Efficacy and Safety of Once Daily Dosing of Aliskiren (300 mg (qd) Once a Day) to Twice Daily Dosing of Aliskiren (150 mg (Bid) Twice a Day) in Treating Moderate Hypertension.: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Efficacy and Safety of Once Daily Dosing of Aliskiren (300 mg (qd) Once a Day) to Twice Daily Dosing of Aliskiren (150 mg (Bid) Twice a Day) in Treating Moderate Hypertension. (NCT00654875), a randomized phase 4 study. The primary outcome is Change From Baseline to Week 6 in the Mean 24-hour Ambulatory Diastolic Blood Pressure (MADBP).

2. Clinical Question

3. Trial Design

This was a Phase 4, randomized, double-blind, parallel-group, multicenter study of aliskiren dosing schedules in participants with essential hypertension. The registry record describes a 10-week study and reports enrollment of 328. The listed study status is completed. The recorded start and primary completion dates are 2008-03 and 2008-11.

The two groups received active aliskiren regimens, with placebo tablets used to match the different dosing schedules. One group received aliskiren 300 mg once daily throughout the 10 weeks. The other received aliskiren 150 mg twice daily for the first 6 weeks. Its description then indicates a change for the next 4 weeks, but the full later-period dosing details are not reported in the registry record. This schedule matters when interpreting later outcomes: the primary comparison is at Week 6, while some secondary measures are reported at Week 10.

Randomization supports a comparison between assigned groups, and double masking is intended to limit influences from treatment knowledge on participants and study conduct. The parallel-group design means participants were assigned to a regimen rather than described as switching between regimens. The registry record does not report the randomization procedure, allocation concealment details, or which parties were masked beyond the recorded double masking.

The primary outcome was change from Baseline to Week 6 in mean 24-hour ambulatory diastolic blood pressure. The posted description says measurements were obtained with an ambulatory blood-pressure monitoring device attached to the non-dominant arm. The analysis used an analysis of covariance with Baseline mean 24-hour ambulatory diastolic pressure as a covariate. Secondary outcomes cover other ambulatory and sitting blood-pressure measures and blood-pressure control at Week 6 and Week 10. The record does not report the original sample-size justification or further design assumptions.

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:

Analysis population for the primary outcome, as defined in the registry: Participants from the Full analysis set (consisting of all randomized patients) for whom data was available at Baseline and Week 6.

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 Change From Baseline to Week 6 in the Mean 24-hour Ambulatory Diastolic Blood Pressure (MADBP), measured over Baseline, Week 6.

The primary endpoint is the change from Baseline to Week 6 in mean 24-hour ambulatory diastolic blood pressure, measured in mm Hg. Ambulatory monitoring collects readings over the daily period rather than relying on a single sitting measurement. The posted description states that the mean of readings over 24 hours was calculated and that Baseline and Week 6 values were used to derive the change.

Change scores express how the measurement at follow-up differs from the participant's Baseline value. Negative values in this study indicate a reduction in mean diastolic blood pressure relative to Baseline. The reported group values are least-squares means, which are model-based estimates rather than simple unadjusted averages. The registry record describes an analysis of covariance model with Baseline mean 24-hour ambulatory diastolic blood pressure as a covariate. Such adjustment accounts statistically for the Baseline measurement when estimating the Week 6 change.

A continuous endpoint preserves the size and direction of changes in the measured quantity, rather than reducing the result to whether a participant crossed a threshold. The 24-hour measure also corresponds to the study's interest in blood pressure across the dosing period. The registry record does not report a clinical threshold for interpreting the size of a change in this endpoint, nor does it state a minimum difference considered important. Statistical evidence about a group difference should therefore be read separately from judgments about clinical importance.

7. Results Posted in the Registry

• Aliskiren 150 mg (Twice a Day): mean -5.24 versus -4.10 on control; difference -1.14 (95% CI -2.86 to 0.58), standardized effect d = -0.16; z-test p = 0.194.

8. Secondary Efficacy Endpoints

The registry also posts results for secondary outcomes. For each outcome below, the endpoint type, the test applied to the posted summary statistics, the result and its interpretation are given in turn. Secondary endpoints are usually not adjusted for multiple testing, so they support rather than confirm the primary finding.

Change From Baseline to Week 6 in the Mean Ambulatory Diastolic Blood Pressure (MADBP) During the Last 3 Hours of the 24-hour Dosing Period

• Endpoint type: Continuous: a mean value per participant, compared as a difference in means.
• Test: Unadjusted two-sample z-test for the difference in means, using the posted standard errors.
• Result:
  • Aliskiren 150 mg (Twice a Day): mean -5.24 versus -5.03 on control; difference -0.21 (95% CI -2.40 to 1.98), standardized effect d = -0.02; z-test p = 0.851.
• Interpretation:
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between Aliskiren 150 mg (Twice a Day) and the control. The interval gives the range of effects that remain compatible with the data.

Change From Baseline to Week 6 in the Mean Ambulatory Systolic Blood Pressure (MASBP) During the Last Three Hours of the 24-hour Dosing Period

• Endpoint type: Continuous: a mean value per participant, compared as a difference in means.
• Test: Unadjusted two-sample z-test for the difference in means, using the posted standard errors.
• Result:
  • Aliskiren 150 mg (Twice a Day): mean -7.12 versus -6.39 on control; difference -0.73 (95% CI -3.70 to 2.24), standardized effect d = -0.06; z-test p = 0.630.
• Interpretation:
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between Aliskiren 150 mg (Twice a Day) and the control. The interval gives the range of effects that remain compatible with the data.

Change From Baseline to Week 6 in the Mean 24-hour Ambulatory Systolic Blood Pressure (MASBP)

• Endpoint type: Continuous: a mean value per participant, compared as a difference in means.
• Test: Unadjusted two-sample z-test for the difference in means, using the posted standard errors.
• Result:
  • Aliskiren 150 mg (Twice a Day): mean -7.44 versus -5.74 on control; difference -1.70 (95% CI -4.18 to 0.78), standardized effect d = -0.16; z-test p = 0.179.
• Interpretation:
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between Aliskiren 150 mg (Twice a Day) and the control. The interval gives the range of effects that remain compatible with the data.

The secondary endpoints broaden the view beyond the primary 24-hour ambulatory diastolic measure. They include blood pressure during the last 3 hours of the dosing period, ambulatory systolic pressure over that period, 24-hour ambulatory systolic pressure, sitting systolic and diastolic pressure, and blood-pressure control at Week 6 and Week 10. The posted continuous results show estimated reductions from Baseline in both groups for the reported ambulatory measures.

The recalculated between-group estimates for the secondary ambulatory measures are small relative to their uncertainty intervals, and each reported interval includes zero. This overall pattern is consistent with the primary result in the limited sense that the posted estimates do not show a precise separation between the schedules. It does not prove that the schedules have identical effects, and it does not establish that every secondary endpoint follows the same pattern. The registry record does not provide numerical results for the sitting-pressure and control outcomes in the posted secondary summaries.

These measures are secondary to the prespecified primary outcome as identified in the registry record. Multiple endpoints create multiple opportunities for a result to appear statistically notable by chance. The record does not report a multiplicity adjustment or a hierarchy for testing secondary outcomes. Consequently, unadjusted secondary p-values and isolated findings carry less confirmatory weight than a primary analysis with a prespecified statistical plan. They can describe patterns and motivate further questions, but should not be treated as independent proof of a treatment difference.

Time point and regimen are also relevant to interpretation. The primary result is at Week 6, while some listed outcomes are measured at Week 10. The twice-daily arm description indicates a regimen change after the first 6 weeks, but the complete dosing details for that later period are not reported in the registry record. Therefore, the later outcomes should not automatically be interpreted as a direct comparison of unchanged once-daily and twice-daily schedules throughout the study.

Secondary outcomes registered for this trial, for reference (only those above were recalculated):

• Change From Baseline to Week 6 in the Mean Ambulatory Diastolic Blood Pressure (MADBP) During the Last 3 Hours of the 24-hour Dosing Period
• Change From Baseline to Week 6 in the Mean Ambulatory Systolic Blood Pressure (MASBP) During the Last Three Hours of the 24-hour Dosing Period
• Change From Baseline to Week 6 in the Mean 24-hour Ambulatory Systolic Blood Pressure (MASBP)
• Change From Baseline to Week 6 in the Mean Sitting Systolic and Mean Sitting Diastolic Blood Pressure
• Percentage of Participants Achieving Blood Pressure Control at Week 6
• Percentage of Participants Achieving Blood Pressure Control at the End of the Study (Week 10)

9. Statistical Interpretation

10. Statistical Methods Explained

The primary result combines a model-adjusted estimate of change within each group with a comparison between the groups. The endpoint is continuous, and the reported group estimates are least-squares means with standard errors. The separate comparison described as recalculated is an unadjusted calculation from the posted summary statistics. These quantities answer related but distinct questions: the arm estimates describe change from Baseline, while the contrast estimates the difference between the arm changes.

What does the analysis of covariance do?

Analysis of covariance, often abbreviated ANCOVA, models an outcome while including a baseline measurement as a covariate. In this study, the registry description says that Baseline mean 24-hour ambulatory diastolic blood pressure was included in the model. Adjusting for Baseline can account for differences in starting measurements and can improve precision when baseline and follow-up values are related. The adjusted estimates are conditional on the model and its assumptions; they are not simply the raw averages of all recorded readings.

The registry record does not report the complete model specification, such as any additional covariates, the exact handling of missing outcome data, or diagnostic checks. The displayed least-squares means should therefore be interpreted as the estimates reported under the stated ANCOVA approach, without assuming further adjustments or modeling details. The record also does not report whether the model included any treatment-by-baseline term or other interaction.

What do the group changes and contrast mean?

A group change is the estimated Week 6 value relative to Baseline. Here the posted changes are negative, indicating that the group estimates are below their Baseline values. A difference between group changes puts the two schedules on the same scale. The reported comparison is oriented as twice-daily minus once-daily: a negative estimate means the twice-daily group has a more negative estimated change. The recalculated contrast is -1.14 mm Hg. Its direction is descriptive, while its interval and uncertainty determine how much evidence the data provide about a true difference.

Standard errors describe the estimated sampling variability of a statistic under the analysis. They are not the spread of individual participants' measurements. The primary arm standard errors are 0.6 and 0.64. They accompany the least-squares mean changes; they do not describe how much individual blood-pressure readings varied. A confidence interval uses uncertainty around an estimate to show a range of values compatible with the data and specified statistical procedure.

How should the p-value be read?

The primary comparison's unadjusted p-value is 0.194. In general, a p-value measures how unusual data at least as incompatible with a specified null hypothesis would be if that null hypothesis and the model assumptions held. It is not the probability that the null hypothesis is true, and it does not quantify the probability that a treatment effect is real. The value should be considered alongside the estimated difference and confidence interval, not used as a stand-alone measure of importance.

The word unadjusted is important because the record does not report an adjustment for the multiple outcomes or comparisons. A threshold applied to one test does not automatically account for the wider set of analyses. The registry record does not report a prespecified multiplicity procedure. General statistical guidance is that repeated testing can increase the chance of at least one apparently unusual result, so secondary p-values require cautious interpretation when multiplicity handling is unknown.

Why does over-dispersion matter for count outcomes?

Over-dispersion is a general issue for count data when the observed variability is greater than expected under a simple model. In such settings, standard errors can be too small if the extra variation is ignored, making intervals too narrow and tests appear more conclusive than warranted. The primary endpoint in this study is a continuous blood-pressure change, not a count outcome, so over-dispersion is not the main concern for its stated analysis. The registry record does not report a count-based efficacy endpoint requiring an over-dispersion adjustment.

What limits the recalculated comparison?

The comparison labeled recalculated is based on posted summary statistics and is unadjusted. It is not a substitute for a sponsor's full analysis model or patient-level data. Recalculation can be useful for understanding the direction and approximate precision of the posted arm estimates, but it may not reproduce the original analysis exactly when model details, covariance information, or missing-data handling are unavailable. The registry record does not report those additional details for an independent reconstruction.

The posted standard errors are used in the summary-based calculation, and the pooled standard deviation is marked as approximate in the statistical output. This means any standardized effect-size description derived from that dispersion estimate should be regarded as approximate as well. A standardized effect can help compare effects across measurement scales in general, but it does not replace interpretation in mm Hg or establish clinical importance. The primary interpretation should remain anchored to the endpoint's original units, the uncertainty interval, and the study's stated analysis.

Finally, sample-size planning illustrations based on an observed effect answer a hypothetical design question: how many participants per arm might be needed under stated assumptions to detect an effect of a chosen size. They do not describe the probability that the completed trial detected its true effect. The trial's original design assumptions and sample-size justification are not reported in the registry record.

11. Confidence Intervals and Precision

The primary contrast is -1.14 mm Hg, with a 95% confidence interval whose lower limit is -2.859 and whose upper limit is positive. Because the interval spans zero, the summary statistics are compatible with no between-group difference as well as with differences in either direction. The interval is the main guide to precision: it makes clear that the estimated difference is not pinned down to a narrow range on only one side of zero.

A confidence interval is a range produced by a statistical procedure that, over repeated comparable studies under its assumptions, would contain the underlying parameter at the stated rate. It is not a range containing a specified proportion of individual participants, and it is not a probability statement that the true value lies inside this particular interval. The interval depends on the estimate, its uncertainty, and the method used to construct it.

The arm standard errors, 0.6 for once-daily dosing and 0.64 for twice-daily dosing, describe uncertainty in the estimated group means. They do not show individual variation. The recalculated interval for the difference is based on summary information and should not be mistaken for a sponsor-reported interval from the ANCOVA model. The registry record does not report the sponsor's own interval for the primary between-group contrast.

The secondary comparisons also have intervals that include zero: -2.4 to 1.98 for the last 3 hours of ambulatory diastolic pressure; -3.697 to 2.237 for the last three hours of ambulatory systolic pressure; and -4.182 to 0.782 for 24-hour ambulatory systolic pressure. These intervals reflect uncertainty for separate secondary outcomes, and should not be read as a joint interval or as evidence that the outcomes are identical. The record does not report intervals for the categorical blood-pressure-control outcomes.

12. 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.

The sample-size planning figures are participants per arm, not total events. They are planning illustrations calculated from the observed effect, not the trial's original design justification. The assumptions listed for these illustrations are a two-sided significance level of 0.05, equal allocation between the two arms, a normal approximation, and an effect to detect equal to the stated fraction of the observed effect. The trial's own original sample-size assumptions are not reported in the registry record.

The 80% power column gives the number of participants per arm that the planning calculation estimates would yield an 80% chance of detecting the chosen effect under those assumptions, if the assumed effect and model are appropriate. The 90% power column describes the corresponding calculation for a 90% chance. These are design probabilities for hypothetical future studies, not probabilities that the current result is true or that a treatment will have a particular effect.

Rows using 100%, 75%, and 50% of the observed effect illustrate how the required enrollment changes if the effect targeted by a future study is smaller than the one estimated in this trial. Smaller effects are harder to distinguish from random variation and require more participants under otherwise comparable assumptions. For the primary endpoint, the illustration ranges from 616 participants per arm for 80% power when targeting 100% of the observed effect to 2,464 participants per arm when targeting 50%; the corresponding 90% figures are 825 and 3,298. These are planning examples, not enrollment recommendations.

The observed effect is uncertain, particularly when its confidence interval includes zero. Planning directly from a single observed estimate can therefore produce figures that are sensitive to that estimate. The illustrations should be read as conditional calculations, not as a claim that the completed study had a particular probability of success. This is not observed power.

13. 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 = -1.140; pooled standard deviation σ = 7.140.
2. n = 2 × (1.96 + 0.842)² × 7.140² / -1.140² = 615.8, rounded up to 616 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 <- -1.14                      # observed difference in means
sigma <- 7.14035140464516                     # 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(654875)
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 = 616 (80% power), 825 (90% power)
 75% of observed effect: n per arm = 1,095 (80% power), 1,466 (90% power)
 50% of observed effect: n per arm = 2,464 (80% power), 3,298 (90% power)
power.t.test: 616.8 
Simulated power at n = 616 per arm: 0.801 (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.

14. Multiplicity, Missing Data and Analysis Populations

The registry record lists one primary blood-pressure endpoint and several secondary endpoints, including continuous measures and blood-pressure-control outcomes at more than one time point. It does not report a statistical plan describing how the family of endpoints was handled, whether any outcomes were prioritized for formal testing, or whether p-values were adjusted for multiple comparisons. Without that information, the unadjusted secondary results are best treated as descriptive or exploratory evidence rather than as a set of independent confirmatory tests.

Multiplicity matters because assessing several outcomes can increase the chance of observing at least one apparently unusual result even when there is no underlying effect. General methods for handling multiplicity include prespecified testing sequences or adjustments to the significance threshold. Which method, if any, was used in this trial is not reported in the registry record. It would not be appropriate to infer that an adjustment was performed simply because the trial had a listed primary endpoint.

The primary endpoint population is described as participants in the Full analysis set, consisting of all randomized patients, for whom Baseline and Week 6 data were available. That definition indicates that availability of both measurements was required for the displayed primary analysis. The record does not report the number of randomized participants lacking measurements at either time point, the reasons for missingness, or the assumptions used to address missing data. It also does not report whether missing values were imputed, whether sensitivity analyses were conducted, or how participants with incomplete follow-up contributed to other outcomes.

The registry record reports group-specific counts for the posted primary summaries, but it does not explain all changes in analysis counts across outcomes. Such differences can arise from outcome availability or analysis-specific eligibility, but the reason for any particular difference is not reported in the registry record. The counts should not be used to infer unreported reasons for missing observations.

The record does not report the original sample-size justification, interim analyses, stopping rules, or a complete prespecified analysis plan. These omissions limit assessment of whether the analyses and outcomes were selected before results were known. They do not establish that the study lacked such procedures; they mean that those details are not reported in the registry record. A careful reading therefore distinguishes the endpoint description and posted estimates from unreported choices about multiplicity, missing data, and analysis conduct.

15. 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 5% reporting threshold.

Most frequent serious adverse event terms

Serious events with the highest arm-level rate: appendicitis (0.6%), contusion (0.6%), head injury (0.6%), blood creatine phosphokinase increased (0.6%), syncope (0.6%).

The serious adverse event figures list 2 affected participants in each group. The reported serious-event population at risk is 164 in each group. The record lists Appendicitis, Contusion, Head injury, Blood creatine phosphokinase increased, and Syncope among the serious event terms, each with a reported frequency of 0.6%. No non-serious adverse events are listed in the posted counts. Death counts are not reported in the registry record.

These figures describe the registry's reported event counts and terms. A serious adverse event is a classification of an event's seriousness, not a statement that the event was caused by the assigned treatment. The listed terms do not establish causality, and the equal reported counts do not prove that the groups have equivalent safety. The record does not provide event timing, participant-level detail, exposure-adjusted rates, or a fuller explanation of how events were assessed.

The reported percentages should be read as registry entries, not as independently recalculated rates. With limited detail about event duration, recurrence, relatedness, and follow-up, the listings support only a narrow description of reported serious events. They should not be used alone to draw broad conclusions about comparative safety.

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

The posted primary result is an estimate of average change in 24-hour ambulatory diastolic blood pressure from Baseline to Week 6 under the study's analysis. Both group estimates are negative. The estimated difference between the group changes is -1.14 mm Hg, in the direction of a more negative estimated change in the twice-daily group. Its interval includes zero, and the unadjusted p-value is 0.194. Together, these statistics indicate substantial uncertainty about the size and direction of a between-group difference.

This result does not show that the dosing schedules are equivalent. Equivalence requires a prespecified margin defining differences considered small enough to be practically unimportant, followed by an analysis designed to assess that margin. A non-inferiority claim likewise requires a prespecified margin and suitable analysis. Neither margin is reported in the registry record. Failure to demonstrate a difference in a conventional superiority test is not evidence that the regimens have the same effect.

The result also does not establish whether a difference of the estimated size is clinically important. The registry record does not state a minimum clinically important difference for this endpoint. Statistical uncertainty and clinical importance are related but distinct questions: an estimate can be uncertain even when its point estimate is nonzero, and clinical interpretation requires context not provided in the record.

The primary endpoint is a group-level continuous measure, not an individual prediction. Its mean change does not indicate how every participant's blood pressure changed, nor does it provide the distribution of individual responses. The posted summary does not describe participant-level variability beyond the standard errors of the estimated means. It also does not establish effects outside the measured outcomes and study period.

The study compared active aliskiren schedules in a randomized, double-blind, parallel-group design. Its Week 6 primary result pertains to the participants included in the stated available-data analysis. The complete handling of missing data, original sample-size justification, and multiplicity plan are not reported in the registry record. Those limits matter when judging how broadly the estimate can be generalized or how definitive the secondary findings are.

Finally, the serious adverse event listings are descriptive. They do not establish causal relationships or demonstrate equivalent safety. The result should be understood as a report of the recorded estimates and their uncertainty, not as medical advice or a conclusion about what treatment an individual should receive.

17. Why This Trial Matters Statistically

This trial illustrates why an estimated difference should be read alongside its uncertainty. The primary point estimate is not zero, but the confidence interval includes zero and extends in both directions. A reader who focused only on the direction of the estimate could overstate the evidence; a reader who focused only on the p-value could miss the range of effects compatible with the data. Reporting the estimate, interval, and analysis context together gives a more complete statistical interpretation.

It also shows the distinction between change within each group and difference between groups. Both group estimates indicate decreases from Baseline, but that fact alone does not show that one schedule produces a larger decrease than the other. The randomized comparison is about the difference in changes between assigned groups. This distinction is central to interpreting trials that compare active regimens.

The endpoint's measurement strategy is another useful feature to consider. Ambulatory blood-pressure monitoring summarizes readings over 24 hours, while the secondary outcomes consider different periods and systolic as well as diastolic measures. Results across related endpoints can be informative, but multiple outcomes raise questions about multiplicity and selective emphasis. The registry record does not report the detailed plan needed to judge those issues fully.

Finally, the planning illustrations make clear that a sample-size calculation depends on the effect a future study aims to detect. Calculations based on the observed effect are conditional and may change substantially when a smaller effect is targeted. They cannot be interpreted as observed power or as a retrospective verdict on whether the completed study was adequate. The original design justification is not reported in the registry record, so the planning figures answer a different question from the trial's historical design.

18. 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 leaves several trial-specific details unavailable for interpreting the estimates. Although it describes the primary analysis as ANCOVA adjusted for Baseline mean 24-hour ambulatory diastolic blood pressure, the complete model specification is not reported. The record does not state whether additional covariates were included, how model assumptions were checked, or how missing outcomes were handled. The primary analysis population is defined by availability of Baseline and Week 6 data, but counts and reasons for unavailable measurements are not reported in the registry record.

The twice-daily group's treatment description indicates a change after the first 6 weeks, while the complete details of the subsequent regimen are not reported in the registry record. This makes it important to distinguish the Week 6 primary comparison from outcomes measured later. The record also does not report a minimum clinically important difference, an equivalence margin, or a non-inferiority margin. Therefore, the posted results cannot support a formal conclusion of equivalence or non-inferiority.

The original sample-size justification, interim analyses, stopping rules, and full statistical analysis plan are not reported in the registry record. The handling of multiple secondary outcomes is also not reported. As a result, the secondary comparisons should be interpreted cautiously, and the planning illustrations based on the observed effect should not be confused with the study's original design calculations.

The serious-event reporting is limited to the posted counts and terms. The registry record does not provide participant-level event descriptions, timing, relatedness assessments, or death counts. These limitations restrict conclusions about comparative safety. More generally, a registry summary of group estimates cannot show the full distribution of individual outcomes or resolve questions requiring patient-level data.

19. Related Tutorials

20. Related Statistical Calculators

21. Sources

• ClinicalTrials.gov: Efficacy and Safety of Once Daily Dosing of Aliskiren (300 mg (qd) Once a Day) to Twice Daily Dosing of Aliskiren (150 mg (Bid) Twice a Day) in Treating Moderate Hypertension. — NCT00654875.
• Registry record last updated 2011-06-28; status last verified 2011-06.
• Results first posted 2011-06-15.
• 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.

22. Record Summary

The registry record describes a completed Phase 4, randomized, double-blind, parallel-group, multicenter study of aliskiren schedules in essential hypertension. Enrollment was 328, and the study duration was 10 weeks. The primary endpoint was change from Baseline to Week 6 in mean 24-hour ambulatory diastolic blood pressure.

The posted least-squares mean changes were -4.1 mm Hg for once-daily aliskiren and -5.24 mm Hg for twice-daily aliskiren. The unadjusted recalculated contrast was -1.14 mm Hg, with a confidence interval including zero and an unadjusted p-value of 0.194. Secondary ambulatory estimates also show reductions from Baseline in both groups, while their recalculated intervals include zero.

The registry record reports two participants with serious adverse events in each group and lists five serious-event terms at 0.6% each. The original sample-size justification, detailed missing-data methods, multiplicity plan, and complete later-period dosing description for the twice-daily group are not reported in the registry record.