The registry does not report the original design's sample-size assumptions or justification. The trial's actual allocation involved three groups; the illustration's equal allocation refers to each two-arm comparison used for planning.

In plain language, 80% power means that, if the assumed effect and other planning conditions were true, a study of the indicated size would have an 80% chance of finding statistical evidence under the specified test. The 90% column makes the analogous calculation with a higher target chance of detection and therefore generally requires more participants. The rows for fractions of the observed effect show that smaller effects need more participants to detect with the same target power. This is not observed power.

The figures depend on the observed effects used as planning inputs and on the stated simplifying assumptions. They do not account for every possible feature of a future study, such as different variability, missing data, or a different analysis strategy. They should therefore be read as conditional planning examples, not as a guarantee that a future study will achieve a particular result.

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 = -3.200; pooled standard deviation σ = 4.835.
2. n = 2 × (1.96 + 0.842)² × 4.835² / -3.200² = 35.8, rounded up to 36 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 <- -3.2                      # observed difference in means
sigma <- 4.83512290708003                     # 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(721955)
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 = 36 (80% power), 48 (90% power)
 75% of observed effect: n per arm = 64 (80% power), 86 (90% power)
 50% of observed effect: n per arm = 144 (80% power), 192 (90% power)
power.t.test: 36.8 
Simulated power at n = 36 per arm: 0.797 (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. Analyses Reported by the Sponsor

The sponsor's reported primary comparisons use ANCOVA and are labeled as superiority: placebo versus loxapine 5 mg has p < 0.001, and placebo versus loxapine 10 mg has p < 0.001. No sponsor-adjusted effect estimates or confidence intervals are reported in the registry record.

The recalculated estimates are simple unadjusted mean differences from posted arm summaries: -3.2 for 5 mg versus placebo and -4.1 for 10 mg versus placebo. Their recalculated confidence intervals and p-values are based on that unadjusted approach, not the sponsor's ANCOVA. The two analyses address the same placebo comparisons but are not interchangeable: ANCOVA can account for covariates, while the recalculation uses only the posted summary statistics.

No discrepancy is flagged between the posted results and the recalculation. The sponsor's own analysis remains the primary reported inferential analysis; the recalculation offers a transparent, unadjusted comparison rather than a replacement for it. Since the record does not state the ANCOVA covariates or provide its adjusted effect sizes, readers cannot determine from the registry alone how much adjustment changed the estimates or their precision.

15. Multiplicity, Missing Data and Analysis Populations

The registry reports a primary endpoint and two secondary outcomes, with comparisons of each active dose against placebo. It does not report whether the sponsor adjusted for multiple comparisons, used a prespecified testing hierarchy, or controlled a family-wise error rate. Those details are important because multiple tests create more opportunities for a chance-positive finding than a single test. The sponsor's reported p-values can be described as recorded, but the registry does not establish whether they are adjusted for multiplicity.

The record identifies the primary analysis population as ITT Population with LOCF. It does not report the number of participants with missing primary outcome data, reasons for missingness, timing of missing observations, or the precise LOCF rules. Nor does it report whether alternative missing-data analyses were performed. Without those details, it is not possible to assess how sensitive the findings are to the missing-data approach.

The original statistical analysis plan, including planned covariate adjustment, endpoint hierarchy, and analysis timing, is not reported in the registry record. An interim analysis plan and any interim results are also not reported in the registry record. The record does not report a sample-size justification for the original trial. These are unknowns, not evidence that a particular method was or was not used.

General explanation: multiplicity and missing data affect different parts of inference. Multiplicity concerns the chance of false-positive conclusions across a set of tests; missing data concerns how incomplete outcome observations may affect estimates. Neither issue can be resolved simply by noting that individual p-values are small. A complete assessment would require the prespecified analysis plan and sufficient information about missing outcomes and the analyses applied to them.

16. 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 non-serious adverse event terms

For serious adverse events, the registry reports 0 affected participants among 105 at risk in the placebo group, 0 among 104 at risk with loxapine 5 mg, and 0 among 105 at risk with loxapine 10 mg. Deaths are reported as 0 in each group. No serious adverse event terms are listed in the registry record.

These are counts for the participants at risk recorded in the safety results. A zero count means no serious adverse events were reported in these groups in this registry result; it does not establish that an event could never occur or characterize risks outside the observed study. The registry also lists other, non-serious adverse-event counts, but those are distinct from the serious-event figures and do not change what the serious-event counts mean.

The safety figures do not provide event timing, duration, severity beyond the serious classification, or detailed participant-level information. The registry record does not report enough information to make a broader comparison of safety profiles or to characterize uncommon events. These counts are descriptive and should be interpreted within the study's recorded sample and follow-up.

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

The posted primary results show that mean PEC scores declined from baseline in all three groups by the 2-hour assessment, with larger average declines in the two loxapine groups than in the placebo group. The sponsor reports ANCOVA superiority comparisons against placebo for both doses, each with p < 0.001. The unadjusted recalculation likewise gives negative mean differences and p-values <0.001. Together, these describe the direction and statistical evidence of the recorded short-term comparisons.

They do not show that every participant experienced a decrease, that one active dose is better than the other, or that the estimated differences meet a threshold for clinical importance. No direct comparison between the active doses is reported. The registry also does not report a minimum clinically important difference for the PEC score. Statistical significance and clinical importance are separate questions.

The endpoint concerns change after dose #1 at a 2-hour timeframe. It does not answer questions about longer-term outcomes, durability, functioning, or effects outside the study population. The listed eligibility criteria identify participants with bipolar I disorder and acute agitation meeting specified PEC criteria; findings should be understood in that context rather than generalized automatically to other populations or settings.

The safety counts record no serious adverse events and no deaths in the listed groups, but the registry record alone cannot establish absence of risk. The record provides limited detail about missing data, multiplicity, the sponsor's adjusted estimates, and the original statistical plan. Those limitations affect how completely the results can be evaluated. The results are statistical evidence about the posted comparisons, not medical advice or a guarantee of an individual outcome.

18. Why This Trial Matters Statistically

This trial illustrates how a randomized, placebo-controlled design can estimate short-term differences in a continuous clinical outcome across multiple assigned groups. The primary measure is defined by five agitation-related PANSS items, and the registry specifies both eligibility criteria and an assessment time. That level of endpoint definition helps readers understand what the reported mean changes represent and what they do not cover.

It also demonstrates why it is useful to distinguish a sponsor's model-based analysis from a simple unadjusted recalculation. The sponsor reports ANCOVA p-values and superiority labels, while the registry does not provide the model-adjusted effect estimates or confidence intervals. Unadjusted differences and intervals can make the group summaries easier to interpret, but they cannot recover unreported covariates or substitute for the prespecified analysis.

The result further highlights the importance of precision, multiplicity, and missing-data reporting. Confidence intervals help communicate uncertainty around effect estimates, while a record that omits their confidence level, missingness details, or multiplicity procedures leaves important interpretive questions open. The secondary outcomes show why a family of results needs context rather than a collection of isolated p-values.

Finally, the study's safety record illustrates the boundary between observed counts and broader claims. Zero reported serious events in these groups is informative as a description of the recorded experience, but does not establish that serious events are impossible. Statistical reporting is most useful when its conclusions stay aligned with the endpoint, follow-up, population, and analysis details actually documented.

19. 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 does not report the sponsor's adjusted effect estimates or confidence intervals, the covariates in the ANCOVA model, or the confidence level for the recalculated intervals. This limits assessment of adjusted effect size and precision. The unadjusted calculations are based on summary statistics and cannot reproduce the sponsor's full model.

The primary population is described as ITT Population with LOCF, but the record does not provide the number or pattern of missing values, the exact implementation of LOCF, or sensitivity analyses. The original statistical analysis plan, sample-size justification, and interim analysis details are not reported in the registry record. Multiplicity handling for the several comparisons and secondary outcomes is also not reported.

The record does not define CGI-I responder status or report a sponsor analysis for that outcome. It does not report a clinically important change threshold for PEC or identify the masked roles. Although the trial is labeled quadruple-masked, the record does not say which groups of people were masked. There are no serious adverse event terms listed, and the available safety summaries do not give event timing or detailed descriptions.

The primary assessment is at baseline and 2 hours, following dose #1. It therefore provides a short-term endpoint rather than information about longer-term outcomes. The results are reported for a specific eligible population with bipolar I disorder and acute agitation, and the registry record alone does not establish applicability beyond that population. These limitations do not negate the reported comparisons; they define what cannot be evaluated from the record.

20. Related Tutorials

21. Related Statistical Calculators

22. Sources

• ClinicalTrials.gov: Staccato Loxapine in Agitated Patients With Bipolar Disorder — NCT00721955.
• Registry record last updated 2017-07-26; status last verified 2008-10.
• Results first posted 2017-06-29.
• 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.

23. Record Summary

NCT00721955 is a completed phase 3 randomized, quadruple-masked, parallel-group, placebo-controlled study of inhaled Staccato loxapine in people with bipolar I disorder and acute agitation. The registry records enrollment of 314, a study start of 2008-07, and primary completion in 2008-10. The three groups received inhaled placebo, loxapine 5 mg, or loxapine 10 mg.

The primary endpoint was change in PANSS Excited Component score from baseline to 2 hours after dose #1, analyzed in the ITT Population with LOCF. Mean changes were more negative in both loxapine groups than placebo. The sponsor reports ANCOVA superiority comparisons, each with p < 0.001. Recalculated unadjusted comparisons also indicate negative mean differences versus placebo.

Secondary outcomes include CGI-I score and CGI-I responders. Serious adverse events and deaths are recorded as 0 in each group. Important details—including the original sample-size justification, analysis plan, multiplicity procedure, missing-data counts, and adjusted effect estimates—are not reported in the registry record.