Open-Labeled PK-PD Studies of Metoprolol ER: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Open-Labeled PK-PD Studies of Metoprolol ER (NCT02417246), a randomized phase 4 study. The primary outcome is Area Under the Plasma Concentration Versus Time Curve (AUC).

2. Clinical Question

The question is about both pharmacokinetics and pharmacodynamics. Pharmacokinetics describes how the body processes a drug; here, the primary endpoint was intended to summarize plasma concentration over time. Pharmacodynamics describes the body’s response. The listed secondary outcomes concern heart rate variability, systolic and diastolic blood pressure, and heart rate.

The registry summary explains that the investigators were interested in variability associated with product and subject factors. That rationale identifies the research concern, not a finding that either type of variability occurred. The posted record does not establish how the formulations compared, how precise any comparison was, or whether a prespecified bioequivalence criterion was met. Those conclusions would require the relevant estimates, uncertainty measures, and analysis details, which are not reported in the registry record.

3. Trial Design

This was a Phase 4, randomized, open-label crossover study sponsored by the University of Florida. The registry lists enrollment as 61, a start of 2015-08, primary completion on 2018-06-06, and status as completed. Randomized allocation indicates that participants were assigned to a study sequence; the record does not describe the randomization method or how assignment was implemented.

The interventions were brand-name metoprolol ER, Generic A, and Generic B. In Study Sequence A, participants started with the brand-name product, switched to Generic B, returned to the brand-name product, and then switched to Generic A. In Study Sequence B, participants started with the brand-name product, switched to Generic A, returned to the brand-name product, and then switched to Generic B. Thus, the sequences differed in the order of the two generics. The registry calls the primary analysis a 2-way crossover analysis.

Open-label means that masking was listed as none. The record does not describe procedures intended to conceal product identity from participants or study staff. It also does not report the duration of each treatment period, any washout periods, adherence procedures, or reasons for the sequence structure.

The study’s stated purpose was to compare pharmacokinetic and cardiovascular responses among equivalent labeled doses. The primary outcome description specifies AUC values for 50mg, 100mg, and 150mg doses, with measurements described at a series of post-dose times. The registry lists five outcome measures and 16 analyses. These counts indicate that the record covers several measurements or comparisons, but do not by themselves describe the analysis plan or show which comparisons were considered primary for inference.

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: 61 participants were consented with 10 participants as screen fails, 2 declining to further participate, and 1 unable to fit standard monitoring equipment.

Phase 1 Brand Name Metoprolol ER

Reasons for not completing this period:

Phase 2 1st Generic Administered

Reasons for not completing this period:

Phase 3 Brand Name Metoprolol ER #2

Phase 4 2nd Generic Administered

Analysis population for the primary outcome, as defined in the registry: This is a 2-way crossover 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.

Population: 18 participants who were administered both brand name metoprolol ER and Generic B and 18 participants who were administered both brand name metoprolol ER and Generic A were analyzed

6. Primary Endpoint

The registry lists the primary outcome as Area Under the Plasma Concentration Versus Time Curve (AUC), measured over 0.0, 0.30, 1.0, 2.0, 3.0, 4.0, 6.0, 8.0, 12.0, 16.0, 20.0, 24.0 hours post dose.

The primary endpoint was the area under the plasma concentration-versus-time curve, abbreviated AUC and reported in ng.hr/ml. The registry describes concentration measurements at 0.0, 0.30, 1.0, 2.0, 3.0, 4.0, 6.0, 8.0, 12.0, 16.0, 20.0, and 24.0 hours post dose. It states that mean and standard deviation values were entered separately for the 50mg, 100mg, and 150mg doses, for the brand-name product and both generics.

In general, AUC summarizes drug exposure across the time interval represented by the concentration measurements. It is used in pharmacokinetic comparisons because it captures more of the concentration-time profile than a single measurement does. The registry says that the AUC of the brand-name product would be compared with each generic to assess bioequivalence. That stated purpose does not itself establish bioequivalence: interpretation requires the observed estimates, their uncertainty, and the relevant decision criteria.

The record describes a 2-way crossover analysis, but the AUC means, standard deviations, and inferential comparisons are not reported in the registry record. The endpoint description therefore explains what was intended to be measured, not what the posted results show about the formulations.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The methods need to be read in light of what the registry record actually states. It identifies the study as randomized, open-label, and crossover, and describes AUC as the primary outcome. It does not report a complete statistical analysis plan, the model used for the primary comparisons, or the inferential results. The explanations below distinguish general statistical concepts from trial-specific details.

What does a crossover design mean?

In general, a crossover study assigns participants to treatment sequences so that they receive more than one intervention at different times. Comparing measurements from the same participant can be useful because personal characteristics that remain stable over time may influence all of that participant’s measurements. The study lists two sequences. Both begin with the brand-name product and include a return to it, while the order of Generic A and Generic B differs.

The registry describes the primary analysis as a 2-way crossover analysis. That label does not specify the exact statistical model. A full interpretation would need to know how treatment, sequence, period, and participant were represented, and whether any other factors were included. The registry record does not report those details. Nor does it report treatment-period durations or washout procedures, so it is not possible to assess those aspects from the record alone.

What does AUC summarize?

In general, AUC is an aggregate measure of drug concentration over a stated time interval. It uses the concentration-time profile rather than relying on a single time point. The registry describes the interval through measurements from 0.0 to 24.0 hours post dose, including the listed intermediate times. AUC is expressed in ng.hr/ml. The endpoint description says that means and standard deviations were entered separately for each of the 50mg, 100mg, and 150mg doses, for the brand-name product and both generics.

For a statistical comparison, the observed AUC summaries would need to be paired with an estimate of the contrast between products and a measure of uncertainty. A confidence interval, in general, gives a range of values compatible with the data and the assumptions of the analysis; it conveys precision as well as the estimated direction and magnitude. The registry record does not report the AUC estimates, comparison estimates, confidence intervals, p-values, or a bioequivalence decision rule. Therefore, no inferential conclusion about the primary endpoint can be drawn from the endpoint description alone.

Why can variability matter?

In general, variability is the extent to which observations differ from one another. The registry’s use of means and standard deviations is one way of describing the observed distribution of a continuous outcome. If data are more variable, a comparison may be less precise, all else being equal. A standard deviation is not a confidence interval, and it does not directly state the uncertainty in a treatment comparison. The record does not give the AUC standard deviations or the comparison uncertainty, so precision cannot be assessed.

Over-dispersion is a general concern when observed variability exceeds what a chosen statistical model expects. In that situation, standard errors can be too small if the model does not account for the extra variability, potentially making uncertainty appear lower than it is. This is a general explanation, not a description of a problem documented in this trial. The registry record does not report an over-dispersion assessment or model diagnostics.

What can the analysis counts tell us?

The registry lists five outcome measures and 16 analyses. These counts indicate that the posted record encompasses multiple outcomes or comparisons. They do not reveal how many tests were conducted for each outcome, which comparisons were planned in advance, or which results were treated as confirmatory. The record does not report a multiplicity adjustment or a hierarchy for interpreting the analyses.

When many statistical comparisons are considered, general statistical practice recognizes that the chance of at least one apparently notable result can increase if each comparison is interpreted separately without accounting for the set of tests. Possible approaches vary by scientific objective. The record does not say which approach, if any, was used here, so no adjustment should be assumed.

How should the planning illustration be read?

The sample-size section is described as a planning illustration based on the observed effect, not as the trial’s own design calculation. Its stated assumptions are a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation; the effect to detect is a stated fraction of the observed effect. In general, such illustrations explore how a hypothetical design might perform under specified assumptions. They are not observed power, and they do not establish what the original investigators planned.

The registry does not report the trial’s sample-size justification or the planning assumptions used by investigators. It also does not report an interim-analysis plan or the original statistical plan. Any numerical planning illustration should therefore be kept separate from the trial’s observed findings and from claims about the protocol.

10. Multiplicity, Missing Data and Analysis Populations

The registry lists five outcome measures and 16 analyses, including the primary AUC outcome and secondary measures of heart rate variability, blood pressure, and heart rate. Multiple outcomes, doses, formulations, or time-related measurements can create a multiplicity question: how should evidence across a set of comparisons be interpreted without treating each result as if it were the only test? This is a general statistical issue, not evidence that the trial’s analyses were inappropriate.

The registry record does not report a multiplicity adjustment, a testing hierarchy, or which analyses were designated as confirmatory. It does not state whether the listed analyses correspond to every comparison made or only those posted. Accordingly, the analysis count should not be used to infer how the investigators controlled the interpretation of multiple results.

Missing-data handling is also not reported in the registry record. The record does not state how missing endpoint measurements were treated, whether incomplete sequences were included, or what rules determined eligibility for each analysis. It does not report endpoint-specific analysis populations or the number of participants contributing to the primary AUC comparisons. The enrollment figure of 61 does not by itself establish how many participants contributed measurements at each dose or to each endpoint.

The study is described as randomized and crossover, but the record does not provide the analysis model or details about sequence and period effects. It also does not report interim analyses or a full statistical plan. These omissions limit assessment of how the planned comparisons were implemented and how robust they are to missing observations or analytic choices. They should be treated as unreported information, not as evidence that a particular method was or was not used.

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.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: ecg signs of myocardia ischemia (2.1%).

The registry lists serious and other adverse-event figures separately for Brand Name, Generic A, and Generic B. For serious adverse events, the groups show 1 affected among 48 at risk for Brand Name, 0 among 38 at risk for Generic A, and 0 among 40 at risk for Generic B. Deaths are listed as 0 in each group. These are descriptive counts in the registry record; they are not, by themselves, estimates of comparative risk.

For other adverse events, the record lists 33 affected among 48 at risk for Brand Name, 21 among 38 at risk for Generic A, and 16 among 40 at risk for Generic B. The numbers at risk differ across groups. Since this is a crossover study with sequences involving multiple products, the group figures should not be treated as though they were independent, parallel groups with identical follow-up. The registry does not report the event collection period or a statistical comparison of these figures.

The listed top serious adverse-event term is ECG signs of myocardia ischemia, with 2.1%. The registry excerpt does not explain the denominator or further context for that term. Adverse-event counts describe what was recorded during the study; they do not establish that a product caused an event or that an unlisted event did not occur. The record does not provide enough information for a comparative safety conclusion.

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

This record shows that investigators conducted a randomized, open-label crossover study of brand-name metoprolol ER and two generic formulations in people with high blood pressure. Its primary endpoint was AUC, intended to compare pharmacokinetic exposure at equivalent labeled doses. The posted record also identifies cardiovascular response measures and summarizes adverse-event counts.

What the record does not show is the numerical result of the primary comparison. AUC means and standard deviations, comparison estimates, confidence intervals, and inferential results are not reported in the registry record. As a result, this page cannot state how similar or different the products were on AUC, how precisely any difference was estimated, or whether a bioequivalence criterion was satisfied. The same limitation applies to the listed secondary outcomes: their names and purposes are present, but their comparative results are not reported in the registry record.

In general, a non-significant statistical test would not by itself prove equivalence, and a difference in sample summaries would not by itself establish a meaningful product difference. Equivalence or bioequivalence interpretation depends on the endpoint, the planned comparison, the uncertainty around its estimate, and the decision criteria. Those results and criteria are not reported. This is a general statistical distinction, not a claim about the outcome of this trial.

The enrollment figure and the sample-size planning illustration should also be kept distinct. Enrollment describes the registry entry; a planning illustration based on an observed effect is not the trial’s original sample-size justification and is not observed power. The record does not report the investigators’ sample-size rationale.

The appropriate conclusion is therefore limited: the registry describes a completed study design and its intended outcomes, but the material in this record does not establish a comparative pharmacokinetic or cardiovascular result. The adverse-event counts are descriptive and do not, on their own, establish a causal or comparative safety effect.

13. Why This Trial Matters Statistically

This trial is statistically interesting because it combines repeated product exposure with several kinds of outcome. The crossover sequences include the brand-name product and both generics, while the primary endpoint summarizes a concentration-time profile. That design raises questions about within-participant comparisons, treatment sequence, period, and how observations from multiple treatment periods should be analyzed. The registry calls the primary analysis a 2-way crossover analysis, but does not report the model details needed to evaluate those choices.

The outcome structure also matters. AUC addresses pharmacokinetic exposure, whereas heart rate variability, blood pressure, and heart rate are pharmacodynamic or cardiovascular response measures. These endpoints answer related but distinct questions. A result on one cannot automatically be treated as a result on the others. The record lists five outcomes and 16 analyses, making clear that interpretation may involve more than one comparison, while leaving multiplicity procedures unreported.

Another important statistical distinction is between a study’s objective and evidence that answers it. The objective refers to comparing generic and brand-name formulations and assessing bioequivalence. The registry’s description of that aim does not demonstrate that equivalence was found. Numerical estimates and uncertainty are essential for evaluating how close the observed results were and how precisely they were measured; these are not reported in the registry record.

Finally, the study offers a useful example of why registry design details and posted results need to be considered together. The crossover structure and planned dose-specific AUC summaries are described, but missing details about the analysis plan, populations, and results limit independent statistical interpretation. Separating what the design intended to measure from what the posted evidence can establish is central to reading this record carefully.

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 main limitation for interpreting this trial from the registry record is that the primary outcome estimates and comparisons are not reported in the information. The record describes dose-specific AUC means and standard deviations but does not state their values, the treatment contrasts, or the uncertainty around those contrasts. It therefore does not permit an assessment of magnitude, precision, or the stated bioequivalence objective.

The design is described as open-label, with masking listed as none. This indicates that masking was not recorded, but the entry does not explain how knowledge of product identity might have affected measurement or conduct. The record also does not describe treatment-period duration, washout intervals, adherence, or the randomization procedure. These are design details that could inform appraisal of a crossover comparison, but they are not reported in the registry record.

The number enrolled is listed as 61, while the safety denominators vary by product group. The record does not provide the analysis population for each endpoint, participant flow, or an explanation of the differences in denominators. Missing-data methods and handling of incomplete treatment sequences are also not reported. The registry does not state how sequence or period effects were modeled.

Although five outcome measures and 16 analyses are listed, the record does not describe multiplicity handling, a prespecified hierarchy, or which comparisons were confirmatory. The sample-size illustration is explicitly a planning exercise based on an observed effect, not the trial’s own design calculation; the original sample-size justification is not reported. Interim analyses and a full statistical plan are also not reported. These limitations concern what can be evaluated from the registry entry and should not be taken as proof that the study did not address these issues elsewhere.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: Open-Labeled PK-PD Studies of Metoprolol ER — NCT02417246.
• Registry record last updated 2020-02-10; status last verified 2020-02.
• Results first posted 2019-11-08.
• 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 NCT02417246, Open-Labeled PK-PD Studies of Metoprolol ER, as a completed Phase 4 randomized, open-label crossover study sponsored by the University of Florida. It lists enrollment of 61, a start of 2015-08, and primary completion on 2018-06-06.

The study compared brand-name metoprolol ER with Generic A and Generic B. Its primary endpoint was dose-specific AUC, with measurements described through 24.0 hours post dose. Listed secondary outcomes concern heart rate variability, systolic and diastolic blood pressure, and heart rate. The record lists five outcome measures and 16 analyses.

The registry describes the study question and design but does not report the AUC estimates or statistical comparison results in the information. It also does not report the full analysis plan, missing-data methods, or multiplicity procedures. Safety counts are descriptive and should not be interpreted as comparative causal estimates.