The Effects of Antihypertensive Agents on Central Blood Pressure in Healthy Participants and Participants With Hypertension (MK-0000-166) (COMPLETED): Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for The Effects of Antihypertensive Agents on Central Blood Pressure in Healthy Participants and Participants With Hypertension (MK-0000-166) (COMPLETED) (NCT01130168), a randomized phase 1 study. The primary outcome is Time-weighted Average (TWA) Change From Baseline (0 Hours) to 12 Hours in Heart-Rate-Corrected Augmentation Index (AIx) After A Single Dose of Treatment.

2. Clinical Question

The study examined whether antihypertensive agents changed central arterial measures after dosing, with the primary endpoint focused on heart-rate-corrected augmentation index (AIx). The registry describes a study of healthy participants and participants with hypertension, while its brief summary describes testing the relationship between central and peripheral blood pressure effects in participants with hypertension. The posted primary outcome compares the time-weighted average change in AIx over the 12-hour period after a single dose of ISMN ER or amlodipine with the change after placebo.

3. Trial Design

This was a completed, randomized, double-blind, Phase 1, three-period crossover study. The registry records enrollment of 38. The official title describes a placebo-controlled comparison of antihypertensive agents and central blood pressure in healthy subjects and patients with hypertension. Three treatments were evaluated: placebo, ISMN ER, and amlodipine.

Participants followed one of six treatment sequences. Each listed sequence includes the three treatments in a different order, with each treatment period lasting 4 weeks and a 2-week washout between periods. The listed doses were ISMN ER 30 mg and amlodipine 10 mg, described as two 5 mg capsules. The placebo capsule was dose-matched. The registry describes the study as double-blind but does not report who was masked or how masking was maintained.

A crossover design means participants receive multiple treatments in sequence, so treatment comparisons can use information from more than one treatment period for a participant. Sequence and period may matter when interpreting such studies; the registry record does not report details of any checks or adjustments for period effects, carryover, or sequence effects. The primary endpoint is specifically a single-dose outcome, measured from baseline through 12 hours post-dose on Day 1, although the treatment periods themselves lasted 4 weeks.

The study started in 2010-05, had primary completion in 2010-11, and is recorded as completed. The registry record does not report the original design assumptions or a sample-size justification.

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.

Period 1

Reasons for not completing this period:

Period 2

Period 3

Analysis population for the primary outcome, as defined in the registry: 33 participants completed all study periods and provided more than 1 period of BP data, and were thus evaluable for the BP analyses. Unreliable SphygmoCor® data were collected for one participant in the ISM ER treatment group, therefore this participant was excluded from the single dose AIx 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.

6. Primary Endpoint

The registry lists the primary outcome as Time-weighted Average (TWA) Change From Baseline (0 Hours) to 12 Hours in Heart-Rate-Corrected Augmentation Index (AIx) After A Single Dose of Treatment, measured over Baseline (0 hrs), 12 hours post-dose (Day 1).

The primary endpoint was the time-weighted average change from baseline (0 hours) to 12 hours in heart-rate-corrected augmentation index after a single dose of treatment. AIx is a measure of systemic arterial stiffness, defined in the record as augmented aortic pressure divided by central pulse pressure and expressed as a percent. A time-weighted average summarizes measurements across the post-dose observation period while accounting for the time represented by those measurements.

Heart rate affects AIx, so the study corrected AIx to a heart rate of 75 beats per minute using the formula stated in the registry. The corrected value was used for all AIx analyses. This adjustment is intended to make AIx comparisons less dependent on variation in heart rate; it does not turn AIx into a direct measure of a clinical event or establish the consequences of a change in the measure.

The endpoint is useful for studying central arterial responses to treatment because it captures a physiologic measure over the post-dose period rather than a single isolated reading. The registry describes the primary result as a least-squares mean and its dispersion as a standard deviation. It reports group summaries and treatment comparisons, but the registry record does not report all details of the measurement schedule or the statistical model used to derive those summaries.

7. Results Posted in the Registry

• ISMN ER: mean -11.10 versus 2.10 on control; difference -13.20 (95% CI -15.39 to -11.01), standardized effect d = -2.93; z-test p = <0.001.
• Amlodipine: mean -0.70 versus 2.10 on control; difference -2.80 (95% CI -4.97 to -0.63), standardized effect d = -0.62; z-test p = 0.011.

8. Statistical Interpretation

9. Statistical Methods Explained

The registry reports group estimates and ANOVA comparisons, alongside simple unadjusted recalculations from posted summary statistics. These approaches answer related but not identical questions. The reported ANOVA is the sponsor’s analysis; the recalculation is a simplified check and does not reproduce all the information that may enter a crossover analysis.

What does a mean difference describe?

A mean difference expresses the separation between two group averages on the outcome scale. For these comparisons, the reported contrasts are active treatment versus placebo. A negative estimate indicates a lower average change for the active-treatment group than for placebo, given the order used in the reported contrast. It is a comparison of average changes, not a statement that every participant had a lower value.

The recalculation uses the posted group means and a pooled standard deviation, with standard errors approximated from the group sizes and dispersion. Because the record flags a discrepancy and the calculation is a simple unadjusted re-analysis, it should not be treated as a reconstruction of the sponsor’s ANOVA. In a crossover study, the same participant contributes measurements under different treatments. Information about within-participant correlation and treatment sequence can be important, and those details cannot be recovered fully from group means and standard deviations alone.

What does the ANOVA contribute?

ANOVA is a general method for comparing mean outcomes across treatment conditions. The registry reports ANOVA estimates for the active-treatment versus placebo comparisons. The record does not give enough detail to identify the exact model specification, covariates, or handling of period and sequence. It is therefore appropriate to describe the method as the registry does, without assuming additional model features.

In general, analysis models can account for aspects of study design and can estimate treatment contrasts while representing variability. In a crossover trial, a suitable model may take account of repeated observations within a participant. Whether and how those features were handled in this specific analysis is not reported in the registry record. The sponsor’s posted results remain the primary reported analysis, while the summary-statistic calculations provide a transparent but limited secondary check.

Why does variation matter?

The standard deviation describes the spread of observations around a mean. The posted group standard deviation is 4.5 for each treatment. Greater variation generally makes a mean difference less precisely estimated when other aspects of a study are held constant. The recalculation assumes a pooled standard deviation and approximates standard errors from the group summaries. Such calculations do not use the individual-level pattern of repeated measurements, and their precision can differ from that of a model that uses the crossover structure.

AIx is heart-rate-corrected in this study because heart rate affects the measure. The registry gives the correction formula and states that the corrected value was used for all AIx analyses. Adjustment of the outcome for heart rate is distinct from adjustment of a treatment comparison for other design factors. The record does not report additional adjustment details for the ANOVA.

How should p-values be read?

A p-value describes how compatible the observed data are with a specified null model, under the assumptions of the analysis. It is not the probability that the null hypothesis is true, nor does it measure the size or practical importance of a difference. The sponsor reports p < 0.001 for the ISMN ER comparison and p = 0.016 for the amlodipine comparison. The simple recalculations report p < 0.001 and p = 0.011, respectively. Given the recorded discrepancy, the sponsor’s reported analysis takes precedence.

Confidence intervals complement p-values by giving a range of values compatible with the analysis and its assumptions. They communicate both the estimated direction and the precision of a contrast. They do not account automatically for every possible source of uncertainty, such as missing data, model misspecification, or multiplicity.

What does a crossover structure mean statistically?

In a crossover study, a participant can serve as their own comparison across treatment periods. This can reduce the influence of stable differences between participants, but it also makes period order, within-participant correlation, and possible carryover relevant to interpretation. Washout periods are listed between the treatment periods, but their presence alone does not demonstrate that carryover was absent. The registry record does not report tests or sensitivity analyses for these issues.

The endpoint is a time-weighted average across the 12-hour post-dose observation period. In general, time weighting gives measurements influence according to the time intervals they represent. The record does not report the detailed measurement schedule or the precise weighting procedure, so those implementation details should not be inferred.

10. Confidence Intervals and Precision

The sponsor’s reported 95% confidence interval for the ISMN ER versus placebo mean difference is -15.3 to -10.9. For amlodipine versus placebo, it is -4.9 to -0.6. Each interval is entirely below zero, indicating that the reported estimates are compatible with a negative mean difference across the respective interval under the analysis assumptions. The intervals also show that the estimated contrast for ISMN ER is more separated from zero than the contrast for amlodipine.

A confidence interval is not a guarantee that the true effect falls inside the reported range. It is a measure of uncertainty produced by a statistical method, conditional on the model and assumptions used. It does not capture uncertainties that were not represented in that method, including possible effects of missing observations, analysis choices, or multiple comparisons. The registry record does not report enough modeling detail to evaluate all such assumptions.

The recalculated intervals are based on approximations from posted summary statistics, including an approximate standard deviation, rather than the sponsor’s ANOVA. The recalculated estimates and sponsor estimates differ, and the record flags a discrepancy. For that reason, the sponsor’s intervals should be used when describing the registry’s inferential results. The unadjusted recalculated intervals should not be conflated with them.

The width of an interval reflects precision: narrower intervals indicate less statistical uncertainty under the method used, while wider intervals indicate more. The estimate for amlodipine is closer to zero and its interval is correspondingly situated closer to zero than the ISMN ER interval. Neither interval resolves questions about generalizability, longer-term outcomes, or the clinical importance of a change in AIx.

11. Planning a Similar Trial: Sample Size

This is a planning illustration, not a re-evaluation of the original trial. It asks: if a new study wanted to detect a difference like the one observed, or a smaller one, how large would it need to be? It is deliberately not “observed power” of the finished trial, which is not a meaningful quantity.

The sample-size figures are planning illustrations expressed as participants per arm for the two-arm comparisons. They are not total event counts. The calculations use a two-sided significance level of 0.05, equal allocation between the two arms, and a normal approximation. The effect to detect is set as the stated fraction of the observed effect. These assumptions describe the illustration, not the trial’s original design; the original sample-size assumptions are not reported in the registry record.

The 80% power column gives the number of participants per arm estimated to yield an 80% chance of detecting the selected effect under those planning assumptions, if that effect is the true one and the model assumptions hold. The 90% power column uses a higher target chance of detection and therefore generally calls for more participants per arm. These columns are not evidence about the power achieved by the completed trial.

For the ISMN ER comparison, the illustration includes planning for 100% of the observed effect, 75% of the observed effect, and 50% of the observed effect. The corresponding participant-per-arm figures are 2 and 3, 4 and 5, and 8 and 10 for the 80% and 90% targets. For amlodipine, the corresponding figures are 41 and 55, 73 and 97, and 163 and 218. Smaller effects require more participants under these assumptions because they are harder to distinguish from random variation. This is a planning illustration, not observed power.

The trial used a crossover design, whereas these planning illustrations describe equal allocation between two arms. They should therefore be read as generic planning calculations based on the observed summary effect, not as a design analysis tailored to the trial’s sequence structure. The sample-size curve represents the same general relationship between the assumed effect and the number needed for planning; it does not add evidence about the observed treatment outcomes.

12. 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 = -13.200; pooled standard deviation σ = 4.500.
2. n = 2 × (1.96 + 0.842)² × 4.500² / -13.200² = 1.8, rounded up to 2 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 <- -13.2                      # observed difference in means
sigma <- 4.5                     # 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(1130168)
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 = 2 (80% power), 3 (90% power)
 75% of observed effect: n per arm = 4 (80% power), 5 (90% power)
 50% of observed effect: n per arm = 8 (80% power), 10 (90% power)
power.t.test: 3.1 
Simulated power at n = 2 per arm: 0.380 (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.

13. Analyses Reported by the Sponsor

The sponsor’s own analysis is reported as ANOVA. For ISMN ER versus placebo, it gives a mean difference of -13.1, a 95% confidence interval of -15.3 to -10.9, and p < 0.001. For amlodipine versus placebo, it gives a mean difference of -2.7, a 95% confidence interval of -4.9 to -0.6, and p = 0.016.

The simple recalculations from posted summary statistics give mean differences of -13.2 for ISMN ER and -2.8 for amlodipine. Their unadjusted p-values are p < 0.001 and p = 0.011, respectively. The small differences between these estimates and the sponsor’s estimates reflect that these are not the same analysis; the recalculations use summary statistics and approximations rather than the sponsor’s full ANOVA.

The record flags a discrepancy. Accordingly, the sponsor’s own analysis takes precedence when reporting the trial’s inferential results. The recalculations are best treated as a check on the general direction and approximate size of the reported contrasts, not as a correction to the sponsor’s results or a substitute for the crossover analysis.

14. Multiplicity, Missing Data and Analysis Populations

The registry lists 10 outcome measures and 20 analyses, while the count of posted secondary outcomes is 0. These entries do not by themselves show that there were no other planned outcomes or analyses; they describe what is recorded in the registry. The primary endpoint is the time-weighted average change in heart-rate-corrected AIx after a single dose.

When a study tests multiple outcomes, treatment contrasts, time points, or subgroups, the chance of at least one apparently positive result can increase. Statistical procedures can address multiplicity, but the registry record does not report whether an adjustment was used, which comparisons were considered confirmatory, or how the reported primary comparison fits into an analysis hierarchy. The reported p-values should therefore be read as posted for their respective analyses, without assuming a multiplicity correction.

The population description states that 33 participants completed all study periods and provided more than 1 period of BP data, making them evaluable for BP analyses. It also states that unreliable SphygmoCor data were collected for one participant in the ISM ER treatment group, and that this participant was excluded from the single-dose AIx analysis. The registry record does not report a fuller account of missing observations, reasons for incomplete data across all participants, or the missing-data method used for the ANOVA.

The record gives enrollment of 38, but enrollment does not mean that every enrolled participant contributed usable data to every endpoint. A crossover study can have different available observations across periods and outcomes. The extent of such variation and its effect on the estimates are not reported in the registry record.

The record does not report a detailed analysis-population definition beyond the BP-evaluable description, nor does it state whether all randomized participants were included in a particular analysis. Details on interim analyses, multiplicity control, and the original statistical analysis plan are not reported in the registry record. These gaps limit assessment of how outcome selection and missingness may have influenced the presented results.

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 5.0% reporting threshold.

Most frequent non-serious adverse event terms

The serious adverse event figures list 0 affected in the placebo group, 0 in the ISMN ER group, and 0 in the amlodipine group. The numbers at risk shown for these groups are 34, 38, and 37, respectively. These are the registry’s arm-specific entries; they should not be added together to create a participant total, particularly in a crossover study where participants can receive more than one treatment.

The absence of recorded serious adverse events in these entries does not establish that a treatment has no safety risks. These figures describe the posted record for the study and do not provide a complete assessment of all possible harms or risks in other populations and settings. Death values are not present in the record, so deaths are not reported in the registry record.

The registry also lists other adverse events affecting 7 participants in the placebo group, 18 in the ISMN ER group, and 9 in the amlodipine group. Those counts are separate from the serious adverse event figures. The registry record does not provide enough detail in these entries to describe event types, timing, severity beyond the serious-event distinction, or the relationship of each event to treatment.

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

The posted results describe differences in a physiologic endpoint: heart-rate-corrected AIx over the 12 hours after a single dose. In the sponsor’s analysis, both active-treatment comparisons with placebo have mean differences below zero, and both reported 95% confidence intervals are below zero. The results provide evidence of differences in the average endpoint change under the analysis used, with the ISMN ER contrast farther from zero than the amlodipine contrast.

That statistical result does not establish that either treatment improves health, reduces cardiovascular events, or produces a clinically important effect. AIx is a measure of systemic arterial stiffness, and the trial’s primary endpoint is a short-term physiologic measure. Clinical consequences, longer-term effects, and the meaning of a particular change in AIx are not established by these results.

The trial title includes healthy participants and participants with hypertension, but the posted primary result does not describe separate estimates for those populations. The record’s outcome population description instead states that participants were evaluable for BP analyses based on completing all periods and providing more than 1 period of BP data. The registry record does not report subgroup results that would clarify whether estimates differed by health status.

The study also cannot answer every question raised by its broader objective. The brief summary refers to central and peripheral blood-pressure effects after single and multiple doses, but the primary result is a single-dose AIx endpoint. Longer-term treatment response, direct comparisons of active agents, and effects on peripheral BP are not established by the reported primary comparison.

Finally, the result is specific to this Phase 1 crossover study and its recorded analysis. Missing-data details, multiplicity handling, and complete model specifications are not reported in the registry record. The sponsor’s ANOVA should be used for the inferential findings because the record identifies a discrepancy with the simple recalculations.

17. Why This Trial Matters Statistically

This trial illustrates why study design and analysis need to be read together. A crossover design exposes participants to multiple treatments in sequence, so a treatment comparison is not automatically equivalent to a comparison between unrelated groups. Period, sequence, and within-participant dependence may be relevant, while a basic recalculation from group summaries cannot fully represent those features.

It also demonstrates the distinction between a posted sponsor analysis and a secondary calculation based on summary statistics. The recalculated estimates are close to the sponsor’s estimates, but they do not match exactly. Since a discrepancy is recorded, the sponsor’s ANOVA takes precedence. Reporting both types of results transparently helps distinguish the trial’s own inference from a simplified statistical check.

The confidence intervals contribute information beyond whether a p-value is below a conventional threshold. They show the range of contrasts compatible with the sponsor’s analysis and make the difference in precision between the comparisons visible. At the same time, a confidence interval cannot answer questions the analysis did not address, such as multiplicity, incomplete outcome data, or the generalizability of a short-term physiologic endpoint.

The sample-size illustrations add another statistical lesson: planning requirements depend strongly on the effect size one aims to detect. A smaller assumed effect requires more participants under the stated planning assumptions. Those calculations are not evidence of the trial’s achieved power and do not reproduce the original design rationale, which is not reported in the registry record.

Together, these features make the study useful for understanding how endpoint definition, crossover structure, inferential methods, precision, and reporting gaps shape interpretation of a clinical-trial result.

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 result is a short-term, single-dose measure, observed from baseline through 12 hours. It does not establish what happens with longer-term use, and the posted primary analysis does not report the effects of repeated dosing. Although the brief summary refers to central and peripheral BP, the primary endpoint described in the results is AIx.

The registry describes a crossover design with six treatment sequences, 4-week periods, and 2-week washouts. It does not report the statistical handling of period, sequence, or possible carryover effects. Washout intervals are part of the design description, but the registry does not report evidence demonstrating that carryover was absent.

The primary-outcome population description gives limited information about evaluability and one exclusion due to unreliable SphygmoCor data. A full account of missing measurements, exclusions across all outcomes, and missing-data methods is not reported in the registry record. The model details for the sponsor’s ANOVA are also limited, and the record does not describe multiplicity handling.

The registry’s title refers to healthy participants and participants with hypertension, while the condition entry lists hypertension and the brief summary describes participants with hypertension. The posted primary results do not give separate estimates by population, and therefore do not clarify whether the endpoint differences were similar across those groups.

The simple recalculations use summary statistics and approximations. They do not reproduce the sponsor’s crossover analysis, and the recorded discrepancy means the sponsor’s results take precedence. Finally, safety entries are limited to arm-level event counts; the registry record does not give full event descriptions or death results.

19. Related Tutorials

20. Related Statistical Calculators

21. Sources

• ClinicalTrials.gov: The Effects of Antihypertensive Agents on Central Blood Pressure in Healthy Participants and Participants With Hypertension (MK-0000-166) (COMPLETED) — NCT01130168.
• Registry record last updated 2015-10-09; status last verified 2015-10.
• Results first posted 2012-05-28.
• 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

NCT01130168 is a completed, randomized, double-blind, Phase 1 crossover study sponsored by Merck Sharp & Dohme LLC. The registry records enrollment of 38 and study dates from 2010-05 to primary completion in 2010-11. Participants received placebo, ISMN ER, and amlodipine in different treatment sequences.

The primary endpoint was time-weighted average change from baseline to 12 hours in heart-rate-corrected AIx after a single dose. The sponsor’s ANOVA reported mean differences versus placebo of -13.1 for ISMN ER and -2.7 for amlodipine. A discrepancy is recorded between these analyses and simple recalculations from posted summaries, so the sponsor’s results take precedence.

The registry record does not report several details needed for fuller assessment, including the original sample-size rationale, complete model specification, multiplicity handling, and comprehensive missing-data methods.