Clinical Pharmacology Study of Oral Edaravone in Healthy Adult Males (Drug Interaction Study and Preliminary Regimen-Finding Study): Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Clinical Pharmacology Study of Oral Edaravone in Healthy Adult Males (Drug Interaction Study and Preliminary Regimen-Finding Study) (NCT04481789), a non-randomized phase 1 study. The primary outcome is Area Under the Concentration Versus Time Curve From Time Zero to Infinity (AUC0-inf) of Rosuvastatin, Sildenafil and Furosemide..

2. Clinical Question

This is a clinical pharmacology study, not a trial of clinical benefit in patients. Its central focus was drug exposure and tolerability in healthy volunteers. The first cohort assessed possible drug interactions involving three named co-medications. The second cohort explored edaravone pharmacokinetics in healthy Japanese and Caucasian adult males and included dosing conditions that differed by meal timing for Japanese participants. These aims should be kept distinct: the first concerns coadministration, while the second concerns edaravone exposure and dosing conditions. The registry record does not report a clinical disease outcome or a treatment comparison intended to establish patient benefit.

3. Trial Design

The study is listed as Phase 1, completed, non-randomized, unmasked, and sequential, with enrollment of 84. Its recorded start date is 2018-10-17, and its primary completion date is 2018-12-20. It involved two cohorts with different pharmacology questions rather than a single parallel-group comparison.

Cohort 1 assessed drug interactions, safety, and tolerability. Group 1 used a single sequence: participants received rosuvastatin and sildenafil on separate initial study days, followed by MT-1186 dosing from Day 6 to 13 and coadministration with rosuvastatin and sildenafil on Day 9 and Day 12. Group 2 used a sequence involving furosemide on Day 1, MT-1186 from Day 3 to 7, and coadministration with furosemide on Day 6. The registry descriptions do not give every detail of these sequences.

Cohort 2 evaluated edaravone pharmacokinetics in healthy Japanese and Caucasian adult males. The Japanese participants were described as receiving single doses under several dosing conditions, with a three-way crossover and a 3-day washout between doses. The registry also lists a Japanese fasting condition and dosing 1 hour and 4 hours after a high-fat meal, and a Caucasian fasting condition. The complete treatment-sequence details are not reported in the registry record.

Because assignment was non-randomized and the cohorts used sequential or crossover procedures, the listed groups should not be treated as randomized, interchangeable arms. The registry itself warns that the arms are not a like-for-like control comparison. Further details about eligibility criteria, the planned sample-size justification, and the statistical plan are 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.

Period 1

Reasons for not completing this period:

Period 2

Period 3

Analysis population for the primary outcome, as defined in the registry: This study was conducted in 2 cohorts; the first cohort assessed DDIs with multiple doses of oral edaravone, and the second cohort evaluated PK and racial differences in PK parameters with oral administration of edaravone. DDI effects of oral edaravone was evaluated based on the number of subjects in each period in Cohort 1 (Group 1: Period 1 to 3, Group 2: Period 1 and 2).

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 Area Under the Concentration Versus Time Curve From Time Zero to Infinity (AUC0-inf) of Rosuvastatin, Sildenafil and Furosemide., measured over Before rosuvastatin dosing and 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 48 hrs post-dose, Before sildenafil dosing and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48 hrs post-dose, Before furosemide dosing and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48 hrs post-dose.

The primary endpoint is the area under the concentration-versus-time curve from time zero to infinity (AUC0-inf) for rosuvastatin, sildenafil, and furosemide. It is reported as a mean with standard deviation, in ng*h/mL. AUC represents drug exposure over time: it combines concentration measurements across the specified sampling period rather than describing concentration at only one moment. Extending the measure to infinity is intended to represent exposure beyond the last observed concentration as well as exposure during observed sampling; the registry record does not describe the calculation procedure used for that extension.

In a drug-interaction study, AUC is useful because a change in exposure to a co-medication can indicate that its pharmacokinetic handling differs when another drug is given. It is not, by itself, a measure of clinical benefit or harm. Interpretation depends on the actual estimates, the comparison being made, and the precision of those estimates. Numerical AUC results, comparison estimates, and confidence intervals are not reported in the registry record, so the endpoint's observed direction, size, and precision cannot be described from the registry information.

The listed sampling schedule includes predose and multiple post-dose time points. Rosuvastatin measurements include 0.5 through 48 hrs post-dose; sildenafil measurements include 0.25 through 48 hrs post-dose; and furosemide measurements include 0.5 through 48 hrs post-dose, with the specific intermediate times differing by drug. The endpoint is therefore a pharmacokinetic measure built from serial concentration observations, not a single clinical event.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

What does AUC measure? As a general statistical and pharmacokinetic explanation, an area under a concentration-time curve summarizes exposure across time. It differs from a peak concentration, which focuses on the highest measured concentration, and from the time to peak, which concerns when that peak occurs. AUC0-inf extends the exposure summary from the start of observation toward infinity. The primary endpoint is expressed as a mean and standard deviation in ng*h/mL. The registry record does not explain the exact calculation method used for AUC0-inf, including the handling of the terminal portion of the curve.

What does the standard deviation tell the reader? As a general statistical explanation, a standard deviation describes how dispersed individual observations are around their group mean. It is not the same as a confidence interval and does not directly show how precisely a difference between conditions has been estimated. Precision for a comparison depends on the analysis and the amount and variability of information available. The primary outcome description specifies means and standard deviations, but numerical summaries and confidence intervals are not reported in the registry record.

Why does the design matter? The registry describes Cohort 1 as single-sequence groups and the study allocation as non-randomized. In general, non-randomized sequential data do not have the same protection against systematic differences as a randomized concurrent comparison. A before-and-after or within-sequence contrast may be influenced by study timing or sequence, and an analysis needs to account for the design to support a clear interpretation. Which model, adjustment, or comparison procedure was used is not reported in the registry record. The registry also cautions that the arms are not a like-for-like control comparison.

For a crossover, general statistical reasoning recognizes that repeated measurements from the same participant are related. A suitable analysis can account for this within-participant structure; treating all observations as independent could misrepresent uncertainty. The Japanese Cohort 2 description includes a three-way crossover and a 3-day washout between doses. The actual analysis of participant-level dependence, period effects, or possible carryover is not reported in the registry record. The Caucasian fasting condition is not described as part of that Japanese crossover, so the registry information does not support assuming a shared analysis structure.

How should confidence intervals and p-values be read? As a general explanation, a confidence interval describes statistical uncertainty around an estimate under the analysis assumptions. A narrow interval indicates greater precision than a wide interval, while an interval spanning values that would imply materially different interpretations signals uncertainty. A p-value measures how compatible the data are with a specified null model; it does not give the probability that a hypothesis is true, nor does it describe the size or clinical meaning of an effect. No primary endpoint p-values or confidence intervals are reported in the registry record, so neither statistical significance nor comparative precision can be assessed from the posted registry information.

What is the role of the sampling schedule? AUC is based on concentration observations taken at multiple time points. The registry lists predose measurements and serial post-dose sampling for each named co-medication, with different schedules for rosuvastatin, sildenafil, and furosemide. In general, the timing and completeness of samples can affect the estimation of exposure, particularly when the curve changes quickly or when the late concentration profile is informative. The registry record does not report missing-sample handling, assay details, or rules for excluding pharmacokinetic observations.

How should planning calculations be interpreted? General sample-size calculations can illustrate the number of participants per arm that would be needed under stated assumptions to detect an effect of a chosen size. The planning assumptions described for this analysis include a two-sided significance level of 0.05, equal allocation, a normal approximation, and an effect defined as a stated fraction of the observed effect. Such calculations are planning illustrations, not observed power and not evidence that the study was designed with those assumptions. They do not replace the trial's own protocol justification; that justification is not reported in the registry record. The registry information also does not state whether the sponsor used interim analyses or a particular statistical analysis plan.

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("Rosuvastatin Alone: Group 1 of Cohort 1", "Rosubastatin + Edaravone: Group 1 of Cohort 1", "Sildenafil Alone: Group 1 of Cohort 1", "Sildenafil + Edaravone: Group 1 of Cohort 1", "Furosemide Alone: Group 2 of Cohort 1", "Furosemide + Edaravone: Group 2 of Cohort 1")
n   <- c(32, 31, 31, 31, 34, 34)
m   <- c(161, 165, 532, 482, 3861, 3906)
sp  <- c(66.8, 60.2, 236, 195, 1031, 736.2)
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  Rosuvastatin Alone: Group 1 of Cohort 1  32  161.000  66.800  136.916  185.084
CARM  Rosubastatin + Edaravone: Group 1 of Cohort 1  31  165.000  60.200  142.918  187.082
CARM  Sildenafil Alone: Group 1 of Cohort 1  31  532.000  236.000  445.435  618.565
CARM  Sildenafil + Edaravone: Group 1 of Cohort 1  31  482.000  195.000  410.473  553.527
CARM  Furosemide Alone: Group 2 of Cohort 1  34  3861.000  1031.000  3501.267  4220.733
CARM  Furosemide + Edaravone: Group 2 of Cohort 1  34  3906.000  736.200  3649.128  4162.872

11. Multiplicity, Missing Data and Analysis Populations

The study record lists 30 outcome measures and 10 analyses. Those counts indicate that multiple outcomes or analyses were recorded, but they do not reveal how many statistical hypotheses were formally tested, which were considered confirmatory, or how the analyses were organized. The primary endpoint names AUC0-inf for rosuvastatin, sildenafil, and furosemide, while secondary outcomes include AUCinf, Cmax, Tmax, and T1/2 measures for edaravone and its conjugates. How the study handled multiplicity across drugs, pharmacokinetic parameters, cohorts, conditions, or time points is not reported in the registry record.

As a general statistical point, assessing many outcomes can increase the chance of observing an apparently notable result by chance if each is tested separately. Procedures such as prespecifying a hierarchy or adjusting inference can address some multiplicity concerns, but the registry record does not identify whether any such procedure was used. It would therefore be inappropriate to infer an adjustment method or interpret the listed outcomes as a defined confirmatory testing family.

Missing-data methods and analysis populations are also not reported in the registry record. The record does not specify how many participants contributed to each pharmacokinetic estimate, whether every enrolled participant completed each period, how incomplete concentration profiles were handled, or whether any participants or observations were excluded. It also does not define an intention-to-treat, per-protocol, safety, or pharmacokinetic analysis population. These details matter because AUC requires serial measurements and because the denominators contributing to different conditions may vary.

The record does not report the statistical analysis plan, interim analyses, or a sample-size justification. The planning illustrations described with the posted analysis use stated assumptions and should be treated as hypothetical design calculations, not as the trial's documented prospective plan or as observed power.

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 lists serious adverse events, other adverse events, and deaths by exposure group or condition. In every listed group, the number with serious adverse events is 0, and the number of deaths is 0. Counts of participants affected by other adverse events range from 0 to 8 across the displayed groups. These are descriptive counts; they are not comparative estimates and do not establish that one condition is safer than another.

The groups represent different periods or conditions, including drug-alone and coadministration periods in Cohort 1 and meal-related or fasting conditions in Cohort 2. Some records are explicitly combined-period summaries. Participants may therefore contribute to more than one listed condition, and the group counts should not be added to create a total number of unique participants with events. The registry does not provide participant-level overlap or event timing that would clarify repeated reporting across conditions.

The counts of participants at risk differ across groups, and the registry lists both that denominator and the number affected. They should be read together rather than as stand-alone event counts. No serious adverse event terms are listed, and details such as severity, relatedness, and duration are not reported in the registry record. A zero count in these summaries means no such event was recorded for the listed group in the posted results; it does not establish the absence of risk beyond the observed study conditions.

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

The study addresses a narrow, early-phase pharmacology question: the exposure of selected co-medications when administered in sequences involving oral edaravone, together with pharmacokinetic and tolerability observations in healthy adult males. The registry record documents two cohorts, the named interventions, the primary endpoint definition, and selected adverse-event counts. It does not report numerical primary-endpoint findings, so the magnitude and direction of the exposure comparisons cannot be established from the registry information.

This is not a patient-outcome trial. It enrolled healthy adult males and was designed around pharmacokinetics, safety, and tolerability. The record does not report an outcome demonstrating clinical benefit, nor does it support conclusions about treatment effects in people with a disease. AUC is an exposure measure, not a direct measure of symptom improvement or disease progression.

The study's non-randomized, sequential structure also limits comparative interpretation. The registry cautions that its arms are not like-for-like control comparisons. The described crossover in Japanese participants may support within-participant pharmacokinetic comparisons when analyzed appropriately, but the analysis details and numerical results are not reported in the registry record. The information therefore cannot establish how precisely any condition differed from another.

The safety summaries report zero serious adverse events and zero deaths in the listed groups, and counts of other adverse events. These small descriptive summaries should not be read as proof of safety or as a comparative safety conclusion. The registry does not provide event terms, severity, relatedness, or enough participant-level detail to interpret overlap across conditions.

In short, the record defines the intended pharmacology questions and offers limited descriptive design and safety information. It does not contain the numerical exposure estimates, uncertainty intervals, or analysis details needed to determine the observed size or precision of the primary comparisons. No conclusion about efficacy or treatment benefit follows from this study record.

14. Why This Trial Matters Statistically

This study is statistically notable because it combines distinct pharmacology objectives in two cohorts and uses more than one design structure. Cohort 1 addresses coadministration in sequential groups, whereas Cohort 2 examines edaravone pharmacokinetics under different dosing conditions, including a Japanese crossover description. These structures generate different statistical questions: a drug-interaction contrast is not interchangeable with a comparison of dosing conditions, and a crossover requires attention to repeated observations within participants.

The registry also illustrates why endpoint definitions and results must be considered together. AUC0-inf is an interpretable measure of overall exposure, but the endpoint name alone does not reveal the estimated exposure contrast or its uncertainty. The record gives the summary statistic type and unit yet does not report the numerical primary results. Without those estimates and their precision, the pharmacokinetic question remains quantitatively unanswered in the registry.

Another important feature is the registry warning that the arms are not like-for-like controls. Statistical comparisons can be misleading if design differences are ignored, especially in non-randomized sequences. A sound interpretation must distinguish descriptive measurements from causal or comparative claims, and must be informed by the analysis model and analysis populations. Those methods are not reported in the registry record.

Finally, the adverse-event summaries show why denominators and study structure matter. Participants appear under multiple exposure conditions, and some groups are combined-period summaries. Reading counts as independent groups or adding them across conditions would risk misrepresenting the number of unique participants. The trial is a useful example of how pharmacokinetic endpoints, repeated measurements, design limitations, multiplicity, and incomplete reporting all affect statistical interpretation.

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 limitation of interpretation is that numerical primary-endpoint results are not reported in the registry record. Means, standard deviations, comparison estimates, confidence intervals, and p-values are absent, preventing assessment of the direction, magnitude, and precision of the AUC findings. The registry describes the endpoint and sampling schedule but not the computation details for AUC0-inf.

The study is non-randomized, unmasked, and sequential, and the registry warns that the arms are not like-for-like controls. The available descriptions therefore do not support treating the listed conditions as randomized parallel groups. The analysis methods needed to account for sequence, period, or within-participant structure are not reported in the registry record. The full details of Cohort 2 treatment sequences are also not reported.

The registry information does not provide the planned sample-size justification, eligibility details beyond the healthy male population, missing-data rules, analysis populations, or the statistical analysis plan. It does not state whether interim analyses were conducted or how multiplicity was handled across the listed outcomes and analyses. These omissions leave important uncertainty about how the planned questions were tested.

Safety information is limited to counts of participants at risk, participants affected by other adverse events, serious adverse events, and deaths in listed groups. Serious event terms, event severity, relatedness, timing, and overlap between conditions are not reported. Because groups can reflect different periods for the same participants, their counts should not be treated as independent totals. The record's limitations restrict both comparative safety interpretation and conclusions beyond the healthy-volunteer pharmacology setting.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Clinical Pharmacology Study of Oral Edaravone in Healthy Adult Males (Drug Interaction Study and Preliminary Regimen-Finding Study) — NCT04481789.
• Registry record last updated 2026-07-15; status last verified 2026-06.
• Results first posted 2024-08-02.
• 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

NCT04481789 is a completed Phase 1, non-randomized, unmasked, sequential clinical pharmacology study sponsored by Shionogi. It enrolled 84 healthy adult males and had two cohorts. Cohort 1 assessed oral edaravone with rosuvastatin, sildenafil, or furosemide; Cohort 2 assessed edaravone pharmacokinetics in healthy Japanese and Caucasian adult males.

The primary endpoint was mean AUC0-inf for rosuvastatin, sildenafil, and furosemide, reported in ng*h/mL with standard deviation. The record lists 30 outcome measures and 10 analyses. It does not report numerical primary endpoint comparisons or their precision. Safety listings report zero serious adverse events and zero deaths in each displayed group, with varying counts of other adverse events. The registry cautions that the arms are not like-for-like control comparisons. Further details on the statistical plan, missing-data methods, analysis populations, and multiplicity are not reported in the registry record.