This page provides an independent statistical analysis and educational interpretation of publicly reported results. ClinicalTrials.gov provides the official trial registry record. Numerical trial results on this page are restricted to the results posted in the ClinicalTrials.gov record; calculations added by Clinical Biostats are labelled as such.
1. Trial at a Glance
This page covers the registry results for Phase 3/Safety & Efficacy of Esomeprazole in Infants (NCT00468559), a randomized phase 3 study. The primary outcome is Number of Participants Discontinuing Due to Symptom Worsening in the Randomized Treatment Withdrawal Phase (Treatment Withdrawal Phase Endpoint).
| Feature | Registry value |
|---|---|
| ClinicalTrials.gov identifier | NCT00468559 |
| Phase | Phase 3 |
| Condition | Gastroesophageal Reflux Disease (GERD) |
| Allocation | Randomized |
| Design model | Parallel |
| Masking | Quadruple |
| Enrollment | 98 |
| Arms in the primary outcome | n/a |
| Lead sponsor | AstraZeneca |
| Results posted | Yes |
2. Clinical Question
Population
Infants aged 1 to 11 months, inclusive, with gastroesophageal reflux disease (GERD). The record describes screening followed by an open-label esomeprazole phase and a randomized withdrawal phase. Enrollment is recorded as 98; the randomized groups are described separately in the safety record.
Intervention
During the withdrawal phase, infants randomized to continue their open-label esomeprazole dose received double-blind esomeprazole. The open-label dose was 2.5mg, 5.0mg or 10.0mg based on weight.
Comparator
Infants randomized to the comparison group received placebo during the double-blind withdrawal phase. The study description says participants had an equal chance of receiving esomeprazole or placebo.
Primary question
The primary endpoint counted participants who discontinued during the randomized treatment-withdrawal phase after meeting the prespecified symptom-worsening criteria. The timeframe was up to 4 weeks following randomization, or until earlier discontinuation. The registry record does not report a single numerical comparison between groups for this endpoint, so it does not establish how the recorded counts differed or how precisely any difference was estimated.
3. Trial Design
This was a Phase 3, randomized, quadruple-masked, parallel-group study of esomeprazole and placebo in infants with GERD. Its official title describes a multicenter, double-blind, placebo-controlled treatment-withdrawal study. The registry lists enrollment as 98 and the status as completed. The recorded start was 2007-04, and primary completion was 2008-06.
The study had screening, open-label and double-blind treatment-withdrawal phases. Screening assessed eligibility, and no study medication was dispensed during that phase. During the open-label phase, all patients received esomeprazole, at a dose of 2.5mg, 5.0mg or 10.0mg based on weight. In the withdrawal phase, participants were randomized to receive either their open-label dose or placebo. The study description says the physician, parent and patient would not know the assigned treatment during the double-blind phase.
The adverse-event record lists 98 participants at risk in the open-label phase, followed by 39 in the double-blind esomeprazole group and 41 in the double-blind placebo group. These are phase-specific figures; the registry record does not give a complete participant-flow account explaining movement between phases, exclusions, or the analysis population for each endpoint.
The primary endpoint concerned discontinuation due to symptom worsening during the withdrawal phase. Secondary outcomes included discontinuation for any reason, treatment success at the end of the 4-week withdrawal phase, physician assessments, parent or guardian assessments of several symptom areas, and improvement after open-label esomeprazole. The registry record does not report numerical results for those outcomes.
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: All participants received 2-weeks open label esomeprazole (Open-label phase) according to baseline weight (3 to 5kg: 2.5mg; \>5 to 7.5kg:5mg; \>7.5-12kg:10mg). Following the open-label phase, those with symptom improvement of at least one category in the physician global assessment were eligible to be randomized into the withdrawal phase.
Open-label Treatment Phase
| Stage | Open Label Esomeprazole | Double Blind Esomeprazole | Double Blind Placebo |
|---|---|---|---|
| STARTED | 98 | 0 | 0 |
| COMPLETED | 80 | 0 | 0 |
| NOT COMPLETED | 18 | 0 | 0 |
Reasons for not completing this period:
| Reason | Open Label Esomeprazole | Double Blind Esomeprazole | Double Blind Placebo |
|---|---|---|---|
| Adverse Event | 5 | 0 | 0 |
| Lack of Efficacy | 9 | 0 | 0 |
| Withdrawal by Subject | 4 | 0 | 0 |
Double-blind, Treatment-withdrawal Phase
| Stage | Open Label Esomeprazole | Double Blind Esomeprazole | Double Blind Placebo |
|---|---|---|---|
| STARTED | 0 | 39 | 41 |
| COMPLETED | 0 | 29 | 24 |
| NOT COMPLETED | 0 | 10 | 17 |
Reasons for not completing this period:
| Reason | Open Label Esomeprazole | Double Blind Esomeprazole | Double Blind Placebo |
|---|---|---|---|
| Lack of Efficacy | 0 | 8 | 17 |
| Adverse Event | 0 | 2 | 0 |
Analysis population for the primary outcome, as defined in the registry: reporting cumulative discontinuations
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.
| Characteristic | Unit | Double Blind Esomeprazole | Double Blind Placebo | Total |
|---|---|---|---|---|
| Participants analysed | 39 | 41 | 80 | |
| Age, Continuous | Months | 4.9 (SD 2.6) | 4.9 (SD 3.2) | 4.9 (SD 2.9) |
| Sex: Female, Male: Female | Participants | 9 | 14 | 23 |
| Sex: Female, Male: Male | Participants | 30 | 27 | 57 |
6. Primary Endpoint
The registry lists the primary outcome as Number of Participants Discontinuing Due to Symptom Worsening in the Randomized Treatment Withdrawal Phase (Treatment Withdrawal Phase Endpoint), measured over Treatment-withdrawal phase (up to 4 weeks following randomization, or until earlier discontinuation from the study).
| Element | Registry entry |
|---|---|
| Result type | Number |
| Measure of spread | not applicable |
| Unit | Participants |
| Endpoint classification | Binary Endpoint |
The primary endpoint was the number of participants who discontinued during the randomized double-blind withdrawal phase after meeting the prespecified definition of symptom-worsening criteria. The timeframe was up to 4 weeks following randomization, or until earlier discontinuation from the study. It is a count endpoint: it records how many participants experienced the specified event, rather than describing the intensity of symptoms or the time taken for symptoms to worsen.
A discontinuation endpoint can be useful when the event is defined in advance and relevant to the study question. In a withdrawal design, the count can describe how often participants met a criterion for worsening after assignment to continued active treatment or placebo. Interpretation depends on applying the same definition and observation process across groups. The registry record gives the endpoint definition, but does not report the group-specific primary counts or a comparative estimate, such as a risk difference or confidence interval.
The record labels the primary population as reporting cumulative discontinuations. It does not provide further detail about how repeated events, missing observations, or discontinuations for reasons other than symptom worsening were handled for this primary endpoint. Those details are not reported in the registry record.
7. Why No Re-analysis Is Shown
8. Statistical Interpretation
The registry record identifies a randomized comparison of continued esomeprazole with placebo after an open-label esomeprazole phase. That design frames the primary question as whether participants met the predefined symptom-worsening criteria and discontinued during the withdrawal period. However, the record does not report a numerical primary-outcome comparison. It therefore does not support a conclusion about the size, direction, or precision of a difference between the randomized groups on that endpoint.
The record lists 39 participants at risk in the double-blind esomeprazole group and 41 in the double-blind placebo group for adverse-event reporting. Those figures are not, by themselves, primary-outcome event counts, and should not be substituted for the missing primary results. The primary endpoint description specifies what was to be counted, not how many participants met the criterion in either group.
The study also lists secondary endpoints involving treatment success, physician assessment, and parent or guardian reports of vomiting or regurgitation, irritability, respiratory disturbances and feeding difficulties. These outcomes cover different aspects of symptoms and study response. Their inclusion does not establish that numerical findings were reported or that they agreed with one another. Numerical results for them are not reported in the registry record.
Randomization and masking are design features intended to support a fair comparison and limit the influence of expectations or knowledge of treatment assignment. They do not replace the need for observed outcome counts, a clearly described analysis, and an estimate of uncertainty. The registry record reports the randomized, quadruple-masked, parallel-group design, but does not report an inferential analysis of the primary endpoint. It also does not give a confidence interval or p-value for that comparison.
The safety information is separate from the efficacy endpoint. It reports serious and other adverse-event counts for the open-label and double-blind groups, with selected serious-event terms and percentages. These descriptive data can be read as recorded events in the specified groups, but the record does not provide a statistical comparison or enough context to interpret the figures as a causal treatment effect. The open-label phase and the randomized phase also represent different treatment settings, so their adverse-event figures should not be treated as direct arms of one randomized comparison.
Overall, the record supports a description of the study question, sequence and endpoint definition. It does not provide the numerical primary outcome needed to assess the observed randomized comparison. Conclusions about the magnitude or precision of an effect are therefore not reported in the registry record.
9. Statistical Methods Explained
Several statistical ideas help explain what this study’s design and endpoint can address. The distinction between a planned comparison, an observed outcome and an estimate of uncertainty is important: a study can specify a question and collect outcome information without the registry record presenting enough results to quantify the comparison.
What does randomization contribute?
In general, randomization assigns participants to treatment groups using a chance-based process. It is intended to make treatment assignment independent of participants’ measured and unmeasured characteristics, on average. This supports interpreting a between-group comparison as an effect of assignment, provided the trial is conducted and analyzed appropriately. Randomization does not guarantee that groups are identical, especially in a trial, and it does not correct missing outcome data, measurement problems or selective reporting. The registry record describes random assignment to continued esomeprazole or placebo in the withdrawal phase; it does not provide details of the randomization sequence or allocation concealment.
Why use a withdrawal design?
In general, a treatment-withdrawal design begins with an open-label treatment period and then randomizes participants to continue treatment or switch to a comparison condition. The randomized comparison concerns the subsequent withdrawal phase, not the initial open-label experience. Here, the record says all patients received esomeprazole during the open-label phase, with dose based on weight, and were then assigned to their dose or placebo. A result from such a comparison would describe the randomized phase among the participants who entered it; it should not automatically be interpreted as a comparison in all infants with GERD. The record does not explain participant progression from open-label treatment to randomization or report detailed eligibility criteria for that transition.
What does masking help control?
In general, masking can reduce bias in treatment delivery, symptom assessment, reporting and decisions to discontinue. The registry describes the study as quadruple-masked and says the physician, parent and patient would not know whether esomeprazole or placebo was being taken during the double-blind phase. The identity of every role included in the quadruple-masking label is not reported in the registry record. Masking cannot ensure that all outcomes are measured without error, and it does not establish that masking remained intact.
How should a count endpoint be analyzed?
In general, a count endpoint records the number of participants who meet an event definition. To compare randomized groups, an analysis can report group-specific counts and denominators, then estimate a contrast with uncertainty. Depending on the endpoint and analysis plan, a comparison might use a difference in event proportions or another suitable measure. A confidence interval describes the range of values compatible with the data and statistical model at a stated confidence level; it conveys precision, not the probability that a particular treatment effect is true. The registry record defines symptom-worsening discontinuation as the primary event, but does not report its group counts, a comparative estimate or a confidence interval.
The endpoint is cumulative over the withdrawal period, with a stated maximum follow-up of 4 weeks after randomization or earlier discontinuation. In general, event counts over a fixed observation period require attention to whether each participant had comparable opportunity for observation. Earlier discontinuation can affect how outcomes are observed, and its handling should be specified in the analysis plan. The registry record does not report enough analysis detail to determine how observation time or early discontinuation was handled in the primary analysis.
What does a planning calculation mean?
In general, a sample-size calculation is a planning exercise based on assumptions about the effect to detect, statistical significance level, allocation and analysis method. It is not an observed result and is not a measure of the trial’s observed power. The stated planning assumptions for this study describe a two-sided significance level of 0.05, equal allocation between arms, a normal approximation, and effects expressed as fractions of an observed effect. These assumptions describe an illustrative calculation, not necessarily the trial’s own design rationale. The sample-size justification and the trial’s own statistical plan are not reported in the registry record. No numerical planning results are reported in the registry record.
In general, over-dispersion matters when count data vary more than a chosen model expects; ignoring it can make uncertainty estimates too small. The primary endpoint is described as a participant count, not a rate of recurrent events, and the record does not report an over-dispersion model or a need for one. This illustrates why the outcome definition and analysis model must be considered together rather than inferred from the word “count” alone.
Finally, statistical significance and clinical importance are different concepts. A small estimated difference can be precisely estimated, while a larger estimate can be uncertain; interpretation depends on the estimate, its uncertainty and the clinical context. Since the primary comparative estimate and its uncertainty are not reported in the registry record, neither statistical significance nor clinical importance can be assessed from that record.
10. Multiplicity, Missing Data and Analysis Populations
The registry record lists a primary endpoint and multiple secondary outcomes. These include discontinuation for any reason, treatment success, physician global assessment, and parent or guardian assessments of several symptom domains. When a study evaluates multiple outcomes, the chance of at least one apparently notable result can increase if each is tested without an adjustment or a prespecified hierarchy. In general, a statistical plan can address multiplicity by defining a primary outcome, ordering tests, adjusting significance thresholds, or treating secondary outcomes as descriptive. The registry record does not report a multiplicity strategy or a statistical testing hierarchy.
The record identifies the primary endpoint as cumulative discontinuations meeting symptom-worsening criteria, but the primary result is not presented as a single numerical comparison. It states that the primary outcome has several categories or time points and is not reduced to one comparison. The registry record does not explain those categories or time points further, or identify which contrast would be considered primary for inferential testing.
Missing-data handling is not reported in the registry record. In general, missing observations can affect a result when the probability of having an observed outcome is related to treatment assignment or the outcome itself. The handling of early withdrawal, incomplete symptom assessments, and participants who do not complete follow-up can therefore matter, especially for an endpoint based on discontinuation and a defined follow-up period. The record does not describe imputation, sensitivity analyses, or rules for classifying incomplete observations.
Analysis populations are also not described in sufficient detail to determine which participants were included in each outcome analysis. The registry reports enrollment and phase-specific safety denominators, but it does not identify an intention-to-treat or per-protocol population for the primary endpoint. It also does not report a protocol-based analysis plan or interim-analysis information. These details are not reported in the registry record.
11. Safety Results
The registry reports serious adverse events as affected participants divided by participants at risk.
| Arm | Participants with serious adverse events | Participants at risk | Percentage |
|---|---|---|---|
| Open-label Phase | 4 | 98 | 4.1% |
| Double Blind Esomeprazole | 3 | 39 | 7.7% |
| Double Blind Placebo | 0 | 41 | 0.0% |
Other (non-serious) adverse events
Participants with at least one non-serious event at or above the registry's 1% reporting threshold.
| Arm | Participants affected of at risk |
|---|---|
| Open-label Phase | 26 of 98 |
| Double Blind Esomeprazole | 19 of 39 |
| Double Blind Placebo | 20 of 41 |
Most frequent serious adverse event terms
| Event term | Organ system | Open-label Phase | Double Blind Esomeprazole | Double Blind Placebo |
|---|---|---|---|---|
| Chlamydial Infection | Infections and infestations | 1 of 98 | 1 of 39 | 0 of 41 |
| Apnoea | Respiratory, thoracic and mediastinal disorders | 0 of 98 | 1 of 39 | 0 of 41 |
| Bronchospasm | Respiratory, thoracic and mediastinal disorders | 0 of 98 | 1 of 39 | 0 of 41 |
| Failure To Thrive | Metabolism and nutrition disorders | 1 of 98 | 0 of 39 | 0 of 41 |
| Poor Peripheral Circulation | Vascular disorders | 0 of 98 | 1 of 39 | 0 of 41 |
| Respiratory Syncytial Virus Bronchiolitis | Infections and infestations | 0 of 98 | 1 of 39 | 0 of 41 |
| Rotavirus Infection | Infections and infestations | 1 of 98 | 0 of 39 | 0 of 41 |
| Urinary Tract Infection | Infections and infestations | 1 of 98 | 0 of 39 | 0 of 41 |
Most frequent non-serious adverse event terms
| Event term | Organ system | Open-label Phase | Double Blind Esomeprazole | Double Blind Placebo |
|---|---|---|---|---|
| Upper Respiratory Tract Infection | Infections and infestations | 5 of 98 | 6 of 39 | 4 of 41 |
| Pyrexia | General disorders | 4 of 98 | 5 of 39 | 3 of 41 |
| Cough | Respiratory, thoracic and mediastinal disorders | 3 of 98 | 3 of 39 | 4 of 41 |
| Rhinitis | Infections and infestations | 3 of 98 | 4 of 39 | 3 of 41 |
| Bronchitis | Infections and infestations | 4 of 98 | 3 of 39 | 2 of 41 |
| Diarrhoea | Gastrointestinal disorders | 3 of 98 | 4 of 39 | 2 of 41 |
| Nasopharyngitis | Infections and infestations | 2 of 98 | 4 of 39 | 3 of 41 |
| Teething | Gastrointestinal disorders | 4 of 98 | 3 of 39 | 2 of 41 |
| Constipation | Gastrointestinal disorders | 1 of 98 | 1 of 39 | 4 of 41 |
| Vomiting | Gastrointestinal disorders | 2 of 98 | 2 of 39 | 2 of 41 |
Serious events with the highest arm-level rate: apnoea (2.6%), bronchospasm (2.6%), chlamydial infection (2.6%), poor peripheral circulation (2.6%), respiratory syncytial virus bronchiolitis (2.6%).
The serious adverse-event figures are descriptive counts among participants recorded at risk in each phase or group. In the open-label phase, 4 of 98 participants were recorded as affected by serious adverse events, and 26 of 98 were recorded for other adverse events. In the double-blind esomeprazole group, the corresponding counts were 3 of 39 and 19 of 39. In the double-blind placebo group, they were 0 of 41 and 20 of 41. These are counts, not comparative estimates, and no new percentages are calculated.
The listed serious-event terms include Apnoea, Bronchospasm, Chlamydial Infection, Poor Peripheral Circulation and Respiratory Syncytial Virus Bronchiolitis, each recorded as 2.6%, and Failure To Thrive, recorded as 1.0%. The denominator and calculation basis for these term percentages are not reported in the registry record. These terms should not be read as a complete description of all safety outcomes or as proof that a particular treatment caused an event.
The open-label figures come from a different phase than the randomized groups, so they are not a randomized comparison with either double-blind group. The record does not report a statistical comparison of adverse-event rates, exposure-adjusted rates, or a detailed account of event timing. The safety figures describe what the registry lists, while leaving uncertainty about comparative safety unquantified.
12. What the Result Does, and Does Not, Mean
The study’s design addresses a specific question: among participants who entered the randomized withdrawal phase after open-label esomeprazole, how many discontinued after meeting the symptom-worsening definition when assigned to continue esomeprazole or receive placebo? The registry record defines that endpoint and describes the treatment sequence. It does not report a numerical primary comparison, so the observed direction and magnitude of any difference cannot be stated from this record.
This absence of a reported comparison is not evidence that the groups had identical outcomes. It also is not evidence that one treatment produced more symptom-worsening discontinuations. Without group-specific primary counts and a suitable estimate of uncertainty, neither claim is supported. The record likewise does not provide a p-value or confidence interval for the primary comparison.
The study’s secondary outcomes could add information about treatment success, physician assessments and parent or guardian reports, but their names alone do not indicate their results. Numerical findings for those outcomes are not reported in the registry record. They cannot be used to fill the gap in the primary-outcome comparison.
The safety record shows serious and other adverse-event counts for the open-label and double-blind groups. These counts can be described as recorded, but they do not establish a causal effect or provide a complete comparative safety assessment. The open-label group and randomized groups differ in study phase, and the record does not provide comparative analyses or detailed exposure information.
More broadly, a completed study does not necessarily have a complete results record. The registry gives useful information about the question, design, endpoints and some safety reporting, but it does not report the primary efficacy comparison or enough analysis detail to assess its precision. Any conclusion should remain limited to those documented details.
13. Why This Trial Matters Statistically
This trial is statistically informative as an example of how design determines the population and question to which a result would apply. The open-label esomeprazole phase preceded randomization, so the randomized withdrawal comparison is distinct from a trial that randomizes participants before any study treatment. If outcomes were available, they would speak to the assigned treatments during the withdrawal phase among participants who reached randomization, rather than automatically describing every infant with GERD.
The primary endpoint also illustrates why a precise operational definition matters. “Discontinuation due to symptom worsening” combines a clinical worsening criterion with a decision to discontinue. Both the criterion and the process for applying it influence what is counted. Masking can help limit differences in assessment and decision-making, but a clear report of outcome counts and analysis methods is still needed to judge the comparison.
The registry record gives a defined follow-up timeframe and identifies randomized groups, but it does not give the primary comparative estimate. This gap matters statistically because a design alone cannot show the observed treatment contrast or its uncertainty. Reporting group-specific outcomes, denominators, analysis populations and missing-data methods is necessary to distinguish a result from a research question.
The record’s safety figures offer another useful distinction: descriptive adverse-event counts are not the same as a comparative causal analysis. The open-label phase and randomized phase should be interpreted in their own contexts. Overall, this study demonstrates why readers need endpoint definitions and design information alongside numerical results and transparent analysis reporting.
14. 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 principal limitation for interpreting efficacy is that the registry record does not report a numerical result for the primary endpoint. It defines symptom-worsening discontinuation and its follow-up period, but gives no group-specific primary counts, comparative estimate, confidence interval or p-value. As a result, the magnitude, direction and precision of the randomized comparison cannot be assessed.
The primary outcome is described as having several categories or time points and is not reduced to one comparison. The registry record does not explain those categories or identify a single contrast for interpretation. Analysis methods, analysis populations, missing-data handling and sensitivity analyses are not reported in the registry record. The multiplicity strategy and any interim analyses are also not reported in the registry record.
The study sequence limits the scope of the randomized question: screening and open-label esomeprazole preceded randomization to continued esomeprazole or placebo. Participant progression between phases, reasons for not entering randomization, and detailed eligibility criteria are not reported in the registry record. The recorded enrollment and adverse-event denominators do not replace a participant-flow account or establish the denominator used for every efficacy outcome.
The safety data are limited to the adverse-event counts and selected serious-event terms recorded. The basis for the term percentages, exposure duration by group, event timing, and comparative safety analysis are not reported in the registry record. The listed counts should therefore be treated as descriptive rather than as a complete evaluation of comparative safety.
15. Related Tutorials
16. Related Statistical Calculators
17. Sources
- ClinicalTrials.gov: Phase 3/Safety & Efficacy of Esomeprazole in Infants — NCT00468559.
- Registry record last updated 2014-06-02; status last verified 2014-04.
- Results first posted 2014-06-02.
- 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.
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18. Record Summary
The registry describes a completed Phase 3 randomized, quadruple-masked, parallel-group, placebo-controlled withdrawal study of esomeprazole in infants aged 1 to 11 months, inclusive, with GERD. Screening and an open-label esomeprazole phase preceded randomization to continued esomeprazole or placebo. Enrollment is recorded as 98.
The primary endpoint was the number of participants discontinuing after meeting symptom-worsening criteria during the withdrawal phase, up to 4 weeks following randomization or earlier discontinuation. The registry record does not report a single numerical primary comparison or its uncertainty. Secondary outcomes are listed without numerical results in the record.
Safety counts are reported for the open-label phase and the two double-blind groups, along with selected serious-event terms. Those figures are descriptive and do not constitute a comparative safety analysis. Details about missing data, analysis populations, multiplicity and the statistical plan are not reported in the registry record.