Effects of a Common Cold Treatment on Cognitive Function: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Effects of a Common Cold Treatment on Cognitive Function (NCT01466348), a randomized phase 4 study. The primary outcome is Adjusted Mean Change From Baseline in Number of Valid Responses to Rapid Visual Information Processing (RVIP) Cognitive Test.

2. Clinical Question

3. Trial Design

This was a randomized, single-masked, Phase 4 crossover trial of a paracetamol-and-caffeine tablet versus paracetamol powder in participants with the common cold. The registry records 72 participants enrolled and a completed study. The recorded start was 2011-02, and primary completion was 2011-04. GlaxoSmithKline is listed as the sponsor.

A crossover design means that participants receive more than one study treatment condition over the course of the trial, allowing comparisons to be made within participants. That general feature can be useful when outcomes vary substantially between people. However, the registry record does not report the treatment sequences, period structure, washout interval, or the model's handling of period or sequence effects. Those details matter for understanding exactly how the crossover was implemented and analysed, so they cannot be inferred from the design label alone.

The primary endpoint was an adjusted mean change from baseline in valid RVIP responses, assessed from baseline to 30 minutes after treatment administration. The primary population was defined as randomized participants with at least one post-baseline efficacy evaluation. The posted results report 71 participants in each treatment group for this endpoint. Because this is a crossover study, those group counts should not be interpreted as evidence that the study included separate sets of 71 people in the two conditions.

The registry lists 11 outcome measures and 2 analyses. It records one primary outcome and 10 secondary outcomes. Although the trial is marked completed, the original protocol's detailed statistical plan, its sample-size justification, and any interim-analysis plan are not reported in the registry record.

4. Participant Flow and Accounting

The registry reports how participants moved through each stage of the study. All counts below are exactly as posted; missing counts are not inferred from other stages.

Before assignment: A total of 75 participants were screened, and 72 were randomized. 3 participants did not meet the study criterion. A 5 hour washout period was maintained between treatment periods.

Period I - First Intervention

Reasons for not completing this period:

Period II - Second Intervention

Analysis population for the primary outcome, as defined in the registry: Intent-To-Treat (ITT) population: All randomized participants who were randomized and had at least one post-baseline efficacy evaluation.

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 Adjusted Mean Change From Baseline in Number of Valid Responses to Rapid Visual Information Processing (RVIP) Cognitive Test, measured over Baseline to 30 minutes post treatment administration.

The primary endpoint was adjusted mean change from baseline in the number of valid responses to the Rapid Visual Information Processing (RVIP) cognitive test. The assessment period was baseline to 30 minutes post treatment administration. A valid response is a response meeting the task's criteria for a correct response to the relevant stimulus.

The task was designed to assess visual attention and the ability to remain vigilant for periodically occurring events. Participants watched single numbers from 0 to 9 appear in the centre of a screen and responded to consecutive sequences of three odd or three even numbers by pressing the corresponding button as quickly and accurately as possible. The test lasted approximately 9 minutes, and the mean number of valid responses to stimuli was calculated.

Change from baseline expresses the endpoint in relation to each participant's baseline assessment, while the adjusted mean is the model-based group summary reported for the treatment condition. The endpoint is used as a performance measure for this particular attention task; it is not, by itself, a direct measure of every aspect of alertness, mood, or everyday functioning. The registry record does not report a threshold for a change that would be considered important to participants or an interpretation of what size of difference would be meaningful in practice.

7. Results Posted in the Registry

• Paracetamol Powder: mean 1.30 versus 4.80 on control; difference -3.50 (95% CI -3.76 to -3.24), standardized effect d = -4.38; 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.

Adjusted Mean Change From Baseline in Number of Valid Responses to RVIP Cognitive Test

• 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:
  • Paracetamol Powder: mean 0.60 versus 7.10 on control; difference -6.50 (95% CI -6.81 to -6.19), standardized effect d = -6.99; z-test p = <0.001.
• Interpretation:
  • The 95% confidence interval excludes no difference, so the mean is statistically lower for Paracetamol Powder than for the control. This is an unadjusted, secondary comparison, so it is suggestive rather than confirmatory.

The registry lists 10 secondary outcomes spanning RVIP, sustained attention, and divided attention measures, including valid responses, reaction time, and incorrect or missed responses. Numerical results for most of those outcomes are not reported in the registry record, so a complete pattern across all secondary endpoints cannot be assessed from the posted results.

The additional RVIP result with numerical results concerns valid responses at 60 minutes post treatment administration. Its reported adjusted comparison is directionally consistent with the primary RVIP result at 30 minutes: the combination condition has the larger adjusted mean change. This provides a concordant finding for the same cognitive task at a different assessment time, but it is not independent confirmation across all measured domains. Results for the remaining listed secondary outcomes cannot be characterized without their numerical estimates.

Secondary outcomes generally carry less evidential weight than the primary outcome because they are additional comparisons and may not have been the main basis for the trial's planned inference. When multiple outcomes are examined, the chance of finding at least one apparently strong result by chance can increase unless the analysis plan addresses multiplicity. Whether the sponsor used a multiplicity adjustment, or prespecified a hierarchy for secondary outcomes, is not reported in the registry record.

Accordingly, the secondary RVIP result can be described as directionally aligned with the primary result, while conclusions across cognition as a whole remain limited. The registry does not report enough numerical secondary findings or multiplicity details to judge the consistency of every outcome or to treat the secondary results as a comprehensive set of confirmatory tests.

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

• Adjusted Mean Change From Baseline in Number of Valid Responses to RVIP Cognitive Test
• Adjusted Mean Change in Baseline in Valid Reaction Time to RVIP Cognitive Test
• Mean Change From Baseline in Number of Incorrect and Missed Responses to RVIP Cognitive Test
• Adjusted Mean Change From Baseline in Number of Valid Responses to Sustained Attention Tasks (SAT) Cognitive Test
• Mean Change From Baseline in Number of Incorrect and Missed Responses to SAT Cognitive Test
• Adjusted Mean Change From Baseline in Valid Reaction Time to SAT Cognitive Test
• Adjusted Mean Change From Baseline in Number of Valid Responses to Divided Attention Task (DAT) Cognitive Test
• Adjusted Mean Change From Baseline in Valid Reaction Time to DAT Cognitive Test

9. Statistical Interpretation

10. Statistical Methods Explained

The primary endpoint is continuous: it is a numerical measure of valid responses, and the posted summaries describe means and standard deviations. For a continuous outcome, a mean gives a group-level average, while the standard deviation describes how dispersed individual values are around that average. The standard deviation is not the uncertainty of the mean difference; uncertainty about an estimated contrast is conveyed more directly by its confidence interval.

What does the adjusted mean difference represent?

The sponsor reports an adjusted mean difference from an ANOVA analysis. In general, an adjusted comparison estimates the difference between treatment conditions after accounting for terms included in the fitted model. The registry identifies the analysis as ANOVA and labels the estimate an adjusted mean difference, but it does not report the full model specification, the covariates, or which crossover-related terms were included. It is therefore possible to describe the reported estimate, but not to reconstruct all of the adjustment from the registry record.

The sponsor's primary estimate is 3.6 valid responses in the direction of paracetamol/caffeine relative to paracetamol, with a 95% confidence interval from 1.5 to 5.6 and p < 0.001. The posted group means are 4.8 and 1.3, respectively. The registry also reports standard deviations of 0.8 in both groups. These are descriptive summaries; the adjusted ANOVA estimate is the sponsor's model-based comparison and need not be identical to a contrast formed directly from the displayed group means.

Why is there a recalculated estimate as well?

The recalculation is a simple, unadjusted comparison using the posted summary statistics. It expresses the primary contrast as paracetamol powder minus paracetamol/caffeine, yielding -3.5, with a 95% confidence interval from -3.763 to -3.237 and p < 0.001. The reverse sign compared with the sponsor estimate is explained by the reverse comparison direction. This is a summary-statistic calculation, not a second fitted ANOVA model, and it does not reproduce the study's crossover analysis. The registry marks the discrepancy flag as false, but the two estimates still represent different analytic summaries.

In general, a p-value measures how incompatible the observed data are with a specified null model, assuming the analysis model and its assumptions. A small p-value is not the probability that the null hypothesis is true, and it does not measure the size or practical importance of an effect. The confidence interval gives a range of estimates compatible with the data and model at its stated confidence level. In this case, both the sponsor's reported interval and the recalculated interval exclude zero in their respective comparison directions.

How does the crossover design affect interpretation?

In general, crossover studies compare conditions within participants, which can account for stable differences between people when the analysis uses the paired structure appropriately. The treatment observations are therefore not necessarily independent as they would be in a conventional parallel-group comparison. The registry's design label is crossover, but the detailed analysis specification and information about treatment periods are not reported in the registry record.

The simple recalculation is based on the posted group summaries and should not be mistaken for a paired crossover estimate. Its interval and p-value are useful as unadjusted summaries of the posted group-level information, but they cannot replace the sponsor's reported model-based result. A complete assessment of whether the crossover structure, sequence, period, or within-participant correlation was handled appropriately is not possible from the registry record alone.

What assumptions apply to the planning illustrations?

The sample-size planning illustrations are calculated from the observed effect and assume a two-sided significance level of 0.05, equal allocation between the two arms, and a normal approximation. The effect targeted is a stated fraction of the observed effect. These figures illustrate how many participants per arm would be needed under those assumptions; they are not the trial's original design justification. The original sample-size assumptions are not reported in the registry record. The planning calculations also do not tell us the trial's observed power.

In general, greater dispersion makes a mean difference harder to estimate precisely, while a larger sample can reduce uncertainty. For crossover data, within-participant correlation and the analysis of paired observations can also affect precision. Those features are not fully specified in the posted record, so the summary-statistic recalculation should be treated as distinct from a full reanalysis of participant-level crossover data.

11. Confidence Intervals and Precision

The sponsor's primary estimate is an adjusted mean difference of 3.6 valid responses, with a 95% confidence interval from 1.5 to 5.6. Read in the sponsor's comparison direction, the interval is compatible with a positive difference for the paracetamol/caffeine condition relative to paracetamol powder under the reported ANOVA. It excludes zero, as does the recalculated interval when the contrast is written in the reverse direction.

A confidence interval describes uncertainty around an estimate under the analysis model. It is not a range that contains a fixed proportion of individual participants' results, nor does it guarantee that the true effect falls inside the interval. The interval width reflects both the amount of information and the variability represented by the analysis. A narrower interval indicates greater statistical precision than a wider interval, but precision does not by itself establish that an effect is important in practice.

The unadjusted recalculation estimates -3.5 for powder relative to the combination condition, with a 95% confidence interval from -3.763 to -3.237. Its interval is much narrower than the sponsor's reported interval. The two intervals come from different calculations: the sponsor reports an adjusted ANOVA analysis, while the recalculation uses posted summary statistics. Differences in adjustment and the treatment of the crossover structure can affect estimated uncertainty. The registry record does not provide enough model detail or participant-level information to reconcile the interval widths fully.

For the secondary RVIP assessment at 60 minutes, the sponsor reports an adjusted mean difference of 6.5, with a 95% confidence interval from 4.5 to 8.4. That interval also excludes zero in the reported direction. The secondary result adds information about a later assessment, but it does not remove uncertainty about unreported analysis details or establish practical importance, for which no threshold is reported in the registry record.

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 events. They are illustrative calculations from the observed effect, using a two-sided significance level of 0.05, equal allocation between the two arms, and a normal approximation. Each row targets the stated fraction of the observed effect. The trial's original design assumptions and sample-size justification are not reported in the registry record.

The 80% power column gives the calculated participants per arm under which the specified planning assumptions would yield an 80% chance of detecting the targeted effect if that effect were the true one. The 90% power column describes the corresponding calculation for a 90% chance. These are planning concepts: power refers to the probability of detecting an effect under a particular set of assumptions, not a guarantee that a study will find a difference.

The rows targeting smaller fractions of the observed effect require more participants per arm in the displayed planning calculations. That is the general relationship: smaller effects are harder to distinguish from random variation, so more information is usually needed to detect them with the same planned power. The values are generated from the observed effect and the stated assumptions; they do not establish that the original trial was designed with these numbers or assumptions. These calculations are not observed power.

The illustrations use a normal approximation and equal allocation, and they do not replicate the sponsor's adjusted crossover analysis. In particular, the registry record does not report the original sample-size rationale or the detailed statistical assumptions used to plan the completed trial. The calculations should therefore be read as conditional planning examples, rather than as a reconstruction of the study's protocol.

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 = -3.500; pooled standard deviation σ = 0.800.
2. n = 2 × (1.96 + 0.842)² × 0.800² / -3.500² = 0.8, rounded up to 1 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 <- -3.5                      # observed difference in means
sigma <- 0.8                     # 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(1466348)
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 = 1 (80% power), 2 (90% power)
 75% of observed effect: n per arm = 2 (80% power), 2 (90% power)
 50% of observed effect: n per arm = 4 (80% power), 5 (90% power)
power.t.test: 2.3 
Simulated power at n = 1 per arm: NA (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 reports the primary comparison as an adjusted mean difference of 3.6 from an ANOVA, with a 95% confidence interval from 1.5 to 5.6 and p < 0.001. This is the registry's own inferential result for the primary endpoint. The estimate is reported in the direction of the paracetamol/caffeine tablet relative to paracetamol powder.

The recalculation uses the posted group summaries and expresses the contrast in the opposite direction: paracetamol powder relative to paracetamol/caffeine. It gives -3.5, with a 95% confidence interval from -3.763 to -3.237 and p < 0.001. The signs differ because the comparison direction differs. The recalculation is unadjusted and does not reproduce the sponsor's ANOVA or a participant-level crossover analysis, so its estimate and interval are not substitutes for the sponsor's model-based result.

The registry does not flag a discrepancy between the reported analysis and recalculation. Their results are directionally consistent when the contrast direction is aligned, while their numerical estimates and uncertainty summaries differ because the analyses are not identical. Details needed to reproduce the sponsor's adjustment are not reported in the registry record.

15. Multiplicity, Missing Data and Analysis Populations

The registry identifies one primary endpoint and 10 secondary outcomes. Multiple outcome assessments create a multiplicity issue: in general, the more statistical comparisons that are made, the greater the chance that at least one will appear unusual even when there is no underlying difference. Methods such as prespecified testing hierarchies or adjustments can address that concern, but the registry record does not report whether such a plan was used or how secondary tests were interpreted.

The record lists 2 analyses but does not provide a complete statistical analysis plan, a detailed outcome hierarchy, or a multiplicity adjustment method. It is therefore not possible to determine from the registry record whether the reported p-values were adjusted for the range of outcomes and assessment times. The primary endpoint remains the main focus for interpretation, while unadjusted secondary findings should be regarded as less conclusive.

The primary population is defined as randomized participants who had at least one post-baseline efficacy evaluation. This specifies who could be included in that efficacy population, but the registry does not report the number of randomized participants excluded from the primary analysis, the amount or pattern of missing data, or the methods used to handle missing observations. The enrollment was 72, while the primary endpoint summaries list 71 participants in each condition. Because the design is crossover, those treatment-condition counts should not be added or assumed to represent separate participants.

Missing-data methods can affect estimates if participants with unavailable measurements differ from those with observed measurements. The registry does not report whether missing values were imputed, whether analyses used all available observations, or whether sensitivity analyses were conducted. The full analysis population definitions beyond the posted ITT description are not reported in the registry record.

The record also does not report interim analyses, stopping rules, or the trial's original sample-size justification. Their absence from the registry record does not establish that such procedures were or were not used; it means their details cannot be evaluated from the posted information.

16. Safety Results

The registry reports serious adverse events as affected participants divided by participants at risk.

Other (non-serious) adverse events

Participants with at least one non-serious event at or above the registry's 5% reporting threshold.

For the paracetamol/caffeine tablet condition, the registry reports 0 serious adverse events among 71 participants at risk and 0 other adverse events among 71 at risk. For the paracetamol powder condition, it likewise reports 0 serious adverse events among 71 at risk and 0 other adverse events among 71 at risk. The serious-adverse-event term list is empty.

These are the adverse-event counts recorded for the treatment groups in the registry. In a crossover trial, condition-specific counts do not necessarily describe separate sets of participants; the registry reports 71 at risk for each condition. The record does not report the observation period or further details about how adverse events were collected and attributed across treatment periods.

Death counts are not reported in the registry record. The absence of reported serious or other adverse events in these entries should be understood as a description of the posted record, not as proof that no events occurred outside the recorded definitions, observation periods, or reporting process. The available entries do not support broader conclusions about safety.

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

The posted primary analysis describes a difference in adjusted mean change in valid responses on a visual attention task between the paracetamol/caffeine tablet and paracetamol powder conditions. The sponsor's estimate is positive in the combination-versus-paracetamol direction, and its 95% confidence interval excludes zero. The unadjusted recalculation gives a negative estimate because it uses the reverse comparison direction; it is consistent in direction once the contrasts are aligned.

The outcome is a specific laboratory-style cognitive task. It measures responses to sequences of numbers under the RVIP procedure, not all aspects of alertness, mood, cognition, or daily activity. The registry does not report a threshold that would indicate whether the measured difference is noticeable or important to participants. Statistical evidence of a difference therefore should not be equated with a conclusion about practical importance.

The trial compares a combination containing paracetamol and caffeine with paracetamol alone. It does not compare either condition with placebo, and the posted results do not isolate the effect of caffeine from every other feature of the treatment conditions. The record supports a description of the comparison that was conducted, rather than a broad claim about the independent effect of either ingredient.

The results also depend on the analysis. The sponsor reports an adjusted ANOVA estimate, while the simple recalculation is unadjusted and does not reproduce the crossover model. The registry does not report enough detail to assess all model terms, missing-data handling, or multiplicity procedures. The most defensible interpretation is therefore limited to the reported RVIP contrast and its model-based uncertainty, with the incomplete methodological details kept in view.

18. Why This Trial Matters Statistically

This trial illustrates why an endpoint's measurement scale and timing matter. The primary outcome is a mean change in valid responses on a defined cognitive task, assessed 30 minutes after treatment administration. A statistical comparison can quantify a difference in that outcome, but interpreting what it represents requires attention to the task, the assessment time, and the limits of the measure.

It also highlights the distinction between a sponsor's adjusted analysis and a simple recalculation from group summaries. Both can describe the same treatment contrast while differing in sign convention, model adjustment, and uncertainty. Clear reporting of which condition is subtracted from which is essential: a negative estimate for powder relative to the combination condition can align with a positive estimate for the reverse comparison.

The crossover label raises a further statistical issue. In general, within-participant comparisons can make efficient use of data, but valid inference depends on a model that reflects the repeated treatment conditions and relevant period structure. Summary-level recalculations cannot reproduce that analysis. The registry's limited reporting of crossover details makes it especially important not to treat a simple recalculation as equivalent to the sponsor's ANOVA.

Finally, the primary result should be separated from the broader set of secondary outcomes. One additional RVIP assessment is directionally concordant, but numerical results for the other listed measures are not reported in the registry record, and multiplicity procedures are not described. This example demonstrates how an apparently clear primary comparison can coexist with limits on what can be concluded about a wider family of cognitive measures.

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 leaves important design and analysis details unspecified. Although the study is labelled randomized, single-masked, and crossover, it does not report treatment sequences, period structure, washout interval, or how period and sequence effects were handled. These details are relevant when assessing whether the analysis reflects the crossover structure.

The sponsor's adjusted ANOVA is identified, but the model terms and adjustment variables are not described. The simple recalculation is based on posted summary statistics and is not a paired crossover reanalysis. Participant-level observations and the detailed analysis plan are not reported in the registry record, so the recalculation cannot verify the sponsor's model or account for within-participant correlation.

The primary population is described, but the record does not report a full accounting of missing observations, exclusions, or the methods used to handle missing data. The registry lists 10 secondary outcomes, while numerical results are not reported for most of them. Multiplicity adjustments or a prespecified hierarchy are also not reported, limiting interpretation of the secondary outcome family.

The record does not state the original sample-size justification, interim-analysis plan, or threshold for a meaningful difference on the RVIP task. The planning illustrations based on the observed effect cannot fill those gaps. In addition, adverse-event observation details and death counts are not reported in the registry record. These limitations constrain how fully the posted result can be audited and how broadly it can be interpreted beyond the measured task and comparison.

20. Related Tutorials

21. Related Statistical Calculators

22. Sources

• ClinicalTrials.gov: Effects of a Common Cold Treatment on Cognitive Function — NCT01466348.
• Registry record last updated 2013-11-25; status last verified 2013-09.
• Results first posted 2013-11-25.
• 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

NCT01466348 is a completed, randomized, single-masked, Phase 4 crossover trial sponsored by GlaxoSmithKline. It enrolled 72 participants with the common cold and compared a paracetamol/caffeine tablet with paracetamol powder.

The primary outcome was adjusted mean change from baseline in valid responses on the RVIP cognitive test, from baseline to 30 minutes post treatment administration. The sponsor reports an adjusted mean difference of 3.6, with a 95% confidence interval from 1.5 to 5.6 and p < 0.001. The unadjusted summary-statistic recalculation gives -3.5 for powder relative to the combination condition, with a 95% confidence interval from -3.763 to -3.237 and p < 0.001.

The registry also reports a directionally concordant secondary RVIP result at 60 minutes. Numerical results for most listed secondary outcomes and several details of the crossover analysis, missing-data handling, multiplicity procedures, and original sample-size planning are not reported in the registry record.