Azilsartan/Amlodipine Combination Tablets LD & HD Specified Drug-use Survey "Long-term Use Survey": Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Azilsartan/Amlodipine Combination Tablets LD & HD Specified Drug-use Survey "Long-term Use Survey" (NCT02181816), a registered phase not stated study. The primary outcome is Percentage of Participants Who Had One or More Adverse Events.

2. Clinical Question

3. Trial Design

This completed study is a specified drug-use survey titled “Long-term Use Survey” for azilsartan/amlodipine combination tablets. The registry describes its purpose as evaluating safety and efficacy during long-term use in hypertensive patients in daily medical practice. Takeda is listed as the sponsor. The recorded start date is 2014-06-26, and the primary completion date is 2017-01-31.

The treatment description specifies oral use once daily of either 20 mg/2.5 mg or 20 mg/5 mg tablets for up to 12 months, with treatment given as part of routine medical care. The registry does not describe random assignment, and allocation is not stated. It does not identify a comparator. Consequently, the design information supports describing a treatment-exposed survey population, not a controlled contrast between treatment groups.

The registry lists enrollment of 1090. Its primary outcome is the percentage of participants who had one or more adverse events, assessed up to Month 12. The safety analysis set is defined as all participants who completed the study. The record does not explain the relationship between the enrollment figure and that analysis-set definition, or give a participant flow account explaining who completed follow-up.

Systolic office blood pressure and diastolic office blood pressure are listed as secondary outcomes. The registry record does not report numerical results for these outcomes in the registry record. It also does not state the visit schedule, details of clinical assessments, adherence procedures, or how changes in routine treatment were handled. Those omissions limit assessment of both follow-up and the way care may have varied across participants.

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: Participants with a historical diagnosis of hypertension were enrolled. Participants received interventions as part of routine medical care.

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: Safety Analysis Set; The safety analysis set was defined as all participants who completed the study.

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: Safety Analysis Set; The safety analysis set was defined as all participants who completed the study.

6. Primary Endpoint

The registry lists the primary outcome as Percentage of Participants Who Had One or More Adverse Events, measured over Up to Month 12.

The primary endpoint is the percentage of participants who had one or more adverse events up to Month 12. It is a binary participant-level measure: each participant is classified according to whether at least one event was recorded during the stated period. A participant with multiple events still contributes to the endpoint as a participant with one or more events; the endpoint is not a count of all event episodes.

This kind of measure is used to describe how common an event experience was in a defined group over a specified period. It can provide a broad summary of safety observations during treatment in routine practice. It does not, by itself, describe the type, severity, timing, duration, or clinical consequences of every event. Nor does it show whether an event was caused by the treatment.

The registry specifies that the safety analysis set includes participants who completed the study. That definition matters because an endpoint percentage depends on which participants are included in its denominator. The record does not report the primary endpoint’s observed percentage in the registry record for this analysis. It also does not report a confidence interval or an endpoint-specific account of missing observations, so precision and the influence of incomplete follow-up cannot be assessed from the stated information.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

What does a percentage endpoint represent?

The primary outcome is a binary participant-level endpoint: whether a participant had one or more adverse events during the stated observation period. A percentage for this type of outcome describes the proportion of the defined analysis population meeting that condition. It differs from an event count because one participant can experience more than one event. The endpoint counts participants meeting the condition, not the number of event episodes.

The denominator is central to interpreting any such percentage. Here, the registry defines the safety analysis set as all participants who completed the study. A percentage calculated for that set would describe participants in that set, not automatically everyone enrolled. The registry lists enrollment of 1090 and separately gives 1031 at risk in the adverse-event fields, but does not explain the relationship between these figures. It would be inappropriate to infer reasons for the difference or to treat the two quantities as interchangeable.

How should uncertainty be assessed?

In general, a confidence interval expresses the range of values compatible with the observed data under a specified statistical method. It communicates sampling uncertainty and is not a guarantee that the true value lies in the interval. For a percentage, uncertainty depends in part on the number of participants contributing information and the event frequency. The registry entries for the primary endpoint do not report an observed percentage or confidence interval, so its statistical precision cannot be assessed.

A point estimate without an interval would also be incomplete for judging precision. Conversely, an interval would not remedy limitations in the design, such as the absence of a comparator or uncertainty about missing observations. Precision concerns random uncertainty under a model; validity also depends on how participants entered the analysis and how outcomes were captured.

What does the design allow?

The record describes use in routine medical care, does not state allocation, and does not identify a comparator. In general, an uncontrolled treatment-use survey can describe outcomes observed among people receiving the treatment, but it cannot isolate the treatment’s effect from other explanations. Patient characteristics, other care, and the circumstances that lead to treatment may also be related to outcomes. These are general interpretive cautions, not additional findings about this survey.

The registry lists a primary endpoint and two secondary outcomes: systolic and diastolic office blood pressure. It reports zero analyses in the record details. The numerical results for the blood-pressure outcomes and the primary endpoint are not reported in the registry record for this analysis. The listed serious and other adverse-event counts can be read descriptively, but no comparative effect estimate is available from the stated information.

What is the role of the planning assumptions?

In general, a sample-size calculation describes the number of participants that a proposed design might require under stated assumptions. The planning assumptions associated with this record specify a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation; the effect to detect is expressed as a fraction of the observed effect. The assumptions also distinguish time-to-event calculations, which use total events, from other calculations, which use participants per arm.

These are planning illustrations based on an observed effect, not the survey’s own design justification and not observed power. The registry record does not report the protocol’s sample-size justification. Since the design details describe no comparator or stated allocation, a two-arm planning framework should not be mistaken for the design that generated the survey results. No conclusion about required sample size follows from the assumptions alone.

Why can event categories be difficult to compare?

In general, adverse-event summaries may count participants, events, or event types, and those are not interchangeable quantities. A participant can contribute to more than one event category. The registry lists counts for serious adverse events, other adverse events, and deaths, but does not explain category overlap or provide a detailed event-level account. The counts should therefore be read as separate descriptive fields, not added together or treated as mutually exclusive groups.

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("Azilsartan/Amlodipine")
n      <- c(1031)
events <- c(86)
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  Azilsartan/Amlodipine  1031  86  8.3  6.7  10.2  6.8  10.2  6.8  10.2

11. Multiplicity, Missing Data and Analysis Populations

The registry names one primary outcome, the percentage of participants with one or more adverse events, and two secondary outcomes: systolic office blood pressure and diastolic office blood pressure. It reports zero analyses in the registry entries used for this analysis. Numerical results for the blood-pressure outcomes are not reported in the registry record, and the observed percentage for the primary endpoint is also not reported in the registry record.

Multiplicity concerns arise when several outcomes or statistical tests are considered. In general, testing multiple outcomes can increase the chance of at least one apparently notable result unless an appropriate strategy is specified. The registry record does not report a multiplicity adjustment or a strategy for interpreting the primary and secondary outcomes together. It also does not report interim analyses or a statistical analysis plan. No such procedures should be assumed.

Missing-data handling is not reported in the registry record. The primary safety population is defined as all participants who completed the study, but the record does not describe incomplete follow-up, reasons for non-completion, missing outcome values, or any imputation method. Without those details, it is not possible to determine how missing observations were handled or whether the completed-participant population differs systematically from the enrolled population.

The record does not report additional analysis populations or sensitivity analyses. These omissions limit evaluation of how robust the reported safety counts would be under alternative population definitions or assumptions about missing data.

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 0.5% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: bile duct cancer (0.2%), cholecystitis (0.2%), peritonitis (0.1%), pneumonia (0.1%), plasma cell myeloma (0.1%).

The registry lists 1031 at risk and 16 affected for serious adverse events in the azilsartan/amlodipine group. For other adverse events, it lists 1031 at risk and 15 affected. It also records 6 deaths. These figures should be treated as descriptive registry fields. The record does not explain whether participants could appear in more than one category, nor does it give causes of death or establish that deaths were related to treatment.

The listed serious-event terms are Bile duct cancer and Cholecystitis, each at 0.2%, and Peritonitis, Pneumonia, Plasma cell myeloma, and Renal cancer, each at 0.1%. These percentages are reported for the named terms. The record does not give further detail about event timing, severity beyond the serious classification, clinical course, or attribution. The percentages should not be interpreted as evidence that the treatment caused those conditions.

In general, safety counts describe events observed within a recorded population; they do not by themselves establish causation. There is no comparator in the registry record, and the definition of the primary safety analysis set is based on study completion. The available details do not support a comparison with another treatment or a complete assessment of safety beyond the listed fields.

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

The record describes a long-term drug-use survey of azilsartan/amlodipine combination tablets in hypertensive patients receiving routine medical care. It identifies the primary safety question, the observation period of up to Month 12, the treatment strengths, and selected adverse-event counts. It also lists office systolic and diastolic blood pressure as secondary outcomes. These details establish the scope of what the survey intended to assess.

The record does not report the numerical result for the primary percentage endpoint in the registry record for this analysis, nor does it report numerical results for the secondary blood-pressure outcomes. It therefore does not support a conclusion about the observed percentage of participants with one or more adverse events or the degree of blood-pressure change. The serious-event counts and listed terms are descriptive and do not provide a treatment comparison.

The absence of a stated comparator and allocation means that the survey cannot establish what would have happened to similar participants under another treatment or without this treatment. General differences between people receiving routine care can affect observed outcomes. In addition, the safety analysis set includes participants who completed the study, while the registry does not report how incomplete follow-up was handled.

The listed adverse-event information is not proof that treatment caused an event, and the record does not attribute the recorded deaths to treatment. Equally, the absence of detailed results in the registry entries cannot establish that an event did not occur. A treatment-use survey can contribute descriptive information about observed use, but causal and comparative conclusions require evidence that addresses the limitations of uncontrolled observation.

Accordingly, the most defensible reading is narrow: the registry documents a completed routine-care survey with a defined safety endpoint and selected safety counts. It does not provide a complete numerical account of the primary or secondary outcome results, and the design information does not support a controlled estimate of treatment effect.

14. Why This Trial Matters Statistically

This study illustrates why outcome definitions and analysis populations are essential when reading a safety percentage. “One or more adverse events” is a participant-level endpoint, whereas adverse-event counts can also refer to event episodes or categories. A percentage has meaning only in relation to its denominator and observation period. Here, the endpoint is defined through Month 12 and the safety analysis set is defined by study completion, but the registry does not report the primary percentage in the registry record for this analysis.

The record also illustrates the distinction between an observational description and a comparative treatment estimate. Routine-care data can describe events recorded among people receiving a treatment. Without a stated comparator and allocation, however, the observed outcomes cannot be separated from other differences among patients or care circumstances. That distinction matters whenever a registry summary is read as evidence about treatment effects rather than as an account of treatment use.

Another statistical issue is the relationship between enrollment and the analysis population. The registry lists enrollment of 1090 and gives 1031 at risk in the adverse-event fields, while defining the safety analysis set as participants who completed the study. The record does not reconcile these details. This makes participant flow and the handling of incomplete follow-up important questions, not quantities to infer from the listed counts.

Finally, the record lists multiple outcomes but reports zero analyses in the registry entries, with no reported multiplicity plan or missing-data method. These limitations affect how fully the results can be assessed. The survey is statistically informative as an example of why descriptive counts, denominators, population definitions, and comparative design must be considered together.

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 main design limitation is the absence of a stated comparator and allocation. The registry describes routine medical care and one intervention, so the record does not support a like-for-like treatment comparison. Any observed event experience may reflect factors other than treatment, and the survey cannot isolate a treatment effect from the available information.

The primary endpoint is defined for a safety analysis set consisting of participants who completed the study. The registry does not explain how completion was determined, how many participants had incomplete follow-up, why follow-up might be incomplete, or how missing outcome information was handled. It also does not explain the relationship between enrollment of 1090 and the 1031 at risk listed in the adverse-event fields. This prevents a complete assessment of the analyzed population.

The primary endpoint’s numerical percentage and its precision are not reported in the registry entries available for this analysis. Numerical results for the listed systolic and diastolic office blood pressure outcomes are also not reported. The event counts do not include the detailed timing, event-level descriptions, or attribution information needed to interpret individual categories fully. Causes of the 6 deaths are not reported in the registry record.

The record does not report the protocol’s sample-size justification, a statistical analysis plan, interim analyses, a multiplicity strategy, or sensitivity analyses. The planning assumptions are illustrative and do not establish how the survey was designed or analyzed. These limitations constrain assessment of precision, robustness, and causal interpretation; they do not establish that any particular result is biased or incorrect.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Azilsartan/Amlodipine Combination Tablets LD & HD Specified Drug-use Survey "Long-term Use Survey" — NCT02181816.
• Registry record last updated 2019-06-03; status last verified 2019-02.
• Results first posted 2019-06-03.
• 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

NCT02181816 is a completed specified drug-use survey of azilsartan/amlodipine combination tablets for hypertensive patients in daily medical practice. Takeda is listed as sponsor. The record lists enrollment of 1090, a start date of 2014-06-26, and primary completion on 2017-01-31. Treatment was oral once daily, at 20 mg/2.5 mg or 20 mg/5 mg, for up to 12 months as part of routine care.

The primary outcome is the percentage of participants with one or more adverse events up to Month 12. The safety analysis set is defined as all participants who completed the study. The registry also lists systolic and diastolic office blood pressure as secondary outcomes. It reports selected safety fields, including 16 affected among 1031 at risk for serious adverse events, 15 affected among 1031 at risk for other adverse events, and 6 deaths. The primary endpoint percentage, secondary outcome results, missing-data handling, and comparator are not reported in the registry record.