Drug-drug Interaction (DDI) Study of Spironolactone (Perpetrator) and Digoxin (Substrate Drug): Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Drug-drug Interaction (DDI) Study of Spironolactone (Perpetrator) and Digoxin (Substrate Drug) (NCT03909529), a randomized phase 1 study. The primary outcome is Dogoxin Plasma Data for Cmax.

2. Clinical Question

3. Trial Design

This was a phase 1, randomized, open-label, two-treatment, two-sequence, two-period crossover study of spironolactone and digoxin in healthy adult human subjects under fasting conditions. The registry record reports 28 enrolled participants and a completed study. The recorded start date was 2019-03-10 and the primary completion date was 2019-04-19.

The record describes the study as balanced and randomized. Participants were assigned to treatment sequences, with the two treatment conditions arranged across separate periods. In general, a crossover design allows each participant to receive more than one condition, so a comparison can use within-participant information. That feature can reduce the influence of stable differences between participants, but it does not remove the need to account for treatment period and sequence when analyzing the results.

One described sequence began with digoxin 250 mcg on day 6 after overnight fasting, followed by a 28-day washout period before spironolactone was administered. The other described sequence gave spironolactone oral suspension 100 mg from day 1 to day 5, followed by digoxin 250 mcg on day 6 after overnight fasting. The brief study description characterizes the conditions as single-dose treatments. The registry does not provide a complete statistical account of how sequence, period, or possible carryover were handled.

Masking was listed as none, consistent with an open-label design. The study was sponsored by CMP Development, LLC. The registry status is completed, but completion status does not mean that outcome values or analyses are available. The record lists additional pharmacokinetic and ECG assessments, but does not report their numerical results. The distinction between the planned design and reported findings is important: the design defines what was intended to be compared, while the absence of results prevents an assessment of the observed treatment contrast.

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.

Open Label, Balanced, Randomized DDI

Open Label, Balanced, Randomized DDI

Analysis population for the primary outcome, as defined in the registry: The following pharmacokinetic parameters for Digoxin were obtained using non-compartmental method (WinNonlin, version 8.1, Pharsight Corporation, USA): Cmax, AUC0-96, and tmax using plasma data, Renal clearance (CLR) /Percent Recovered, Unchanged drug excreted in urine (fe)/Amount Recovered using urine data.

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: On Day 6 of each period, after overnight fasting for at least 10.00 hours the subjects were dosed either with the Treatment (A) \[LANOXIN® (digoxin) USP 250 mcg (substrate drug)\] or Treatment (B) \[LANOXIN® (digoxin) USP 250 mcg (substrate drug) + Spironolactone Oral Suspension 100 mg (Perpetrator; Carospir® Oral Suspension 20 mL of 25 mg / 5 mL)\] as per the randomization scheme.

6. Primary Endpoint

The registry lists the primary outcome as Dogoxin Plasma Data for Cmax, measured over 4 days.

The primary endpoint was digoxin plasma Cmax, described as a mean with standard deviation and a timeframe of 4 days. Cmax is the highest measured plasma concentration after a dose. In general, it is used as a pharmacokinetic measure of peak exposure and can help characterize whether one treatment condition changes the concentration profile relative to another. It is not, by itself, a direct measure of clinical benefit or harm.

The registry describes the pharmacokinetic parameters as obtained using a non-compartmental method. It also identifies AUC0-96 and tmax from plasma data, and renal clearance, percent recovered, unchanged drug excreted in urine, and amount recovered from urine data. Digoxin plasma data for Tmax and ECG measurement to evaluate changes in the QT interval are listed as secondary outcomes. These additional measures provide context about concentration over time, excretion, and ECG monitoring, but the primary endpoint named in the record is Cmax.

No Cmax mean, standard deviation, treatment contrast, confidence interval, or test result is reported in the registry record. Consequently, the endpoint definition can be described, but the size and precision of any difference between treatment conditions cannot be assessed.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The registry identifies a randomized crossover design and a continuous primary measure summarized as a mean with standard deviation. It says the pharmacokinetic parameters were obtained by a non-compartmental method. These labels describe broad features of the intended measurements, but they do not give enough detail to reconstruct the statistical analysis. The specific analysis model, handling of missing observations, and inferential procedures are not reported in the registry record.

What does a crossover design contribute?

In general, a crossover study assigns participants to treatment sequences and observes outcomes under different treatment conditions in separate periods. Because a participant can contribute measurements under more than one condition, the treatment comparison can use within-person differences. This may control for stable participant characteristics that would otherwise contribute to variation between groups. The observations remain related, however; the analysis should reflect that dependence rather than treat every measurement as independent.

Crossover results can also be influenced by period effects, such as systematic changes across study periods, and by carryover, when a prior treatment affects a later period. Randomization of sequence can help balance some sources of bias, but it does not establish that a particular analysis handled them appropriately. The study record describes a washout period of 28 days in one sequence and reports two periods and two sequences. It does not report a model for period or sequence effects, a carryover assessment, or the rationale for the washout duration. Those details are not reported in the registry record.

What does Cmax measure?

In general, Cmax is the highest concentration measured in plasma after administration of a drug. It describes peak concentration, while measures such as AUC describe exposure over a period and Tmax describes when the peak occurs. Cmax can therefore contribute one part of a pharmacokinetic profile, but it does not capture every aspect of that profile. Here, the record names digoxin plasma Cmax as the primary measure and lists AUC0-96 and tmax among the parameters obtained from plasma data. It also lists renal clearance, percent recovered, unchanged drug excreted in urine, and amount recovered among the urine measures.

The record describes use of a non-compartmental method. In general, non-compartmental pharmacokinetic methods summarize observed concentration or excretion data without requiring a particular compartment structure for the body. That label does not specify the sampling schedule, rules for handling observations below assay limits, or the exact derivation used for each parameter. Those implementation details are not reported in the registry record.

How should a mean and standard deviation be read?

A mean describes the arithmetic average of the measured values, and a standard deviation describes how dispersed those values are around the mean. In general, a standard deviation is a description of variability among observations, not a confidence interval for the mean and not an estimate of the treatment effect. For a treatment comparison, the important quantities would include the values under each condition and a contrast that respects the paired crossover structure. The registry does not report those quantities for Cmax.

Pharmacokinetic measurements can be unevenly distributed, and variability can increase with the level of a measurement. In general, this kind of over-dispersion means that a simple model with constant variance may not describe the data well. Analysts may consider transformations or models suited to the observed distribution, but the choice depends on the data and prespecified plan. No distributional assessment, transformation, or variance model is reported in the registry record, so none should be attributed to this study.

What information is needed for statistical inference?

In general, a confidence interval gives an estimate together with its uncertainty under a specified model, while a hypothesis test evaluates compatibility with a stated null hypothesis. Neither can be recovered from the outcome definition alone. A p-value, even if reported, would not by itself describe the size or practical importance of a treatment difference. In this registry record, no primary outcome estimate, confidence interval, or test result is reported, and the record lists zero analyses.

The record describes a sample-size planning illustration based on the observed effect, with a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation. It also says the planning illustration is unavailable for this primary outcome because fewer than two arms are present. Such planning estimates, when available, are hypothetical illustrations based on assumptions; they are not observed power and do not substitute for an estimate with uncertainty from the trial. The record does not report the trial’s own sample-size justification or the assumptions used when enrolling participants.

Thus, the available methods description is enough to identify the broad design and measurement approach, but not enough to assess whether the analysis appropriately handled pairing, distribution, period, missing data, or multiplicity. Those statistical details are not reported in the registry record.

10. Multiplicity, Missing Data and Analysis Populations

The registry lists a primary pharmacokinetic measure, digoxin plasma Cmax, and several additional measures. The description names AUC0-96 and tmax from plasma data, renal clearance and urine recovery measures, a secondary Tmax outcome, and ECG measurement to evaluate changes in the QT interval. Multiple outcomes can create a multiplicity issue: in general, testing or interpreting many outcomes increases the chance that at least one result appears notable by chance. A prespecified hierarchy or adjustment can help address this concern, but the analysis plan and any multiplicity procedure are not reported in the registry record.

The record lists zero analyses and does not report numerical outcome results. It is therefore not possible to tell which measures were analyzed, whether all planned measures were available, or how any outcome selection was handled. No corrections, hierarchy, or other multiplicity strategy should be assumed.

Missing-data handling is also not reported. The record does not describe the number of participants with evaluable Cmax measurements in each period, reasons for missing measurements, exclusions, or imputation procedures. These details matter in a crossover study because the treatment comparison may depend on paired observations from both periods. The analysis population is not described in sufficient detail to determine whether the primary analysis included all enrolled participants, only participants completing both periods, or another group.

The record reports enrollment of 28 but does not report participant flow through the treatment periods or the number contributing to the primary endpoint. It does not describe protocol deviations or how they were handled analytically. These absences limit assessment of the completeness and robustness of any treatment comparison, in addition to the absence of reported results.

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 registry reports serious adverse events for two treatment groups: Treatment-A- Single Dose of Digoxin (LANOXIN) and Treatment-B-Digoxin (LANOXIN) + Spiranolactone (Carospir). Each group lists 28 participants at risk, zero participants affected by a serious adverse event, and zero deaths. The record also lists 28 at risk and zero affected for other adverse events in each group.

These are the registry’s reported counts, not an estimate of comparative risk. In general, zero reported events in a group means that no events were recorded for that category in the registry entry; it does not establish that the underlying risk is zero. The record does not provide further detail about event definitions, collection procedures, severity grading for non-serious events, or follow-up completeness.

The study is a crossover trial, and the same participants may contribute to both treatment conditions. Accordingly, the at-risk counts in the two groups should not be added and treated as distinct people. The counts describe each treatment group as recorded and do not supply a paired safety comparison or an uncertainty estimate. They also do not replace the missing pharmacokinetic results, which are a separate set of outcomes.

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

The record shows that investigators planned a randomized, open-label crossover comparison of digoxin alone with digoxin following spironolactone pretreatment in healthy adults under fasting conditions. It identifies digoxin plasma Cmax as the primary pharmacokinetic measure and describes additional plasma, urine, and ECG assessments. This establishes the question the study was designed to address.

The record does not report the primary outcome values or analyses. It therefore does not establish whether the measured digoxin Cmax differed between conditions, how large any difference was, or how precisely it was estimated. The absence of results must not be read as proof of no difference, and no direction of effect can be inferred from the design description alone.

In general, a pharmacokinetic interaction study assesses drug concentration or handling under defined study conditions. Even a reported change in a concentration measure would not, on its own, answer every question about clinical outcomes. Conversely, without concentration results, this record cannot establish the presence or absence of a pharmacokinetic effect. The registry does not report a clinical outcome comparison.

The enrolled participants were healthy adults studied under fasting conditions, and the described interaction regimen involved spironolactone pretreatment before a single digoxin dose. Those conditions define the scope of the question. They do not establish how findings would apply to other populations, dosing patterns, or circumstances. No such broader conclusions can be drawn from the information reported in the registry record.

The serious adverse event counts are also limited to the counts recorded for the two treatment groups. They do not provide a detailed safety analysis or evidence about unreported outcomes. Overall, the record documents the study’s design and selected outcomes but does not provide a result that can quantify the interaction or its uncertainty.

13. Why This Trial Matters Statistically

This trial is statistically interesting because a crossover design can be well suited to comparing pharmacokinetic measures when the same participant receives more than one treatment condition. In general, within-participant comparisons can reduce the influence of stable differences among participants. That advantage depends on suitable conduct and analysis, including attention to period, sequence, and possible carryover effects.

The study also illustrates why endpoint definitions and outcome results need to be read separately. Naming Cmax identifies the intended primary concentration measure, while the record’s description of a non-compartmental method identifies a broad way of deriving pharmacokinetic parameters. Neither description gives the observed treatment contrast or its uncertainty. Without those quantities, a reader cannot evaluate the size or precision of the interaction estimate.

The additional measures make the intended assessment broader than peak plasma concentration alone: the record names other plasma parameters, urine measures, and ECG evaluation. Multiple outcomes raise general questions about prespecification and multiplicity, but the registry does not report how those questions were addressed. The absence of analyses and numerical results also means there is no basis to compare primary and secondary findings.

The statistical lesson is one of restraint. A completed study record and a clearly described design do not replace outcome reporting. For this trial, the available information supports an account of the intended comparison, but not a numerical conclusion about digoxin exposure or the precision of an interaction estimate.

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 is the absence of reported primary outcome values and statistical analyses. Although the registry identifies Cmax as the primary measure and describes its summary format, it does not provide treatment-specific means, standard deviations, a treatment contrast, or an uncertainty interval. The magnitude and precision of the primary comparison are therefore unknown from the registry record.

Important analytic details are also not reported. The record does not specify the statistical model, how the crossover pairing was handled, whether period or sequence effects were assessed, or how carryover was considered. It does not report a missing-data strategy, the primary analysis population, or the handling of protocol deviations. These gaps prevent assessment of the analysis assumptions and the completeness of the data.

The record reports enrollment of 28, but does not provide a trial-specific sample-size justification or participant flow for the primary outcome. The planning illustration is unavailable for the primary outcome because fewer than two arms are present. Enrollment alone cannot establish that the study had adequate precision for its intended comparison, and no observed power can be inferred.

The study setting also constrains interpretation: the registered population was healthy adults under fasting conditions, and the described regimen involved spironolactone pretreatment followed by a single digoxin dose. The record’s safety counts do not include further event detail. These limitations do not determine what the unreported results would have shown; they define what can and cannot be assessed from the registry record.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: Drug-drug Interaction (DDI) Study of Spironolactone (Perpetrator) and Digoxin (Substrate Drug) — NCT03909529.
• Registry record last updated 2023-05-01; status last verified 2022-06.
• Results first posted 2023-05-01.
• 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

NCT03909529 is a completed phase 1, randomized, open-label crossover study sponsored by CMP Development, LLC. It enrolled 28 healthy adult human subjects under fasting conditions and compared digoxin alone with digoxin after spironolactone pretreatment. The recorded start date was 2019-03-10, and the primary completion date was 2019-04-19.

The primary measure was digoxin plasma Cmax, summarized as a mean with standard deviation over a timeframe of 4 days. The record also names plasma, urine, and ECG assessments. It reports zero serious adverse events and zero deaths in each listed treatment group, with 28 at risk in each group. Primary outcome values, statistical analyses, and detailed analysis methods are not reported in the registry record, so the treatment contrast and its precision cannot be evaluated.