Candesartan Effect in Second Stage Arterial Hypertension: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Candesartan Effect in Second Stage Arterial Hypertension (NCT00621153), a randomized phase 4 study. The primary outcome is Changes in Mean Sitting DBP From Baseline After 4 Weeks of Therapy.

2. Clinical Question

This is a question about a continuous blood-pressure measurement and its average change over a specified treatment period. The outcome is not the proportion of participants reaching a blood-pressure target, nor does it summarize changes across the full 8-week study. The registry lists target attainment and several other measures as secondary outcomes, including systolic blood pressure, hs-CRP, adverse events, and compliance. Numerical analyses for those secondary outcomes are not reported in the registry record.

The result therefore addresses the registered four-week mean-change comparison in the two groups represented in the primary outcome data. It does not, by itself, answer every question about the study’s secondary outcomes, longer follow-up, or the additional regimen descriptions in the record.

3. Trial Design

The study is identified as a Phase IV, randomized, open-label, parallel-group trial. Its official title describes a two-arm, multicentre study with an 8-week duration. The record lists 214 participants and a completed status. The study start is recorded as 2008-02 and primary completion as 2009-03.

The primary outcome is assessed after 4 weeks, even though the study duration is described as 8 weeks. Participants in the reported comparison were assigned to candesartan cilexetil 16 mg/HCT combination therapy or candesartan cilexetil 16 mg monotherapy. The two primary-result groups contain 111 and 113 participants, respectively. The record identifies randomized allocation but does not report the method used to generate or conceal the allocation sequence.

Open-label means the registry identifies no masking. Knowledge of treatment assignment can matter when outcomes involve judgment or participant and clinician behavior. The primary endpoint is a measured blood-pressure change, but the registry does not describe measurement procedures, assessor masking, or safeguards against influence from treatment knowledge. Those details are not reported in the registry record.

The record’s arm descriptions also include candesartan cilexetil 32 mg monotherapy and candesartan cilexetil 32 mg/HCT combination therapy. However, the official title specifies a two-arm comparison, and the posted primary outcome results identify only the 16 mg combination and 16 mg monotherapy groups. How the additional arm descriptions relate to the reported two-group study is not reported in the registry record. The primary result should therefore be read as the comparison actually represented by the posted outcome values, not as evidence about the additional regimens.

The sponsor is AstraZeneca. No details of the randomization procedure, adherence to assigned therapy, participant flow, or protocol deviations are reported in the registry record. Those omissions limit assessment of how participants entered the analysis and how closely the reported comparison reflects the planned randomized groups.

4. Participant Flow and Accounting

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

Overall Study

Reasons for not completing this period:

5. Baseline Characteristics

The table reproduces the baseline characteristics posted in the registry, which describe the participants analysed at baseline and help show whether the randomized groups were comparable.

6. Primary Endpoint

The registry lists the primary outcome as Changes in Mean Sitting DBP From Baseline After 4 Weeks of Therapy, measured over 4 weeks.

The primary endpoint is change from baseline in mean sitting diastolic blood pressure after 4 weeks of therapy, measured in mmHg. Diastolic blood pressure is the lower of the two blood-pressure values. The registry describes the outcome as the mean change and reports least-squares means for the two groups. A negative change indicates that the measured value at follow-up was lower than baseline; the reported group changes are -17.0 mmHg and -14.1 mmHg.

A change-from-baseline endpoint uses each participant’s starting measurement as a reference, then summarizes the follow-up change across a group. In general, this can make the treatment-period contrast easier to interpret than comparing follow-up values alone, because it explicitly describes movement from baseline. The registry does not report baseline group summaries or explain how the least-squares means were adjusted, so the extent to which baseline values or other covariates contribute to these estimates is not stated.

Mean change is useful for describing the average response on a continuous scale. It does not show the distribution of individual changes, the number of participants whose measurements increased, or how many reached a specified target. Those are distinct questions. The registry lists target attainment as a secondary outcome, but numerical results for that outcome are not reported in the registry record. The primary endpoint is specifically a four-week result; the posted primary estimate is not an eight-week estimate.

7. Results Posted in the Registry

• Candesartan Cilexetil Monotherapy: mean -14.10 versus -17.00 on control; difference 2.90 (95% CI 2.67 to 3.13), standardized effect d = 3.28; z-test p = <0.001.

8. Statistical Interpretation

9. Statistical Methods Explained

What does a mean change represent?

The endpoint is a continuous measure, expressed in mmHg. A participant’s change is the follow-up measurement relative to baseline; the group estimate summarizes changes for participants in that group. Negative values indicate a decrease from baseline. In general, a group mean is a compact description of the center of the observed changes, but it does not tell how changes were distributed among individuals. Participants may have had different experiences even when their group average is similar.

The record reports least-squares means. In general, a least-squares mean is a model-based group estimate, often adjusted for variables included in an analysis model. The name alone does not identify which variables were included, how the model was specified, or how missing observations were handled. Those details are not reported in the registry record. The registry also lists standard deviations of 0.89 and 0.88, but does not explain how those spread measures relate to the least-squares means.

How should the group comparison be understood?

The reported comparison is a mean difference of 2.9 mmHg. It summarizes the contrast between the two group changes, rather than describing either group in isolation. Because the group estimates are -17.0 mmHg for combination therapy and -14.1 mmHg for monotherapy, the positive difference corresponds to monotherapy minus combination therapy in the posted comparison. The comparison is not a ratio, a percentage change, or a count of participants reaching a target.

The confidence interval from 2.668 to 3.132 and p-value of <0.001 are based on unadjusted recalculations from the posted summary statistics. The calculation uses an approximate pooled standard deviation, as indicated in the comparison details. It is not a substitute for a fully specified trial analysis. In general, an unadjusted calculation describes the contrast under its own assumptions; an analysis that accounts for a design or model can yield a different estimate or uncertainty. The registry does not report enough detail to reconstruct a model-based sponsor analysis.

What does a confidence interval add?

In general, a confidence interval gives a range of estimates compatible with the data and a stated statistical procedure. It reflects sampling uncertainty under that procedure; it does not capture every source of uncertainty. It cannot account automatically for bias from missing data, measurement practices, deviations from assignment, selective reporting, or an incorrectly specified model. The interval is for the reported unadjusted mean difference, not for every possible outcome or analysis.

A p-value is also conditional on a statistical model and a null hypothesis. In general, it describes how surprising data at least as inconsistent with the null would be if the null and model assumptions held. It is not a measure of effect size or clinical importance. The interval and p-value address different aspects of the same contrast: the interval conveys a range of plausible values under the calculation, while the p-value summarizes compatibility with a particular null value.

Why does variation matter?

In general, variability among individual measurements affects the uncertainty of an average and the number of participants needed to estimate or detect a group contrast. A standard deviation describes spread around a mean when its definition and calculation are appropriate for the data. The registry’s posted spread values are close to one another, and the comparison calculation uses an approximate pooled standard deviation of 0.885. Since the registry does not explain the derivation of the group spread values or the model behind the least-squares means, the precision calculation should be read as an approximation based on the posted summaries.

Over-dispersion is a general concern when observed variation is greater than a statistical model assumes. If a model understates variability, standard errors can be too small and intervals can be too narrow; if it overstates variability, estimates can be less precise than necessary. The registry does not report a dispersion assessment or model diagnostics, so no conclusion about over-dispersion in this trial can be drawn from the record.

What is and is not reported about the analysis?

The primary measure, time point, group summaries, and unadjusted comparison are reported. The registry does not report a complete statistical analysis plan, model specification, covariate adjustment, assumptions checks, missing-data method, or analysis population. It also does not report interim analyses or a multiplicity strategy. The fact that these items are absent from the registry record does not establish what was done in the full study documentation; it means their methods cannot be evaluated from this record.

The record names seven secondary outcomes, covering changes in systolic pressure, blood-pressure goal attainment, hs-CRP, adverse events, discontinuation due to adverse events, and compliance. It reports no numerical secondary analyses. When multiple outcomes or time points are considered, multiplicity is a general statistical issue: repeated tests can increase the chance of at least one apparently unusual result. The record does not say whether or how that issue was addressed, and the absent secondary estimates cannot be used to evaluate it.

In general, a randomized parallel-group design aims to compare groups formed by random assignment. Randomization can balance prognostic factors on average, but it does not guarantee identical groups in a particular trial, and its value depends on implementation and complete follow-up. The registry identifies randomized allocation but does not describe sequence generation, concealment, participant flow, or adherence. Those design features therefore cannot be assessed from the posted record.

10. Confidence Intervals and Precision

The unadjusted mean difference is 2.9 mmHg, with a 95% confidence interval from 2.668 to 3.132. This interval describes uncertainty around the contrast calculated from the posted summary statistics. It does not describe the range of individual participant responses, and it is not an interval for either group mean separately.

In general, a confidence interval is a range generated by a statistical procedure that would cover the underlying parameter at its stated rate over repeated studies, if the assumptions of the procedure held. It is not a guarantee that the true value lies within this particular interval, nor does it include all uncertainty about study design and conduct. The interval’s relatively narrow span indicates that the summary-statistic calculation is precise in relation to its own assumptions. It does not show that the assumptions are correct or that the result is free from bias.

The comparison uses an approximate pooled standard deviation of 0.885 and group sizes of 111 and 113. The record does not describe the model used to generate the least-squares means, the analysis population, or the handling of missing data. Those details matter when judging whether this interval is the appropriate representation of uncertainty for the intended trial analysis. The result should consequently be understood as an unadjusted recalculation, not as a documented model-based sponsor interval.

The p-value is <0.001. In general, a p-value and a confidence interval are related descriptions of evidence under a statistical model, but neither conveys clinical importance on its own. The interval gives a range for the contrast under the calculation; the p-value evaluates compatibility with a null contrast under its assumptions. Neither answers whether the estimate applies to other treatment regimens, time points, or populations.

11. Planning a Similar Trial: Sample Size

This is a planning illustration, not a re-evaluation of the original trial. It asks: if a new study wanted to detect a difference like the one observed, or a smaller one, how large would it need to be? It is deliberately not “observed power” of the finished trial, which is not a meaningful quantity.

Read the planning entries as participants per arm for 80% power and participants per arm for 90% power, not as total event counts. The planning assumptions are a two-sided significance level of 0.05, equal allocation between the two arms, and a normal approximation. Each row uses a stated fraction of the observed effect as the effect to detect. Time-to-event planning displays use total events, but this trial’s primary outcome is continuous, so its entries are participants per arm.

At 100% of the observed effect, the planning illustration gives 2 participants per arm for 80% power and 2 for 90% power. At 75% of the observed effect, it gives 3 per arm for 80% power and 4 for 90% power. At 50% of the observed effect, it gives 6 per arm for 80% power and 8 for 90% power. These are planning illustrations calculated from the observed contrast, not the trial’s original sample-size justification. The original design assumptions are not reported in the registry record.

In plain terms, the 80% column gives the estimated per-arm sample size for a design intended to have an 80% chance of detecting the specified effect under the stated assumptions. The 90% column describes the corresponding target at 90% power. The higher-power target generally requires more participants for the same assumed effect. Smaller effects also need more participants to distinguish them from random variation, which is why the entries increase as the assumed fraction of the observed effect becomes smaller.

These numbers are not observed power. They do not describe the probability that the completed trial’s result is true, and they are not the number actually enrolled. The study enrolled 214 participants; the primary outcome groups list 111 and 113. Very small planning values can result when the observed effect and estimated variability are used as inputs, so the illustrations should not be read as an independently justified design recommendation.

12. How the Sample Size Is Derived

Power is the probability that a study of a given size rejects the null hypothesis when a specific true effect exists. It depends on four things: the effect to detect, the variability of the outcome, the significance level (here a two-sided α of 0.05, so z_1−α/2 = 1.960) and the desired power (z_1−β = 0.842 for 80% and 1.282 for 90%).

Formula

n is the number of participants in each arm, Δ is the difference in means to detect and σ is the common standard deviation.

Worked calculation for this trial

1. Observed difference Δ = 2.900; pooled standard deviation σ = 0.885.
2. n = 2 × (1.96 + 0.842)² × 0.885² / 2.900² = 1.5, rounded up to 2 participants per arm for 80% power.

The smaller-effect rows in the table above repeat the same calculation with the effect multiplied by 0.75 and 0.5 (for ratios, applied to the logarithm of the ratio).

R code

alpha <- 0.05
z_a   <- qnorm(1 - alpha / 2)          # two-sided
delta <- 2.9                      # observed difference in means
sigma <- 0.884969078708556                     # pooled standard deviation
n_per_arm <- function(power, frac = 1) {
  ceiling(round(2 * (z_a + qnorm(power))^2 * sigma^2 / (delta * frac)^2, 6))
}
for (f in c(1, 0.75, 0.5))
  cat(sprintf("%3.0f%% of observed effect: n per arm = %s (80%% power), %s (90%% power)\n", 100 * f,
              format(n_per_arm(0.80, f), big.mark = ","), format(n_per_arm(0.90, f), big.mark = ",")))

# Check against R's built-in function (t-based, so very slightly larger)
cat("power.t.test:", round(power.t.test(delta = delta, sd = sigma, power = 0.80)$n, 1), "\n")

# Simulation: exact two-sample t-test using simulated means and variances
set.seed(621153)
n    <- n_per_arm(0.80)
reps <- 20000
m_diff <- rnorm(reps, delta, sigma * sqrt(2 / n))             # difference in sample means
s2     <- sigma^2 * rchisq(reps, 2 * (n - 1)) / (2 * (n - 1))   # pooled sample variance
tstat  <- m_diff / sqrt(s2 * 2 / n)
cat(sprintf("Simulated power at n = %s per arm: %.3f (%d replicates)\n", format(n, big.mark = ","), mean(abs(tstat) > qt(0.975, 2 * (n - 1))), reps))

Output from running the code

100% of observed effect: n per arm = 2 (80% power), 2 (90% power)
 75% of observed effect: n per arm = 3 (80% power), 4 (90% power)
 50% of observed effect: n per arm = 6 (80% power), 8 (90% power)
power.t.test: 2.8 
Simulated power at n = 2 per arm: 0.437 (20000 replicates)

The simulation draws many sets of group means and variances at the planned sample size and counts how often the two-sample t-test rejects the null. It should land close to the target power; at very small required sample sizes it can fall below it, because the normal approximation is rough there.

13. Multiplicity, Missing Data and Analysis Populations

The registry identifies one primary outcome and seven secondary outcomes. The primary outcome is change in mean sitting diastolic blood pressure after 4 weeks. The secondary outcome descriptions include systolic-pressure changes, blood-pressure target attainment at 4 and 8 weeks, hs-CRP change, adverse events and discontinuation, and compliance. Numerical analyses for these secondary outcomes are not reported in the registry record.

Multiplicity is a general concern when several outcomes, time points, groups, or statistical tests are considered. If many tests are conducted, the chance of finding at least one apparently unusual result can rise even when there is no underlying difference. Statistical plans may define a hierarchy, adjust significance thresholds, or designate analyses as exploratory. The registry record does not report whether any such approach was planned or used. No multiplicity adjustment should be inferred from the primary result.

The record does not report missing-data amounts, reasons for missingness, imputation methods, or sensitivity analyses. It also does not identify whether the primary analysis included all randomized participants, only participants with an available four-week measurement, or another analysis population. Therefore, the role of incomplete follow-up in the reported estimate cannot be assessed.

Random allocation is reported, but the registry does not describe sequence generation, allocation concealment, participant flow, treatment adherence, or protocol deviations. These details are relevant to assessing a randomized comparison. The absence of these details in the registry record does not establish that the study lacked such procedures; it means their implementation cannot be evaluated from the registry information.

The outcome is reported as a least-squares mean, but the model, covariates, and handling of baseline values are not described. Interim analyses and stopping rules are also not reported in the registry record. Together, these omissions limit assessment of whether the posted unadjusted calculation reflects the prespecified primary analysis and how secondary findings, if analyzed, were interpreted.

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

The posted primary data show negative mean changes in both groups after 4 weeks: -17.0 mmHg for combination therapy and -14.1 mmHg for monotherapy. The reported unadjusted mean difference is 2.9 mmHg, with a 95% confidence interval from 2.668 to 3.132 and p < 0.001. This describes the contrast between the posted group averages, not the experience of every participant.

The result does not establish the value of the treatment comparison at 8 weeks. Although the study is described as lasting 8 weeks and the registry lists secondary outcomes at that time point, numerical eight-week results are not reported in the registry record. The primary estimate is specific to the four-week assessment.

The primary result also does not establish how many participants reached a blood-pressure target. Target attainment is a separate secondary outcome in the registry, and its numerical result is not reported. The same is true of systolic pressure, hs-CRP, compliance, and the listed adverse-event outcomes. Those questions cannot be answered by substituting the primary mean-change result.

In general, a statistically small p-value does not establish the importance of an effect for patients or guarantee that an estimate will recur in another study. The confidence interval describes precision under the unadjusted calculation, not all sources of uncertainty. The record does not provide a stated threshold for interpreting the size of the mean difference or details needed to evaluate the model-based primary analysis.

The open-label design and absence of information about measurement procedures, participant flow, missing data, and analysis populations are relevant limitations when interpreting the result. The registry’s additional 32 mg regimen descriptions are not part of the posted primary comparison, so the result should not be extended to those regimens. The data describe the reported contrast in the two listed groups; broader conclusions about other outcomes, regimens, durations, or populations are not supported by this primary result alone.

15. Why This Trial Matters Statistically

This trial illustrates the distinction between a registered clinical question and the information available to evaluate its statistical answer. The registry identifies a randomized, open-label, parallel-group comparison and a continuous primary endpoint. It also gives group estimates, group sizes, a mean difference, an interval, and a p-value. These elements allow readers to understand the direction and precision of the posted four-week contrast.

At the same time, the result highlights why a p-value is not a complete analysis. The comparison is an unadjusted recalculation from summary statistics, while the endpoint is described as a least-squares mean. The registry does not explain the model behind those means or identify the analysis population. A clear distinction between the reported endpoint and the calculation used to compare it is important for interpreting how closely a result represents a prespecified analysis.

The record also illustrates the limits of incomplete outcome reporting. Several secondary outcomes are named, but their numerical analyses are not reported. Without those results, readers cannot assess whether the primary outcome was considered alongside other measures or what was found at the later time point. Likewise, adverse-event counts appear without denominators, limiting interpretation of how frequently events occurred in each group.

Finally, the planning illustration is based on the observed effect and stated assumptions; it is not the trial’s original design justification. That distinction matters because a planning exercise based on an observed result answers a different question from a prospective sample-size calculation. Separating design information, posted results, and retrospective illustrations helps keep statistical interpretation tied to what the registry actually documents.

16. 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 registry record contains an apparent difference in scope between its two-arm official title and the arm descriptions, which also name 32 mg monotherapy and combination regimens. The posted primary results include the 16 mg combination and 16 mg monotherapy groups only. The relationship of the additional descriptions to the reported comparison is not reported in the registry record, so no conclusions about those regimens can be drawn from the primary data presented.

The group results are labeled least-squares means, but their model specification and adjustment variables are not reported. The comparison interval and p-value are unadjusted recalculations based on posted summary statistics, with an approximate pooled standard deviation. The registry does not provide participant-level data or enough information to reproduce a full model-based analysis.

The record reports group sizes for the primary outcome but does not report participant flow, missing measurements, exclusions, or analysis populations. It is therefore unclear from the registry whether the listed group sizes correspond to all randomized participants or only those contributing to the outcome. Missing-data handling and sensitivity analyses are not reported.

Adverse-event reporting is also limited. The registry lists serious adverse-event counts of 1 and 2 and other adverse-event counts of 6 and 3 for the two groups, but the numbers at risk are not reported. Death counts are not reported. Three serious-event terms are listed with 0.9% each: Anal fistula, Breast clacifications, and Scrub typhus. Without denominators and fuller event definitions, these entries do not provide a complete comparative safety analysis.

The study is open-label, and masking or measurement safeguards are not described. The registry also does not report a full statistical analysis plan, the trial’s original sample-size justification, interim analyses, or multiplicity handling. These limitations concern what can be evaluated from the registry record and should not be taken as proof that procedures or analyses were absent from other study documentation.

17. Related Tutorials

18. Related Statistical Calculators

19. Sources

• ClinicalTrials.gov: Candesartan Effect in Second Stage Arterial Hypertension — NCT00621153.
• Registry record last updated 2010-03-23; status last verified 2009-04.
• Results first posted 2010-03-23.
• 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.

20. Record Summary

NCT00621153 is a completed Phase IV randomized, open-label, parallel-group study sponsored by AstraZeneca. The record describes an 8-week study in adults with stage II hypertension and an enrollment of 214. Its primary endpoint is change in mean sitting diastolic blood pressure after 4 weeks.

The posted primary comparison reports 111 participants in the candesartan cilexetil/HCT combination group and 113 in the candesartan cilexetil monotherapy group. Mean changes are -17.0 mmHg and -14.1 mmHg, respectively. The unadjusted mean difference is 2.9 mmHg, with a 95% confidence interval from 2.668 to 3.132 and p < 0.001.

The registry names seven secondary outcomes but reports no numerical analyses for them. Analysis-population details, missing-data methods, the model specification, and the original sample-size justification are not reported in the registry record.