Proton Pump Inhibitors and Dysbiosis in Cirrhosis: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Proton Pump Inhibitors and Dysbiosis in Cirrhosis (NCT01458990), a non-randomized na study. The primary outcome is Number of Patients With Overgrowth of Oral Microbiota in Their Stool After PPI Therapy Withdrawal or Initiation.

2. Clinical Question

The clinical question concerns a change in the composition of bowel bacteria in relation to acid-suppressing medication. In this study, the endpoint focuses specifically on overgrowth of oral-origin microbiota in stool, rather than on a clinical outcome such as symptoms or disease progression. The measurement period is 2 weeks, and the registry says baseline is compared with the 2-week assessment.

The question has two distinct exposure contexts: starting omeprazole and stopping chronic PPI therapy. Since these are non-randomized arms and are not described as a like-for-like control comparison, an apparent difference between them would not by itself isolate a causal effect of PPI exposure. The registry record does not report a primary endpoint result, so it does not establish whether oral-origin microbiota overgrowth was more or less frequent in either context.

3. Trial Design

This completed study is registered as a non-randomized, unmasked, single-group study. Its listed enrollment is 60. The registry record gives a start date of 2011-10 and a primary completion date of 2018-02. The sponsor is Hunter Holmes Mcguire Veteran Affairs Medical Center. The listed phase is NA.

The intervention descriptions identify two exposure changes. The PPI initiation arm added 40mg omeprazole QD for 14 days. The PPI withdrawal arm systematically withdrew chronic PPI for 14 days. The primary outcome description says that baseline was compared with the assessment at 2 weeks. It also describes comparisons between groups on and off PPI therapy. The record does not explain how participants entered the initiation or withdrawal arm, or whether the same participants contributed data to more than one exposure context.

Non-randomized allocation means treatment assignment was not reported as being determined by random allocation. The registry specifically cautions that the arms are not a like-for-like control comparison. Differences between groups could therefore reflect differences in their starting characteristics, medication history, or other factors; the registry record does not report enough detail to assess those possibilities.

Masking is listed as none. The record describes a microbiota assessment using multitagged sequencing, LEfSe, and the QIIME pipeline. It lists two outcome measures, including the primary microbiota outcome and a secondary outcome concerning adverse events during PPI initiation or withdrawal. The record lists 0 analyses. It does not report a statistical analysis plan, participant flow, baseline characteristics, or reasons for missing assessments. The completed status should therefore be distinguished from the availability of analyzable endpoint results: completion is recorded, but a primary endpoint analysis is not.

4. Participant Flow and Accounting

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

Overall Study

Analysis population for the primary outcome, as defined in the registry: Comparison were made between groups on/off PPI therapy using Linear discriminant analysis effect size (LEFSe) and using the Quantitative Insights Into Microbial Ecology (QIIME) pipeline and also the relative proportion (%) of oral-origin microbiota were studied

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 Patients With Overgrowth of Oral Microbiota in Their Stool After PPI Therapy Withdrawal or Initiation, measured over 2 weeks.

The primary endpoint is the number of participants with overgrowth of oral microbiota in their stool after PPI therapy withdrawal or initiation. The outcome is expressed as a participant count, and the stated timeframe is 2 weeks. The registry says baseline measurements are compared with those at 2 weeks using multitagged sequencing. It also describes LEfSe and the QIIME pipeline, as well as examining the relative proportion of oral-origin microbiota.

This endpoint is used to address the study's microbiota question: whether changes in acid-suppressing medication are associated with a detectable change in stool bacteria originating from the mouth. A participant-count endpoint represents whether the described event was identified, rather than the size of an individual participant's microbiota change. The registry does not state a threshold or operational definition for deciding when oral microbiota have overgrown, nor does it explain how the count was derived from sequencing data.

The registry record does not report the number of participants meeting the endpoint in either arm, an effect estimate, or an uncertainty interval. Thus, the endpoint definition and measurement approach are described, but the posted record does not show the primary outcome result or its precision.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The registry describes a participant-count endpoint and a baseline-to-2-week comparison. It names multitagged sequencing, LEfSe, and the QIIME pipeline as parts of the microbiota assessment. It does not report the specific statistical model, adjustment variables, or inferential procedure used for the primary endpoint; 0 analyses are listed.

What does a participant count represent?

A count records how many participants meet an event definition. For this study, the event is described as overgrowth of oral microbiota in stool after PPI withdrawal or initiation. Counts can be useful when the research question concerns how many people meet a defined condition. Their interpretation depends on a clear event definition and on knowing who was assessed. The registry record does not report the threshold used to define overgrowth, the primary endpoint counts, or the number assessed at each measurement occasion.

A count alone does not describe the full distribution of microbiota composition or the size of a change for an individual. The registry also refers to relative proportions of oral-origin microbiota, which is a different type of measurement from the number of participants meeting an event definition. The relationship between the count endpoint and the relative-proportion assessment is not reported in the registry record.

Why compare baseline with 2 weeks?

A baseline-to-follow-up comparison can describe how a measurement changes over time after an intervention. Here, the stated follow-up point is 2 weeks. In general, within-participant comparisons can account for stable characteristics of a participant when measurements are available at both times. However, that interpretation requires knowing whether the same participants were measured at both occasions, how missing measurements were handled, and how the analysis represented repeated observations. Those details are not reported in the registry record.

The study also describes comparisons between groups on and off PPI therapy. Such comparisons are not equivalent to a randomized comparison. In general, non-randomized groups may differ in characteristics that are related to the outcome, so a group contrast can include both the exposure association and pre-existing differences. The registry itself cautions that the arms are not a like-for-like control comparison. The analysis method for addressing potential differences between groups is not reported.

What do sequencing and the named pipelines contribute?

Sequencing is a measurement approach for characterizing microbial material. The record specifies multitagged sequencing and names LEfSe and QIIME. The description indicates these were used to assess microbiota, including oral-origin organisms in stool. These method names do not, by themselves, reveal which taxa changed, how large any changes were, or how uncertain those findings are. The registry record contains no reported endpoint analysis or taxon-level results.

In general, microbiota data can have features such as many measured organisms, relative rather than absolute abundances, and uneven variability. These features can affect the choice and interpretation of statistical methods. The specific preprocessing, normalization, model assumptions, and diagnostic checks used in this study are not reported in the registry record. Over-dispersion, in general, means that observed variability is greater than a statistical model expects; when present, a model that ignores it can give uncertainty estimates that are too narrow. Whether over-dispersion was assessed or relevant to the analysis in this study is not reported.

How should uncertainty be read?

In general, a confidence interval describes the range of effect values reasonably compatible with the data and the assumptions of the analysis. A narrow interval indicates greater precision than a wide interval, while an interval that includes values near no difference may leave substantial uncertainty about the direction or size of an effect. No confidence interval for the primary endpoint is reported in the registry record, so its precision cannot be assessed.

A p-value, in general, summarizes how unusual data would be under a specified null model; it does not measure the probability that a hypothesis is true or the size of an effect. No primary endpoint p-value is reported. With no posted analysis, neither statistical significance nor lack of statistical significance can be inferred.

What does the planning illustration mean?

The record describes a planning illustration based on the observed effect, with a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation. It describes illustrations for detecting stated fractions of the observed effect and distinguishes participants per arm from total event counts for time-to-event outcomes. The record does not report the numerical planning values in the information available for this analysis.

In general, such calculations explore how a future study's sample size could vary under specified assumptions. They are planning illustrations, not observed power and not evidence that the current study had adequate power. The underlying effect estimate is not reported in the registry record, and sample-size justification for this trial is not reported. The illustration therefore cannot establish whether the current study was designed to detect a particular clinically meaningful difference.

10. Exact Estimates for Each Arm

No two-arm comparison is shown for this trial, but each arm's result can still be summarized with exact interval estimates computed from the posted counts. The Clopper-Pearson interval is exact and conservative; the Wilson interval is a common closer-to-nominal alternative; the Bayesian credible interval uses a uniform Beta(1, 1) prior. For small groups the three can differ noticeably.

R code and output

arm    <- c("PPI Inititation", "PPI Withdrawal")
n      <- c(45, 15)
events <- c(45, 15)
for (i in seq_along(n)) {
  ci <- binom.test(events[i], n[i])$conf.int          # Clopper-Pearson exact interval
  cr <- qbeta(c(0.025, 0.975), 1 + events[i], 1 + n[i] - events[i])   # Bayesian, uniform Beta(1,1) prior
  wi <- (function(x, n) { p <- x / n; z <- qnorm(0.975); d <- 1 + z^2 / n
    c((p + z^2 / (2 * n) - z * sqrt(p * (1 - p) / n + z^2 / (4 * n^2))) / d, (p + z^2 / (2 * n) + z * sqrt(p * (1 - p) / n + z^2 / (4 * n^2))) / d) })(events[i], n[i])
  cat(sprintf("ARM|%s|%d|%d|%.1f|%.1f|%.1f|%.1f|%.1f|%.1f|%.1f\n", arm[i], n[i], events[i], 100 * events[i] / n[i],
              100 * ci[1], 100 * ci[2], 100 * wi[1], 100 * wi[2], 100 * cr[1], 100 * cr[2]))
}

ARM  PPI Inititation  45  45  100.0  92.1  100.0  92.1  100.0  92.3  99.9
ARM  PPI Withdrawal  15  15  100.0  78.2  100.0  79.6  100.0  79.4  99.8

11. Multiplicity, Missing Data and Analysis Populations

The registry lists two outcome measures: the primary microbiota endpoint and a secondary outcome concerning the number of patients with adverse events during PPI initiation or withdrawal. It lists 0 analyses. No multiplicity adjustment, outcome hierarchy, or plan for interpreting multiple analyses is reported in the registry record.

In general, multiplicity arises when several outcomes, comparisons, time points, or analytic choices are examined. Testing many questions can increase the chance of finding an apparently notable result by chance. A prespecified hierarchy or adjustment can help clarify how results should be interpreted. The record does not say whether such a strategy was used, and the absence of a posted primary analysis prevents assessment of how multiple microbiota measures were handled.

Missing-data methods are not reported. The registry does not provide the number of participants with baseline or 2-week microbiota measurements, reasons for missing observations, or whether all available participants were included in each analysis. It also does not report an analysis population definition, such as whether an analysis included all participants assigned to an intervention or only those with complete measurements. These omissions make it impossible to assess whether missing observations could have affected the endpoint findings.

The registry record does not report interim analyses, a sample-size justification, or a complete statistical analysis plan. These details should not be inferred from the study's completed status or from the planning illustration assumptions. Without reported analysis populations, missing-data handling, and multiplicity procedures, the robustness of any primary result cannot be evaluated; in this case, the primary result itself is not reported.

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 registry lists the number at risk and the adverse-event counts separately for PPI initiation and PPI withdrawal. For PPI initiation, 45 were listed at risk, with 0 serious adverse events, 0 other adverse events, and 0 deaths. For PPI withdrawal, 15 were listed at risk, with 0 serious adverse events, 0 other adverse events, and 0 deaths. No top serious-event terms are listed.

These figures are counts reported in the registry. A zero recorded count means that no event was reported for that category in the listed group; it does not establish that the underlying risk is zero. The record does not describe event ascertainment, follow-up completeness, or whether all participants were assessed for adverse events throughout the intervention period.

The groups are non-randomized and are not described as like-for-like controls. Their safety counts should therefore be read descriptively, not as a direct comparative estimate of risk. The registry record does not report a statistical comparison of adverse events, nor does it provide information that would support a broader conclusion about safety beyond these recorded counts.

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

The registry record identifies a focused microbiota question: whether PPI initiation or withdrawal is associated with overgrowth of oral microbiota in stool over a 2-week period. It describes a baseline assessment, a follow-up assessment, and microbiota methods involving multitagged sequencing, LEfSe, and QIIME. It also identifies a secondary adverse-event outcome.

What the record does not show is the primary endpoint result. No event count, comparison estimate, confidence interval, or p-value is reported, and the record lists 0 analyses. There is therefore no basis in the posted results for stating that the microbiota outcome increased, decreased, or did not change. An absent analysis is not evidence of no effect, and it is not evidence that the intervention caused a change.

The design also limits the interpretation of any contrast that might be reported elsewhere. Allocation was non-randomized, masking was none, and the registry cautions that the arms are not a like-for-like control comparison. This means a contrast between the initiation and withdrawal groups would need to be considered in light of possible differences between those groups. The record does not report participant characteristics or an adjustment strategy that would clarify this issue.

The safety counts show no reported serious or other adverse events and no deaths in the listed groups. They are a description of events recorded in the registry, not a guarantee that risk is absent or a comparative safety analysis.

Accordingly, the record is informative about the study's question, its intervention contexts, and its intended measurement approach. It does not establish the presence or absence of an effect on oral-origin microbiota, the magnitude of any effect, or the precision of an estimate. It should not be read as a treatment recommendation or as a definitive answer about the clinical consequences of PPI use.

14. Why This Trial Matters Statistically

This study raises statistical issues that are important in microbiota research and in clinical studies with non-randomized exposure groups. First, the endpoint links a laboratory-based characterization of stool microbiota to a participant-level event count. These are different levels of measurement. Interpretation depends on a clear, reproducible definition of overgrowth and on explaining how sequencing measurements were translated into a count of participants. The registry record does not report that operational threshold.

Second, the study includes distinct exposure changes: adding omeprazole and withdrawing chronic PPI therapy. A baseline-to-follow-up design can be useful for describing changes around an exposure, but a contrast between non-randomized groups can be affected by differences in who starts or stops treatment. The registry's explicit warning that the arms are not like-for-like is therefore central to interpretation.

Third, microbiota analyses may involve multiple taxa and measurements. In general, decisions about processing, normalization, analysis, and multiplicity can influence which patterns are emphasized. The record names sequencing and analysis pipelines but does not report detailed statistical choices or results. Reporting the analysis population, missing-data handling, effect estimates, and uncertainty would be necessary for readers to judge the strength and reproducibility of the findings.

Finally, this record illustrates the difference between a completed study and an interpretable results record. The study status is completed, but 0 analyses are listed and the primary result is not reported. Without outcome estimates, the scientific question remains unanswered in the registry record, regardless of the study's status.

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 most direct limitation for interpreting this study is the absence of a reported primary endpoint analysis. The registry lists 0 analyses and does not give participant counts for oral microbiota overgrowth, an effect estimate, or an uncertainty interval. Although the study is marked completed, the posted information does not permit evaluation of the primary result.

The design is non-randomized and unmasked. The registry specifically warns that the arms are not a like-for-like control comparison. The record does not describe how participants entered the initiation or withdrawal context, give arm-specific baseline characteristics, or report adjustment for potential group differences. These omissions limit any causal interpretation of a comparison between exposure groups.

The endpoint is not fully operationalized in the registry description. It names overgrowth of oral microbiota in stool but does not report a threshold for classifying participants as having the event. While multitagged sequencing, LEfSe, and QIIME are named, the record does not describe the detailed analytic pipeline, preprocessing choices, or relationship between the participant count and relative proportions of oral-origin microbiota.

Other important information is also not reported in the registry record: numbers with microbiota measurements at baseline and 2 weeks, missing-data handling, analysis populations, participant characteristics, a statistical analysis plan, multiplicity procedures, and a sample-size justification. The safety counts are available, but event-ascertainment details and follow-up completeness are not. These limitations constrain both statistical interpretation and assessment of how broadly findings might apply.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Proton Pump Inhibitors and Dysbiosis in Cirrhosis — NCT01458990.
• Registry record last updated 2018-03-19; status last verified 2018-03.
• Results first posted 2018-03-19.
• 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

NCT01458990, titled “Proton Pump Inhibitors and Dysbiosis in Cirrhosis,” is listed as completed, non-randomized, unmasked, and single-group. The registry lists enrollment of 60, with a start date of 2011-10 and primary completion date of 2018-02. The sponsor is Hunter Holmes Mcguire Veteran Affairs Medical Center.

The study described adding 40mg omeprazole QD for 14 days or withdrawing chronic PPI for 14 days. Its primary endpoint concerns the number of participants with oral microbiota overgrowth in stool, assessed over 2 weeks using microbiota sequencing methods. The registry lists a secondary adverse-event outcome and 0 analyses.

The adverse-event record reports 0 serious events, 0 other events, and 0 deaths in each listed group. No primary endpoint result or statistical estimate is reported, so the registry record supports description of the study design and intended question, but not a conclusion about the microbiota outcome.