8-week Randomized, Open-label Study to Evaluate Food Effect on Efficacy and Safety of Oral Aliskiren 300 mg in Patients With Hypertension: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for 8-week Randomized, Open-label Study to Evaluate Food Effect on Efficacy and Safety of Oral Aliskiren 300 mg in Patients With Hypertension (NCT01570686), a randomized phase 4 study. The primary outcome is Change From Baseline (Visit 3) to End of Study (Week 8) in Mean 24 Hour Ambulatory Systolic Blood Pressure (maSBP).

2. Clinical Question

The primary measure was mean 24-hour ambulatory systolic blood pressure, or maSBP, in mmHg. The study compared the groups’ estimated mean changes from baseline to the end of the 8-week study. The comparison concerns the timing and meal conditions under which the same dose was taken; it is not a comparison of aliskiren with an untreated or different-drug control group.

The registry lists secondary measures covering ambulatory diastolic pressure, sitting blood pressure, blood-pressure control and response, pharmacokinetic measures, and plasma renin activity. These outcomes broaden the questions considered, but the main reported statistical comparison is the change in ambulatory systolic pressure. Results for individual secondary measures should be understood as additional evidence rather than as substitutes for the primary endpoint.

3. Trial Design

This was a completed Phase 4 randomized, open-label, multicenter study with a parallel-group design. The registry reports enrollment of 589 participants and describes an 8-week comparison of oral aliskiren 300 mg once daily under light-meal and fasting conditions. Participants assigned to the fed group took the dose 30 minutes after the start of a light breakfast; the fasting group took it after an overnight fast. Both groups received aliskiren.

Because masking was listed as none, the study was open-label. The registry record does not report whether outcome assessors or analysts were masked. Random allocation can help balance group characteristics on average, but open-label assignment means that participants and study staff knew the assigned meal condition. The main outcome was measured using ambulatory blood pressure monitoring, a measurement approach that records blood pressure over a 24-hour period rather than relying only on a clinic reading.

For the primary outcome, the registry describes a Full Analysis Set consisting of randomized patients, with mis-randomized patients excluded. The primary analysis also required ambulatory blood pressure measurements at both baseline and week 8. The posted primary outcome lists 263 participants in the fed group and 266 in the fasting group. These are the group sizes attached to that outcome, not a statement that every enrolled participant contributed to every analysis.

The study started in 2012-04 and had primary completion in 2012-11. The registry record does not report the original sample-size justification, the planned power for the primary endpoint, interim analyses, or detailed procedures for handling missing measurements beyond the stated requirement for measurements at both time points. The posted design therefore supports description of the randomized meal-condition comparison, but not reconstruction of all design decisions.

4. Participant Flow and Accounting

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

Before assignment: A total of 691 patients enrolled in the study with 590 patients randomized. 1 patient was mis-randomized and did not receive study medication, therefore 589 patients actually received study medication.

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: Full Analysis Set (FAS): consisted of all randomized patients. Mis-randomized patients were excluded from the FAS. Patients with ABPM measurements at both baseline and week 8 were included in this analysis.

5. Baseline Characteristics

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

Population: All Randomized patients (including one mis-randomized patient in Aliskiren:Fed arm).

6. Primary Endpoint

The registry lists the primary outcome as Change From Baseline (Visit 3) to End of Study (Week 8) in Mean 24 Hour Ambulatory Systolic Blood Pressure (maSBP), measured over Baseline, week 8.

The primary endpoint was change from baseline at Visit 3 to the end of week 8 in mean 24-hour ambulatory systolic blood pressure. The measure is expressed in mmHg. Ambulatory monitoring was performed at baseline and at the end of 8 weeks using a device attached to the non-dominant arm. The registry describes the endpoint as a least-squares mean and reports standard errors for the group estimates.

Change from baseline focuses the comparison on how the measured value changed during the study rather than on the week-8 value alone. In general, measuring a baseline value can account for initial differences between participants and improve the precision of a treatment-group comparison when baseline is included in the statistical model. Here, the registry says the model included baseline as a covariate and treatment and region as factors.

Ambulatory systolic pressure is relevant to the stated study question because the registry aims to compare blood-pressure outcomes under fed and fasting dosing conditions. A 24-hour measure captures readings across the day and night, while the baseline-to-week-8 change describes the difference in the group’s estimated average over the study period. The endpoint does not, by itself, establish whether a meal condition changes drug exposure or safety; those are separate study questions.

The registry reports a least-squares mean change of -7.03 mmHg in the fed group and -7.79 mmHg in the fasting group. The estimated fasting-minus-fed difference was -0.76 mmHg. This is a group-level comparison; it does not describe the change experienced by every participant.

7. Results Posted in the Registry

• Aliskiren: Fasting: mean -7.79 versus -7.03 on control; difference -0.76 (95% CI -2.15 to 0.63), standardized effect d = -0.09; z-test p = 0.282.

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 (Visit 3) to End of Study (Week 8) in Mean 24 Hour Ambulatory Diastolic Blood Pressure (maDBP)

• 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: Fasting: mean -4.39 versus -4.01 on control; difference -0.38 (95% CI -1.24 to 0.48), standardized effect d = -0.08; z-test p = 0.386.
• Interpretation:
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between Aliskiren: Fasting and the control. The interval gives the range of effects that remain compatible with the data.

Percentage of Patients Achieving Blood Pressure Control

• Endpoint type: Binary: the percentage of participants with the event (counts rebuilt from the posted percentages and group sizes).
• Test: Unadjusted two-proportion z-test, with a Wald 95% confidence interval for the risk difference.
• Result:
  • Aliskiren: Fasting: 41.5% (122/294) versus 44.7% (131/293) on control; risk difference -3.2 percentage points (95% CI -11.2 to 4.8), risk ratio 0.93 (0.77–1.12); unadjusted two-proportion z-test p = 0.432.
• Interpretation:
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between Aliskiren: Fasting and the control. The interval gives the range of effects that remain compatible with the data.

Percentage of Patients Achieving a Successful Response in Systolic Blood Pressure Reduction

• Endpoint type: Binary: the percentage of participants with the event (counts rebuilt from the posted percentages and group sizes).
• Test: Unadjusted two-proportion z-test, with a Wald 95% confidence interval for the risk difference.
• Result:
  • Aliskiren: Fasting: 55.8% (164/294) versus 54.9% (161/293) on control; risk difference 0.8 percentage points (95% CI -7.2 to 8.9), risk ratio 1.02 (0.88–1.17); unadjusted two-proportion z-test p = 0.839.
• Interpretation:
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between Aliskiren: Fasting and the control. The interval gives the range of effects that remain compatible with the data.

The reported secondary outcomes cover more than one kind of measure: ambulatory diastolic pressure, blood-pressure control, and successful systolic response. The posted estimates for these outcomes generally point to small contrasts between the meal-condition groups, and their reported confidence intervals include zero. This broad pattern is consistent with the primary estimate’s uncertainty, but the outcomes differ in scale and definition and should not be collapsed into a single summary.

These measures relate to the primary result by examining other blood-pressure summaries or response classifications over the same general study period. Agreement in direction or lack of a clear separation can provide context, but it does not independently prove the primary finding. Nor does a similar pattern across outcomes establish equivalence. The confidence intervals and the study’s analysis plan remain important to judging what the data can distinguish.

The registry lists additional secondary topics, including pharmacokinetic measures and plasma renin activity. Results for secondary endpoints not represented among the posted outcome results are not reported in the registry record. The absence of a posted result should not be interpreted as a null finding or evidence that no measurement was made.

Unadjusted secondary results carry less weight because examining multiple outcomes creates more opportunities for apparently notable results to arise by chance. In general, multiplicity procedures control or account for this issue, but can change the interpretation of individual p-values. The registry record does not report a multiplicity adjustment or a hierarchy specifying which secondary findings would be confirmatory. Accordingly, these outcomes are best treated as supportive or exploratory evidence rather than as definitive tests.

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

• Change From Baseline (Visit 3) to End of Study (Week 8) in Mean 24 Hour Ambulatory Diastolic Blood Pressure (maDBP)
• Percentage of Patients Achieving Blood Pressure Control
• Change From Baseline (Visit 3) to End of Study (8 Weeks) in Mean Sitting Systolic Blood Pressure (msSBP) and Mean Sitting Diastolic Blood Pressure (msDBP)
• Percentage of Patients Achieving a Successful Response in Systolic Blood Pressure Reduction
• Pharmacokinetic (PK) of Aliskiren: The Observed Maximum Plasma Concentration (Cmax) Following Drug Administration in Fasted vs. Fed
• Pharmacokinetic of Aliskiren: The Area Under the Plasma Concentration-time Curve From Time Zero to the End of the Dosing Interval Tau (AUCtau) in Fasted vs. Fed
• Pharmacokinetic of Aliskiren: Time to Reach the Maximum Concentration (Tmax) After Drug Administration in Fasted vs. Fed
• Change From Baseline to Week 8 in Plasma Renin Activity (PRA)

9. Statistical Interpretation

10. Statistical Methods Explained

The primary endpoint is a continuous measure: change in 24-hour ambulatory systolic blood pressure, expressed in mmHg. The registry reports least-squares means and standard errors for each group, along with a mean difference and confidence interval. The stated analysis is ANCOVA, with treatment and region as factors and baseline blood pressure as a covariate.

What does ANCOVA contribute?

In general, analysis of covariance compares groups while accounting for a measured baseline value and other specified factors. Including baseline in the model can improve precision when baseline is related to the follow-up outcome, and it can adjust the estimated group comparison for baseline values. The registry identifies treatment, region, and baseline in the model description, but it does not report the full model specification, model diagnostics, or the coding of region. Those details should not be inferred.

A least-squares mean is a model-based group estimate adjusted according to the variables in the model. It is not necessarily the same as the unadjusted average of all individual changes. The standard error describes the estimated sampling uncertainty of a model-based mean. It is not the spread of individual participants’ blood-pressure changes. The posted standard error is 0.5 mmHg for each primary group estimate.

How should the group difference be read?

The mean difference compares the estimated fasting-group change with the estimated fed-group change. Its posted estimate is -0.76 mmHg. Given the direction and the group estimates, the negative sign indicates a more negative estimated change in the fasting group. The confidence interval for the difference is reported as -2.146 to 0.626 mmHg. Since that interval includes zero, the data do not rule out no difference at the interval’s stated confidence level. They also remain compatible with differences in either direction within the interval.

In general, a confidence interval is a range generated by a statistical procedure that reflects uncertainty in an estimate under its assumptions. It is not a range containing a fixed proportion of individual outcomes, and it does not assign a probability to the true value after the data have been observed. The registry record does not identify the confidence level in the listed endpoint details, so no confidence level should be inferred from the interval alone.

What does the p-value say?

The unadjusted p-value for the primary comparison is 0.282. In general, a p-value measures how unusual data at least as inconsistent with a specified null model would be if that model were true and the analysis assumptions held. It is not the probability that the null hypothesis is true, nor is it a measure of effect size or clinical importance. The word unadjusted matters: the registry does not report that this value was corrected for testing multiple outcomes or comparisons.

The reported analysis is not described as a simple unadjusted comparison: the endpoint description specifies ANCOVA. The posted p-value is identified as unadjusted, and the registry record does not provide enough detail to determine whether it has any adjustment beyond the stated model. No further features of the inferential procedure should be assumed.

Why can over-dispersion matter?

In general, over-dispersion means that observed variability is greater than a model expects. It matters most when a model assumes a particular variance structure, because an understated variance can make standard errors too small and intervals too narrow. The primary endpoint is continuous, and the registry reports standard errors and an ANCOVA description; it does not report an over-dispersion assessment. Over-dispersion should therefore be understood as a general statistical concept, not as a problem documented for this trial.

How do the binary secondary outcomes differ?

Blood-pressure control and successful systolic response are reported as percentages, and their group contrasts are expressed as risk differences. In general, a risk difference subtracts the event proportion in one group from the proportion in the other, so it is expressed on the probability scale. The registry also lists relative risk and odds-ratio summaries for those outcomes. These measures describe different scales of association, and their numerical values are not interchangeable. The posted p-values for these secondary contrasts are unadjusted.

For a continuous endpoint, a mean difference compares group averages; for a binary endpoint, a risk difference compares proportions meeting a definition. The endpoint type determines what is being estimated and what assumptions are relevant. The registry does not include the precise clinical definitions for every binary response threshold, so these should not be reconstructed from the outcome titles alone.

Finally, statistical significance and practical importance are distinct. In general, a result can be estimated precisely yet be small in practical terms, or be potentially important but too imprecise to distinguish clearly from no difference. Interpreting either requires the scale, uncertainty, and a meaningful threshold. The registry record does not report a threshold for clinical importance for the primary blood-pressure difference.

11. Confidence Intervals and Precision

The primary mean difference is -0.76 mmHg, with a reported confidence interval from -2.146 to 0.626 mmHg. The interval crosses zero, so the estimate is compatible with no difference as well as with differences in either direction. Its span also shows why the point estimate alone is not a complete description: uncertainty around the estimate is substantial relative to the estimate itself.

In general, a confidence interval expresses uncertainty associated with an estimate under the statistical model and procedure used. A narrower interval indicates greater precision on the measurement scale; a wider interval indicates less precision. The interval does not describe the range of individual participant responses. It also does not establish clinical importance, because that requires a context-specific threshold that is not reported in the registry record.

The standard errors for the two primary group estimates are each 0.5 mmHg. These quantify uncertainty in the estimated group means, not variation among participants. The comparison interval is the more direct summary of uncertainty for the difference between groups. The registry record does not state the confidence level alongside the reported interval in the endpoint details, so it is best to describe the bounds as the reported confidence interval without assigning a level not stated there.

The reported interval includes values below and above zero, while the unadjusted p-value is 0.282. Read together, these indicate that the trial’s posted estimate does not precisely distinguish the meal-condition groups on the primary endpoint. This is not proof that their effects are the same. A claim of equivalence or non-inferiority would require a prespecified margin and an analysis designed for that question; such a margin or analysis is not reported in the registry record.

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 this continuous or binary endpoint, rather than total events. The stated illustration assumes a two-sided significance level of 0.05, equal allocation between the two arms, and a normal approximation. The effect to detect is set to the stated fraction of the observed effect. The registry record does not report the assumptions used for the trial’s original design or its original sample-size justification.

The 80% power column gives the planned number of participants per arm for a hypothetical future study to have an 80% chance of detecting the assumed effect under the planning model, if that effect and the other assumptions hold. The 90% power column gives the corresponding number for a 90% chance. These are design probabilities under assumptions, not guarantees for any particular study. The figures are planning illustrations based on the observed effect, not observed power.

Rows described as planning for 100%, 75%, or 50% of the observed effect use progressively smaller assumed effects. Smaller effects are generally harder to distinguish from random variation, so they require more participants under the same planning assumptions. For example, the primary endpoint’s illustration lists 1,798 participants per arm for 80% power when planning for 100% of the observed effect, and 7,189 participants per arm when planning for 50% of it. These hypothetical figures should not be read as evidence that the trial had, or lacked, a particular power for its actual design.

The illustration is sensitive to its assumptions, including the observed effect used as its starting point. If the true effect differs from that estimate, the number needed to detect it can also differ. The registry record does not report the original design target, the effect size assumed by the sponsor, or the method used to choose the enrolled sample. The planning figures are therefore useful for understanding how assumed effect size relates to sample requirements, not for evaluating the original design as if its assumptions were known.

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 = -0.760; pooled standard deviation σ = 8.132.
2. n = 2 × (1.96 + 0.842)² × 8.132² / -0.760² = 1,797.2, rounded up to 1,798 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 <- -0.76                      # observed difference in means
sigma <- 8.13185924157924                     # 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(1570686)
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 = 1,798 (80% power), 2,406 (90% power)
 75% of observed effect: n per arm = 3,195 (80% power), 4,278 (90% power)
 50% of observed effect: n per arm = 7,189 (80% power), 9,624 (90% power)
power.t.test: 1798.1 
Simulated power at n = 1,798 per arm: 0.805 (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

Multiplicity arises when several hypotheses are tested and the results are considered together. In general, the more tests performed, the greater the chance that at least one result appears notable by chance alone if each is assessed without adjustment. A prespecified testing hierarchy or statistical adjustment can address this issue, but the registry record does not report a multiplicity procedure, an endpoint hierarchy, or an allocation of type I error across outcomes.

The primary endpoint is identified, and its comparison has an unadjusted p-value of 0.282. The listed secondary comparisons also have unadjusted p-values. Without a reported plan for handling multiple tests, the secondary p-values should not be read as if they were protected by a family-wise adjustment. The registry record does not report interim analyses or stopping rules, so it is not possible to determine whether repeated looks at accumulating data were planned or performed.

The primary analysis population is described as the Full Analysis Set: randomized patients, excluding mis-randomized patients, with ambulatory blood-pressure measurements at both baseline and week 8. Requiring both measurements means the primary estimate is based on participants with complete readings at these time points. The registry record does not report the number or characteristics of participants lacking either measurement, reasons for missingness, imputation, sensitivity analyses, or other missing-data procedures. It is therefore not possible to assess from the record whether missing outcomes could have affected the comparison.

The record reports enrollment of 589, while the primary endpoint lists outcome group sizes of 263 and 266. These are distinct registry quantities and should not be treated as interchangeable: enrollment is not the same as the number contributing to a particular analysis. The record does not provide a complete participant-flow account explaining all differences among enrolled, randomized, safety, and endpoint populations.

Although a primary ANCOVA model is described, the registry does not report detailed model diagnostics, assumptions checks, or sensitivity analyses. The absence of those details does not show that such procedures were omitted; it means their conduct and results are not reported in the registry record.

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

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: coronary artery stenosis (0.3%), wrist fracture (0.3%), gastritis (0.3%), staphylococcal infection (0.3%), overdose (0.3%).

The registry lists 295 participants at risk in the fed group and 294 in the fasting group for the serious adverse event summary. Serious adverse events affected 4 participants in the fed group and 2 in the fasting group. The record also lists other adverse events affecting 3 participants in the fed group and 16 in the fasting group. These are participant counts, not event totals, and should be read using the group denominators attached to each safety summary.

The registry lists several serious adverse event terms at 0.3% each: coronary artery stenosis, wrist fracture, gastritis, staphylococcal infection, overdose, and hypertension. The posted list does not establish that these terms were evenly distributed between groups or indicate causation. The death counts are null in the registry record, so death results are not reported in the registry record.

These summaries describe reported events in this study; they do not by themselves establish whether an event was caused by the study drug or by meal timing. The registry record does not provide enough detail to assess event timing, duration, severity beyond the serious classification, or the full clinical context. A numerical comparison of counts should also account for the different denominators and the limits of a study of this size and duration.

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

The primary result describes the estimated change in mean 24-hour ambulatory systolic blood pressure during 8 weeks in two groups taking the same daily dose under different meal conditions. The estimated mean change was -7.03 mmHg in the fed group and -7.79 mmHg in the fasting group; the estimated fasting-minus-fed difference was -0.76 mmHg. The confidence interval crosses zero, and the unadjusted p-value is 0.282. These posted statistics do not clearly distinguish the groups on the primary endpoint.

That finding is not proof that the meal conditions have identical effects. A non-significant comparison can reflect a small true difference, uncertainty, or both. Establishing equivalence would require a prespecified equivalence margin and an analysis designed to test whether the difference lies within that margin. Such a margin and analysis are not reported in the registry record.

The result also does not establish that either group experienced a particular change individually. Group-level least-squares means summarize model-based averages; individual responses may vary. Nor does the primary endpoint answer every question identified in the study purpose. Blood-pressure change is distinct from drug concentration, pharmacokinetics, plasma renin activity, and safety. Results for some of those secondary topics are not reported in the registry record.

The interpretation applies to the population and conditions recorded: patients with hypertension, aliskiren 300 mg once daily, light breakfast timing versus an overnight fast, and an 8-week study. The registry record does not support extrapolation to other doses, meal types, administration schedules, follow-up periods, or populations. It also does not provide a threshold for judging whether the estimated difference is clinically important.

Safety counts should be interpreted separately from the blood-pressure comparison. They record adverse events during the study but do not, on their own, determine causality or provide a complete benefit-risk assessment. The record’s event summaries are descriptive and should not be used to make individual treatment decisions.

17. Why This Trial Matters Statistically

This study illustrates how a randomized comparison can isolate a specific administration condition while holding the drug and dose constant across groups. Its question is narrower than a comparison of different drugs: it concerns whether taking aliskiren after a light breakfast versus after an overnight fast is associated with a different estimated blood-pressure change over the study period. That distinction matters when interpreting both the design and the scope of the result.

The example also shows why an estimate should be read together with its uncertainty. The primary difference is -0.76 mmHg, but the reported confidence interval crosses zero. The point estimate alone could encourage an overly definite interpretation; the interval makes clear that the data do not tightly identify the direction or size of the group difference. The unadjusted p-value is another part of the inferential summary, not a verdict about equivalence or importance.

The endpoint analysis demonstrates the role of baseline adjustment. The registry specifies ANCOVA with baseline as a covariate and treatment and region as factors. This makes the estimand model-based and highlights why a least-squares mean is not automatically the same as a raw group average. It also makes transparent reporting of model details and analysis populations important to reproducibility.

Finally, the record exposes common limits of registry results: incomplete reporting of multiplicity, missing-data handling, original sample-size planning, and some secondary findings. Planning illustrations based on the observed effect can help explain how effect assumptions influence sample requirements, but they cannot reconstruct the sponsor’s design rationale. Careful statistical interpretation distinguishes what is actually reported from what would require additional protocol or analysis information.

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 open-label design means participants and study staff knew the assigned meal condition. The primary outcome was assessed with ambulatory monitoring, but the registry record does not state whether those collecting, processing, or analyzing measurements were masked. This limits assessment of possible influence from awareness of assignment.

The primary endpoint analysis required ambulatory measurements at both baseline and week 8. The registry does not report the amount or pattern of missing endpoint data, reasons for missingness, or sensitivity analyses. Consequently, the extent to which the complete-measurement analysis represents all randomized participants cannot be evaluated from the record alone.

The registry identifies an ANCOVA model but does not provide a full statistical analysis plan, diagnostics, model assumptions, or detailed parameterization. It also does not report the original sample-size justification, the planned target effect, multiplicity procedures, or interim-analysis information. Those omissions limit evaluation of whether the analysis followed the original plan and how secondary findings were intended to be interpreted.

Several study questions concern pharmacokinetics and other secondary outcomes, but results for some listed measures are not reported in the registry record. The reported outcome set is therefore not a complete basis for assessing every aim in the study description. The safety summaries give participant counts and selected event terms but do not supply detailed event narratives or attribution information.

Finally, the primary endpoint is a group-level blood-pressure change over 8 weeks. The registry record does not state a threshold for clinical importance, and the comparison is not an equivalence analysis. The result should therefore be interpreted as a limited estimate of the contrast under the specific study conditions, not as a general statement about all meal conditions or patients.

19. Related Tutorials

20. Related Statistical Calculators

21. Sources

• ClinicalTrials.gov: 8-week Randomized, Open-label Study to Evaluate Food Effect on Efficacy and Safety of Oral Aliskiren 300 mg in Patients With Hypertension — NCT01570686.
• Registry record last updated 2014-01-22; status last verified 2014-01.
• Results first posted 2014-01-01.
• 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

NCT01570686 is a completed Phase 4 randomized, open-label, multicenter, parallel-group study in patients with hypertension. It compared oral aliskiren 300 mg once daily taken 30 minutes after the start of a light breakfast with the same dose taken after an overnight fast. The study lasted 8 weeks and enrolled 589 participants.

The primary endpoint was change from baseline to week 8 in mean 24-hour ambulatory systolic blood pressure. The posted least-squares mean changes were -7.03 mmHg for the fed group and -7.79 mmHg for the fasting group. The estimated difference was -0.76 mmHg, with a reported confidence interval crossing zero and an unadjusted p-value of 0.282.

The registry also lists blood-pressure, pharmacokinetic, plasma renin activity, and safety outcomes. Some secondary results, details of multiplicity and missing-data handling, and the original sample-size justification are not reported in the registry record.