Twenty-Four Hour Combined Multi-Channel Impedance and pH Ambulatory Monitoring: Impedance Reflux Episodes of Patients On and Off Proton Pump Inhibitor Therapy: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Twenty-Four Hour Combined Multi-Channel Impedance and pH Ambulatory Monitoring: Impedance Reflux Episodes of Patients On and Off Proton Pump Inhibitor Therapy (NCT01710800), a randomized na study. The primary outcome is Number of Impedance Episodes Following PPI and Placebo.

2. Clinical Question

The study was designed to examine whether proton pump inhibitor treatment was associated with a change in the total number of reflux episodes in the distal esophagus. Its stated rationale is that these medicines change the acidity of refluxate and might also affect the number of episodes through antisecretory effects. The posted primary outcome is the mean number of impedance episodes, rather than acidity itself or a clinical symptom outcome.

The record describes a randomized, double-masked crossover study. A crossover design generally compares conditions experienced by the same participant, but the registry record does not report the treatment sequence, the timing of each period, or any washout interval. It also does not report separate results for participants with and without GERD. The pooled posted results therefore do not answer whether the contrast differed between those groups.

The central statistical question is whether the observed difference in mean episode counts is sufficiently precise to distinguish a treatment-associated change from variation compatible with no difference. The reported means are 53.0 episodes with esomeprazole and 47.0 with placebo. The posted mean difference is 6.0 episodes, with a confidence interval that includes zero. These results describe the analyzed observations; they do not, by themselves, establish a causal or clinically meaningful effect.

3. Trial Design

The registry identifies this as a randomized, double-masked, crossover study, with esomeprazole and placebo as the two interventions. A crossover trial ordinarily evaluates more than one condition within a participant, allowing comparisons to account for stable differences between people. Randomization and masking are design features intended to limit bias, but their presence does not resolve every possible source of bias or uncertainty.

The study record lists enrollment of 41 participants. The primary outcome description says that analysis was per protocol and included only people who completed both 24-hour pH studies with impedance. The posted outcome summaries list 41 observations in each treatment arm. The adverse-event summaries use different at-risk counts: 45 for placebo and 44 for the PPI arm. The registry record does not explain the differences among these counts, so they should not be treated as interchangeable denominators.

The intervention description specifies esomeprazole 40 mg twice daily before impedance monitoring, while the placebo arm description says participants were randomized to receive PPI or placebo before monitoring. The registry record does not report the duration of treatment before each study beyond the primary outcome timeframe of 1 week. It does not report treatment order, period-specific counts, washout procedures, or the method used to handle the paired nature of crossover observations.

The record lists the study as completed and identifies Walter Reed National Military Medical Center as the sponsor. It gives no phase designation beyond not applicable. Although the posted outcome contains arm-level means and standard deviations and a mean-difference estimate, the registry record does not report a detailed statistical analysis plan or a model specification. Consequently, readers can describe the posted contrast and its uncertainty, but cannot establish from the record whether it represents the planned primary crossover analysis.

4. Participant Flow and Accounting

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

Before assignment: Prior to undergoing 24 hour pH with impedance, all participants will receive either one week of esomeprazole or one week of placebo.

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: We analyzed as per protocol. Only patients who completed both 24 hour pH studies with impedance were analyzed.

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 Number of Impedance Episodes Following PPI and Placebo, measured over 1 week.

The primary endpoint is the number of impedance episodes during a 24-hour monitoring study. The registry defines an impedance episode as a 50% decrease from baseline in retrograde movement of liquid from the stomach to the esophagus, describing the measure as a count of retrograde reflux episodes. The unit is number of episodes, and the posted summary measure is the mean with standard deviation.

This endpoint is used to quantify reflux events rather than only their acidity. The study rationale states that proton pump inhibitors may change acidity and hypothesizes that they may also reduce the total number of episodes through antisecretory effects. Counting impedance-detected events therefore addresses the stated question about episode frequency, while pH testing is used in characterizing GERD and monitoring the study outcome.

The primary outcome timeframe is 1 week. The registry record does not provide additional detail about how that timeframe relates to treatment periods or the sequence of monitoring. It also does not report an outcome threshold for a meaningful change, or a separate analysis of acid and non-acid episodes. The endpoint should therefore be read as a count-based physiological measure, not as a direct measure of symptoms, quality of life, or clinical benefit.

7. Results Posted in the Registry

• Esomeprazole: mean 53.00 versus 47.00 on control; difference 6.00 (95% CI -5.14 to 17.14), standardized effect d = 0.23; z-test p = 0.291.

8. Statistical Interpretation

9. Statistical Methods Explained

The primary outcome is continuous in the sense that it is summarized by a mean and standard deviation, although the underlying measurement is a count of episodes. The mean describes the average number of observed episodes in an arm. The standard deviation describes variability among the observations around that arm’s mean. In the posted results, the placebo mean is 47.0 with standard deviation 22.0, and the esomeprazole mean is 53.0 with standard deviation 29.0.

A mean difference expresses the contrast between the two arm means in the outcome’s original units. The posted estimate is 6.0 episodes for esomeprazole compared with placebo. A positive value indicates a higher mean in the esomeprazole arm under that contrast’s direction; it does not, by itself, establish that the intervention caused the difference. The confidence interval communicates uncertainty around the estimate, while the p-value summarizes compatibility with a null difference under the calculation’s assumptions.

In general, a confidence interval is a range generated by a statistical method that reflects sampling uncertainty. It is not a range containing a fixed proportion of individual participants’ results, and it is not the probability that the true effect lies in that particular interval. A confidence interval that includes zero means that the data do not rule out zero difference at the corresponding level of confidence. It does not prove equivalence or demonstrate that an effect is absent.

The registry labels the study randomized, double-masked, and crossover. In general, crossover designs can use within-participant comparisons: each person’s result under one condition is related to that same person’s result under the other. Such an analysis can account for stable person-to-person differences. It also requires attention to sequence, period effects, and possible carryover from one treatment period to another. The registry record does not report the treatment sequence, washout interval, period-specific results, or a crossover analysis model, so those aspects cannot be evaluated from the posted results.

The comparison information includes an unadjusted mean difference and a confidence interval, with a p-value of 0.291. An unadjusted comparison is not necessarily the same as an analysis that accounts for the crossover pairing or other prespecified design features. The registry record reports no detailed analysis method and no posted analysis records. Accordingly, the arm-level means and the contrast are informative descriptions, but the record does not establish the exact model behind a planned primary analysis.

Standard deviations are useful for describing spread, but they are not the same as standard errors. A standard error describes the precision of an estimated quantity, such as a mean; it generally depends on both variability and the amount of information. Neither the standard deviation nor the standard error describes the range of outcomes for every individual. The posted summaries give standard deviations for each arm and standard errors of 3.436 and 4.529, but the record does not explain the method used to derive those standard errors.

General statistical considerations for count outcomes include skewness and over-dispersion. Over-dispersion means that variation in the count data is greater than a chosen model expects. If present, it can make standard errors from an overly restrictive model too small and confidence intervals too narrow. Count outcomes may also contain many low counts or a few high counts, making a mean alone an incomplete description. These are general considerations; the registry record does not report a distributional assessment, an over-dispersion test, or a count-model analysis for this trial.

Randomization helps make treatment assignment independent of measured and unmeasured participant characteristics on average, but the interpretation still depends on whether the analysis preserves the randomized comparison and handles missing observations appropriately. The posted primary population is restricted to those completing both studies. Because the record does not give completion counts, reasons for missing monitoring, or an analysis of all randomized participants, the degree to which this restriction affects the estimated contrast is not known.

The posted p-value is unadjusted. The registry record does not report a multiplicity strategy or any secondary results. When multiple outcomes or comparisons are tested, the chance of at least one small p-value can increase; methods for addressing that issue are general statistical tools. Here, no claim about correction for multiple testing can be made because the registry record does not report such a plan. The main interpretive emphasis should remain on the primary estimate, its interval, its design context, and the limitations in the reported analysis details.

10. Confidence Intervals and Precision

The mean-difference estimate is 6.0 episodes, with a confidence interval from -5.142 to 17.14. This interval is the main guide to the precision of the posted contrast. It includes zero, so the data are compatible with no mean difference under the interval’s calculation. It also includes values below and above zero, indicating that the direction and size of the underlying contrast remain uncertain.

In general, a narrower confidence interval indicates greater precision than a wider interval, when comparing intervals for the same quantity and method. Precision is not the same as validity: an estimate can be precise but biased if the design or analysis is inappropriate. Conversely, a wide interval can reflect limited information even when the point estimate is unbiased. Here, the interval spans a range that does not support a sharply determined estimate of the difference.

The arm-level standard deviations are 22.0 for placebo and 29.0 for esomeprazole. They describe observed variation in episode counts, not uncertainty in the mean difference itself. The crossover structure is also relevant: paired participant-level results can differ in precision from a comparison based only on separate arm summaries. Because the registry record does not report the within-participant correlation or the method used for the contrast, the effect of pairing on precision cannot be assessed.

The unadjusted p-value is 0.291, but it should not replace the confidence interval as a description of the range of estimates compatible with the analysis. The registry record does not report a clinically meaningful difference threshold. Therefore, the interval cannot be classified as excluding or confirming a meaningful effect based on a threshold that is absent from the record.

11. 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 illustrate the sample size that a hypothetical two-arm comparison would require under the stated assumptions, using the observed effect as a reference and considering planning for 100%, 75%, or 50% of that observed effect. The figures are 289 and 387 participants per arm for 80% and 90% power when planning for 100% of the observed effect; 514 and 688 participants per arm when planning for 75%; and 1,156 and 1,547 participants per arm when planning for 50%.

In plain terms, the 80% power column gives the estimated participants per arm for a design with an 80% chance of detecting the specified effect if that effect were the true one and the assumptions held. The 90% power column gives the corresponding estimate for a higher chance of detecting that effect. These are design calculations, not a report of the chance that this completed trial detected an effect.

The planning assumptions listed in the registry record are a two-sided significance level of 0.05, equal allocation between the two arms, and a normal approximation. The target effect is a stated fraction of the observed effect. Smaller target effects require more participants because they are harder to distinguish from random variation. Planning for 75% or 50% of the observed effect therefore produces larger participant requirements than planning for the full observed effect.

These figures are not observed power and should not be read as the trial’s original sample-size justification. The registry record does not report the original design assumptions or the trial’s own sample-size calculation. The illustrations are based on the observed contrast and are useful for understanding how assumptions about the target effect affect planning, not for deciding whether the completed study was adequate or whether its result is true.

12. 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 = 6.000; pooled standard deviation σ = 25.739.
2. n = 2 × (1.96 + 0.842)² × 25.739² / 6.000² = 288.9, rounded up to 289 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 <- 6                      # observed difference in means
sigma <- 25.7390753524675                     # 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(1710800)
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 = 289 (80% power), 387 (90% power)
 75% of observed effect: n per arm = 514 (80% power), 688 (90% power)
 50% of observed effect: n per arm = 1,156 (80% power), 1,547 (90% power)
power.t.test: 289.8 
Simulated power at n = 289 per arm: 0.798 (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.

13. Multiplicity, Missing Data and Analysis Populations

The registry record reports one primary outcome and no posted secondary outcome results. It does not report a multiplicity adjustment, a prespecified hierarchy of outcomes, or a strategy for interpreting multiple comparisons. Multiplicity refers generally to the statistical issue that testing many hypotheses can increase the chance of at least one apparently notable result. Because no additional outcome analyses are posted, the record does not permit an assessment of how multiplicity was handled in the trial’s full analysis.

The primary outcome population is described as per protocol, limited to participants who completed both 24-hour pH studies with impedance. This is important because excluding participants without complete measurements can affect comparability if completion is related to treatment, outcome, or other factors. The registry record does not report the number of participants who did not complete both studies, reasons for noncompletion, or any sensitivity analysis addressing missing outcome data.

The record lists enrollment of 41 and 41 participants in each posted outcome arm, but does not explain how those counts relate to the per-protocol restriction. It also gives adverse-event at-risk counts of 45 for placebo and 44 for the PPI arm. The record does not explain these different counts or identify which population was used for each analysis. They should therefore be reported as separate posted counts rather than reconciled by assumption.

No imputation method, missing-data model, or all-randomized-participant analysis is described. The registry record does not report whether outcome data were missing, how any missing values were handled, or whether exclusions were decided before outcomes were reviewed. These omissions limit assessment of the consequences of the per-protocol population definition.

The record identifies the study as crossover but does not report a treatment sequence, period-specific results, carryover assessment, or an analysis that explicitly accounts for within-person observations. It also does not report subgroup analyses for participants with and without GERD. As a result, it is not possible to determine whether the posted mean comparison reflects the intended paired analysis, whether period effects were considered, or whether the contrast differs across those clinical groups.

14. 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 0% reporting threshold.

The adverse-event record lists zero serious adverse events in each group: 0 among 45 at risk in the Placebo Arm and 0 among 44 at risk in the PPI Arm. It also lists zero other adverse events in each group: 0 among 45 at risk in the Placebo Arm and 0 among 44 at risk in the PPI Arm. These counts describe the posted record and the denominators it gives.

The at-risk counts differ from the primary outcome counts of 41 in each arm. The registry record does not explain the difference, so the safety denominators should not be substituted for the analyzed primary outcome population. It also does not report deaths; the death entries are missing rather than a stated count of zero. No serious adverse-event terms are listed.

Zero reported events in these groups should not be interpreted as proof that no events occurred in any participant or that an intervention is free of risk. The record does not provide further detail about event definitions, collection procedures, follow-up completeness, or the reason for the denominator difference. These safety figures are a concise description of what was posted, not a basis for medical advice.

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

The posted results describe an average of 53.0 impedance episodes during esomeprazole monitoring and 47.0 during placebo monitoring. The reported difference is 6.0 episodes, with a confidence interval from -5.142 to 17.14 and an unadjusted p-value of 0.291. The interval includes zero, and the estimate remains uncertain in both direction and magnitude.

These findings do not establish that esomeprazole increases reflux episodes, because the interval includes values consistent with a decrease as well as values consistent with an increase. They also do not establish that the treatments have equivalent effects: no equivalence margin is reported, and a nonsignificant p-value is not evidence of equivalence. The registry record does not specify what difference would be clinically or physiologically important.

The outcome concerns impedance-detected episode counts. It is not a direct measure of symptoms, quality of life, or patient-important benefit. Nor do the posted pooled results show whether acid exposure changed or whether the number of episodes differs between patients with and without GERD. The study rationale discusses acidity and episode frequency, but the posted primary result addresses the episode count only.

Design details also constrain interpretation. Although the study is described as randomized, double-masked, and crossover, the registry record does not report sequence, washout, paired results, or the analysis model. The primary analysis is per protocol and includes only participants completing both monitoring studies, but completion and missing-data details are not reported. These gaps make it difficult to judge how well the posted contrast represents the planned crossover comparison.

The appropriate reading is therefore descriptive and cautious: the registry reports a small positive point estimate with an interval that allows effects on either side of zero. This is not a treatment recommendation or a definitive conclusion about whether a treatment works. It is the statistical result as posted, interpreted in light of its uncertainty and the incomplete analysis details.

16. Why This Trial Matters Statistically

This trial illustrates why an estimated difference should be read together with its confidence interval rather than as a standalone point estimate or p-value. The observed mean difference is 6.0 episodes, but its interval extends from -5.142 to 17.14. The interval communicates substantial uncertainty about both direction and size, even though the estimate itself is a single number.

It also highlights the importance of matching the analysis to the design. A crossover study can make use of each participant’s observations under both conditions. The registry record identifies a crossover design but does not give paired results or describe the analysis model. Arm-level summaries alone cannot show how within-participant information was handled, and that missing detail matters when evaluating the reported precision.

The per-protocol population is another relevant statistical feature. Restricting analysis to participants who completed both studies may be understandable for paired monitoring, but interpretation depends on who was excluded and why. The record does not report completion information or missing-data methods. This leaves readers unable to assess whether the analyzed participants represent all randomized participants.

Finally, the planning illustrations demonstrate how sample-size requirements depend on the target effect. Planning for a smaller fraction of the observed effect yields larger participant requirements. These calculations are useful for seeing that study planning depends on the effect researchers consider important, but they are not the trial’s original justification and are not evidence about the probability that the completed trial detected a true effect.

Together, these points show the value of transparent reporting: the estimate, interval, design, analysis population, and missing-data procedures all contribute to a sound statistical interpretation. A result can be accurately reported while still leaving important questions unresolved.

17. 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 treatment sequence, washout procedures, period-specific outcome summaries, or an analysis model for the crossover design. Without those details, it is not possible to evaluate carryover or period effects or determine whether the reported contrast accounts for paired measurements within participants.

The primary analysis is described as per protocol and restricted to participants completing both 24-hour studies. The record does not say how many did not complete both studies, why they were excluded, or whether missing values were addressed in any other analysis. Enrollment is listed as 41, while the outcome arm summaries each list 41 participants and the safety summaries list different at-risk counts. The registry record does not explain these counts.

The posted comparison is not accompanied by a reported detailed statistical plan, model specification, or sensitivity analysis. No secondary outcome results or subgroup estimates are posted, including separate results for participants with and without GERD. The record does not state a threshold for a meaningful difference in episode counts, limiting assessment of practical importance.

The adverse-event summary reports zero serious and zero other adverse events, but it does not report deaths and provides no additional event-collection details. These limitations concern the information available in the registry record; they do not establish that additional analyses or details were absent from other records.

18. Related Tutorials

19. Related Statistical Calculators

20. Sources

• ClinicalTrials.gov: Twenty-Four Hour Combined Multi-Channel Impedance and pH Ambulatory Monitoring: Impedance Reflux Episodes of Patients On and Off Proton Pump Inhibitor Therapy — NCT01710800.
• Registry record last updated 2013-01-09; status last verified 2012-11.
• Results first posted 2013-01-09.
• Data retrieved from ClinicalTrials.gov on 2026-11-09.
• Group sizes, means, event counts and sponsor-reported p-values are reproduced as posted. Effect estimates, confidence intervals and p-values not attributed to the sponsor are independently calculated from the posted summary statistics.

21. Record Summary

The registry record describes a completed randomized, double-masked crossover study sponsored by Walter Reed National Military Medical Center. It compares esomeprazole with placebo for the primary outcome of impedance-detected reflux episode count during 24-hour monitoring. The primary analysis population is described as per protocol, including participants who completed both monitoring studies.

The posted means are 53.0 episodes for esomeprazole and 47.0 for placebo, with standard deviations of 29.0 and 22.0, respectively. The reported mean difference is 6.0 episodes, with a confidence interval from -5.142 to 17.14 and an unadjusted p-value of 0.291. The interval includes zero, and the magnitude and direction of the contrast remain uncertain.

The record does not report crossover sequence or model details, missing-data methods, or secondary outcome results. Safety summaries list zero serious and zero other adverse events for the stated at-risk counts, while deaths are not reported.