Candesartan Cilexetil / Hydrochlorothiazide Combination Tablets Special Drug Use Surveillance: Long-term Use (12 Months): Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Candesartan Cilexetil / Hydrochlorothiazide Combination Tablets Special Drug Use Surveillance: Long-term Use (12 Months) (NCT02016183), a registered phase not stated study. The primary outcome is Number of Participants Who Experience at Least One Adverse Drug Reactions (ADRs).

2. Clinical Question

The study asked how safety and blood pressure measures changed during routine clinical use of candesartan cilexetil/hydrochlorothiazide in people with hypertension. It was a surveillance study of long-term use, rather than a randomized comparison of the combination with another treatment or with no treatment. The primary outcome was the number of participants experiencing at least one adverse drug reaction during follow-up of up to 12 months.

3. Trial Design

The record identifies this as a special drug use surveillance study of long-term use in people with hypertension. The study was intended to evaluate safety and efficacy of candesartan cilexetil/hydrochlorothiazide in the routine clinical setting. Its status is completed. The recorded enrollment is 3222; the study start date is 2009-04-01 and the primary completion date is 2012-09-30.

There is one listed intervention: candesartan cilexetil/hydrochlorothiazide. Participants received 4 mg/6.25 mg or 8 mg/6.25 mg combination tablets orally once daily for up to 12 months, as part of routine medical care. A separate control treatment is not listed, and allocation is not stated. The record warns that the drug should not be used as a first-line drug for hypertension treatment. Those features distinguish this surveillance from a randomized trial designed to estimate a comparative treatment effect.

The primary outcome concerns participants experiencing at least one adverse drug reaction. Secondary outcomes are changes from baseline in systolic blood pressure, diastolic blood pressure, and pulse rate at each time point. Although those outcomes are identified, their numerical results are not reported in the registry record. The primary outcome's numerical result is also not reported in the registry record.

The record defines a safety analysis set as all participants who were enrolled and completed the study. The posted adverse-event figures use 3157 participants at risk in each of the serious and other event categories. The record does not explain the relationship between the enrollment count and those denominators or describe how participants with incomplete follow-up were handled. It also does not report the detailed schedule of measurements or the clinical procedures used to collect 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: Participants with a diagnosis of hypertension were enrolled to receive candesartan cilexetil/hydrochlorothiazide 4 mg/6.25 mg or 8 mg/6.25 mg combination tablets, orally, once daily for up to 12 months as per routine medical practice.

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: The safety analysis set was defined as all participants who were enrolled and 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: The safety analysis set was defined as all participants who were enrolled and completed the study.

6. Primary Endpoint

The registry lists the primary outcome as Number of Participants Who Experience at Least One Adverse Drug Reactions (ADRs), measured over Up to 12 months.

The primary endpoint is the number of participants who experienced at least one adverse drug reaction during follow-up of up to 12 months. The record defines an adverse drug reaction as an adverse event that, in the investigator's opinion, has a causal relationship to the study treatment. An adverse event is an unfavorable and unintended sign, symptom, or disease temporally associated with use of the medicinal product, reported from the first dose through the last dose.

This is a participant count: a person meeting the endpoint is counted as having experienced at least one qualifying reaction, rather than being counted once for every occurrence. Such an endpoint can provide a direct description of how many people had a reaction considered treatment-related by the investigator. It does not, by itself, describe the number, duration, severity, or clinical consequences of every event, and it does not establish that treatment caused an event with certainty.

The distinction between an adverse drug reaction and an adverse event matters when reading the posted safety information. The primary endpoint requires an investigator's causal judgment. The serious and other adverse-event figures are separate event-category summaries and should not be treated as the primary endpoint result. A numerical result for the primary outcome is not reported in the registry record.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The registry record identifies a participant-count endpoint and descriptive safety categories, but it does not report the statistical methods used to analyze the clinical outcomes. The explanations below describe general statistical concepts and how they relate to the information recorded, not methods confirmed to have been used in this study.

What does a participant count represent?

For a binary outcome such as whether a participant experienced at least one event, each participant is classified according to whether the event occurred. The count describes people with the outcome, not the total number of event episodes. A participant with several events may still count once for an endpoint defined as at least one event. The primary outcome is explicitly framed this way, but the registry record does not report its result.

A count is most interpretable alongside its denominator and a clear definition of the outcome. The posted adverse-event information gives 3157 at risk for the serious-event category and 3157 at risk for the other-event category. The safety analysis set is defined as participants who were enrolled and completed the study. The record does not report a separate analysis population definition for every outcome or explain how incomplete observation was managed.

Why distinguish adverse events from adverse drug reactions?

An adverse event is an unfavorable or unintended sign, symptom, or disease temporally associated with use of a medicinal product. Temporal association does not, by itself, establish causation. The primary endpoint narrows this concept to adverse events that the investigator considers causally related to treatment; those are termed adverse drug reactions in the record. This judgment is clinically assessed and may be subject to uncertainty. The serious and other adverse-event categories are not identified as equivalent to treatment-related reactions, so their counts answer a different descriptive question.

What can an uncontrolled surveillance design estimate?

In general, a single treated group can describe outcomes observed among participants receiving care in the setting studied. A comparator group can help distinguish changes associated with treatment from changes that might also occur without it, though comparisons still depend on design and analysis. Here, no separate comparator arm is listed, and allocation is not stated. As a result, the recorded counts do not constitute a randomized between-group treatment estimate. Routine clinical care may also include variation in care and follow-up, but the record does not describe those details.

How should uncertainty be assessed?

In general, an estimate is more informative when accompanied by a measure of uncertainty, such as a confidence interval. A confidence interval indicates the range of values compatible with the observed data under the analysis assumptions; it does not guarantee that the true value lies in that range. The registry record does not report confidence intervals or a statistical model for the primary outcome. It also does not report hypothesis tests or adjusted estimates. Therefore, precision cannot be assessed from a primary-outcome estimate in this record.

For count outcomes, the amount of information depends on both the number of participants observed and how often the event occurs. Follow-up duration and completeness also matter: participants observed for different lengths of time may have different opportunities for an event to be recorded. The study followed participants for up to 12 months, but the record does not report participant-level follow-up duration or a time-to-event analysis.

What does over-dispersion mean in general?

Over-dispersion occurs when observed variation in count data is greater than a statistical model assumes. If ignored, a model may understate uncertainty and make estimates appear more precise than warranted. It is a concern for some event-count analyses, especially when outcomes vary substantially across participants. The posted primary endpoint is a count of participants with at least one event, not a reported repeated-event count model. The registry record does not state that an over-dispersion model was used or needed.

What do the planning assumptions mean?

The record describes a sample-size 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; the target effect is expressed as a fraction of the observed effect. In general, such an illustration explores the sample size associated with a stated effect and assumptions. It is not evidence that the study was designed with those assumptions, and it is not observed power. The registry record does not report the study's own sample-size justification or a randomized two-arm design. The posted surveillance design has no listed comparator arm, so a two-arm planning illustration should not be mistaken for the actual study design.

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("Candesartan Cilexetil/Hydrochlorothiazide")
n      <- c(3157)
events <- c(283)
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  Candesartan Cilexetil/Hydrochlorothiazide  3157  283  9.0  8.0  10.0  8.0  10.0  8.0  10.0

11. Multiplicity, Missing Data and Analysis Populations

The record identifies one primary outcome and three secondary outcome types: changes from baseline in systolic blood pressure, diastolic blood pressure, and pulse rate at each time point. Assessing multiple outcomes or time points can raise multiplicity concerns. In general, when many statistical tests are considered, the chance of at least one apparently notable result can increase. Statistical plans may address this through prespecified testing hierarchies or adjustments, but such procedures cannot be assumed. The handling of multiplicity is not reported in the registry record.

The numerical findings for the primary outcome and the listed secondary outcomes are not reported in the registry record. The record lists no analyses. It does not state whether all scheduled measurements were collected, how missing measurements were handled, or whether analyses used imputation, complete cases, or another approach. These omissions make it difficult to assess possible bias from incomplete outcome data or to determine how reported results relate to the planned outcomes.

The safety analysis set is defined as participants who were enrolled and completed the study. The record does not explain how completion was determined, how many participants did not complete, or how they were treated in each analysis. The posted adverse-event categories list 3157 participants at risk, while enrollment is 3222; the record does not explain the relationship between those numbers. This should be treated as an unresolved reporting detail, not as evidence about why participants were not included.

In general, a clear analysis-population definition and an account of missing observations help readers judge how representative outcome estimates may be. Because these details and the statistical plan are not reported in the registry record, the robustness of any outcome analysis cannot be evaluated from the recorded information.

12. Safety Results

The registry reports serious adverse events as affected participants divided by participants at risk.

Other (non-serious) adverse events

Participants with at least one non-serious event at or above the registry's 2% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: pneumonia (0.2%), cerebral infarction (0.2%), cardiac failure (0.1%), fall (0.1%), lung neoplasm malignant (0.1%).

The serious adverse-event category lists 72 participants affected among 3157 at risk. The other adverse-event category lists 158 participants affected among 3157 at risk. These are separate descriptive categories in the posted results. They are not the primary adverse-drug-reaction endpoint, which requires the investigator to judge an adverse event causally related to treatment. The record does not say that all serious or other events were treatment-related.

The serious-event terms listed include Pneumonia and Cerebral infarction at 0.2% each. Cardiac failure, Fall, Lung neoplasm malignant, and Cerebral haemorrhage are each listed at 0.1%. These are term-level percentages; the record does not provide the corresponding term counts in the registry record for interpretation. Nor does it state whether one participant could appear under several terms. The listed percentages should not be added or treated as a participant-level total.

Seriousness is a classification of an event, not evidence that the study treatment caused it. In general, adverse events in an uncontrolled surveillance study can arise for many reasons, and a descriptive count does not establish comparative risk. The registry record does not report a control group, a causal analysis, or confidence intervals for these safety figures.

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

The record establishes that a completed routine-care surveillance study enrolled 3222 participants and followed the listed treatment for up to 12 months. It identifies a primary safety question about participants experiencing at least one adverse drug reaction and names blood pressure and pulse-rate changes as secondary outcomes. It also reports serious and other adverse-event counts among 3157 participants at risk in each category, along with percentages for several serious-event terms.

Those details do not answer every question a reader might have about safety or efficacy. The numerical result for the primary adverse-drug-reaction endpoint is not reported in the registry record. Numerical findings for changes in systolic blood pressure, diastolic blood pressure, and pulse rate are also not reported. The adverse-event counts do not replace these missing outcomes, because they describe different categories and do not establish treatment causation.

The study has no separate comparator arm listed, and allocation is not stated. It therefore cannot supply a randomized comparison with another treatment or with no treatment. The counts describe events observed in the surveillance cohort; without a control comparison, they do not show what would have occurred under an alternative approach. The record also does not report confidence intervals or a statistical analysis for the outcome figures, so the precision of a treatment-effect estimate cannot be assessed.

In general, a statistically careful reading separates what was recorded from what can be inferred. The reported event categories are useful as descriptive safety information, but they are not a causal estimate. Likewise, an outcome being named in the record does not mean that its result is available. The registry record supports a description of the study's stated questions, design features, and posted safety counts, while leaving the primary endpoint result, secondary outcome results, and several analysis details unreported.

14. Why This Trial Matters Statistically

This study is statistically informative as an example of the distinction between surveillance and comparative evaluation. Routine-care surveillance can document events occurring among people receiving a treatment in clinical practice. That kind of description has a different role from a randomized comparison, which is designed to estimate differences between assigned groups. Here, a comparator arm is not listed and allocation is not stated, so the posted counts should be read as descriptions rather than comparative treatment effects.

The endpoint definitions also matter. The primary question concerns adverse drug reactions, which require the investigator to judge a causal relationship. Serious and other adverse-event categories are separate summaries and cannot be presumed to represent treatment-related reactions. Keeping these outcomes distinct prevents a common interpretive error: treating every event observed during treatment as an effect caused by treatment.

The record illustrates why denominator and analysis-population details are important. Enrollment is 3222, the defined safety set includes enrolled participants who completed the study, and the adverse-event categories list 3157 at risk. The record does not explain the relationship between these figures. Without that explanation, readers should not infer a reason for the difference or assume all outcomes use the same population.

Finally, registered outcomes and reported outcomes are not interchangeable. Blood pressure and pulse-rate changes are named, but their numerical results are not reported. The primary outcome result is also not reported. This distinction is central to transparent interpretation: a study's questions and design can be described even when the corresponding estimates, uncertainty, or analysis methods are unavailable in the registry record.

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 limitations specific to this study constrain interpretation. First, the registry record does not list a comparator arm, and allocation is not stated. The surveillance therefore does not provide a like-for-like randomized comparison. Descriptive safety counts cannot establish that treatment caused an event or estimate how event frequency differs under another treatment.

Second, the numerical result for the primary endpoint, participants with at least one adverse drug reaction, is not reported in the registry record. The listed serious and other adverse-event counts are not interchangeable with that outcome. Numerical results for the secondary changes in systolic blood pressure, diastolic blood pressure, and pulse rate are also not reported, leaving the stated efficacy-related measurements uninterpretable from the record.

Third, the registry record does not report confidence intervals, statistical tests, detailed analysis methods, a sample-size justification for the study, or how multiplicity was handled. It does not describe missing-data procedures, participant flow through follow-up, or the relationship between enrollment of 3222 and 3157 participants at risk in the adverse-event categories. The safety analysis set is defined as participants who enrolled and completed the study, but the record does not explain completion or the treatment of participants who did not complete.

Finally, the primary endpoint depends on the investigator's opinion about causal relationship. That judgment is part of the endpoint definition, but the record does not give further details about how such judgments were made or reviewed. These limitations do not erase the descriptive safety information; they define what can and cannot be concluded from the recorded results.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Candesartan Cilexetil / Hydrochlorothiazide Combination Tablets Special Drug Use Surveillance: Long-term Use (12 Months) — NCT02016183.
• Registry record last updated 2018-11-09; status last verified 2018-04.
• Results first posted 2018-11-09.
• Data retrieved from ClinicalTrials.gov on 2026-11-09.
• Group sizes, means, event counts and sponsor-reported p-values are reproduced as posted. Effect estimates, confidence intervals and p-values not attributed to the sponsor are independently calculated from the posted summary statistics.

19. Record Summary

NCT02016183 is a completed special drug use surveillance study of candesartan cilexetil/hydrochlorothiazide in people with hypertension. It enrolled 3222 participants and evaluated use in routine clinical care for up to 12 months. The listed doses were 4 mg/6.25 mg or 8 mg/6.25 mg, orally once daily.

The primary outcome was the number of participants with at least one adverse drug reaction, defined through the investigator's judgment of causal relationship. Secondary outcomes were changes from baseline in systolic blood pressure, diastolic blood pressure, and pulse rate. Their numerical results, including the primary outcome result, are not reported in the registry record.

The posted safety information lists 72 participants in the serious-event category and 158 in the other-event category, with 3157 at risk in each. No separate comparator arm is listed, allocation is not stated, and statistical analysis details are limited. The figures are descriptive and do not establish comparative effects or treatment causation.