Effectiveness and Safety of Combination of Nebivolol and Amlodipine in Hypertensive Patients Versus Each Monotherapy: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Effectiveness and Safety of Combination of Nebivolol and Amlodipine in Hypertensive Patients Versus Each Monotherapy (NCT05513937), a non-randomized phase 4 study. The primary outcome is Change in Mean Sitting Diastolic Blood Pressure (DBP) Between Visit 2 (Week 0) and Visit 4 (Week 8).

2. Clinical Question

3. Trial Design

This was a Phase 4, open-label, multicenter, multinational, non-randomized interventional study. The registry describes a sequential model: a monotherapy run-in lasting 4 weeks, followed by an 8-week combination-therapy period for patients whose blood pressure remained uncontrolled. Participants started the run-in on nebivolol 5 mg or amlodipine 5 mg. The trial enrolled 301 participants and is recorded as completed.

The record’s brief summary describes combination treatment with nebivolol 5 mg and amlodipine 5 mg or 10 mg. The arm descriptions, however, describe nebivolol 5 mg plus amlodipine 5 mg following either monotherapy run-in. Safety counts separately identify combination periods involving amlodipine 5 mg and 10 mg. These descriptions do not fully explain how participants were assigned to the combination dose or how that assignment occurred; those details are not reported in the registry record.

Neither participants nor investigators were masked, and allocation was not randomized. The monotherapy and combination periods therefore should not be interpreted as randomized arms or as concurrent, exchangeable controls. Changes between the periods can reflect the treatment sequence as well as other differences over time. A comparison across those periods does not, by itself, isolate the effect of adding the combination treatment.

The registry identifies Menarini International Operations Luxembourg SA as sponsor. The recorded study start was 2022-05-12, and primary completion was 2022-11-15. More detailed information about sites, recruitment procedures, adherence, dose selection, or treatment changes is not reported in the registry record.

4. Participant Flow and Accounting

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

Before assignment: MONOTHERAPY PERIOD:Patients are treated with NEB 5 mg or AML 5 mg during the Run in period (week -4 to week 0) according the assigned arms. Uncontrolled patients enter the COMBINATION THERAPY PERIOD, a one arm assessment period of 8 weeks (week 0 to week 8), where patient are treated with extemporaneous combination of NEB 5 mg/AML 5mg for 4 weeks. AML 10mg will replace AML 5mg in uncontrolled patients for further 4 weeks while controlled patients will continue with the same combination therapy.

Run in (-4 Week to 0) Monotherapy Phase

Reasons for not completing this period:

Combination Therapy (0 to 4 Weeks)

Combination Therapy (4 to 8 Weeks)

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: Primary endpoint (as per protocol assessed in patients who received combination therapy regardless of AML dose), is defined as mean difference in sitting diastolic blood pressure between Visit 2 (Week 0, Baseline Visit of the combination therapy) and Visit 4 (Week 8, End of Study Visit). This is not a comparison of two different arms, but a comparison of two measurements taken from the same patient treated with combination therapy (single arm paired pre- vs. post-combination therapy comparison)

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 Change in Mean Sitting Diastolic Blood Pressure (DBP) Between Visit 2 (Week 0) and Visit 4 (Week 8), measured over From Visit 2 (week 0) to Visit 4 (week 8) for a total of 8 weeks.

The primary endpoint is the change in mean sitting diastolic blood pressure between Visit 2 at Week 0 and Visit 4 at Week 8, expressed in mmHg. Week 0 is identified as the baseline visit for the combination-therapy period, while Week 8 is the end-of-study visit. The endpoint concerns participants who received combination therapy, regardless of amlodipine dose, after a monotherapy period of at least 4 weeks in which blood pressure remained uncontrolled.

Diastolic blood pressure is the lower of the two blood-pressure readings and is a continuous measurement. A mean change summarizes the average movement in that measurement across the endpoint population. It can make the direction and magnitude of change easier to interpret than a list of individual readings, while concealing variation between participants. The registry identifies standard deviation as the measure of dispersion, which describes how spread out observations are around a mean.

In general, a before-and-after endpoint can describe what happened across a treatment period, but it does not establish that treatment caused the change. That distinction matters especially in a non-randomized sequential study, where there is no randomized concurrent control group. The primary endpoint’s numerical estimate, standard deviation, and other outcome details are not reported in the registry record.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

What does a mean change describe?

For a continuous outcome such as sitting diastolic blood pressure, a mean change summarizes the average difference between measurements taken at two specified visits. In this study the visits are Week 0, at the start of combination therapy, and Week 8, at its end. This summary is about the group average. Individual participants can have changes that differ in size or direction, so the mean does not describe every participant’s experience.

The endpoint is identified as a mean, with standard deviation as the dispersion measure. Standard deviation describes how widely observations vary around the mean. It is not the same as the standard error, which describes the uncertainty of an estimated mean, and it is not a confidence interval. A confidence interval gives a range of values compatible with the data and analysis under the method’s assumptions. The primary endpoint’s numerical mean, standard deviation, and confidence interval are not reported in the registry record.

What would a confidence interval add?

In general, an estimate alone gives a point summary, while a confidence interval conveys its statistical precision. A narrow interval indicates greater precision than a wide interval, subject to the analysis assumptions. A confidence interval does not remove design limitations: an interval around a before-and-after mean change cannot by itself resolve confounding or show what would have happened under a different treatment. No confidence interval for the primary endpoint is reported in the registry record.

How does the design affect inference?

Random allocation is intended to make treatment groups comparable, on average, with respect to both measured and unmeasured baseline factors. This study was not randomized. Its sequential structure also means that people entered combination treatment after monotherapy, and the endpoint population is described as those who received combination therapy. Selection into that period can distinguish the analyzed group from the full enrolled population. Because there is no like-for-like randomized control comparison, the primary endpoint is best understood as a change observed over the treatment period, not as an isolated treatment effect.

Open-label means treatment was not masked. In general, awareness of treatment can influence behavior, co-interventions, reporting, or outcome assessment, depending on how measurements are collected. The registry describes the endpoint as sitting blood pressure, but further details of measurement procedures, repeat readings, assessor practices, or quality control are not reported in the registry record.

Why can over-dispersion matter?

In general, over-dispersion means observed variability is greater than a statistical model expects. If a model assumes less variability than the data contain, uncertainty can be understated and inferential results can appear more precise than warranted. The registry identifies a continuous endpoint and standard deviation, but does not report a model choice or an assessment of over-dispersion. The concept is relevant as a general statistical consideration, not as a finding about this study.

What does the planning illustration mean?

The record describes a planning illustration based on the observed effect, with two-sided significance level 0.05, equal allocation between two arms, and a normal approximation. It specifies that the effect to detect is a stated fraction of the observed effect. The illustration is not the trial’s design justification, and its sample-size values are not reported in the registry record. No sample-size justification for the actual trial is reported in the registry record.

In general, a sample-size calculation asks how many participants would be needed under chosen assumptions to detect a target effect with specified statistical properties. It is a planning exercise, not evidence that a study had a particular probability of finding a result after it was conducted. A planning illustration based on an observed effect is particularly dependent on that effect estimate and its uncertainty. It should not be described as observed power, nor should it be treated as evidence that the trial was adequately or inadequately sized.

The registry identifies one primary outcome measure and one analysis, but does not report the statistical test, model, covariate adjustment, variance assumptions, or confidence-interval method. It also does not report whether any interim analyses were planned or conducted. Those analytic details should not be inferred from the endpoint label or from the planning assumptions.

10. Confidence Intervals for Each Arm

No two-arm comparison is shown for this trial, but each arm's mean can be given with a t-based 95% confidence interval computed from the posted mean, spread and number of participants.

R code and output

arm <- c("Combination Therapy Phase Nebivolol 5mg/Amlodipine")
n   <- c(276)
m   <- c(-15.2)
sp  <- c(8.32)
sd  <- sp      # posted standard deviations
for (i in seq_along(n)) {
  se <- sd[i] / sqrt(n[i]); h <- qt(0.975, n[i] - 1) * se
  cat(sprintf("CARM|%s|%d|%.3f|%.3f|%.3f|%.3f\n", arm[i], n[i], m[i], sd[i], m[i] - h, m[i] + h))
}

CARM  Combination Therapy Phase Nebivolol 5mg/Amlodipine  276  -15.200  8.320  -16.186  -14.214

11. Multiplicity, Missing Data and Analysis Populations

The registry identifies one primary outcome measure and one analysis. It does not report whether additional secondary outcomes or subgroup analyses were conducted, whether multiple doses were formally compared, or whether any multiplicity adjustment was planned. Multiplicity arises when several statistical questions are tested: the more questions examined, the greater the chance that at least one result appears notable by chance. In general, a prespecified hierarchy or adjustment can address that issue, but the relevant procedures are not reported in the registry record.

The record’s endpoint includes participants who received combination therapy regardless of amlodipine dose. The summary describes combination treatment with amlodipine 5 mg or 10 mg, while the arm descriptions specify the 5 mg combination. The registry does not explain whether dose-specific efficacy estimates were analyzed or how any such analyses related to the primary endpoint. A separate dose comparison should not be inferred from the safety group labels.

Missing-data handling is not reported in the registry record. The record does not state how many participants had an endpoint measurement, how missing Week 0 or Week 8 measurements were handled, whether participants who discontinued were included, or whether any imputation or sensitivity analysis was used. In general, missing data can affect an estimate when the probability of missingness is related to participant characteristics or outcomes. The direction and size of any such effect cannot be determined without information about missingness and the analysis.

The analysis population is also not specified beyond the description that the primary endpoint was assessed in patients who received combination therapy regardless of amlodipine dose. The record does not identify an intention-to-treat population, a per-protocol population, or another formal analysis set. The enrolled total should therefore not be assumed to equal the endpoint analysis population.

12. Safety Results

The registry reports serious adverse events as affected participants divided by participants at risk.

Deaths

Other (non-serious) adverse events

Participants with at least one non-serious event at or above the registry's 0% reporting threshold.

Most frequent non-serious adverse event terms

The registry reports zero serious adverse events and zero deaths in each listed treatment period. It also reports other adverse events affecting 4 participants during nebivolol 5 mg monotherapy, 2 during amlodipine 5 mg monotherapy, 35 during the nebivolol 5 mg and amlodipine 5 mg combination period, and 9 during the nebivolol 5 mg and amlodipine 10 mg combination period. The corresponding numbers at risk are 143, 158, 279, and 94, respectively.

These are counts of affected participants, not estimates of comparative risk. The periods are part of a sequential, non-randomized study, and the groups should not be interpreted as exchangeable randomized arms. The registry does not provide exposure-adjusted rates, event-level descriptions, severity details for the other events, or information needed to assess how long each participant was observed. The combination-period counts may also reflect the number of participants exposed in each period. The recorded absence of serious events and deaths is descriptive and does not establish that an event could not occur or that treatments have equivalent safety.

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

The study addresses a defined statistical question: how mean sitting diastolic blood pressure changed between the beginning and end of an 8-week combination-treatment period in participants described as uncontrolled after monotherapy. The registry also records safety-event counts for monotherapy and combination periods. These design and outcome definitions clarify what the study intended to examine.

The registry record does not report the primary endpoint estimate, its standard deviation, a confidence interval, or a test result. It therefore does not permit a reader to determine the observed average blood-pressure change or its precision from the record. The record’s completion status and enrollment total do not substitute for those outcome results.

Even if a numerical before-and-after change were available, its interpretation would remain bounded by the non-randomized sequential design. A change over time is not the same as a causal treatment contrast. Without random assignment and a concurrent control group, other influences cannot be separated from treatment using the endpoint alone. The analysis population is described as combination-treatment recipients, so findings would not necessarily apply to all enrolled participants.

The safety figures show the recorded counts for other adverse events, serious adverse events, and deaths in the specified periods. They do not establish a comparative rate or prove that a treatment is safer or less safe than another. They also do not establish treatment benefit or lack of benefit. The record is best read as documenting the study question, its sequential design, and descriptive safety counts, while leaving the principal efficacy estimate and several analysis details unreported.

14. Why This Trial Matters Statistically

This trial is statistically informative as an example of why endpoint definition and design structure must be read together. The primary measure is a mean change in a continuous outcome, with a clear baseline and follow-up visit for the combination period. That definition tells the reader what quantity was intended to be summarized. It does not, on its own, identify a causal effect or supply the result.

The sequential design is central to interpretation. Participants first received monotherapy, and those who remained uncontrolled proceeded to combination therapy. Thus the combination-period population is selected by its experience in the preceding period. A within-period change may be useful descriptively, but it is not equivalent to a randomized comparison against continued monotherapy. Recognizing this distinction prevents an observed change from being overstated as a treatment effect.

The registry also illustrates the importance of transparent result reporting. The primary outcome is specified, yet its numerical result and precision are not reported in the registry record. Without those details, readers cannot assess the size, variability, or uncertainty of the primary outcome. Similarly, the record does not describe missing-data handling, the formal analysis population, or the statistical model. These omissions constrain independent statistical evaluation.

Finally, safety counts should be interpreted in light of exposure periods and participant numbers rather than as direct head-to-head comparisons. Descriptive counts can summarize what was recorded, but they do not answer every comparative safety question. This distinction between description, estimation, and causal inference is broadly important when interpreting clinical trial records.

15. 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 main trial-specific limitation is the non-randomized, open-label sequential design. Treatment periods are not concurrent randomized groups, and participants proceeded to combination therapy after a monotherapy run-in if blood pressure remained uncontrolled. The combination-period group is therefore selected by the preceding course, limiting direct comparison with monotherapy groups and limiting causal interpretation of change.

The primary endpoint result is not reported in the registry record. No numerical estimate, standard deviation, confidence interval, or test result is available in the record for the endpoint. The number of participants contributing to that analysis is also not reported, so the enrolled total of 301 should not be treated as the analyzed total.

There is a difference in detail between the summary and arm descriptions: the summary refers to amlodipine 5 mg or 10 mg in combination, whereas both arm descriptions specify amlodipine 5 mg. The safety record has separate combination-period entries for amlodipine 5 mg and 10 mg, but the process by which participants received each dose is not reported in the registry record.

Further limitations include unreported missing-data procedures, statistical model, covariate adjustment, analysis-population definitions, interim analyses, and multiplicity procedures. The safety record gives counts but not exposure-adjusted rates or detailed event descriptions. These gaps limit assessment of precision, robustness, and comparability across treatment periods.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Effectiveness and Safety of Combination of Nebivolol and Amlodipine in Hypertensive Patients Versus Each Monotherapy — NCT05513937.
• Registry record last updated 2025-02-04; status last verified 2025-01.
• Results first posted 2025-02-04.
• 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.

19. Record Summary

NCT05513937 is a completed Phase 4, open-label, non-randomized, sequential study sponsored by Menarini International Operations Luxembourg SA. It enrolled 301 participants with hypertension. Participants received nebivolol 5 mg or amlodipine 5 mg during a 4-week monotherapy run-in; those described as uncontrolled proceeded to an 8-week combination period.

The primary endpoint was mean sitting diastolic blood-pressure change from Week 0 to Week 8. The numerical endpoint result and its precision are not reported in the registry record. Safety entries report zero serious adverse events and zero deaths in each listed period, alongside counts of other adverse events. The sequential design does not provide a randomized, like-for-like comparison of combination therapy with monotherapy.