Study to Evaluate the Efficacy and Safety of Aliskiren Alone and in Combination With Amlodipine in Essential Hypertension: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Study to Evaluate the Efficacy and Safety of Aliskiren Alone and in Combination With Amlodipine in Essential Hypertension (NCT00739973), a randomized phase 3 study. The primary outcome is Pairwise Comparison of Aliskiren/Amlodipine 150/5 mg vs. Aliskiren 150 mg on Change in Mean Sitting Diastolic Blood Pressure (msDBP).

2. Clinical Question

3. Trial Design

The registry describes a Phase 3, randomized, triple-masked, multifactorial, placebo-controlled, parallel-group study of aliskiren alone and in combination with amlodipine in participants with essential hypertension. The official title describes an 8-week study; the primary endpoint timeframe is baseline to the end of the study at Week 8. Enrollment was 2694, and the study status is completed. The registry lists Novartis Pharmaceuticals as sponsor.

The listed treatment groups include placebo, aliskiren 150 mg and 300 mg, amlodipine 5 mg and 10 mg, and aliskiren/amlodipine combinations at 150/5 mg, 150/10 mg, 300/5 mg, and 300/10 mg. The primary result is not a comparison of every group: it is the pairwise contrast between aliskiren/amlodipine 150/5 mg and aliskiren 150 mg. Other posted comparisons include systolic blood pressure contrasts involving the 150/5 mg combination, aliskiren, amlodipine, and placebo.

Randomization and masking describe important design protections, but the registry record does not report the allocation ratio, the methods used to generate or conceal the allocation sequence, or which roles were included in triple masking. Details of the factorial structure beyond its designation, such as any planned interaction analysis, are not reported in the registry record. The protocol’s original sample-size assumptions and justification are also not reported in the registry record.

The primary analysis population is described as the Full Analysis Set, comprising randomized participants except those who were mis-randomized because they were not qualified for randomization but were inadvertently randomized. Further detail about eligibility criteria, treatment adherence, withdrawals, or handling of missing measurements is not reported in the registry record.

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.

Only the first 6 of 9 groups are shown.

Single-blind Period (2 to 4 Weeks)

Reasons for not completing this period:

Double-blind:Randomized Period (8 Weeks)

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: Full Analysis Set (FAS): All participants who were randomized. Participants mis-randomized were excluded from the FAS. Mis-randomized participants refer to participants who were not qualified for randomization but were inadvertently randomized into the study. These participants did not receive study drug.

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.

Only the first 6 of 10 groups are shown.

6. Primary Endpoint

The registry lists the primary outcome as Pairwise Comparison of Aliskiren/Amlodipine 150/5 mg vs. Aliskiren 150 mg on Change in Mean Sitting Diastolic Blood Pressure (msDBP), measured over Baseline to end of study (Week 8).

The primary endpoint is the change from baseline to Week 8 in mean sitting diastolic blood pressure, measured in mm Hg. It is a continuous outcome: each participant’s measurement can take a range of values rather than being limited to categories such as improved or not improved. The registry reports least-square means for the treatment groups and a least-square mean difference for the comparison.

Blood pressure was measured at trough with an automated device and an appropriate-size cuff while the participant was seated, with the arm supported at heart level. Participants were seated for at least 5 minutes before measurement. Diastolic pressure was measured three times at 1-2 minute intervals at each visit, and the mean of those readings was calculated. The arm with the highest sitting pressures at study entry was used for subsequent readings.

Repeated measurements help represent a participant’s blood pressure at a visit while reducing reliance on a single reading. A change-from-baseline endpoint compares follow-up measurements with the starting measurement, while the Week 8 timeframe sets the visit used for the primary contrast. Blood pressure is the outcome the study set out to evaluate, but the endpoint alone does not describe every aspect of a participant’s health or the overall balance of benefits and harms.

7. Results Posted in the Registry

• Aliskiren/Amlodipine 150/5 mg: mean -13.98 versus -7.99 on control; difference -5.99 (95% CI -7.78 to -4.20), standardized effect d = -0.68; z-test p = <0.001.

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.

Pairwise Comparison of Aliskiren/Amlodipine 150/5 mg vs. Aliskiren 150 mg on Change in Mean Sitting Systolic Blood Pressure (msSBP)

• 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/Amlodipine 150/5 mg: mean -20.64 versus -10.67 on control; difference -9.97 (95% CI -12.83 to -7.11), standardized effect d = -0.71; z-test p = <0.001.
• Interpretation:
  • The 95% confidence interval excludes no difference, so the mean is statistically lower for Aliskiren/Amlodipine 150/5 mg than for the control. This is an unadjusted, secondary comparison, so it is suggestive rather than confirmatory.

Pairwise Comparison of Aliskiren/Amlodipine 150/5 mg vs. Amlodipine 5 mg on Change in Mean Sitting Systolic Blood Pressure (msSBP)

• 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/Amlodipine 150/5 mg: mean -20.64 versus -15.82 on control; difference -4.82 (95% CI -7.72 to -1.92), standardized effect d = -0.34; z-test p = 0.001.
• Interpretation:
  • The 95% confidence interval excludes no difference, so the mean is statistically lower for Aliskiren/Amlodipine 150/5 mg than for the control. This is an unadjusted, secondary comparison, so it is suggestive rather than confirmatory.

Pairwise Comparison of Aliskiren/Amlodipine 150/5 mg vs. Placebo on Change in Mean Sitting Systolic Blood Pressure (msSBP)

• 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/Amlodipine 150/5 mg: mean -20.64 versus -6.79 on control; difference -13.85 (95% CI -16.69 to -11.01), standardized effect d = -0.99; z-test p = <0.001.
• Interpretation:
  • The 95% confidence interval excludes no difference, so the mean is statistically lower for Aliskiren/Amlodipine 150/5 mg than for the control. This is an unadjusted, secondary comparison, so it is suggestive rather than confirmatory.

The secondary comparisons with posted results include systolic blood pressure change for the aliskiren/amlodipine 150/5 mg group against aliskiren 150 mg, amlodipine 5 mg, and placebo. Across these comparisons, the estimated change for the combination group is more negative than the estimate for each named comparator. The posted estimates and intervals indicate that the direction of the combination-group contrast is consistent across these three comparisons.

This pattern is related to the primary result because the primary endpoint compares the same 150/5 mg combination with aliskiren 150 mg, but measures diastolic rather than systolic blood pressure. The secondary results add context across a different blood-pressure component and different comparators. They do not replace the primary comparison or establish a single overall effect across all doses and groups. The secondary analyses involve separate contrasts, each with its own estimate and uncertainty.

The registry lists 27 outcome measures and 24 analyses, and 15 secondary outcomes are posted. The available results do not establish that every secondary comparison had the same pattern, and the registry record does not report a complete multiplicity plan. The posted secondary results should therefore be interpreted as supporting context rather than treated as independent confirmation with the same weight as the primary result.

When many outcomes or comparisons are tested, the chance of obtaining small p-values can increase if no adjustment or hierarchy is applied. In general, multiplicity procedures can control error rates across a defined family of tests, but the choice depends on how hypotheses were planned and prioritized. The registry does not report whether or how such procedures were used for these secondary analyses. Unadjusted secondary results consequently carry less confirmatory weight, even when their directions appear consistent.

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

• Pairwise Comparison of Aliskiren/Amlodipine 150/5 mg vs. Aliskiren 150 mg on Change in Mean Sitting Systolic Blood Pressure (msSBP)
• Pairwise Comparison of Aliskiren/Amlodipine 150/5 mg vs. Amlodipine 5 mg on Change in Mean Sitting Systolic Blood Pressure (msSBP)
• Pairwise Comparison of Aliskiren/Amlodipine 150/5 mg vs. Placebo on Change in Mean Sitting Systolic Blood Pressure (msSBP)
• Pairwise Comparison of Aliskiren/Amlodipine 150/10 mg vs. Aliskiren 150 mg on Change in Mean Sitting Systolic Blood Pressure (mssBP)
• Pairwise Comparison of Aliskiren/Amlodipine 150/10 mg vs. Amlodipine 10 mg on Change in Mean Sitting Systolic Blood Pressure (msSBP)
• Pairwise Comparison of Aliskiren/Amlodipine 150/10 mg vs. Placebo on Change in Mean Sitting Systolic Blood Pressure (msSBP)
• Pairwise Comparison of Aliskiren/Amlodipine 300/5 mg vs. Aliskiren 300 mg on Change in Mean Sitting Systolic Blood Pressure (msSBP)
• Pairwise Comparison of Aliskiren/Amlodipine 300/5 mg vs. Amlodipine 5 mg on Change in Mean Sitting Systolic Blood Pressure (msSBP)

9. Statistical Interpretation

10. Statistical Methods Explained

The primary outcome is continuous, and the registry reports least-square means and an ANCOVA least-square mean difference. The ANCOVA result is the sponsor’s model-based comparison. The registry record does not report the covariates included in that model, how missing observations were handled, or other detailed model specifications.

What a least-square mean represents

In general, a least-square mean is a model-based estimate of a group mean after accounting for the variables included in the model. It is sometimes called an adjusted mean. It differs from a simple arithmetic average when the model adjusts for covariates or other design features. In this record, the group values are identified as least-square means, but the particular adjustment variables are not reported in the registry record. The estimated contrast should therefore be understood as the sponsor’s ANCOVA estimate without assuming details about the adjustment beyond the method named.

What the mean difference expresses

The reported primary contrast is the difference in change in mean sitting diastolic blood pressure between the two named groups. A negative estimate in this ordering means the combination group’s change is more negative than the aliskiren group’s change. This describes a difference between group means. It does not mean that every person in the combination group had a larger reduction, and it does not describe the spread of individual participant responses.

Standard errors and uncertainty

In general, a standard error describes the sampling uncertainty of an estimated mean or contrast. It is not the same as the standard deviation of individual measurements. The registry gives standard errors for each group’s least-square mean, while the sponsor’s reported analysis gives a 95% confidence interval for the contrast. A confidence interval reflects uncertainty in the estimated comparison under the model; it is not a range containing a stated proportion of individual participants’ outcomes.

How the unadjusted recalculation differs

The recalculated comparison is derived from posted group summary statistics and is labelled a simple unadjusted recalculation. It uses the two group estimates and their standard errors to form a comparison without reproducing the sponsor’s ANCOVA model. The recalculated pooled standard deviation is approximate because the available summaries are least-square means with standard errors, rather than a direct report of the underlying participant-level residual variation. This makes the recalculation useful as a cross-check, not as a replacement for the reported model-based analysis. The record marks no discrepancy between the recalculation and the sponsor analysis.

In general, adjusting for baseline values or other covariates can change an estimate and its uncertainty. That is one reason an unadjusted calculation based on group summaries may not exactly match an ANCOVA result. The registry does not report enough model detail to reproduce the sponsor’s analysis independently. The close agreement in this comparison is descriptive; it does not demonstrate that every modeling decision can be reconstructed from the posted summaries.

How to read the p-value

In general, a p-value measures how incompatible the observed data are with a specified null hypothesis, under the statistical model and assumptions used. The reported p < 0.001 means the p-value is below that threshold; it is not the probability that the null hypothesis is true or the probability that chance alone caused the result. The p-value does not measure the magnitude of the difference, and a small p-value does not remove concerns about bias, missing data, model assumptions, or multiple testing.

Why variance matters

In general, greater variability among participants makes a group mean less precise unless balanced by more information. The registry reports standard errors for the primary group estimates, but it does not report the individual-level distribution or residual diagnostics for this comparison. For count outcomes, over-dispersion means that observed variability exceeds what a simple count model would expect; that issue is not the basis of this continuous blood-pressure endpoint. The primary endpoint is analyzed as a continuous measure, so the relevant uncertainty concerns the distribution and modeling of the measurements and their mean change.

The analysis population is described as the Full Analysis Set. It includes randomized participants except those classified as mis-randomized because they were not qualified for randomization but were inadvertently randomized. The record’s description does not specify a full missing-data strategy, participant-level exclusions beyond that definition, or sensitivity analyses. Those details matter when assessing whether the analyzed data represent the randomized groups as intended, but they are not reported in the registry record.

The registry lists 27 outcome measures and 24 analyses. Those counts indicate that the posted results span more than the single primary comparison, but counts alone do not reveal which hypotheses were confirmatory, how outcomes were prioritized, or whether p-values were adjusted. The registry record does not report the analysis plan’s multiplicity strategy, interim analyses, or the original sample-size justification. Conclusions about those aspects of the statistical plan would therefore go beyond the record.

11. Confidence Intervals and Precision

The sponsor-reported 95% confidence interval for the primary least-square mean difference extends from -7.77 to -4.22 mm Hg. Its endpoints are both negative, so the interval is compatible with a more negative mean change in the aliskiren/amlodipine 150/5 mg group than in the aliskiren 150 mg group, under the reported ANCOVA analysis. The estimate at the center of the comparison is -6.00 mm Hg.

In general, a confidence interval conveys both the direction and the precision of an estimate. A narrower interval indicates less statistical uncertainty than a wider interval, while the interval’s location indicates which effect values are compatible with the data and model. A 95% confidence interval is not a 95% probability statement about this particular fixed effect. It describes the long-run coverage property of the method under its assumptions.

The interval does not show the range of changes among individual participants. Individual responses may vary, and the registry does not report participant-level distributions for this endpoint. The standard errors reported for the two group means also should not be mistaken for standard deviations or for confidence intervals around individual values.

The interval’s precision depends on the data and analysis model, including the sample information and assumptions used. The registry reports the analyzed group sizes and standard errors, but does not report the full ANCOVA specification, diagnostic checks, or sensitivity analyses. Precision should therefore be read in the context of the reported model rather than as a guarantee that every possible analysis would give an identical interval. The posted unadjusted recalculation produces a very similar estimate and uncertainty range, while the sponsor’s ANCOVA interval remains the reported trial analysis.

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 planning figures are participants per arm for the continuous mean comparisons, not total events. They are illustrations based on the observed effect, not a record of the trial’s original design calculation. The listed assumptions are a two-sided significance level of 0.05, equal allocation between the two arms, and a normal approximation. Each planning row uses the stated fraction of the observed effect as the effect to detect.

The 80% power column gives the participants per arm estimated under those assumptions for an 80% chance of detecting the selected effect if that effect is present. The 90% power column gives the corresponding number per arm for a 90% chance. These are conditional planning probabilities, not guarantees about a future study. The calculations concern a two-arm comparison and do not reproduce the study’s multifactorial design or account for features not included in the stated assumptions.

Rows for 100% of the observed effect use the full observed contrast as the planning target; rows for 75% and 50% use smaller target effects. Smaller effects need more participants to detect at the same nominal power under the same assumptions. The entries therefore illustrate how the sample-size requirement changes when the target effect is reduced. They should not be read as evidence that the original study was designed around the observed result.

These planning values are not observed power. Observed power is not a useful post hoc measure of how convincing a result is; the estimate and its confidence interval convey the observed effect and uncertainty more directly. The trial’s own original sample-size assumptions and justification are not reported in the registry record.

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 = -5.990; pooled standard deviation σ = 8.790.
2. n = 2 × (1.96 + 0.842)² × 8.790² / -5.990² = 33.8, rounded up to 34 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 <- -5.99                      # observed difference in means
sigma <- 8.78983036456551                     # 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(739973)
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 = 34 (80% power), 46 (90% power)
 75% of observed effect: n per arm = 61 (80% power), 81 (90% power)
 50% of observed effect: n per arm = 136 (80% power), 182 (90% power)
power.t.test: 34.8 
Simulated power at n = 34 per arm: 0.794 (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. Analyses Reported by the Sponsor

The sponsor’s posted primary analysis is an ANCOVA estimate of the least-square mean difference, with a 95% confidence interval and p-value. The separate recalculation uses posted group summaries for a simple unadjusted comparison. The recalculated estimate is -5.99 mm Hg, compared with the sponsor-reported -6.00 mm Hg; the recalculated and reported intervals are also close. Both analyses report p < 0.001.

The registry record indicates no discrepancy between the sponsor result and the recalculation. The sponsor’s own analysis takes precedence as the trial’s reported analysis, particularly because the registry names ANCOVA as its method. The recalculation can serve as a limited check that the group summaries are broadly consistent with the posted contrast, but it does not recreate the ANCOVA model or establish its specifications.

The registry does not report the ANCOVA covariates or enough detail to reproduce every aspect of the analysis. Agreement between the two estimates therefore should not be taken to mean that the methods are identical. The recalculation is unadjusted and based on summary statistics; the sponsor’s result is the model-based analysis reported for the trial.

15. Multiplicity, Missing Data and Analysis Populations

The study has multiple treatment groups, and the registry lists 27 outcome measures and 24 analyses. The registry also identifies 15 posted secondary outcomes. This is a setting in which multiplicity is relevant: repeated testing across outcomes, treatment contrasts, doses, or timepoints can make isolated p-values harder to interpret as confirmatory evidence.

The registry record does not report whether the statistical plan used a multiplicity adjustment, which comparisons were grouped into a testing family, whether a hierarchy or gatekeeping sequence was used, or whether secondary outcomes were considered exploratory. It also does not report interim analyses or stopping boundaries. Those details are not inferable from the reported p-values or from the number of analyses alone. The primary comparison’s p-value should be read as reported, while the unadjusted secondary results should be treated with appropriate caution.

The primary population is described as the Full Analysis Set: randomized participants, excluding participants who were mis-randomized because they were not qualified for randomization but were inadvertently randomized. The record does not report detailed participant flow, missing endpoint counts by group, reasons for missingness, or the method used to handle missing Week 8 measurements. It also does not report sensitivity analyses addressing missing data. These omissions limit assessment of how missing observations might affect the estimated contrast.

The registry record does not give the original sample-size justification or the assumptions used to plan the trial. The posted planning illustrations are based on the observed effect and stated simplified assumptions, so they cannot establish what the trial was designed to detect. The record also does not provide the full ANCOVA specification, such as its covariates. These are reporting gaps, not evidence that a particular method was or was not used. Interpretation is therefore strongest for the stated endpoint, analysis population, and reported model result, with uncertainty about these unreported design and analysis details.

16. 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

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: gastroenteritis (0.6%), bronchitis (0.6%), pneumonia (0.6%), cerebrovascular accident (0.6%), calculus ureteric (0.6%).

The posted serious adverse event counts are participants affected among those at risk in each group. The registry reports 2 of 198 for placebo, 0 of 194 for aliskiren 150 mg, 0 of 203 for aliskiren 300 mg, 1 of 185 for amlodipine 5 mg, and 1 of 181 for amlodipine 10 mg. For the combination groups, the counts are 1 of 181 for 150/5 mg, 2 of 181 for 150/10 mg, 1 of 178 for 300/5 mg, and 1 of 184 for 300/10 mg.

These are observed counts in the registry’s safety listing; they do not establish that a treatment caused an event or that groups can be compared fairly without considering exposure, participant characteristics, and the safety-analysis methods. The record lists gastroenteritis, bronchitis, pneumonia, cerebrovascular accident, calculus ureteric, and hydronephrosis among the most frequent serious-event terms, each at 0.6%. Death counts are not reported in the registry record. The counts alone do not provide a complete safety assessment or a basis for treatment advice.

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

The primary result describes a difference in mean change in sitting diastolic blood pressure between two randomized groups over the study’s baseline-to-Week 8 timeframe. The sponsor-reported ANCOVA estimate is -6.00 mm Hg, with a 95% confidence interval from -7.77 to -4.22 and p < 0.001. The direction and interval indicate a more negative mean change in the aliskiren/amlodipine 150/5 mg group than in the aliskiren 150 mg group in this analysis.

This result does not say that every participant’s blood pressure changed by the group mean, or that the same difference would occur for every dose, comparator, population, or duration. It is not a comparison of final blood pressure levels, and it does not establish whether participants reached a particular target. The registry record does not report a clinical threshold for judging the importance of this mean difference.

The finding also does not answer all questions about treatment. It does not by itself establish long-term effects, effects on outcomes other than the measured blood-pressure endpoint, or the overall balance of benefits and harms. The study duration described in the title is 8 weeks. The serious adverse event counts are a separate descriptive component and do not resolve those broader questions.

The randomized design supports interpreting the reported contrast as a comparison between assigned groups, subject to the analysis population and the limitations of reporting. However, details about allocation procedures, missing data, model covariates, multiplicity, and the original design assumptions are not reported in the registry record. The result should therefore be read as a precise estimate for the posted comparison and analysis, not as a universal conclusion about all treatment contexts.

18. Why This Trial Matters Statistically

This trial illustrates how a continuous endpoint can be reported as both group-level change estimates and a model-based contrast. The least-square mean difference focuses attention on the question of interest: how the average change in one randomized group compares with that in another. The confidence interval complements the point estimate by showing the uncertainty around that contrast.

It also demonstrates why the analysis method matters. The sponsor’s primary result is an ANCOVA estimate, while the posted recalculation is an unadjusted comparison based on summary statistics. Their close numerical agreement is reassuring as a consistency check, but the methods are not interchangeable. The adjusted model is the trial’s reported analysis, and the unadjusted calculation cannot recover details absent from the registry.

The factorial, multi-group structure makes interpretation broader than a single pairwise result. Several treatments, doses, and outcomes create multiple possible comparisons. A clear primary question helps focus interpretation, while the unreported multiplicity strategy makes it important not to treat every secondary p-value as equally confirmatory. The trial’s posted results also show why safety counts and efficacy endpoints should be read separately rather than collapsed into one claim.

Finally, the sample-size illustrations emphasize the connection between target effect and information needs: smaller effects require more participants under the stated planning assumptions. Those calculations are not evidence of the original planning process and cannot replace the registry’s missing design justification. Distinguishing a planning illustration from the observed analysis is essential when translating a trial result into statistical understanding.

19. 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 does not report the eligibility criteria in detail, allocation ratio, allocation-sequence methods, or which roles were masked under triple masking. The factorial designation is recorded, but details of planned factorial contrasts or interaction analyses are not reported. These gaps constrain assessment of how the design was implemented beyond the basic randomized, masked, placebo-controlled, parallel-group description.

For the primary analysis, the ANCOVA covariates and full model specification are not reported. The record identifies the Full Analysis Set and explains the exclusion of mis-randomized participants, but does not give detailed participant flow or the number with missing Week 8 measurements by group. Missing-data methods, sensitivity analyses, and treatment of protocol deviations are not reported in the registry record. Those details can affect how well the analyzed comparison represents the randomized groups.

The registry lists many outcome measures and analyses, but does not report the multiplicity strategy, the status of secondary comparisons as confirmatory or exploratory, or interim-analysis methods. The original sample-size justification is also not reported. The available observed-effect planning illustrations should not be mistaken for the study’s original design calculation.

The primary endpoint is a short-term blood-pressure measure through Week 8. Longer-term outcomes and outcomes beyond the posted endpoints are not established by this result. The safety record includes counts of affected participants, but death counts are not reported in the registry record, and the presented counts alone do not describe exposure-adjusted risk or establish causation. These limits are specific to what is documented for this study and should accompany interpretation of its efficacy and safety results.

20. Related Tutorials

21. Related Statistical Calculators

22. Sources

• ClinicalTrials.gov: Study to Evaluate the Efficacy and Safety of Aliskiren Alone and in Combination With Amlodipine in Essential Hypertension — NCT00739973.
• Registry record last updated 2011-06-06; status last verified 2011-06.
• Results first posted 2011-05-03.
• 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.

23. Record Summary

This completed Phase 3 trial randomized 2694 participants in an 8-week, triple-masked, factorial, placebo-controlled, parallel-group study of aliskiren alone and with amlodipine for essential hypertension. The primary comparison evaluated baseline-to-Week 8 change in mean sitting diastolic blood pressure for aliskiren/amlodipine 150/5 mg versus aliskiren 150 mg.

The sponsor-reported ANCOVA difference was -6.00 mm Hg (95% confidence interval -7.77 to -4.22; p < 0.001). The posted unadjusted recalculation was close to that result. The registry also lists systolic blood pressure secondary comparisons and serious adverse event counts across the treatment groups. Multiplicity procedures, missing-data methods, detailed ANCOVA specifications, and the original sample-size justification are not reported in the registry record.