Treatment of OSA Associated Hypertension With Nebivolol or Hydrochlorothiazide: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Treatment of OSA Associated Hypertension With Nebivolol or Hydrochlorothiazide (NCT02710071), a randomized phase 4 study. The primary outcome is 24-h, Wake and Sleep Period Systolic and Diastolic Blood Pressure.

2. Clinical Question

3. Trial Design

This is a randomized, triple-masked crossover study listed as phase 4. The registry record lists two treatment sequences. Both start with placebo; one then receives nebivolol followed by hydrochlorothiazide, while the other receives hydrochlorothiazide followed by nebivolol. The opposite order means that each sequence encounters the active treatments in a different order. The record does not specify which people were masked, so the exact implementation of triple masking is not reported in the registry record.

The brief summary describes 2 weeks of placebo followed by 6 weeks of treatment with a study drug. The sequence descriptions give the dose steps: nebivolol 5mg for 2 weeks followed by 10 mg for 4 weeks, or hydrochlorothiazide 12.5 mg for 2 weeks followed by 25 mg for 4 weeks. The primary outcome timeframe places assessments at the end of placebo and at the end of 6 weeks of each active treatment. A washout period, if any, is not reported in the registry record.

The registry lists enrollment of 41 participants and records the study as completed. The recorded study start is 2015-01, and primary completion is recorded as 2016-04. The sponsor is the University of California, San Diego. The record does not report the number of study sites, the allocation procedure in detail, or the intended statistical analysis plan.

A crossover design can make within-participant comparisons possible because a participant may receive each active treatment. That general advantage depends on the outcome being measured reliably and on the analysis accounting appropriately for the design. Order, period effects, and any carryover between treatments may also matter in crossover studies. The registry record does not state how these issues were handled analytically, and it does not report whether treatment periods were separated by a washout.

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: 41 of 405 participants were randomized. Of those not randomized, 364 did not meet inclusion criteria

Placebo (2 Weeks).

First Intervention (6 Weeks).

Reasons for not completing this period:

Second Intervention (6 Weeks).

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: The overall Number of Analyzed Participants for primary outcome (27) differs from the Overall Number of Placebo (baseline) Participants (41) because 14 participants were excluded from the analysis due to either low quality of acquired data or due to missing data. Data Analysis was performed for the same 27 participants and for the each test period.

5. Baseline Characteristics

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

Population: In the study arm 1 ("Placebo, Then Nebivolol, Then Hydrochlorothiazide"): 21 participant first received baseline Placebo for 2 weeks. In the study arm 2 ("Placebo, Then Hydrochlorothiazide, Then Nebivolol" ): 20 participants first received baseline Placebo for 2 weeks.

6. Primary Endpoint

The registry lists the primary outcome as 24-h, Wake and Sleep Period Systolic and Diastolic Blood Pressure, measured over At the end of 2 weeks of placebo therapy, at the end of 6 weeks of Nebivolol therapy and at the end of 6 weeks of hydrochlorothiazide therapy..

The primary outcome is titled 24-h, Wake and Sleep Period Systolic and Diastolic Blood Pressure, measured in mmHg. It covers systolic and diastolic pressure averaged over the full 24-h ambulatory monitoring period, as well as averages during wake and sleep periods. The description says that wake-period readings were recorded every 15 minutes and sleep-period readings every 30 minutes. For the 24-h measure, the listed definition is the average of all ambulatory readings across the 24-h period.

Ambulatory monitoring is used to characterize blood pressure across ordinary waking and sleeping periods rather than relying only on a measurement taken at one clinic visit. Looking at wake and sleep periods separately can describe whether the average differs across those parts of the day. Those are general reasons to use these measures; the registry record does not state a separate clinical rationale for each component.

The outcome is reported as a mean with standard error as its dispersion measure. A mean describes the average measurement in the analyzed group. A standard error describes the precision of an estimated mean, not the spread of individual participants’ measurements. The record gives the measurement definitions and assessment times, but numerical means and standard errors for the treatment periods are not reported in the registry record.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

What does the crossover design imply?

In a crossover study, participants can receive more than one treatment in sequence. A general statistical feature is that measurements from the same participant may be more alike than measurements from different participants. An analysis that appropriately uses within-participant information can account for this dependence. Treating repeated observations as if they came from unrelated participants can misrepresent uncertainty. The registry record identifies a crossover model and two sequences with the active treatments in opposite orders, but it does not report the model used to analyze the data.

Order and time can also matter. Blood pressure could change across study periods for reasons other than the treatment being assessed, and a previous treatment could potentially influence a later period. These are general design considerations, not findings about this trial. The record does not report whether analyses adjusted for sequence or period, tested for carryover, or used a washout. It would not be appropriate to assume that any of these steps were or were not taken.

What does the outcome summary describe?

The primary outcome is continuous: blood pressure is measured on a scale in mmHg, and the record describes the results using means. A mean gives a central summary of measured values. The accompanying standard error describes uncertainty in the estimated mean, rather than the variability among individual readings. General interpretation of a standard error depends on the sampling and analysis model; it is not interchangeable with a standard deviation.

The measurement is repeated across blood pressure components, daily periods, and treatment assessments. The record specifies average systolic and diastolic readings over 24-h, wake, and sleep periods, with measurements at the end of placebo and at the end of each active treatment. Multiple outcome dimensions can give a fuller description, but they also require clear reporting of which comparisons were planned and how the analyses handled repeated measurements. The record does not report those details or numerical outcome summaries.

How should uncertainty be assessed?

In general, an estimated treatment contrast would describe the difference in mean outcome between treatments, and its confidence interval would show the precision of that estimate under the model. A p-value alone would not convey the size or practical importance of a contrast. The registry record does not report treatment contrasts, confidence intervals, or p-values, so none can be interpreted. No treatment effect can be recalculated from the record’s posted outcome information because it does not include the relevant means or measures of uncertainty.

The record lists standard error as the measure of dispersion for the mean outcome, but it does not give the standard errors themselves. It also does not provide participant-level observations or the covariance between repeated measurements. Those details would be needed for independent recalculation of a paired or repeated-measures comparison. A planning illustration based on an observed effect would not replace an actual treatment estimate or its uncertainty.

What can be inferred from the planning assumptions?

The record describes sample-size planning assumptions based on the observed effect, with a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation. It says that a planning effect can be expressed as a stated fraction of the observed effect. These assumptions describe a planning illustration, not necessarily the trial’s original design or analysis. The record does not report the trial’s own sample-size justification, and it does not provide numerical planning outputs in the registry record for this explanation. Such illustrations are not observed power and should not be interpreted as evidence that the study had adequate power to detect a particular treatment difference.

What is not reported about the statistical plan?

The registry record does not report a full statistical analysis plan, the model specification, the exact treatment contrast, handling of repeated observations, covariate adjustment, interim analyses, or a prespecified hierarchy among outcome measures. The absence of a detail in the registry record does not establish that the investigators did not address it elsewhere; it means the approach cannot be evaluated from this record.

10. Multiplicity, Missing Data and Analysis Populations

The outcome spans systolic and diastolic blood pressure, full 24-h averages, wake-period averages, sleep-period averages, and assessments after placebo and each active therapy. Considering multiple measures or time points raises a general multiplicity issue: when many comparisons are examined, the chance of at least one apparently notable result can increase. A prespecified primary contrast or an adjustment strategy can help readers understand how such comparisons were handled. Neither a multiplicity strategy nor a hierarchy of comparisons is reported in the registry record. The record notes that the outcome has several categories or time points and was not reduced to one comparison.

The registry reports 41 participants in the placebo baseline population and 27 analyzed for the primary outcome. It states that 14 participants were excluded because of low-quality acquired data or missing data. The record does not describe which data were missing, how missingness was distributed across treatment periods, or whether excluded participants differed from those analyzed. It does not report imputation, sensitivity analyses, or another method for addressing missing observations. These details matter because an analysis restricted to participants with usable data may be affected if missingness is related to participant characteristics or outcomes; that is a general possibility, not a finding about this study.

The record does not describe whether the primary outcome analysis used an intention-to-treat, per-protocol, or other defined population. Although it reports an analyzed participant count, the population definition and analysis rules are not reported in the registry record. As a result, the relationship between randomized sequence assignment and the reported analysis population cannot be fully assessed.

11. 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.

The adverse-event record lists two sequence groups. For the sequence placebo, then nebivolol, then hydrochlorothiazide, it reports 21 participants at risk for serious events and 0 affected, and 21 at risk for other events and 0 affected. For the sequence placebo, then hydrochlorothiazide, then nebivolol, it reports 20 participants at risk for serious events and 0 affected, and 20 at risk for other events and 0 affected. Deaths are reported as 0 in each sequence group.

These are counts recorded for the sequence groups, not treatment-period-specific comparisons between nebivolol and hydrochlorothiazide. The registry record does not provide event timing or a breakdown by active treatment period. It also does not report the definitions used for the other-event category or a list of serious event terms. The figures therefore describe what was recorded in these groups, rather than establishing that no adverse events occurred beyond the categories and reporting captured in this record.

Zero reported events should not be read as proof that an event is impossible or that the treatments have equivalent safety. The record gives no comparative safety estimate or uncertainty measure, and the displayed counts do not by themselves support a treatment safety comparison.

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

The registry record documents a randomized, triple-masked crossover study of nebivolol and hydrochlorothiazide in the setting of OSA-associated hypertension. It describes the treatment sequences, dose steps, ambulatory blood pressure outcome, assessment timing, enrollment, and the number analyzed for the primary outcome. It also reports zero serious events, zero other events, and zero deaths in each listed sequence group.

However, the record does not report the numerical blood pressure results or statistical comparisons. The mean estimates and standard errors are absent, as are treatment contrasts, confidence intervals, and p-values. It is therefore not possible to determine from the posted results whether the blood pressure measurements differed between treatments, how large any difference was, or how precisely it was estimated. The absence of numerical results in this record is not evidence that the treatments had identical effects.

The missing analysis details also limit assessment of how the crossover structure and multiple outcome dimensions were handled. The record does not describe the statistical model, multiplicity approach, missing-data method, or analysis population definition. Those gaps prevent an independent assessment of the robustness of any treatment comparison.

These results should not be treated as evidence that either treatment works or does not work. The record supports a description of the study and the data it reports, but it does not support a conclusion about comparative efficacy or safety. Interpreting the trial’s treatment effects would require the numerical outcome results and further information about the analysis.

13. Why This Trial Matters Statistically

This study raises statistical questions that are especially relevant to crossover trials. Because treatment order differs between the two listed sequences, a treatment comparison can depend on how the analysis handles repeated observations, period effects, and possible carryover. These are general considerations for the design, not claims that a particular problem occurred in this study. The registry record does not report how these features were addressed.

The primary outcome is also multidimensional. Systolic and diastolic pressure are considered over the full 24-h period and separately during waking and sleeping periods, with assessments after placebo and each active therapy. Reporting an outcome across these dimensions can be informative, but interpretation depends on clear specification of the principal comparison and transparent treatment of multiplicity. The registry record does not report a single comparison or a multiplicity plan.

Missing and low-quality data are another important issue. The record reports that 14 participants were excluded from the primary outcome analysis for those reasons, leaving 27 analyzed from the placebo baseline population of 41. Without details about the timing, pattern, or handling of missing measurements, readers cannot determine how much those exclusions may affect estimates.

Finally, the difference between an outcome being registered and an outcome being numerically reported is consequential. The record gives a detailed description of the blood pressure measures but not the estimated results or their uncertainty. That distinction prevents readers from assessing effect size, precision, or compatibility with a range of possible effects. It also illustrates why transparent reporting of analysis methods and outcome estimates is necessary for statistical interpretation.

14. 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 registry record does not include numerical results for the primary blood pressure outcome. As a result, there is no reported mean, standard error, treatment contrast, confidence interval, or p-value with which to assess the magnitude or precision of a comparison. The record lists no analyses and notes that the primary outcome has several categories or time points rather than one reduced comparison.

The analysis population is incompletely described. The record reports 27 participants analyzed for the primary outcome, compared with 41 placebo baseline participants, and attributes 14 exclusions to low-quality acquired data or missing data. It does not give the distribution or timing of missing measurements, the criteria used to judge data quality, or the method used to handle missingness.

Important design and analysis details are not reported in the registry record. These include the statistical model, treatment contrast, handling of repeated measurements, assessment of period or carryover effects, multiplicity strategy, and definition of the analysis population. A washout period and details of masking are also not reported. The registry record does not provide detailed eligibility criteria or baseline participant characteristics.

The safety record gives counts by sequence group but does not provide treatment-period-specific event counts or event timing. These limits mean that neither comparative blood pressure effects nor treatment-specific safety can be evaluated from the posted information. They are limitations of what is reported in the registry record and do not establish what information may exist elsewhere.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: Treatment of OSA Associated Hypertension With Nebivolol or Hydrochlorothiazide — NCT02710071.
• Registry record last updated 2020-10-19; status last verified 2020-09.
• Results first posted 2020-10-19.
• 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.

18. Record Summary

The registry record describes NCT02710071, a completed randomized, triple-masked crossover study sponsored by the University of California, San Diego. It concerns nebivolol and hydrochlorothiazide treatment for OSA-associated hypertension. The two sequences begin with placebo and then place the active treatments in opposite orders, with dose increases during each treatment period.

The primary outcome is mean systolic and diastolic blood pressure over 24-h, wake, and sleep periods, assessed after placebo and after each active treatment. The record reports enrollment of 41 and primary outcome analysis of 27, with 14 exclusions attributed to low-quality data or missing data. It does not report numerical primary outcome results or statistical comparisons. Serious events, other events, and deaths are recorded as 0 for each sequence group, but treatment-specific safety comparisons are not reported.