Efficacy and Safety of Valsartan and Amlodipine in Patients With Essential Hypertension: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Efficacy and Safety of Valsartan and Amlodipine in Patients With Essential Hypertension (NCT00425373), a randomized phase 2, phase 3 study. The primary outcome is Change in Mean Sitting Diastolic Blood Pressure (MSDBP) From Baseline to End of Study (Week 8).

2. Clinical Question

3. Trial Design

This was a randomized, double-blind, parallel-group, placebo-controlled factorial study of treatment for essential hypertension. The registry lists the trial as Phase 2 and Phase 3, with an enrollment of 1474. The study status is completed. The listed start was 2006-11 and primary completion was 2008-03.

The factorial treatment set included two valsartan doses, two amlodipine doses, their four dose combinations, each drug alone, and placebo. This arrangement makes it possible to examine a range of regimens within one trial; however, the posted comparisons are active-arm comparisons with placebo. The registry record does not report an interaction analysis or an analysis separating the individual contributions of each drug in the combinations.

The registry describes masking as triple. It does not explain which study roles were masked, so no more specific account of masking can be given. The listed primary timeframe is baseline to the end of study at Week 8. For the primary outcome population, baseline is the Week 0 value, while the end-of-study value is the Week 8 value or the last observation carried forward value.

The registry reports enrollment and analyzed arm counts, but these quantities need not describe the same analysis population. The primary population definition requires a baseline and at least one post-baseline assessment of the measure being analyzed. Further details about participant flow, exclusions, treatment adherence, and deviations from assigned treatment are not reported in the registry record.

The registered study aim was to evaluate the efficacy and safety of combinations, monotherapies, and placebo in reducing blood pressure, including dose-response relationships. The original protocol’s sample-size justification, allocation ratio rationale, and full statistical analysis plan are 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.

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: Intent-to-treat (ITT): All randomized patients who had a baseline and at least one post-baseline assessment of the variable analyzed. Baseline is the Week 0 value and end of study is the value at Week 8 or the last observation carried forward (LOCF) value.

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 Change in Mean Sitting Diastolic Blood Pressure (MSDBP) From Baseline to End of Study (Week 8), measured over Baseline to end of study (Week 8).

The primary endpoint is change in mean sitting diastolic blood pressure (MSDBP) from baseline to the end of study at Week 8, measured in mm Hg. The registry reports a least-squares mean for each arm and its standard error. A negative value indicates lowered blood pressure; it does not represent an individual participant’s response or the proportion of participants who reached a threshold.

The protocol description says that blood pressure was measured in both arms at study entry, and that the arm with the higher diastolic reading was used for subsequent measurements. At each assessment, participants rested in a seated position for at least 5 minutes, and the measurement was repeated three times at intervals of 1 to 2 minutes. These repeated readings are a way of obtaining the blood-pressure measure used for the endpoint; the registry record does not give additional details about how those readings were combined.

A continuous change outcome retains information about the magnitude and direction of blood-pressure change, whereas a threshold outcome classifies participants according to whether a specified target or reduction was reached. That distinction matters when interpreting the primary result alongside the secondary responder outcomes. The primary endpoint was chosen to assess average change over the stated treatment period. The registry record does not report the rationale for selecting this endpoint over other blood-pressure measures.

The primary population is described as intent-to-treat, but with an assessment requirement: randomized participants had to have a baseline and at least one post-baseline assessment of the analyzed variable. The end-of-study value could be the Week 8 observation or a last-observation-carried-forward value.

7. Results Posted in the Registry

• Valsartan + Amlodipine 40/2.5 mg: mean -13.50 versus -4.80 on control; difference -8.70 (95% CI -10.40 to -7.00), standardized effect d = -1.11; z-test p = <0.001.
• Valsartan + Amlodipine 40/5 mg: mean -16.50 versus -4.80 on control; difference -11.70 (95% CI -13.38 to -10.02), standardized effect d = -1.50; z-test p = <0.001.
• Valsartan + Amlodipine 80/2.5 mg: mean -12.60 versus -4.80 on control; difference -7.80 (95% CI -9.50 to -6.10), standardized effect d = -0.99; z-test p = <0.001.
• Valsartan + Amlodipine 80/5 mg: mean -17.00 versus -4.80 on control; difference -12.20 (95% CI -13.89 to -10.51), standardized effect d = -1.56; 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.

Change in Mean Sitting Systolic Blood Pressure (MSSBP) From Baseline to End of Study (Week 8)

• 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:
  • Valsartan + Amlodipine 40/2.5 mg: mean -16.70 versus -4.40 on control; difference -12.30 (95% CI -14.71 to -9.89), standardized effect d = -1.11; z-test p = <0.001.
  • Valsartan + Amlodipine 40/5 mg: mean -22.00 versus -4.40 on control; difference -17.60 (95% CI -19.98 to -15.22), standardized effect d = -1.59; z-test p = <0.001.
• Interpretation:
  • The 95% confidence interval excludes no difference, so the mean is statistically lower for Valsartan + Amlodipine 40/2.5 mg than for the control. This is an unadjusted, secondary comparison, so it is suggestive rather than confirmatory.
  • The 95% confidence interval excludes no difference, so the mean is statistically lower for Valsartan + Amlodipine 40/5 mg than for the control. This is an unadjusted, secondary comparison, so it is suggestive rather than confirmatory.

Percentage of Patients Achieving MSDBP < 90 mmHg or a => 10 mm Hg Decrease Compared to Baseline at the End of the Study (Week 8)

• 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:
  • Valsartan + Amlodipine 40/2.5 mg: 77.4% (123/159) versus 36.1% (60/166) on control; risk difference 41.2 percentage points (95% CI 31.4 to 51.0), risk ratio 2.14 (1.72–2.66); unadjusted two-proportion z-test p = <0.001.
  • Valsartan + Amlodipine 40/5 mg: 88.0% (147/167) versus 36.1% (60/166) on control; risk difference 51.9 percentage points (95% CI 43.1 to 60.7), risk ratio 2.44 (1.97–3.00); unadjusted two-proportion z-test p = <0.001.
• Interpretation:
  • The 95% confidence interval excludes no difference, so the proportion with the event is statistically higher for Valsartan + Amlodipine 40/2.5 mg than for the control. This is an unadjusted, secondary comparison, so it is suggestive rather than confirmatory.
  • The 95% confidence interval excludes no difference, so the proportion with the event is statistically higher for Valsartan + Amlodipine 40/5 mg than for the control. This is an unadjusted, secondary comparison, so it is suggestive rather than confirmatory.

Percentage of Patients Achieving MSDBP < 90mmHg at the End of the Study (Week 8)

• 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:
  • Valsartan + Amlodipine 40/2.5 mg: 67.3% (107/159) versus 31.9% (53/166) on control; risk difference 35.4 percentage points (95% CI 25.2 to 45.5), risk ratio 2.11 (1.65–2.70); unadjusted two-proportion z-test p = <0.001.
  • Valsartan + Amlodipine 40/5 mg: 82.6% (138/167) versus 31.9% (53/166) on control; risk difference 50.7 percentage points (95% CI 41.6 to 59.8), risk ratio 2.59 (2.05–3.27); unadjusted two-proportion z-test p = <0.001.
• Interpretation:
  • The 95% confidence interval excludes no difference, so the proportion with the event is statistically higher for Valsartan + Amlodipine 40/2.5 mg than for the control. This is an unadjusted, secondary comparison, so it is suggestive rather than confirmatory.
  • The 95% confidence interval excludes no difference, so the proportion with the event is statistically higher for Valsartan + Amlodipine 40/5 mg than for the control. This is an unadjusted, secondary comparison, so it is suggestive rather than confirmatory.

The secondary outcomes extend the primary question in two ways: the systolic measure provides another continuous blood-pressure endpoint, while the responder outcomes classify participants using diastolic blood-pressure thresholds or reductions. The posted pattern is broadly aligned with the primary endpoint in that the reported active-arm results generally show greater changes or higher responder percentages than placebo. These measures nevertheless answer different questions, so they should not be treated as interchangeable confirmations of one single effect.

The systolic endpoint is reported as mean change from baseline to Week 8. The registry also lists responder outcomes based on achieving MSDBP below 90 mm Hg, a specified decrease from baseline, or combined systolic and diastolic thresholds. The registry record does not report results for every listed secondary outcome, so the available findings do not give a complete account of all secondary measures identified in the record.

Secondary outcomes can support interpretation by showing whether the pattern is consistent across related measurements, but they usually have less evidential weight than a prespecified primary analysis. Each additional outcome or contrast creates another opportunity for a result to appear notable by chance. The posted comparisons are unadjusted, and the record does not report a multiplicity procedure or a sponsor analysis for these secondary results. Thus, individual p-values should be interpreted cautiously rather than as definitive evidence across the entire outcome family.

Differences in endpoint definition also affect comparisons. A responder measure depends on its threshold and on where participants began, while a mean change reflects the average shift. The registry provides the endpoint definitions and group-level results, but it does not report participant-level distributions that could show how many participants were close to a threshold or how response varied within each arm. The secondary findings are best read as complementary descriptions of the short-term blood-pressure results, not as a substitute for the primary analysis or as evidence about outcomes not measured in the trial.

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

• Change in Mean Sitting Systolic Blood Pressure (MSSBP) From Baseline to End of Study (Week 8)
• Percentage of Patients Achieving MSDBP < 90 mmHg or a => 10 mm Hg Decrease Compared to Baseline at the End of the Study (Week 8)
• Percentage of Patients Achieving MSDBP < 90mmHg at the End of the Study (Week 8)
• Percentage of Patients Achieving MSDBP < 90 mm Hg and MSSBP < 140 mm Hg at the End of the Study (Week 8)

9. Statistical Interpretation

10. Statistical Methods Explained

For a continuous endpoint such as change in MSDBP, the basic comparison is the difference between the average changes in two arms. The registry reports least-squares mean changes and standard errors for the arms. A least-squares mean is a model-based mean; the registry record does not describe the model or the covariates used to obtain these values. The recalculated contrasts use the posted arm summaries to estimate each active treatment’s mean difference from placebo.

What does a standard error describe?

In general, a standard error describes the uncertainty in an estimated quantity, such as a mean, rather than the spread of measurements among participants. A smaller standard error generally indicates a more precise estimate, all else being equal. The primary arm results report standard errors of 0.60, 0.61, or 0.62 mm Hg, depending on the arm. These values should not be interpreted as the range of individual blood-pressure changes.

The recalculated comparison intervals require an estimate of variability for the contrast. The posted analysis indicates that the pooled standard deviations were approximate, derived from arm standard errors and sample sizes. That makes the recalculated intervals and p-values useful as unadjusted summaries of the posted data, but they are not reported sponsor analyses. The registry record does not supply the original model details needed to reproduce the sponsor’s analysis independently.

How should the p-values be read?

In general, a p-value measures how compatible the observed data are with a specified null hypothesis, under the assumptions of the statistical test. It is not the probability that the null hypothesis is true, nor does it measure the size or clinical importance of an effect. The recalculated p-values are labeled unadjusted and are <0.001 for each primary active-treatment comparison with placebo. Since the record does not report a multiplicity adjustment for these contrasts, the values should not be treated as if they controlled the chance of a false positive across the full set of comparisons.

The sign of a mean difference depends on the order of subtraction used. In these posted comparisons, the estimate is the active-arm change minus the placebo change. Because negative changes indicate lowered blood pressure, a negative contrast means the active arm’s estimated change is more negative than placebo’s. This is a comparison of arm means; it does not imply that every participant in that arm had a greater reduction.

Why use both continuous and threshold outcomes?

In general, continuous outcomes preserve the measured magnitude of change, while binary outcomes classify people into categories such as achieving a threshold. A continuous average may capture shifts that do not move participants across a cutoff. Conversely, a responder percentage can be easier to interpret as the share meeting a defined target, but it discards information about how far individual measurements lie from that target. The secondary outcomes include mean systolic blood-pressure change and several diastolic blood-pressure responder definitions.

For a binary outcome, a risk difference expresses the difference between the proportions meeting the specified outcome in two arms. The recalculated secondary comparisons report risk differences for the posted responder outcomes. In general, an interval around a risk difference reflects uncertainty in that difference; a range that excludes no difference is evidence against equal proportions under the assumptions used. These secondary comparisons are also unadjusted, and the record does not report sponsor analyses for them.

What does the factorial design contribute?

In general, a factorial design can arrange treatments so that the effects of separate factors and their combinations may be assessed efficiently. Here the treatments cover two valsartan doses, two amlodipine doses, and the combinations of those doses, alongside monotherapies and placebo. However, the design label alone does not establish which factorial effects were estimated. The registry record does not report an interaction analysis, a dose-response model, or a model comparing the combination with each of its individual components. Interpretation should therefore remain with the reported arm estimates and posted comparisons.

Randomization is intended to balance measured and unmeasured characteristics across assigned groups on average. It does not guarantee identical groups in a particular trial, and the registry record does not provide baseline characteristics for evaluating balance. Double-blind design can limit some forms of bias related to knowledge of treatment assignment, but the record’s masking description does not specify which roles were masked. The analysis population definition and use of last observation carried forward are also relevant to how the recorded endpoint represents participants’ follow-up.

11. Confidence Intervals and Precision

The posted primary comparison intervals give a range of estimates compatible with the recalculated data and assumptions. For example, the mean difference for valsartan/amlodipine 40/2.5 mg versus placebo is -8.7 mm Hg, with an interval from -10.4 to -6.995. For valsartan/amlodipine 80/5 mg, the estimate is -12.2 mm Hg, with an interval from -13.89 to -10.51. The interval limits for all eight primary comparisons are on the negative side of zero. The recalculated p-values are <0.001 for each comparison.

In general, a confidence interval conveys both the estimated direction and the uncertainty around an estimate. A narrow interval indicates greater precision than a wide interval, assuming the same method and estimand. The confidence level used for the recalculated intervals is not reported in the registry record, so it should not be inferred from the interval limits alone. These intervals were recalculated from posted summary statistics, with approximate pooled variability, rather than reported as the sponsor’s own model-based intervals.

Precision is not the same as clinical importance. A relatively precise estimate can still require interpretation in light of the outcome, study duration, analysis population, and limits of the design. The standard errors of the arm means describe uncertainty around those means; they should not be substituted for intervals around the treatment contrasts. Conversely, the contrast intervals do not describe the range of responses among individual participants.

The posted sample sizes for each arm and their standard errors contribute to the precision of the recalculated comparisons. The registry record does not provide participant-level data, the full sponsor model, or further information about missing observations, so other sources of uncertainty cannot be assessed from the posted results alone. Interval estimates for the secondary outcomes also reflect unadjusted recalculations, and multiple comparisons remain relevant to their interpretation.

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 illustrative estimates for future comparisons, not the trial’s original sample-size justification. For the non-time-to-event outcomes shown, the figures are participants per arm, not a total across arms. The planning assumptions are a two-sided significance level of 0.05, equal allocation between the two arms, and a normal approximation. Each planning scenario targets the stated fraction of the observed effect. The original trial’s own design assumptions and sample-size justification are not reported in the registry record.

The 80% power column gives the estimated participants per arm for a design with an 80% chance of detecting the assumed effect under those planning assumptions, if that effect is present. The 90% power column uses a higher chance of detecting the same assumed effect, and therefore generally requires more participants per arm. These are planning illustrations and not observed power.

The rows use the full observed effect, 75% of the observed effect, and 50% of the observed effect. An effect closer to the observed estimate is larger than a reduced fraction of that estimate; smaller effects are harder to distinguish from random variation and need more participants. The figures can therefore rise as the assumed effect is reduced. They depend on the observed data and simplifying assumptions, so they should not be taken as a replacement for a design-specific calculation using an independently justified target effect, the intended analysis, and allowances for missing data or other design features.

The curve should be read as a visual counterpart to these planning scenarios: it illustrates how the estimated participant requirement changes with the assumed effect size. It does not describe enrollment or power actually achieved in this completed trial. The registry record does not report the original protocol’s assumptions, and the planning values should not be used to infer them.

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 = -8.700; pooled standard deviation σ = 7.839.
2. n = 2 × (1.96 + 0.842)² × 7.839² / -8.700² = 12.7, rounded up to 13 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 <- -8.7                      # observed difference in means
sigma <- 7.83907727399979                     # 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(425373)
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 = 13 (80% power), 18 (90% power)
 75% of observed effect: n per arm = 23 (80% power), 31 (90% power)
 50% of observed effect: n per arm = 51 (80% power), 69 (90% power)
power.t.test: 13.8 
Simulated power at n = 13 per arm: 0.771 (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 lists a primary outcome and several secondary blood-pressure outcomes, with multiple treatment arms compared against placebo. The posted recalculations report unadjusted p-values. The registry record does not report a multiplicity adjustment, a hierarchical testing sequence, or another procedure for controlling error across the many potential comparisons. As a result, the individual p-values do not by themselves establish that the overall set of findings has a controlled false-positive rate. This is particularly relevant for secondary outcomes and for interpreting patterns across the different doses and combinations.

The record does not report a statistical analysis plan specifying which comparisons were prespecified as confirmatory, how the factorial structure was modeled, or how the listed endpoints were prioritized. It also does not report interim analyses. These details should not be assumed from the randomized factorial design or from the presence of posted results.

The primary population is described as intent-to-treat, but it is operationally defined as randomized participants with a baseline and at least one post-baseline measurement of the variable analyzed. The end-of-study value may be the Week 8 observation or the last observation carried forward value. This definition means the analysis does not simply include every randomized participant regardless of available outcome measurements. The registry record does not state how many randomized participants lacked qualifying assessments, how missingness differed by arm, or whether sensitivity analyses were conducted.

In general, last observation carried forward fills a missing later measurement with the participant’s most recently recorded value. This can make an analysis possible when a planned endpoint is missing, but it relies on an assumption that the carried-forward value is an adequate stand-in for the unobserved value. That assumption may not hold if the measure would have changed after the last observation. The registry record does not report a comparison with other missing-data methods or an evaluation of the robustness of the findings to missingness.

Reported analyses for the comparisons are absent from the registry record. The posted recalculations are therefore descriptive, unadjusted comparisons based on the arm summaries, rather than a reconstruction of an undocumented sponsor model.

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: compression fracture (0.6%), supraventricular tachycardia (0.6%), ulcerative keratitis (0.6%), pyelonephritis acute (0.6%), gastroenteritis (0.6%).

The adverse-event results report serious adverse events and other adverse events by arm. The serious adverse-event counts are 2 in the placebo group, 1 in the amlodipine 2.5 mg group, 1 in the valsartan/amlodipine 80/2.5 mg group, and 1 in the valsartan/amlodipine 40/5 mg group. The other treatment arms report zero serious adverse events. For other adverse events, the arm counts range from 9 in the valsartan/amlodipine 80/2.5 mg group to 23 in the valsartan 40 mg group. These are counts as recorded, not adjusted comparisons of risk.

The registry lists five serious adverse-event terms with a frequency of 0.6% each: compression fracture, supraventricular tachycardia, ulcerative keratitis, acute pyelonephritis, and gastroenteritis. These terms should not be read as a complete description of all events or as evidence that a particular treatment caused them. The record does not report deaths by arm, so death counts are not reported in the registry record.

In general, adverse-event counts need context about event definitions, follow-up, and attribution. The trial’s listed treatment period was 8 weeks, and these results alone do not establish comparative safety over longer periods. No inference about rare events or small between-arm differences should be based solely on these counts.

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

The posted primary results describe average changes in sitting diastolic blood pressure through Week 8. The active-treatment arm means are more negative than the placebo mean, and the recalculated active-versus-placebo mean differences are negative, with unadjusted p-values of <0.001. In the endpoint’s stated direction, a negative change represents lowered blood pressure. The estimates indicate differences in group averages; they do not describe the experience of every participant.

These results do not establish the long-term effect of treatment, effects on outcomes other than the blood-pressure measures recorded, or how the results apply to people outside the trial population. The registry identifies essential hypertension but does not provide further demographic or clinical characteristics in the information. The study’s primary endpoint is a short-term measurement, with the Week 8 result potentially replaced by a last observation carried forward value.

The posted recalculations are not the same as a complete trial analysis. Their variability estimates are approximate, their p-values are unadjusted, and the registry record does not include the sponsor’s reported analyses or full statistical model. The comparison intervals describe uncertainty in the recalculated contrasts but do not establish that every plausible source of uncertainty has been addressed. The record also does not report a multiplicity plan, detailed missing-data analyses, or a factorial interaction analysis.

Safety counts should likewise be interpreted within the reported follow-up and as descriptive event totals. The registry does not report deaths, and the posted event information cannot alone determine whether observed events were caused by a study treatment or whether uncommon risks differ between arms.

Overall, the record supports a description of the measured, short-term blood-pressure patterns and the adverse events recorded during the trial. It does not by itself justify treatment recommendations or conclusions beyond the studied outcomes, participants, follow-up, and analyses. Further details not reported in the registry record would be needed to resolve questions about longer-term outcomes, subgroup effects, or the robustness of results to alternative analysis choices.

17. Why This Trial Matters Statistically

Statistically, this trial is useful because it places several dose combinations, the component drugs, and placebo within a randomized factorial framework. The posted results make it possible to compare the reported short-term mean changes across a broad set of regimens, while the secondary outcomes add systolic and threshold-based views of blood-pressure response. The design therefore illustrates how the choice of endpoint changes the question being answered: a mean change concerns average magnitude, while a responder endpoint concerns the share meeting a defined criterion.

The record also illustrates why a trial’s design label and its reported analyses are not the same thing. A factorial design may support questions about separate factors and their combinations, but the registry’s posted comparisons are against placebo. Without a reported interaction or dose-response analysis, the design alone does not provide those conclusions. Similarly, randomized allocation and masking are relevant design features, but they do not replace inspection of the endpoint definition, analysis population, missing-data handling, and comparison plan.

There is also an important distinction between sponsor analyses and calculations reconstructed from posted summaries. The recalculated estimates can help readers understand the scale and precision of group contrasts, but the approximate variability and lack of a reported sponsor analysis limit how far they can stand in for a full model-based result. The unadjusted comparisons additionally show why multiplicity matters when many arms and endpoints are considered together.

Finally, this record links statistical interpretation to the scope of measurement. The primary outcome concerns sitting diastolic blood pressure over the stated follow-up, not a broader set of clinical outcomes. Reading the results within those boundaries helps prevent a precise numerical contrast from being mistaken for a complete assessment of efficacy, safety, or longer-term consequences.

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 primary outcome is measured over baseline to Week 8, which limits interpretation to the stated short-term period. The registry record does not report longer-term follow-up results. The arm descriptions do not provide additional treatment-administration or adherence details, and participant flow and reasons for missing assessments are not reported in the registry record.

The primary analysis population requires a baseline and at least one post-baseline assessment. The endpoint at the end of study may use the Week 8 observation or last observation carried forward. Without reported missingness counts, sensitivity analyses, or comparisons with other missing-data approaches, it is difficult to assess how missing measurements may affect the estimates.

The outcome description specifies sitting blood-pressure measurement and the use of the arm with the higher diastolic reading at study entry for subsequent measurements. This makes the results specific to the stated measurement procedure and endpoint definition. The registry does not report baseline blood-pressure summaries, participant characteristics, or detailed subgroup results, limiting assessment of generalizability and baseline comparability from the record alone.

The study includes several treatment arms and multiple outcomes, but the registry does not report a multiplicity strategy, full analysis plan, interim analyses, factorial interaction results, or dose-response model. The posted comparisons are unadjusted recalculations, with approximate pooled variability derived from arm summaries. Their confidence level is not reported in the registry record. These features counsel against interpreting the recalculations as replacements for sponsor analyses or treating every individual comparison as confirmatory.

Safety information is limited to posted adverse-event counts and listed serious event terms. Death counts are not reported in the registry record, and the record does not provide further detail on event attribution or longer-term safety follow-up. The information available therefore supports a limited descriptive account of recorded events rather than a complete comparative safety assessment.

19. Related Tutorials

20. Related Statistical Calculators

21. Sources

• ClinicalTrials.gov: Efficacy and Safety of Valsartan and Amlodipine in Patients With Essential Hypertension — NCT00425373.
• Registry record last updated 2011-04-29; status last verified 2011-04.
• Results first posted 2011-02-04.
• 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

NCT00425373 is a completed randomized, double-blind, parallel-group, placebo-controlled factorial study in essential hypertension. It evaluated valsartan, amlodipine, their combinations, and placebo, with a listed treatment period of 8 weeks. The registry reports enrollment of 1474 and identifies Phase 2 and Phase 3.

The primary outcome is change in mean sitting diastolic blood pressure from baseline to Week 8. Posted arm means are negative, and the unadjusted recalculated active-versus-placebo mean differences are also negative, with p-values <0.001. Secondary outcomes include systolic blood-pressure change and threshold-based blood-pressure responder measures. Adverse-event counts are reported by arm.

The posted comparison estimates are recalculations from summary results, with approximate variability; sponsor analyses and several details of the statistical plan are not reported in the registry record. Interpretation is limited to the stated outcomes, analysis population, and follow-up.