Assessment of End Expiratory Lung Volumes in Healthy Subjects Using High Flow Oxygen (Vapotherm®): Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Assessment of End Expiratory Lung Volumes in Healthy Subjects Using High Flow Oxygen (Vapotherm®) (NCT01672242), a randomized na study. The primary outcome is Change in End-expiratory Lung Volume.

2. Clinical Question

The study’s stated purpose is to evaluate the mechanism by which Vapotherm, a high-flow oxygen system, provides breathing support. The registry summary says the investigators believed the system might provide support similar to CPAP. That statement describes the rationale for the study; it is not itself a result.

The primary outcome is a continuous measurement in mL, recorded as change from a baseline arbitrarily set at 0 mL. The posted results report a mean and standard deviation for each condition. The record does not provide a posted statistical comparison between the conditions, so the reported arm summaries do not establish the size or precision of a within-participant difference.

3. Trial Design

This was a randomized, unmasked, crossover study of HFNC and CPAP in healthy adult volunteers. The registry lists an enrollment of 6 and marks the study status as completed. It identifies the sponsor as the University of Maryland, Baltimore. The study was listed as phase NA.

In a crossover design, participants receive more than one study condition, allowing measurements under different conditions to be made in the same participants. General statistical context: within-participant comparisons can account for stable characteristics shared by a participant’s measurements. However, the analysis must respect that the observations are paired; treating measurements from the same person as independent can misstate uncertainty. The registry does not report the treatment sequence, how randomization was implemented, whether periods or washout were used, or the specific statistical approach to the crossover.

The listed devices were HFNC and CPAP. The HFNC arm description is high-flow nasal cannula oxygen, and the CPAP arm description is continuous positive airway pressure. The record does not describe the actual flow rates, pressure levels, duration at each level, or the sequence of those levels. The outcome timeframe is baseline and after 3-5 minutes after each level of flow or pressure.

The study dates are listed as starting in 2012-07, with primary completion in 2014-04. No design rationale, sample-size justification, or protocol-specific analysis plan is reported in the registry record. The sample-size planning assumptions described for illustrative calculations are not evidence of the trial’s original design or its enrollment rationale.

The registry lists one primary outcome measure and no secondary outcomes posted. It reports no analyses. Consequently, the record gives descriptive outcome summaries but does not supply an inferential comparison that accounts for the randomized crossover structure.

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: Volunteers were asked briefly about their health status and given spirometry to document no evidence of obstructive airways disease or other chronic lung disease that would impact their FRC measurements with high flow nasal cannula therapy or CPAP.

Period 1

Period 2

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: Normal healthy adult volunteers

6. Primary Endpoint

The registry lists the primary outcome as Change in End-expiratory Lung Volume, measured over baseline and after 3-5 minutes after each level of flow or pressure.

The primary endpoint is change in end-expiratory lung volume, measured in mL. End-expiratory lung volume refers to the amount of air remaining in the lungs at the end of a normal expiration. In this study, the registry defines change relative to a baseline arbitrarily set at 0 mL. Measurements were specified at baseline and after 3-5 minutes after each level of flow or pressure.

A continuous measure can capture the size and direction of a physiological change rather than reducing the observation to a category. The mean describes the average change in the reported group, while the standard deviation describes how spread out individual measurements are around that mean. The standard deviation is not a confidence interval and does not directly quantify the precision of the mean or of a comparison between conditions.

The registry reports an HFNC mean change of -144 mL with a standard deviation of 317 mL, and a CPAP mean change of 103 mL with a standard deviation of 274 mL. These summaries describe the reported outcome in each arm. They do not, by themselves, provide the within-participant contrast needed to assess the randomized crossover comparison. The registry does not state a threshold for a clinically important change, nor does it report an adjusted or unadjusted treatment-effect estimate with a confidence interval.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The registry identifies the endpoint as continuous and reports the mean with standard deviation for each arm. A mean is the arithmetic average of the recorded changes. A standard deviation describes the dispersion of measurements around that average. These are descriptive statistics: they characterize the recorded data but do not alone test a hypothesis or quantify the uncertainty of a difference between conditions.

Why does the crossover design matter?

General statistical explanation: crossover studies collect responses under multiple conditions from the same participants. The analysis therefore usually considers within-participant changes or contrasts. Measurements from one person tend to share personal characteristics, so a paired analysis uses information about how the two responses belong together. A comparison that ignores pairing may give an inappropriate estimate of uncertainty. The registry identifies the design as crossover but does not report the specific paired analysis, treatment sequence, period structure, or any adjustment for period or sequence effects. No paired treatment estimate is posted.

What does a standard deviation tell the reader?

General statistical explanation: a standard deviation describes participant-level variability around a mean. It is different from the standard error, which describes uncertainty in an estimated mean, and different again from a confidence interval, which expresses a range of values compatible with the data and analysis under repeated-sampling assumptions. The registry reports standard deviations of 317 mL for HFNC and 274 mL for CPAP. It does not report standard errors or confidence intervals for the means or the treatment contrast. Without the crossover pairing information, the arm-level standard deviations cannot reconstruct the precision of a within-participant comparison.

Why is no inferential result available?

The registry reports zero analyses and says values are missing or not estimable for a two-arm comparison of this continuous endpoint. There is consequently no posted p-value or confidence interval for the comparison. General statistical explanation: a p-value is a measure, under a specified model and null hypothesis, of how incompatible the observed data are with that hypothesis. A confidence interval conveys uncertainty about the estimated effect. Neither is a measure of clinical importance on its own. Since neither is reported for this endpoint, readers should not infer a test result from the descriptive means.

What do the planning assumptions mean?

The record describes sample-size illustrations based on the observed effect, using a two-sided significance level of 0.05, equal allocation between arms, and a normal approximation. It says that the effect to detect is a stated fraction of the observed effect. These are planning assumptions, not the trial’s documented design justification. The record does not report that justification. Nor should an illustrative sample-size estimate be interpreted as observed power, which is not a measure of the evidence in the completed study. No numerical planning estimates are reported in the registry entries.

General statistical explanation: over-dispersion means that data vary more than a simple statistical model expects. When present, it can make standard errors too small if a model does not account for the extra variability. The registry provides standard deviations but no model-based analysis, so there is no basis for diagnosing or adjusting for over-dispersion in this study. More generally, the appropriate analysis must reflect both the outcome scale and the crossover structure.

The reported change is defined relative to a baseline arbitrarily set at 0 mL. This makes the arm values changes rather than absolute lung-volume measurements. The registry does not report whether baseline measurements were averaged, whether repeated observations were combined, how measurements at different levels were analyzed, or how missing observations were handled. Those details matter for evaluating the estimand and the uncertainty of any contrast.

10. Confidence Intervals for Each Arm

No two-arm comparison is shown for this trial, but each arm's mean can be given with a t-based 95% confidence interval computed from the posted mean, spread and number of participants.

R code and output

arm <- c("HFNC", "CPAP")
n   <- c(6, 6)
m   <- c(-144, 103)
sp  <- c(317, 274)
sd  <- sp      # posted standard deviations
for (i in seq_along(n)) {
  se <- sd[i] / sqrt(n[i]); h <- qt(0.975, n[i] - 1) * se
  cat(sprintf("CARM|%s|%d|%.3f|%.3f|%.3f|%.3f\n", arm[i], n[i], m[i], sd[i], m[i] - h, m[i] + h))
}

CARM  HFNC  6  -144.000  317.000  -476.671  188.671
CARM  CPAP  6  103.000  274.000  -184.545  390.545

11. Multiplicity, Missing Data and Analysis Populations

The registry lists one primary outcome measure and no secondary outcomes posted. It reports zero analyses. A formal multiplicity strategy, such as adjustment for testing several outcomes or time points, is not reported in the registry record. Although the outcome description refers to measurements after each level of flow or pressure, the record does not specify how many levels were used or whether each level was treated as a separate analysis. It is therefore not possible to assess the extent of any multiplicity from the posted record.

Missing-data methods are not reported in the registry record. The record does not state whether any outcome observations were missing, how missing measurements were treated, or whether any sensitivity analyses were planned or conducted. The reported arm counts are 6.0 for HFNC and 6.0 for CPAP; the record does not explain whether those counts represent complete endpoint data at every specified measurement occasion.

The analysis population is not reported in the registry record. There is no description of an intention-to-treat, per-protocol, or other analysis set, and no account of exclusions from the outcome analysis. The registry’s statement that values are missing or not estimable for a two-arm comparison of the continuous endpoint means no comparative analysis is available to clarify these questions. As a result, the posted arm summaries should not be treated as a full account of how all randomized participants or measurements were handled.

12. Safety Results

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

Deaths

Other (non-serious) adverse events

Participants with at least one non-serious event at or above the registry's 0% reporting threshold.

The adverse-event record reports zero serious adverse events among the 6 participants at risk in each condition. It also reports zero other adverse events among the 6 participants at risk in each condition, and zero deaths in both groups. No serious adverse-event terms are listed.

These are counts recorded in the registry, not evidence that the conditions have no risk. With a small study of healthy adult volunteers, an absence of reported events provides limited information about uncommon events or safety in people with illness. The record does not describe the method or duration of adverse-event surveillance, whether participants were exposed to each condition for the same length of time, or how events were attributed in the crossover design.

General statistical explanation: an observed count of zero does not establish that the underlying event risk is zero. The precision of a safety estimate depends on the amount and duration of observation and on the study population. Those details are not reported in the registry record. The figures should therefore be read narrowly as the adverse-event counts posted for this study, not as a comprehensive safety comparison.

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

The registry records mean changes in end-expiratory lung volume of -144 mL with HFNC and 103 mL with CPAP. The corresponding standard deviations are 317 mL and 274 mL. The outcome is defined relative to baseline arbitrarily set at 0 mL, with measurements specified after 3-5 minutes at each level of flow or pressure. These summaries describe the observed changes in the two listed conditions.

They do not give the randomized crossover contrast. The registry reports no analysis and no estimate of the within-participant difference, so there is no confidence interval or p-value with which to assess comparative precision. The arm summaries alone cannot establish whether the conditions differ, whether they are similar, or whether one meets a prespecified criterion. No equivalence or non-inferiority margin is reported.

The study’s rationale mentions evaluating how Vapotherm provides breathing support and a belief that high-flow oxygen might provide support similar to CPAP. The posted outcome is a physiological measurement in healthy adult volunteers, not a direct measure of patient-centered benefit. These results do not establish an effect on respiratory distress, clinical outcomes, or treatment decisions in patients.

The record is marked completed, but the limited posted analysis constrains what can be learned from it. Information about participant characteristics, the treatment sequence, detailed exposure levels, missing-data handling, and the analysis population is not reported in the registry record. Interpretation should remain confined to the descriptive endpoint summaries and the study conditions recorded.

14. Why This Trial Matters Statistically

This study illustrates a common statistical challenge: a trial can have a clearly stated continuous physiological endpoint and still lack a reported comparative analysis. The means and standard deviations provide a useful description of the recorded changes, but the design is crossover. The key comparison should account for the fact that measurements under different conditions come from the same participants. Without that paired contrast and its uncertainty, the central comparative question remains unresolved in the registry results.

It also shows why variability and precision should not be conflated. The standard deviations describe spread among observations; they do not indicate how precisely the treatment contrast is estimated. That precision depends on the pairing and the analysis, neither of which is reported as an inferential result. A numerical difference between arm summaries should not be substituted for a trial’s estimated within-participant effect.

The record also separates mechanistic rationale from clinical evidence. A short-term change in end-expiratory lung volume in healthy volunteers is a physiological endpoint. It does not directly answer whether a respiratory support approach changes clinical outcomes in people experiencing respiratory distress. That distinction matters when interpreting the scope of a trial and the population to which its findings might apply.

Finally, the zero adverse-event counts need context. They accurately describe what the registry records, but they do not establish absence of risk. The enrollment and population limit what can be inferred about uncommon events or use in other populations. Transparent reporting of the crossover analysis, uncertainty, and outcome completeness would be needed for a fuller statistical interpretation.

15. Limitations

• The posted summary statistics are the only data these results rest on; patient-level data, full protocols and statistical analysis plans are not available.
• Recalculated results are simple, unadjusted calculations from posted summaries. They do not replace the sponsor's prespecified analysis.

The main limitation is that the registry reports arm-level means and standard deviations but no comparative analysis, even though the design is crossover. Without the paired contrast and its uncertainty, the primary comparative question cannot be evaluated from the posted results. The registry specifically indicates that values are missing or not estimable for a two-arm comparison of the continuous endpoint.

The enrollment was 6, and the reported arm counts are 6.0 for HFNC and 6.0 for CPAP. The registry does not report participant characteristics beyond healthy adult volunteers. The findings therefore have limited reach beyond the study population, and the posted record does not support extrapolation to people with respiratory distress.

Important procedural and analytic details are not reported in the registry record. These include the randomized sequence, the actual flow rates and pressure levels, period structure, any washout, the handling of repeated measurements, the analysis population, missing-data methods, and the model used for the crossover comparison. The registry also does not report a clinically important threshold for the lung-volume change.

There are no posted confidence intervals, p-values, or secondary outcomes. Formal multiplicity handling and a sample-size justification are not reported. The adverse-event counts are zero, but surveillance details and duration are not reported. These gaps limit assessment of precision, completeness, and safety beyond the narrow counts recorded.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Assessment of End Expiratory Lung Volumes in Healthy Subjects Using High Flow Oxygen (Vapotherm®) — NCT01672242.
• Registry record last updated 2022-03-08; status last verified 2022-03.
• Results first posted 2018-01-10.
• Data retrieved from ClinicalTrials.gov on 2026-11-09.
• Group sizes, means, event counts and sponsor-reported p-values are reproduced as posted. Effect estimates, confidence intervals and p-values not attributed to the sponsor are independently calculated from the posted summary statistics.

19. Record Summary

NCT01672242 is a completed, randomized, unmasked crossover study sponsored by the University of Maryland, Baltimore. It enrolled 6 healthy adult volunteers and compared HFNC with CPAP. The study started in 2012-07, with primary completion in 2014-04.

The primary outcome was change in end-expiratory lung volume, in mL, from a baseline arbitrarily set at 0 mL. The registry reports an HFNC mean of -144 mL with a standard deviation of 317 mL and a CPAP mean of 103 mL with a standard deviation of 274 mL. It reports no analyses and no comparative estimate for the continuous endpoint.

No secondary outcomes are posted. The registry records zero serious adverse events, zero other adverse events, and zero deaths in each condition. Details of the crossover analysis, missing-data handling, analysis population, and safety surveillance are not reported in the registry record.