A Pharmacodynamic Study to Evaluate the Effect of a Fixed Dose Combination Pill on Blood Pressure: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for A Pharmacodynamic Study to Evaluate the Effect of a Fixed Dose Combination Pill on Blood Pressure (NCT01005290), a randomized phase 2 study. The primary outcome is Difference in the Adjusted Mean 24-h Systolic Pressure Results (Using ABPM) Between the Basal and the Final Visit of Each Treatment Period..

2. Clinical Question

The study concerns a pharmacodynamic comparison of blood-pressure changes, not a comparison of clinical events. Its primary endpoint is the change in systolic pressure over a treatment period. The listed treatment conditions both contain ramipril, but the combination pill also contains acetylsalicylic acid and simvastatin. The question is therefore about the observed pressure change under these regimens, not about the effect of any single added ingredient in isolation.

The registry describes a randomized crossover design, so treatment conditions were compared across treatment periods. The specific treatment sequence, period-assignment details, and any washout arrangements are not reported in the registry record. The registry also does not report enough detail to establish how the posted summaries account for the paired nature of crossover measurements.

3. Trial Design

This was a Phase 2, randomized, open-label crossover study sponsored by Ferrer Internacional S.A. The registry lists hypertension as the condition under study and enrollment of 38. The study began in 2009-10, had primary completion in 2010-10, and its status is recorded as terminated. The reason for termination is not reported in the registry record.

The two treatment conditions were the cardiovascular combination pill and ramipril alone. The record describes the combination as containing acetylsalicylic acid, simvastatin, and ramipril. Its arm description is truncated after the initial dosing information, so the full treatment-period regimen cannot be reconstructed from the registry record. For ramipril alone, the description states 5 mg once daily for one week followed by 10 mg once daily for 4 weeks.

A crossover design means treatment conditions are given in different periods, allowing measurements under more than one condition within a participant. That design can make comparisons sensitive to within-participant changes, but interpretation also depends on the order of treatment, timing, and possible carryover between periods. The registry record does not report the sequence details or a washout plan. The primary endpoint timeframe lists days 7 and 36 of Period 1 and days 49 and 85 of Period 2.

The primary analysis population is described as the PP set: randomized subjects who received at least one dose of investigational medicinal product, had a baseline primary endpoint measurement and at least one post-baseline primary endpoint measurement, and had no major protocol deviations. The posted primary summaries contain 17 participants for the combination pill and 17 for ramipril. The registry does not report how participants outside that analysis set were handled or why the endpoint summaries include these counts.

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: 52 subjects enrered the run-in period with ramipril 2.5 mg, 38 subjects were randomized. 20 subjects were randomized to Sequence Combination pill/ Ramipril and 18 subjects to sequence Ramipril /Combination pill.

Run-In

Period 1 (5 Weeks)

Washout Period (2 Weeks)

Period 2 (5 Weeks)

Analysis population for the primary outcome, as defined in the registry: The PP set included all randomized subjects who received at least one dose of IMP, had a baseline primary endpoint measurement, had at least one post baseline primary endpoint measurement, and who had no major protocol deviations. The PP set served as the primary analysis set for analysis of the primary endpoint.

5. Baseline Characteristics

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

6. Primary Endpoint

The registry lists the primary outcome as Difference in the Adjusted Mean 24-h Systolic Pressure Results (Using ABPM) Between the Basal and the Final Visit of Each Treatment Period., measured over Days 7 and 36 of Period 1 and days 49 and 85 of Period 2.

The primary endpoint is the difference in adjusted mean 24-hour systolic pressure, measured by ambulatory blood pressure monitoring, between the basal and final visit of each treatment period. The listed visits are days 7 and 36 of Period 1 and days 49 and 85 of Period 2. The unit is mm Hg, and the registry describes the endpoint as a mean with standard deviation in the PP population.

Systolic pressure is the pressure recorded when the heart contracts. A 24-hour ambulatory measurement characterizes pressure across an extended monitoring period rather than relying on a single clinic reading. In general, repeated measurements over time can give a broader picture of a continuous physiological measure. The endpoint is used to assess whether the recorded pressure change differs between treatment conditions.

The registry calls the endpoint an adjusted mean result, but the adjustment variables and statistical model are not reported in the registry record. The posted summaries give mean changes for each treatment condition and a mean-difference comparison. Those summaries do not, by themselves, establish the exact analysis used by the sponsor or how the crossover structure was modeled. The endpoint addresses blood-pressure change during the recorded treatment periods; it is not a direct measure of long-term cardiovascular outcomes.

7. Results Posted in the Registry

• Ramipril: mean -4.40 versus -2.40 on control; difference -2.00 (95% CI -7.68 to 3.68), standardized effect d = -0.24; z-test p = 0.490.

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.

Difference in the Adjusted Mean 24-h Diastolic Pressure Results Between the Basal and the Final Visit of Each Treatment Period

• Endpoint type: Continuous: a mean value per participant, compared as a difference in means.
• Test: Unadjusted two-sample z-test for the difference in means, using the posted standard deviations.
• Result:
  • Ramipril: mean -2.88 versus -1.85 on control; difference -1.03 (95% CI -5.23 to 3.17), standardized effect d = -0.17; z-test p = 0.630.
• Interpretation:
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between Ramipril and the control. The interval gives the range of effects that remain compatible with the data.

The registry posts one secondary endpoint: change in adjusted mean 24-hour diastolic pressure. Its broad pattern is consistent with the primary endpoint in that mean changes are negative under both treatment conditions, while the contrast between conditions remains uncertain. Thus, the secondary result does not materially alter the overall reading of the primary systolic comparison. It does not resolve the uncertainty about the direction or size of the difference.

Diastolic and systolic pressure are related but distinct continuous outcomes. Agreement in their broad direction can be informative descriptively, but it is not equivalent to independent replication: both outcomes come from the same study, participants, treatment periods, and registry record. The secondary result should be interpreted in the context of the study design and the limitations in analysis reporting rather than treated as a separate experiment.

The registry identifies two outcome measures and posts one secondary endpoint, but lists no reported analyses. It does not state whether the secondary endpoint was prespecified in the analysis plan, how it was modeled, or whether adjustment for multiple comparisons was planned. When multiple outcomes are examined, unadjusted results have less confirmatory weight because the chance of apparently notable findings can increase across tests. Without a reported multiplicity strategy, the secondary endpoint is most appropriately treated as supportive description.

The secondary information does not establish that the two treatment conditions are equivalent, nor does it establish a meaningful difference. Its role is to provide additional context about a related blood-pressure measure, while the interpretation remains constrained by imprecision, the per-protocol analysis population, and the limited detail on crossover analysis methods.

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

• Difference in the Adjusted Mean 24-h Diastolic Pressure Results Between the Basal and the Final Visit of Each Treatment Period

9. Statistical Interpretation

10. Statistical Methods Explained

The primary outcome is continuous: it is a mean change in systolic pressure measured in mm Hg. For a continuous outcome, a group mean describes the center of the observed measurements, while a standard deviation describes their spread around that mean. The posted primary summaries report a mean of -2.4 with standard deviation 8.726 for the combination pill, and a mean of -4.4 with standard deviation 8.173 for ramipril. A negative change indicates a reduction from the basal measurement as represented by the endpoint definition; the magnitude and interpretation depend on the study's measurement and analysis details.

The comparison is expressed as a mean difference. With ramipril as the comparison condition against the combination pill, the reported estimate is -2.0 mm Hg. The sign depends on the order of subtraction, so the estimate should be read alongside its stated contrast rather than by its sign alone. A mean difference describes the difference between average changes; it does not say that every participant experienced that difference. Variation among participants is reflected in the dispersion and the uncertainty around the comparison.

What does a confidence interval express?

A confidence interval gives a range of values compatible with the observed data under the statistical procedure used to construct it. It communicates precision as well as direction: a narrow interval indicates a more precise estimate, while a wide interval leaves greater uncertainty about the size and direction of the underlying contrast. For the primary result, the interval extends from -7.683 to 3.683 mm Hg. Because zero lies within that range, the data do not distinguish the estimated contrast from no difference using this interval alone. The interval also includes values on either side of zero, so it does not pin down which condition has the larger mean reduction.

What does the p-value add?

The unadjusted p-value for the primary comparison is 0.49. In general, a p-value describes how unusual data at least as incompatible with a specified null hypothesis would be if that null hypothesis and the model assumptions were true. It is not the probability that the null hypothesis is true, nor a measure of the probability that a treatment is beneficial. It also does not convey the range of plausible effect sizes, so it should be read alongside the estimate and confidence interval. The registry does not report a multiplicity adjustment or a detailed analysis plan for the p-value.

Why does the crossover design matter?

In a crossover study, each participant can receive treatment conditions in distinct periods. Observations from the same participant may be related; a comparison that accounts for this pairing can use information about within-participant changes. Period effects, sequence effects, and carryover can also affect interpretation. The registry identifies the design as crossover, but does not report the treatment sequence, washout details, or an analysis model specifying how these features were handled. The posted arm summaries and comparison are not enough to determine whether the sponsor's analysis used a paired model or another crossover-specific method.

The endpoint description uses the phrase adjusted mean, but the adjustment factors and model are not stated. No sponsor-reported analyses are listed in the registry record. Thus, the posted endpoint summaries should not be treated as a complete account of the model-based analysis, and it is not possible to verify from the record whether covariates, period, or sequence were included in the sponsor's analysis.

What does the analysis population represent?

The primary population is described as PP, a per-protocol set. It includes randomized subjects who received at least one dose, had a baseline primary endpoint measurement, had at least one post-baseline primary endpoint measurement, and had no major protocol deviations. This definition focuses on participants with specified exposure and measurements who met the stated protocol criteria. It is not identical in principle to an analysis of all randomized participants, because people can be excluded for missing measurements or major deviations.

The registry does not report the number or reasons for exclusions, the amount of missing endpoint data, or the method used to address missing data. It also does not report whether an intention-to-treat analysis was conducted. Without those details, the effect of analysis-population choices on the estimated contrast cannot be assessed.

How should secondary testing be viewed?

The registry lists a secondary continuous endpoint for adjusted mean 24-hour diastolic pressure. Multiple outcomes can create multiple opportunities to observe apparently noteworthy results by chance, especially if results are interpreted as confirmatory without an adjustment strategy. The registry does not report a multiplicity procedure, and it lists no reported analyses. The secondary endpoint is therefore best understood as additional descriptive evidence, with its own uncertainty, rather than as a definitive confirmation of the primary result.

11. Confidence Intervals and Precision

The primary mean difference is -2.0 mm Hg, with a 95% confidence interval from -7.683 to 3.683 mm Hg. The interval includes zero and extends to values on either side of it. This means the posted estimate is not precise enough to establish a clear direction for the contrast. The estimate alone may appear to favor a more negative change under ramipril, but the interval shows that substantially different underlying contrasts remain compatible with the data.

Precision concerns how tightly the data locate the comparison, not whether the result is important in a clinical context. The registry record does not specify a clinically important difference or an equivalence margin. It is therefore not possible to judge the interval against such a threshold. Nor does the interval establish that the treatments have the same effect: a broad interval that crosses zero can reflect limited information rather than evidence of equivalence.

The posted summaries include 17 participants for each treatment condition, with standard deviations of 8.726 and 8.173 mm Hg. Those standard deviations describe variation in the reported group measurements. The registry does not state how the uncertainty calculation accounts for the crossover pairing. Because within-participant correlation can matter in crossover analyses, uncertainty estimates should be interpreted with that reporting limitation in mind.

The secondary endpoint also has an interval that includes zero, and its estimate is not a precise standalone resolution of the treatment comparison. Taken together, the endpoint summaries leave considerable uncertainty about the size and direction of the underlying differences. The estimates describe the recorded data; they should not be read as proof of no difference or as a precise measure of a lasting effect.

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, not total event counts. The stated planning assumptions are a two-sided significance level of 0.05, equal allocation between the two arms, and a normal approximation. The planning effect is set to the stated fraction of the observed effect. The registry does not report the original trial's sample-size assumptions or justification.

For each assumed effect size, the 80% power column gives the number of participants per arm estimated to provide an 80% chance of detecting that effect under the listed assumptions, if the effect and model assumptions are correct. The 90% power column applies the same interpretation at a higher target chance of detection. These figures are planning illustrations based on the observed estimate, not observed power.

Planning for 100% of the observed effect gives 281 participants per arm for 80% power and 376 participants per arm for 90% power. Planning for 75% of the observed effect gives 499 participants per arm for 80% power and 668 participants per arm for 90% power. Planning for 50% of the observed effect gives 1,122 participants per arm for 80% power and 1,502 participants per arm for 90% power. Smaller effects require more participants because they are harder to distinguish from random variation under the same assumptions.

These calculations are not a reconstruction of the trial's original design and do not establish what enrollment would have been appropriate for a different target effect. They depend on the observed estimate, which is itself uncertain. The trial's own design assumptions 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 = -2.000; pooled standard deviation σ = 8.454.
2. n = 2 × (1.96 + 0.842)² × 8.454² / -2.000² = 280.5, rounded up to 281 participants per arm for 80% power.

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

R code

alpha <- 0.05
z_a   <- qnorm(1 - alpha / 2)          # two-sided
delta <- -2                      # observed difference in means
sigma <- 8.45402285897075                     # 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(1005290)
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 = 281 (80% power), 376 (90% power)
 75% of observed effect: n per arm = 499 (80% power), 668 (90% power)
 50% of observed effect: n per arm = 1,122 (80% power), 1,502 (90% power)
power.t.test: 281.4 
Simulated power at n = 281 per arm: 0.793 (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 systolic endpoint and a secondary diastolic endpoint. It reports two outcome measures, one posted secondary outcome, and no reported analyses. The statistical analysis plan, including any hierarchy among outcomes or adjustment for multiple testing, is not reported in the registry record. Consequently, the posted unadjusted secondary result should not be treated as if a multiplicity-controlled confirmatory analysis had been documented.

Missing-data methods are also not reported. The registry does not state how many participants lacked baseline or post-baseline measurements, whether missing observations were imputed, or whether another method was used. The primary analysis population requires baseline and at least one post-baseline primary endpoint measurement and excludes major protocol deviations. These criteria make the PP set different from a population that includes every randomized participant, but the record does not explain the exclusions or their reasons.

The registry reports enrollment of 38 and endpoint summaries with 17 participants per treatment condition. It does not provide a participant-flow account connecting enrollment with the analyzed summaries. No reason for the difference is reported, and it would be inappropriate to infer whether it reflects missing measurements, protocol deviations, withdrawal, or another cause.

The record identifies randomization, no masking, and a crossover model, but does not provide the treatment sequence, washout details, crossover-specific model, or handling of period and carryover effects. It also does not report whether an intention-to-treat analysis was undertaken. These omissions limit assessment of the analysis population, missingness, multiplicity, and the statistical model behind the posted comparisons.

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 non-serious adverse event terms

The registry reports serious adverse events for 29 participants at risk in the combination pill group and 31 at risk in the ramipril group. It records zero affected participants in each group. No serious adverse event terms are listed. Death counts are not reported in the registry record.

These figures describe the serious adverse event information posted for the groups; they do not establish that no serious events occurred outside the recorded reporting and observation framework. The registry does not provide additional detail about event definitions, follow-up completeness, or how the at-risk counts relate to the endpoint analysis population. The different at-risk counts should therefore be read as reported, without assuming that they represent the same set of participants as the primary endpoint summaries.

For other, non-serious adverse events, the record lists 3 affected participants among 29 at risk with the combination pill and 1 among 31 at risk with ramipril. These counts are distinct from the serious-event figures. The registry record does not provide enough information in these summaries to compare safety profiles or draw a broader conclusion about tolerability.

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

The results describe observed changes in 24-hour blood pressure during the treatment periods represented in the registry. The primary estimate is a mean difference of -2.0 mm Hg for ramipril relative to the combination pill. Its 95% confidence interval, from -7.683 to 3.683 mm Hg, includes zero and spans differences in either direction. The available result therefore leaves uncertainty about whether, and by how much, the average changes differed.

A non-significant unadjusted p-value of 0.49 is not evidence that the treatments are identical. It indicates that the posted comparison does not provide strong statistical evidence against a null difference under the assumptions of the calculation. A claim of equivalence would require a defined margin and an appropriate analysis; neither is reported in the registry record. The broad interval is compatible with small differences as well as larger differences in either direction.

The findings do not show what would happen to long-term cardiovascular outcomes, and the primary endpoint is a blood-pressure measure over the recorded periods. The comparison also does not isolate the contribution of acetylsalicylic acid or simvastatin, because the combination pill is compared with ramipril alone as a regimen. No inference about the individual components follows from the regimen comparison.

Interpretation is further limited by the per-protocol analysis population, incomplete participant accounting, open-label design, and lack of reported details on crossover sequence and analysis methods. The status is recorded as terminated, but the reason is not reported. These limitations do not erase the posted observations; they constrain how far those observations can support conclusions beyond the analyzed participants and recorded treatment periods.

17. Why This Trial Matters Statistically

This trial is statistically informative as an example of how an estimate, its uncertainty, and the analysis context need to be read together. The primary result gives a numerical contrast, but its confidence interval is broad and includes zero. A single point estimate does not convey that uncertainty, and a p-value alone cannot show the range of contrasts compatible with the data.

The crossover design makes the statistical model especially relevant. Measurements across treatment periods can be related within a participant, and period or carryover considerations may matter. The registry identifies the design but does not report the sequence, washout details, or crossover-specific model. This illustrates why endpoint summaries alone may not reveal how a comparison was estimated.

The per-protocol population and the absence of a participant-flow account also matter. The registry reports enrollment of 38 while the endpoint summaries list 17 participants per treatment condition. Without reasons for exclusions or missingness, it is difficult to assess how representative the analyzed set is of everyone randomized. The lack of a reported multiplicity plan further limits the confirmatory weight of the secondary result.

Finally, planning figures based on an observed effect can illustrate how sample-size needs respond to assumptions about effect size and desired power. They do not explain the original design or tell whether an observed result is reliable. The trial's original sample-size rationale is not reported. Taken together, the record demonstrates the value of reading estimates, precision, design, populations, and reporting completeness as connected parts of statistical interpretation.

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.

Several limitations are specific to this record. It is an open-label randomized crossover study, but the registry does not report treatment order, sequence allocation details, washout arrangements, or an assessment of carryover. Those details are relevant because the treatment conditions occur in separate periods and may be compared within participants. The posted summaries do not show how those design features were handled.

The primary endpoint is described as adjusted mean change, but the adjustment variables and statistical model are not reported. The registry includes no sponsor-reported analyses. The relationship between the adjusted endpoint wording and the posted group summaries is therefore not fully transparent. It is also not possible to establish whether the reported comparison accounts for within-participant correlation.

The primary population is per protocol, and the record gives no participant-flow explanation for the difference between enrollment of 38 and the 17 participants listed for each treatment condition in the primary summaries. Missing-data handling, reasons for exclusions, and any intention-to-treat analysis are not reported. These omissions make it difficult to assess potential selection effects.

The combination-pill arm description is truncated, so its complete dosing schedule is not available in the registry record. The study is marked terminated, but no reason is reported. The record also lacks a stated clinically important difference for the primary endpoint and does not report the original sample-size assumptions. Together, these gaps limit interpretation of treatment exposure, analysis robustness, and the practical meaning of the estimated contrast.

19. Related Tutorials

20. Related Statistical Calculators

21. Sources

• ClinicalTrials.gov: A Pharmacodynamic Study to Evaluate the Effect of a Fixed Dose Combination Pill on Blood Pressure — NCT01005290.
• Registry record last updated 2012-07-26; status last verified 2012-06.
• Results first posted 2012-07-26.
• 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

NCT01005290 is a Phase 2 randomized, open-label crossover study of a cardiovascular fixed dose combination pill compared with ramipril alone in people with hypertension. Enrollment was 38; the registry lists the study as terminated. The primary endpoint was change in adjusted mean 24-hour systolic pressure measured by ambulatory monitoring across the treatment periods.

The posted primary summaries list 17 participants for each treatment condition. The mean difference, expressed as ramipril relative to the combination pill, was -2.0 mm Hg, with a 95% confidence interval from -7.683 to 3.683 mm Hg and an unadjusted p-value of 0.49. The interval includes zero and leaves substantial uncertainty about the direction and magnitude of the contrast.

The registry also posts a diastolic-pressure secondary endpoint. Analysis-model details, missing-data methods, participant flow, multiplicity procedures, and the reason for termination are not reported in the registry record. The results should be interpreted as limited summaries of the recorded blood-pressure outcomes, rather than as a complete account of the study's statistical analysis.