A Study to Evaluate the Efficacy and Safety of Vonoprazan Compared to Placebo for Relief of Heartburn in Participants With Symptomatic Non-Erosive Gastroesophageal Reflux Disease (NERD): Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for A Study to Evaluate the Efficacy and Safety of Vonoprazan Compared to Placebo for Relief of Heartburn in Participants With Symptomatic Non-Erosive Gastroesophageal Reflux Disease (NERD) (NCT05195528), a randomized phase 3 study. The primary outcome is Percentage of Days Without Daytime or Nighttime Heartburn.

2. Clinical Question

The clinical question concerns whether participants with symptomatic non-erosive gastroesophageal reflux disease (NERD) assigned to vonoprazan had a different percentage of heartburn-free days during the placebo-controlled treatment period than participants assigned to placebo. The registry describes two vonoprazan doses, 10 mg and 20 mg once daily, and a placebo group. The primary endpoint covers Day 1 to Day 28.

“Heartburn-free” was defined using both morning and evening electronic diary entries: both had to be free of heartburn, and there could be no reported use that day of rescue antacid, H2RAs, or PPIs. The outcome is therefore not merely a count of diary entries without symptoms. It is a percentage of days satisfying the diary and rescue-medication criteria. The registry’s primary objective was to assess relief over 4 weeks. The official title also describes evaluation over 6 months, with a 20-week extension following the 4-week placebo-controlled period.

The posted primary comparisons are vonoprazan 10 mg versus placebo and vonoprazan 20 mg versus placebo. The statistical question is about the estimated difference in the endpoint and the uncertainty around that difference, rather than about whether an individual participant experienced relief on every day.

3. Trial Design

This was a Phase 3, randomized, double-blind, parallel-group study sponsored by Phathom Pharmaceuticals, Inc. The registry lists enrollment of 776 and records the study as completed. The start date was 2022-01-17 and the primary completion date was 2022-11-21. The conditions listed are non-erosive gastro-esophageal reflux disease and heartburn.

During the 4-week placebo-controlled treatment period, participants were assigned to vonoprazan 10 mg once daily, vonoprazan 20 mg once daily, or placebo once daily. The posted primary outcome compares each vonoprazan group separately with placebo. The outcome group sizes shown for this measure are 256 for placebo, 256 for vonoprazan 10 mg, and 257 for vonoprazan 20 mg. These are the endpoint group counts, not a substitute for the registry’s enrollment figure or a description of every analysis population.

The arm descriptions state that participants assigned to either vonoprazan dose continued the same dose in a 20-week extension. Participants assigned to placebo were re-randomized to vonoprazan 10 mg or 20 mg for that extension. Thus, the placebo-controlled comparisons described for the primary outcome concern the first treatment period; the extension had a different treatment arrangement for participants initially assigned to placebo. The official title refers to evaluation after 6 months, while the arm descriptions identify a 4-week period and a 20-week extension.

Although the registry identifies randomization and double masking, it does not report the randomization procedure, allocation concealment details, which study roles were masked, or the methods used to maintain masking. The registry record also does not report the rationale for the enrollment target or a sample-size justification. Those details should not be inferred from the listed enrollment or from the outcome group counts.

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: Participant were randomized in a 1:1:1 ratio to receive vonoprazan 10 mg , vonoprazan 20 mg, or placebo during the Part 1 Placebo-controlled Treatment Period. In the Part 2 Extension Period participants who had been assigned vonoprazan in Part 1 continued with their assigned treatment while those assigned placebo in Part 1 were re-randomized to receive vonoprazan 10 mg or 20 mg.

Placebo-controlled Treatment Period

Reasons for not completing this period:

Extension Period

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: Intent-to-treat (ITT) was defined as all participants randomized into the placebo-controlled treatment period who received at least one dose of study drug and had available data.

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: Data is presented for the Placebo-controlled treatment Period, ITT population.

6. Primary Endpoint

The registry lists the primary outcome as Percentage of Days Without Daytime or Nighttime Heartburn, measured over Day 1 to Day 28.

The primary endpoint is the percentage of days without daytime or nighttime heartburn from Day 1 to Day 28. Participants completed an electronic diary twice daily, in the morning and evening. A diary day counted as heartburn-free only when both entries were free of heartburn and there was no reported use of rescue antacid, H2RAs, or PPIs that day. The endpoint therefore combines symptom reports across the day with a rescue-medication condition.

The registry reports least squares means, with 95% confidence intervals, for each treatment group. A least squares mean is a model-based estimate of a group mean; in general, it can account for terms in the fitted model. The registry names a general linear model for the treatment comparisons, but the model terms and any covariates are not reported in the registry record. The group estimates should therefore be read as the posted model-based summaries, without assuming which adjustments were used.

As a continuous percentage-of-days measure, the endpoint retains information about the frequency of qualifying symptom-free days rather than reducing each participant’s experience to a single yes-or-no status. The diary definition also makes the interpretation specific: it captures days meeting the stated symptom and rescue-use criteria, not all aspects of reflux symptoms, treatment experience, or longer-term outcomes. It is the registry’s primary endpoint for the 4-week placebo-controlled period, not a direct summary of the later extension.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The registry reports a general linear model for the two primary treatment comparisons. It presents least squares means for the three groups and estimates of the difference between each vonoprazan group and placebo. The endpoint is continuous: each participant’s outcome is represented as a percentage of days meeting the diary definition, and the group result is summarized by a mean. In general, a linear model estimates relationships between an outcome and specified explanatory terms. The specific terms, covariates, and any stratification factors used in this trial’s model are not reported in the registry record.

What does a least squares mean represent?

In general, a least squares mean is an estimated group mean derived from a statistical model. It may differ from a simple arithmetic average when the model includes other terms, such as baseline characteristics or design factors. The registry identifies the reported values as least squares means, but does not state which terms were included. The numbers should therefore be described as the posted model-based means rather than assumed to be raw averages or adjusted for particular participant characteristics.

The group estimates are 27.7 for placebo, 44.8 for vonoprazan 10 mg, and 44.4 for vonoprazan 20 mg. Each is expressed in percentage of days. The treatment contrasts are stated as differences in least squares means: 17.1 for 10 mg versus placebo and 16.7 for 20 mg versus placebo. Because the outcome is a percentage, those contrasts are interpreted in percentage points, not as relative percentage increases. No additional transformation is needed to describe the posted contrasts.

How should the confidence intervals be read?

A confidence interval communicates uncertainty in an estimate. In general, a narrower interval indicates greater precision than a wider interval, given the same type of estimate and method. The posted 95% intervals for the group means are 23.92 to 31.46 for placebo, 41.06 to 48.58 for vonoprazan 10 mg, and 40.62 to 48.15 for vonoprazan 20 mg. The intervals for the treatment differences are 11.81 to 22.45 and 11.36 to 22.04, respectively. These intervals concern estimates of group means and contrasts; they do not describe the range of individual participant outcomes.

For a difference, zero represents no difference between the compared model-based means. Both reported difference intervals lie above zero. This is consistent with the reported superiority analyses, but it does not replace consideration of model assumptions, outcome definition, data completeness, or clinical context. The registry does not report diagnostic checks for the model or details of how the confidence intervals were constructed.

What do the p-values communicate?

The reported p-values are p < 0.001 for both comparisons. In general, a p-value measures how incompatible the observed data are with a specified null hypothesis under the assumptions of the analysis. A small p-value is not the probability that the null hypothesis is true, nor does it measure the probability that the result occurred by chance in an everyday sense. It also does not quantify the clinical importance of a difference. The registry identifies the analyses as superiority comparisons, but details of the testing procedure beyond the named model and reported results are not reported in the registry record.

The p-values should be read alongside the estimated differences and confidence intervals. Here, the posted effects are expressed in the endpoint’s units, while the intervals show their statistical uncertainty. A p-value alone would not communicate either the estimated magnitude or its precision. Conversely, the interval does not answer whether the registry’s broader family of analyses was adjusted for multiple testing.

What is the analysis population?

The registry defines the intent-to-treat (ITT) population as all participants randomized into the placebo-controlled treatment period who received at least one dose of study drug and had available data. This definition is not identical to an unrestricted population of everyone randomized, because it includes the stated dose and available-data conditions. The registry does not report how many randomized participants lacked endpoint data, how missing diary entries were handled, or whether additional analysis populations were used for the primary outcome.

In general, missing observations can affect a continuous diary outcome if the availability of data is related to symptoms, treatment, or other participant factors. Analyses may address incomplete data using different assumptions and procedures, but the registry record does not report the method used for missing observations or the assumptions underlying it. It is therefore not possible from the record to assess how sensitive the estimates are to missing diary data.

How do planning illustrations differ from observed results?

Any sample-size values associated with these results are planning illustrations based on the observed effect, not the trial’s own design calculation. The stated illustration assumptions are a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation; the effect to detect is a stated fraction of the observed effect. Such values describe hypothetical planning under those assumptions. They are not observed power, do not establish the probability that the trial would detect a true effect, and should not be treated as a rationale for the original enrollment. The registry does not report its sample-size justification.

10. Analyses Reported by the Sponsor

The registry’s inferential results are the sponsor-reported general linear model analyses. For vonoprazan 10 mg versus placebo, the reported least squares mean difference is 17.1, with a 95% confidence interval from 11.81 to 22.45 and p < 0.001. For vonoprazan 20 mg versus placebo, the reported difference is 16.7, with a 95% confidence interval from 11.36 to 22.04 and p < 0.001.

A recalculation from posted summary statistics, when included, is a simple unadjusted calculation. It need not reproduce a model-based contrast, because the sponsor’s analysis may use model terms that are not available from the arm summaries. The registry does not report those terms. The discrepancy indicator is false, so the record does not flag a conflict between the sponsor analysis and the recalculation. The sponsor’s reported analysis remains the relevant source for the inferential results, while a recalculation is best understood as a separate summary-statistic check rather than a replacement analysis.

No recalculated contrast values are stated in the registry record. The posted sponsor results should therefore be interpreted using their own stated model, outcome, analysis population, and confidence intervals. Neither analysis should be extended to a direct comparison between the two doses, which is not among the reported primary contrasts.

11. Multiplicity, Missing Data and Analysis Populations

The registry lists two outcome measures and four analyses. It identifies percentage of days without daytime or nighttime heartburn as the primary outcome and percentage of days without rescue antacid use as a secondary outcome. The posted primary results include two comparisons, each vonoprazan dose against placebo. The registry record does not report whether the two primary comparisons, the secondary outcome, or other analyses were handled within a multiplicity-adjustment strategy. It also does not describe a prespecified hierarchy or a family of hypotheses. The reported p-values should therefore be read as posted, without assuming whether they were adjusted.

The registry describes the ITT population as randomized participants in the placebo-controlled treatment period who received at least one dose of study drug and had available data. It does not report the number of participants with missing endpoint data, the amount or pattern of missing diary entries, or the handling of incomplete diary days. It does not state whether missing observations were imputed, whether a model-based approach was used to accommodate them, or whether sensitivity analyses explored alternative assumptions. These details matter because the primary endpoint is built from repeated diary entries and a qualifying-day rule; absent entries can affect whether a day can be classified.

The specific analysis population used for each reported contrast is described through the ITT definition, but participant flow into the available-data population is not reported in the registry record. The record also does not report the model covariates, assumptions concerning the distribution of residuals, or diagnostic checks. These omissions limit independent assessment of the robustness of the model-based estimates and p-values.

There is no basis in the registry record to infer interim analyses, stopping rules, prespecified multiplicity procedures, or a missing-data plan. General statistical practice may use such procedures, but their use in this trial is not reported. The reported results can be interpreted as the registry’s posted analyses, with these uncertainties kept distinct from the numerical estimates themselves.

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 2% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: angina pectoris (0.8%), cerebrovascular accident (0.8%), cholecystitis acute (0.8%), abdominal pain upper (0.8%), non-cardiac chest pain (0.8%).

The registry lists serious adverse events and other adverse events for the 4-week placebo-controlled groups and for the 20-week extension groups. During Part 1, the serious adverse event counts are 0 for placebo, 1 for vonoprazan 10 mg, and 2 for vonoprazan 20 mg. The corresponding at-risk counts are 256, 259, and 257. No deaths are listed for these groups.

For the extension groups, the serious adverse event counts are 2 for placebo/vonoprazan 10 mg, 4 for placebo/vonoprazan 20 mg, 7 for vonoprazan 10 mg/vonoprazan 10 mg, and 3 for vonoprazan 20/vonoprazan 20 mg. Their listed at-risk counts are 118, 121, 248, and 236. No deaths are listed in these groups. The treatment labels distinguish participants’ initial treatment and extension treatment; the extension groups should not be read as if they were the original placebo-controlled assignments.

The record lists six serious-event terms, each with a frequency of 0.8%: angina pectoris, cerebrovascular accident, acute cholecystitis, upper abdominal pain, non-cardiac chest pain, and bipolar disorder. The record does not give group-specific denominators for those terms or indicate which treatment periods they represent. The counts are descriptive safety summaries, not adjusted comparisons. Definitions, event collection details, exposure-adjusted rates, and formal statistical comparisons are not reported in the registry record. These figures should not be combined across groups or periods to create a new overall rate.

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

The primary result is a comparison of mean percentages of diary days meeting a specific heartburn-free definition during Day 1 to Day 28. The registry reports higher least squares means for both vonoprazan dose groups than for placebo, together with positive differences and confidence intervals that exclude zero. The reported p-values for both placebo comparisons are p < 0.001. This describes the statistical evidence and estimated magnitude for the posted endpoint and analysis, not every dimension of participants’ experience.

The outcome requires both morning and evening diary entries to be heartburn-free and no reported use of rescue antacid, H2RAs, or PPIs. A day that did not meet all of these conditions was not counted as a qualifying heartburn-free day. The endpoint therefore reflects this combined operational definition rather than a general claim about all symptoms, all uses of medication, or complete symptom resolution. Because it is summarized as a group mean percentage, it also does not reveal the distribution of individual outcomes.

The results do not establish a direct difference between vonoprazan 10 mg and 20 mg. The reported primary contrasts compare each dose with placebo. They also do not establish the duration of any effect beyond the Day 1 to Day 28 outcome, since the primary result presented is from the placebo-controlled period. The registry describes a later extension, but the placebo group was re-randomized for that period, so the extension does not represent the same placebo comparison.

Statistical significance does not by itself determine clinical importance. The registry does not provide a threshold for a clinically meaningful difference, nor does it report participants’ interpretation of the diary outcome. Precision, missing-data handling, model specification, and multiplicity are also relevant to a full assessment, and several of these details are not reported in the registry record.

The posted results should consequently be understood as evidence about a defined short-term continuous endpoint in the stated analysis population. They are not a stand-alone account of long-term outcomes, safety, comparative dose effects, or the experiences of participants whose endpoint data were unavailable.

14. Why This Trial Matters Statistically

This trial illustrates how a clinical endpoint can depend on an explicit operational definition. A heartburn-free day required agreement between morning and evening diary entries and no reported use of specified rescue medicines. That rule makes the endpoint more specific than a broad symptom label, but also means its interpretation must stay tied to the diary schedule and rescue-use criterion.

The primary outcome is continuous, expressed as a percentage of days, and reported through least squares means and treatment differences. This allows the posted analysis to retain differences in the frequency of qualifying days rather than reducing participants to a simple responder category. At the same time, a mean does not show how varied individual participant outcomes were. The confidence intervals communicate uncertainty in the estimated group means and contrasts, while not describing individual variation.

The parallel placebo-controlled period supplies two distinct dose-versus-placebo contrasts. The registry reports a general linear model and small p-values, but does not specify the model terms or whether the testing strategy accounted for multiple outcomes and comparisons. Those missing details are not reasons to disregard the reported estimates; they are reasons to distinguish the numerical findings from the fuller design and analysis information needed to evaluate robustness.

The extension also highlights why treatment periods should be interpreted separately. Participants initially assigned to placebo were re-randomized to vonoprazan for the extension, whereas participants initially assigned to vonoprazan continued their dose. Thus the extension has a different comparison structure from the initial placebo-controlled period. The primary endpoint results relate to the first period, not a maintained placebo contrast over the full study duration.

For biostatistical interpretation, the record is a useful example of reading effect estimates, confidence intervals, p-values, population definitions, diary rules, and safety counts together, while not inferring unreported features of the protocol or analysis plan.

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 details needed to assess the primary analysis are not reported in the registry record. The model is identified as a general linear model, but its terms, covariates, assumptions, and diagnostic checks are not described. The record also does not report a missing-data strategy, the extent or pattern of missing diary data, or sensitivity analyses. Because the endpoint depends on repeated morning and evening entries, these omissions limit assessment of how incomplete diaries affected the estimates.

The primary analysis population is defined as randomized participants who received at least one dose and had available data. The registry does not provide participant flow into that population or explain how data availability was determined for the endpoint. The enrollment figure and endpoint group counts describe different registry summaries and should not be treated as a complete account of participant disposition.

The registry lists two outcome measures and four analyses, but does not report a multiplicity plan or explain how the analyses relate to a prespecified testing hierarchy. This makes it difficult to determine whether the reported p-values were adjusted for the broader set of analyses. The sample-size justification is also not reported; planning illustrations based on the observed effect do not establish the trial’s original design assumptions.

The primary results cover Day 1 to Day 28. Although the official title refers to evaluation after 6 months and the arm descriptions specify a 20-week extension, the posted primary contrasts are for the placebo-controlled period. The extension changes treatment assignment for participants initially assigned to placebo, limiting direct comparison with the initial period.

For safety, the registry gives counts and at-risk figures by treatment period, but does not report event definitions, exposure-adjusted rates, formal comparative analyses, or the treatment-group attribution of the listed serious-event terms. These are descriptive counts and do not support an adjusted safety comparison on their own. Participant characteristics and detailed eligibility criteria are not reported in the registry record used for these explanations.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: A Study to Evaluate the Efficacy and Safety of Vonoprazan Compared to Placebo for Relief of Heartburn in Participants With Symptomatic Non-Erosive Gastroesophageal Reflux Disease (NERD) — NCT05195528.
• Registry record last updated 2023-12-29; status last verified 2023-12.
• Results first posted 2023-12-29.
• 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

NCT05195528 is a completed, randomized, double-blind, parallel-group Phase 3 study sponsored by Phathom Pharmaceuticals, Inc. The registry lists enrollment of 776. Its primary objective was to assess vonoprazan 10 mg and 20 mg once daily compared with placebo for relief of heartburn over 4 weeks in participants with symptomatic NERD.

The primary endpoint was percentage of days without daytime or nighttime heartburn from Day 1 to Day 28, based on twice-daily electronic diaries and a rule requiring no reported rescue-medication use. The registry reports least squares means and general linear model comparisons against placebo, with positive estimated differences and p < 0.001 for both doses. The posted findings pertain to the defined endpoint and placebo-controlled period. Details of model specification, missing-data handling, multiplicity, and the original sample-size justification are not reported in the registry record.