Effect of Gamma Tocopherol Enriched Supplementation on Response to Inhaled O3 Exposure: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Effect of Gamma Tocopherol Enriched Supplementation on Response to Inhaled O3 Exposure (NCT02911688), a randomized phase 2 study. The primary outcome is Change From Baseline in Sputum Percent Neutrophils (%PMN) Following Ozone Exposure.

2. Clinical Question

3. Trial Design

This was a phase 2, randomized, double-masked crossover study sponsored by the University of North Carolina, Chapel Hill. The condition listed is allergic asthma. The registry record gives an enrollment of 18 and a completed status. It records a study start of 2016-09 and primary completion on 2019-02-13.

A crossover design means that participants receive more than one study condition in sequence, so each person may contribute observations under both conditions. This can allow within-person comparisons, which account for some differences between participants. The registry record identifies the study as crossover but does not report the treatment sequences, period structure, washout interval, or whether period or carryover effects were assessed. Those details therefore cannot be evaluated from the record.

The study involved pretreatment with gamma tocopherol or placebo followed by ozone exposure. The brief summary describes 1200mg gamma tocopherol given daily. The arm description instead specifies gamma tocopherol 1400 mg, taken as 2 700 mg capsules every 12 hours for a total of 4 doses. The placebo description specifies safflower oil in 2 capsules every 12 hours for a total of 4 doses. The dosing descriptions differ, and the registry record does not resolve that discrepancy.

The primary endpoint was change in sputum percent neutrophils, measured before and 6 hours after ozone exposure. The record says that paired primary assessments were limited to 7 volunteers because of variability in induced sputum sample quality. The primary arm results report N=7 for each condition. The record also describes secondary sputum inflammatory measures and whole-lung clearance. Numerical results are posted for only some of those listed outcomes.

The registry record does not report a sample-size justification, a detailed statistical analysis plan, treatment-sequence details, or interim analyses. The planning illustrations associated with the secondary comparisons are based on observed effects and are not evidence about the study's original design or power.

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: 18 volunteers were randomized

First Intervention

Washout

Reasons for not completing this period:

Second Intervention

Analysis population for the primary outcome, as defined in the registry: Due to variability in quality of induced sputum samples, paired assessments of pre and post-ozone sputum endpoints were limited to 7 volunteers.

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 Sputum Percent Neutrophils (%PMN) Following Ozone Exposure, measured over baseline and 6 hours post-ozone exposure.

The primary endpoint was change from baseline in sputum percent neutrophils (%PMN) following ozone exposure. Participants provided induced sputum before exposure and again 6 hours after exposure, and inflammatory cells were measured. Neutrophils are one type of inflammatory cell; the endpoint expresses their proportion in the sputum sample as a percentage.

A before-and-after measurement is intended to describe change associated with the exposure period, while comparing the pretreatment conditions addresses whether those changes differed between gamma tocopherol and placebo. In a crossover study, the most direct comparison would ordinarily make use of measurements from the same participants under each condition. The registry record does not report the paired treatment contrast or its uncertainty for the primary endpoint, so the posted arm means alone do not establish the size or precision of a within-person treatment comparison.

The reported primary means are 34.1 for gamma tocopherol and 36.5 for placebo, and each arm has a reported standard deviation of 20.2. These are summaries of the endpoint, not a reported inferential comparison. The record states that paired assessments were limited to 7 volunteers because of variability in sputum sample quality. This limitation matters because an endpoint based on induced samples can be difficult to analyze when the samples do not meet quality requirements. The registry record does not report additional details about the quality criteria or how unavailable measurements were handled.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

Continuous outcomes are often summarized by a mean and a standard deviation. The mean describes the average value in the analyzed group, while the standard deviation describes how spread out individual values are around that average. In this trial, the primary endpoint is a change in sputum percent neutrophils, and the registry record reports means of 34.1 and 36.5 and standard deviations of 20.2 for the two conditions. These summaries do not by themselves provide a treatment-effect estimate with uncertainty.

Why does the crossover design matter?

In a crossover study, a participant can receive both study conditions, usually in different periods. A comparison can then use the difference within each participant, rather than comparing unrelated groups. The within-person approach can be informative because a participant's measurements may be more similar to one another than to measurements from other participants. But a valid analysis also needs to account for the design, including treatment sequence and period. The registry record identifies a crossover model but does not report its sequence structure, period-specific results, washout details, or analyses of period or carryover effects.

For a paired comparison, the uncertainty depends not only on the variability under each condition but also on how measurements from the same participant relate to each other. The two separate standard deviations do not supply that relationship. The primary endpoint is described as paired, but the record does not provide the paired treatment estimate, its standard error, confidence interval, or p-value. As a result, a paired primary comparison cannot be reconstructed from the posted summaries.

What does a confidence interval communicate?

A confidence interval gives a range of values compatible with the estimate under the statistical method used. A narrow interval indicates greater precision than a wide interval, while an interval spanning values on either side of zero can be compatible with effects in either direction for a mean difference. It is not a guarantee that the true effect lies inside the interval, and it does not by itself establish clinical importance.

The registry record includes unadjusted confidence intervals for three secondary mean differences. All three include zero, and each interval spans a broad range. This indicates that the secondary estimates are not precise enough to distinguish clearly between values on either side of no mean difference under the reported calculations. The intervals do not resolve whether differences of practical importance are present, because the record does not define a threshold for such importance.

How should the p-values be read?

A p-value measures how unusual data at least as discrepant as those observed would be under a specified null model and its assumptions. It is not the probability that the null hypothesis is true, and it does not measure the size or importance of an effect. The posted secondary p-values are unadjusted, and the registry record reports no corresponding primary p-value. They should be interpreted alongside estimates and confidence intervals, not in isolation.

Unadjusted means that the p-values have not been corrected to account for testing multiple outcomes. When many outcomes are examined, the chance of observing one apparently notable result by chance can increase. The record lists multiple secondary outcomes and does not report a multiplicity adjustment or a hierarchy specifying which outcomes were confirmatory. This makes the secondary results exploratory in interpretation.

What are the planning illustrations?

The sample-size illustrations use the observed secondary effect as a reference and show hypothetical numbers of participants per arm under stated assumptions. Those assumptions include a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation; the target effect is a stated fraction of the observed effect. The illustrations include planning for 100%, 75%, and 50% of the observed effect, with targets of 80% and 90% power.

These calculations are not the trial's original sample-size justification. The registry record does not report that justification, and the planning exercise does not establish what power the completed study had. It is also not an observed-power calculation. The illustrations are based on the observed secondary summaries and assumptions that may not represent the crossover design or the uncertainty in the observed effects. Small or noisy pilot estimates can make planning figures especially unstable. They should be viewed as hypothetical planning aids, not as evidence about the study's success or failure.

Why can over-dispersion matter?

In general, over-dispersion means that observed variability is greater than a statistical model expects. For continuous outcomes, high variability relative to the effect estimate makes estimates less precise and can produce wide confidence intervals. A mean difference that is small compared with the spread in measurements may be difficult to distinguish from random variation. The posted secondary outcomes include large standard deviations relative to their means, and their confidence intervals are broad. This general consideration helps explain why the estimates require cautious interpretation, but does not supply a missing primary analysis.

The registry record does not report model diagnostics, transformations, covariate adjustments, or a detailed statistical plan. It also does not describe analysis populations beyond the endpoint-specific counts and the statement that paired primary assessments were limited by sample quality. Therefore the appropriateness of particular modeling choices, handling of incomplete paired data, and assumptions behind the reported analyses cannot be independently assessed.

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("Gamma Tocopherol (N=7)", "Placebo (N=7)")
n   <- c(7, 7)
m   <- c(34.1, 36.5)
sp  <- c(20.2, 20.2)
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  Gamma Tocopherol (N=7)  7  34.100  20.200  15.418  52.782
CARM  Placebo (N=7)  7  36.500  20.200  17.818  55.182

11. Multiplicity, Missing Data and Analysis Populations

The registry record lists several secondary outcomes, but does not report a multiplicity adjustment, a testing hierarchy, or a prespecified distinction between confirmatory and exploratory outcomes. When multiple outcomes are tested, chance alone can produce some apparently notable results. Adjusting for multiplicity or specifying a hierarchy can help control that risk, but the registry record does not say whether either approach was planned or used. The reported secondary p-values are unadjusted and should be interpreted with that limitation in mind.

Numerical results are posted for three secondary outcomes. The other listed secondary outcomes do not have numerical results reported in the registry record. The record also states that no analyses are reported for the primary comparison, while its primary description says paired sputum assessments were limited to 7 volunteers because of variability in sample quality. It does not report the number screened for sample quality, the criteria used, or whether exclusion from paired assessment was related to participant characteristics or treatment results.

For the secondary outcomes with numerical results, the reported sample sizes vary by measure. The registry record does not explain the differences, identify the analysis population for each outcome, or describe an approach to missing observations. It does not report whether all randomized participants were included in any analysis or how crossover-period data were handled when a measurement was unavailable.

Other relevant analysis details are also not reported in the registry record. These include treatment sequences, period effects, carryover assessment, the statistical model, covariate adjustments, and any interim analyses. A sample-size justification is not reported. Without these details, it is not possible to determine whether the posted summaries reflect the intended analysis plan or to assess the robustness of the results to missing data and design features.

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.

Most frequent non-serious adverse event terms

The registry record reports serious adverse events for 0 participants in the gamma tocopherol group among 17 at risk and 0 participants in the placebo group among 16 at risk. It reports no deaths in either group. For other, non-serious adverse events, the record reports 6 affected participants among 17 at risk in the gamma tocopherol group and 1 among 16 at risk in the placebo group.

These counts should be read with their group-specific denominators. The denominators for the adverse-event summaries differ from the primary endpoint sample size, which reflects a distinct endpoint-specific analysis population. A count of participants with at least one event does not convey event severity beyond the registry's serious-versus-other classification, timing, duration, or whether multiple events occurred in one participant. The record does not provide a list of serious-event terms and does not report a causal assessment for the other events.

The posted figures are descriptive safety counts from a small study. Zero serious adverse events recorded in these groups does not establish that serious events cannot occur, and the other-event counts do not by themselves establish that the intervention caused those events. The registry record does not provide enough detail to compare event types or timing.

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

The registry record shows that the primary endpoint was measured before and 6 hours after ozone exposure and that the posted primary arm means were 34.1 for gamma tocopherol and 36.5 for placebo. It also reports a standard deviation of 20.2 in each arm. These values are descriptive summaries. Because the registry record does not report an estimable primary comparison or its uncertainty, they cannot establish the size or precision of a treatment effect on sputum percent neutrophils.

The small number of paired primary assessments is an important constraint. Only 7 volunteers had paired assessments, according to the record, because induced sputum sample quality was variable. The crossover design makes within-participant comparisons relevant, but the record does not report the paired contrast or the information needed to assess that contrast. The primary result therefore remains incomplete as an inferential finding in the registry record.

The posted secondary comparisons are also uncertain. Their confidence intervals include zero, and the record does not report a multiplicity adjustment. They are based on secondary outcomes and summary statistics, not a reported crossover-model analysis. They cannot be taken as confirmation of the primary question or as evidence of a definitive pattern across all outcomes.

These results do not establish that gamma tocopherol does or does not alter the airway response to ozone. They describe what was posted and the limits of the associated precision and analysis detail. They also do not determine whether the intervention is appropriate for any individual or clinical setting. The registry record concerns a specific study population and ozone exposure protocol, and it does not report enough detail to support broader conclusions.

The distinction between absence of a reported comparison and evidence of no effect is essential. Without a primary estimate and confidence interval, the registry record does not show how large a difference is compatible with the paired data. The posted means should not be interpreted as proof of equivalence, and the missing inferential result should not be replaced by a calculation from unpaired arm summaries.

14. Why This Trial Matters Statistically

This study illustrates a central issue in clinical biostatistics: a descriptive result is not always enough to answer the study question. The registry record provides primary means and standard deviations, but the primary comparison is not estimable from the posted information. In a crossover study with paired measurements, the within-participant relationship is a key part of the analysis. Reporting the paired estimate and its uncertainty would make the primary finding much easier to evaluate.

The trial also shows why analysis populations can differ across endpoints. The primary paired assessments were limited to 7 volunteers because of induced sputum sample quality, while the secondary measures with posted numerical results have different arm counts. Those differences can affect precision and interpretation. Clear reporting of sample flow, endpoint-specific availability, and missing-data handling helps readers understand which participants contributed to each result and whether observed results may be selective.

Multiplicity is another important statistical issue. Several secondary outcomes are listed, but the registry record does not report an adjustment strategy or a hierarchy. A set of unadjusted secondary results can be useful for describing patterns and generating questions, but should not carry the same weight as a prespecified primary analysis. The results also illustrate why estimates and confidence intervals matter alongside p-values: broad intervals convey uncertainty that a single significance label would conceal.

Finally, the planning illustrations demonstrate how observed effects can be translated into hypothetical study-size scenarios, while also showing why such calculations must be separated from the original design and from observed power. Their assumptions are explicitly described, but the original sample-size justification is not reported. Careful separation of observed results, recalculated summaries, and planning exercises is necessary to avoid making the evidence appear more conclusive than the record supports.

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.

Several trial-specific limitations restrict interpretation. The primary endpoint relies on induced sputum measurements, and the registry record says sample-quality variability limited paired assessments to 7 volunteers. It does not report the quality criteria, the number of unusable samples, or whether sample usability differed across treatment conditions. This leaves uncertainty about how representative the paired primary sample is.

The record identifies the trial as crossover but does not provide treatment sequences, period-specific results, washout details, or analyses of period and carryover effects. Those are relevant design features because responses may vary by period or depend on the treatment received earlier. Their absence from the registry record prevents assessment of how the analysis accounted for the crossover structure.

The primary arm summaries do not include an estimable paired contrast, confidence interval, or p-value. The secondary comparisons are unadjusted recalculations from posted summary statistics and do not include reported paired covariance. Their sample sizes vary, and the record does not explain the variation or describe missing-data handling. Numerical results for several listed secondary outcomes are not reported in the registry record.

The brief summary and arm description give different gamma tocopherol dosing descriptions: daily 1200mg in the brief summary and a regimen described as 1400 mg in the arm description. The record does not reconcile these statements. It also does not report a detailed statistical plan, a sample-size justification, or interim analyses. These reporting limitations do not determine the direction of an effect, but they limit reproducibility and the strength of conclusions that can be drawn from the posted results.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Effect of Gamma Tocopherol Enriched Supplementation on Response to Inhaled O3 Exposure — NCT02911688.
• Registry record last updated 2020-01-18; status last verified 2019-02.
• Results first posted 2020-01-18.
• 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

This completed phase 2 study was randomized, double-masked, and crossover, with an enrollment of 18. It examined gamma tocopherol versus placebo before ozone exposure in people with allergic asthma. The primary outcome was change in sputum percent neutrophils from baseline to 6 hours after ozone exposure.

The primary arm summaries report means of 34.1 for gamma tocopherol and 36.5 for placebo, with a standard deviation of 20.2 in each arm. Paired primary assessments were limited to 7 volunteers because of induced sputum sample-quality variability. The registry record does not report an estimable primary comparison or its uncertainty.

Numerical secondary comparisons are posted for sputum IL-1b, IL-6, and IL-8. Their unadjusted confidence intervals include zero, and results for other listed secondary outcomes are not reported in the registry record. The record reports no serious adverse events or deaths in either group and reports other adverse events in both groups. Missing analysis details, variable endpoint counts, and the absence of a reported primary contrast limit interpretation.