This page provides an independent statistical analysis and educational interpretation of publicly reported results. ClinicalTrials.gov provides the official trial registry record. Numerical trial results on this page are restricted to the results posted in the ClinicalTrials.gov record; calculations added by Clinical Biostats are labelled as such.
1. Trial at a Glance
This page covers the registry results for A Study to Assess the Effect of Cefiderocol on the Pharmacokinetics (PK) of Midazolam in Healthy Participants (NCT05395104), a na phase 1 study. The primary outcome is Maximum Observed Plasma Concentration (Cmax) of Midazolam.
| Feature | Registry value |
|---|---|
| ClinicalTrials.gov identifier | NCT05395104 |
| Phase | Phase 1 |
| Condition | Healthy Volunteers |
| Allocation | Not applicable (single group) |
| Design model | Sequential |
| Masking | None (open label) |
| Enrollment | 14 |
| Arms in the primary outcome | n/a |
| Lead sponsor | Shionogi |
| Results posted | Yes |
2. Clinical Question
The study asks whether repeated doses of cefiderocol are associated with a change in the pharmacokinetics of midazolam in healthy adult participants. Its primary outcome is midazolam maximum observed plasma concentration (Cmax), assessed when midazolam was given alone at baseline and when it was given with cefiderocol on Day 15. The registry describes the study as a Phase 1, open-label, one-sequence crossover drug-interaction study.
Population
Healthy adult participants. The registry reports enrollment of 14 participants. The pharmacokinetics analysis population is defined as participants with at least one pharmacokinetics parameter appropriately estimated; participants in the Midazolam plus Cefiderocol population with available data were analyzed.
Intervention
Repeated cefiderocol dosing alongside midazolam. The arm description says each participant received a total of 45 doses of cefiderocol and 2 doses of midazolam according to the specified dosing schedule.
Comparator
Midazolam alone at baseline, on Day -1, is the within-participant reference for midazolam given on Day 15 with cefiderocol. This is a sequential comparison, not a randomized parallel-group comparison.
Primary question
How does midazolam Cmax compare between baseline dosing alone and dosing on Day 15 after repeated cefiderocol dosing? Numerical Cmax estimates and the resulting comparison are not reported in the registry record.
The question is pharmacokinetic rather than a comparison of clinical outcomes. Cmax describes the highest measured plasma concentration over the stated sampling interval. The study also lists cefiderocol pharmacokinetic outcomes, including Cmax, time to maximum concentration, AUC over the 8-hour dosing interval, and clearance. Those secondary measures do not replace the stated primary question about midazolam Cmax.
3. Trial Design
The registry describes a Phase 1, open-label, one-sequence crossover drug-interaction study. It is marked as sequential, with allocation listed as not applicable and masking listed as none. These details indicate that the record does not describe a randomized, masked comparison between separate treatment groups. Instead, the stated comparison is within participants: midazolam alone at baseline and midazolam with repeated cefiderocol dosing on Day 15.
The study enrolled 14 healthy participants. The arm description states that each participant received 2 doses of midazolam and 45 doses of cefiderocol according to a specified dosing schedule. The record identifies the primary outcome sampling periods as 0 (predose) up to 24 hours postdose on Day -1 and Day 15. Day -1 is defined as baseline. The exact dose amounts, timing details beyond the stated schedule, and any washout arrangements are not reported in the registry record.
The study is marked completed. The recorded start date is 2022-05-24, and the primary completion date is 2022-07-13. These administrative dates describe the registry timeline; they do not supply information about the size or precision of the pharmacokinetic effect.
A sequential within-participant design can compare measurements from the same person under different dosing conditions. In general, this can reduce the influence of stable differences between people, but it does not by itself remove possible period effects, changes over time, or carryover between conditions. Whether and how the study assessed such issues is not reported in the registry record. The record also does not report a separate control group, random sequence assignment, or a rationale for the chosen design.
The main analysis population is described as the pharmacokinetics parameter population: participants with at least one parameter appropriately estimated. For the primary outcome, the record says participants in the Midazolam plus Cefiderocol population with available data were analyzed. The number with usable Cmax measurements at each assessment 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.
Overall Study
| Stage | Cefiderocol Plus Midazolam |
|---|---|
| STARTED | 14 |
| Received At Least 1 Dose Of Study Drug | 14 |
| COMPLETED | 12 |
| NOT COMPLETED | 2 |
Reasons for not completing this period:
| Reason | Cefiderocol Plus Midazolam |
|---|---|
| Met Liver Stopping Criteria | 1 |
| Withdrawal by Subject | 1 |
Analysis population for the primary outcome, as defined in the registry: Pharmacokinetics Parameter Population: All participants with at least 1 pharmacokinetics parameter estimated appropriately. Participants in the "Midazolam + Cefiderocol" population with available data were analyzed.
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: Safety Analysis Population: all participants who were exposed to study intervention.
| Characteristic | Unit | Cefiderocol Plus Midazolam |
|---|---|---|
| Participants analysed | 14 | |
| Age, Continuous | Years | 40.9 (SD 14.58) |
| Sex: Female, Male: Female | Participants | 9 |
| Sex: Female, Male: Male | Participants | 5 |
| Ethnicity (NIH/OMB): Hispanic or Latino | Participants | 5 |
| Ethnicity (NIH/OMB): Not Hispanic or Latino | Participants | 9 |
| Ethnicity (NIH/OMB): Unknown or Not Reported | Participants | 0 |
| Race (NIH/OMB): American Indian or Alaska Native | Participants | 0 |
| Race (NIH/OMB): Asian | Participants | 0 |
| Race (NIH/OMB): Native Hawaiian or Other Pacific Islander | Participants | 0 |
| Race (NIH/OMB): Black or African American | Participants | 7 |
| Race (NIH/OMB): White | Participants | 7 |
| Race (NIH/OMB): More than one race | Participants | 0 |
| Race (NIH/OMB): Unknown or Not Reported | Participants | 0 |
6. Primary Endpoint
The registry lists the primary outcome as Maximum Observed Plasma Concentration (Cmax) of Midazolam, measured over 0 (predose) up to 24 hours postdose on Day -1 (Midazolam alone at Baseline) and Day 15.
| Element | Registry entry |
|---|---|
| Result type | Geometric Mean |
| Measure of spread | Geometric Coefficient of Variation |
| Unit | ng/mL |
| Endpoint classification | not reduced to a single comparison |
The primary endpoint is maximum observed plasma concentration (Cmax) of midazolam, expressed in ng/mL. It covers sampling from 0 (predose) up to 24 hours postdose on Day -1, when midazolam was given alone at baseline, and on Day 15, when midazolam was assessed after repeated cefiderocol dosing. The endpoint is reported as a geometric mean, with geometric coefficient of variation as its dispersion measure.
Cmax is used in pharmacokinetic studies to describe the highest measured plasma concentration during a defined sampling period. Comparing Cmax between the baseline and Day 15 conditions addresses whether the concentration peak differs when midazolam is administered after repeated cefiderocol exposure. It is one aspect of a drug’s concentration profile; it does not describe the full profile by itself. Other aspects can include the timing of the peak and the concentration accumulated over an interval, which are distinct quantities.
The geometric mean is appropriate for describing measurements that are analyzed on a multiplicative scale, such as pharmacokinetic concentrations that may be skewed. The geometric coefficient of variation describes relative variability on that scale. It is not a confidence interval and does not, on its own, indicate the precision of a comparison between conditions.
The registry record does not report the numerical Cmax estimates, the geometric coefficients of variation, a treatment comparison estimate, or a confidence interval for the primary endpoint. Consequently, the direction and magnitude of the observed difference, and its statistical precision, are not reported in the registry record.
7. Why No Re-analysis Is Shown
8. Statistical Interpretation
The registry identifies a clear pharmacokinetic question: whether midazolam Cmax differs between baseline dosing alone and Day 15 dosing after repeated cefiderocol. It also describes the population, dosing sequence, assessment periods, and the type of summary used for the primary outcome. However, the numerical primary outcome results are not reported in the registry record. There is therefore no registry-based estimate to interpret for the size, direction, or precision of the Cmax comparison.
This distinction matters because a study question and its outcome definition do not reveal what the observed data were. The outcome is stated as a geometric mean with geometric coefficient of variation, but those labels alone do not show whether the values were similar or different across the two conditions. Nor do they show how much uncertainty surrounds a comparison. The treatment comparison estimate and its confidence interval are not reported in the registry record.
The within-participant structure means the intended contrast is between conditions experienced by the same participants, rather than between randomized groups. In general, paired data can be informative because each participant contributes measurements under both conditions. The strength of that interpretation depends on the completeness and quality of the paired measurements and on how the analysis handles sequence, period, and possible carryover effects. Those analysis details are not reported in the registry record, so the extent to which these considerations were addressed cannot be determined from the record.
Enrollment was 14, but enrollment alone does not establish how many participants contributed evaluable Cmax data at both assessments. The registry defines an analysis population using appropriately estimated pharmacokinetic parameters and available data. It does not report the count of participants included in the primary outcome analysis or explain any exclusions. The precision of the primary comparison therefore cannot be inferred from enrollment alone.
The registry lists 13 outcome measures and 3 analyses. It does not report how the primary result relates to the other analyses, whether any adjustment for multiple testing was used, or whether the analyses were prespecified in a statistical plan. The presence of multiple outcomes does not itself establish that a particular adjustment was necessary or performed; the analysis plan and its rationale are not reported in the registry record.
Any sample-size figures associated with planning illustrations should be read as hypothetical planning calculations, not as observed trial findings or observed power. The registry describes those illustrations as based on a fraction of the observed effect, with a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation. That planning setup is distinct from this one-sequence crossover study. The illustrations do not replace the missing primary estimate, uncertainty interval, or account of the actual analysis.
The record reports no serious adverse events among 14 participants and reports other adverse events in 11 participants. These counts are descriptive safety information and do not establish a causal relationship with either study drug. The registry lists no serious adverse event terms. Interpretation of these safety figures is limited by the small enrolled group, the study’s healthy-participant setting, and the absence of detailed event descriptions in the record.
9. Statistical Methods Explained
The registry describes the primary endpoint as a geometric mean of midazolam Cmax, with geometric coefficient of variation as the measure of dispersion. These are summaries on a multiplicative scale. Concentration measurements can be analyzed on such a scale because proportional differences may be more meaningful than equal absolute differences, and the distribution of measurements may be asymmetric. This is a general explanation of the statistical concepts, not a claim about the unreported analysis details of this study.
What does a geometric mean describe?
A geometric mean is calculated by working with logarithms of positive measurements, averaging on the logarithmic scale, and transforming the result back to the original scale. In general, it can be useful when values vary proportionally or are right-skewed. A geometric mean is not the same as an arithmetic average. It also does not describe the spread around the mean by itself.
For this outcome, the geometric mean summarizes observed midazolam Cmax values for the relevant dosing condition. To interpret the drug-interaction question, the key quantity would ordinarily be a comparison between the baseline and Day 15 conditions, with an uncertainty measure. The record identifies the summary type but does not report the numerical estimates or the comparison method. A reader therefore cannot reconstruct the treatment contrast or its precision from the endpoint definition alone.
What does geometric coefficient of variation describe?
The geometric coefficient of variation (GCV) expresses relative variability on a multiplicative scale. In general, it characterizes how dispersed individual measurements are around a geometric mean. It is different from a confidence interval, which describes uncertainty in an estimated quantity, and different from a standard error, which describes the sampling variability of an estimate under a particular model. A GCV value alone would not answer whether the two dosing conditions differ or how precisely that difference was estimated.
The registry record does not give GCV values for either condition. It also does not specify whether confidence intervals, standard errors, or other uncertainty summaries were calculated for the primary comparison. These quantities should not be inferred from the outcome’s stated summary format.
Why does the sequence matter?
The study is identified as sequential and as a one-sequence crossover. The stated contrast uses baseline midazolam alone and midazolam on Day 15 after repeated cefiderocol dosing. In general, a crossover design can make within-person comparisons, which may account for stable participant characteristics without estimating them as between-group differences. But observations from the same person are related, so an analysis should account for that dependence rather than treating all measurements as independent.
General crossover considerations include period effects, changes in measurements over time, and carryover from an earlier treatment condition. The possibility and importance of these issues depend on the dosing schedule and study conduct. The registry does not report the methods used to evaluate or address them, and it does not provide a washout description. It would therefore be inappropriate to assume a particular model, adjustment, or carryover assessment.
Because the record identifies a single sequence rather than randomized treatment orders, the comparison should not be described as a randomized contrast. The within-participant structure is a design feature, but it does not make the conditions exchangeable by itself. The sequence, timing, and analysis choices remain relevant to interpretation.
What would an uncertainty interval add?
In general, a confidence interval gives a range of values compatible with the data and the assumptions of the statistical method. Its width conveys precision: a narrower interval indicates less statistical uncertainty under those assumptions, while a wider interval indicates more. The interval does not show every source of uncertainty, and it does not guarantee that the method’s assumptions are satisfied.
For a pharmacokinetic comparison, an interval around the estimated contrast would help readers judge which magnitudes remain compatible with the data. The registry does not report such an interval for midazolam Cmax. No conclusion about the precision of the primary comparison can be drawn from the enrollment count or from the description of the outcome statistic alone.
Why can over-dispersion matter?
In general, over-dispersion occurs when data vary more than a statistical model assumes. If a model understates the variability, standard errors may be too small and uncertainty intervals may be too narrow. If variability is modeled appropriately, the resulting uncertainty can better reflect the spread in the observations. This is a general statistical consideration; the registry does not report a model or identify over-dispersion as an issue in this study.
For pharmacokinetic outcomes, variability between participants and within participants can both be relevant. A model may need to distinguish those sources, depending on the design and data structure. The registry record does not specify such a model, so no particular variance structure or adjustment can be attributed to the analysis.
How should planning illustrations be read?
The registry describes sample-size planning illustrations based on a stated fraction of the observed effect, a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation. These assumptions describe hypothetical planning calculations; they are not evidence of the study’s actual design rationale. The trial itself is listed as a one-sequence crossover, so an equal-allocation, two-arm illustration should not be mistaken for the enrollment structure used in the study.
Such calculations can illustrate how a hypothetical sample size may depend on the assumed effect and statistical variability. They are not observed power, and they do not reveal the probability that the study detected an effect after the data were collected. The registry does not report a sample-size justification for this trial, and no numerical planning result is reported in the registry record in the registry record described for this analysis.
In short, the design and endpoint definitions identify what the trial intended to assess, while the available statistical descriptions do not include the numerical result or enough analysis detail to evaluate its estimate and precision. General concepts such as geometric summaries, paired comparisons, and confidence intervals can explain what those methods would mean, but they cannot supply unreported study results.
10. Multiplicity, Missing Data and Analysis Populations
The registry lists 13 outcome measures and 3 analyses. It identifies midazolam Cmax as the primary outcome and lists cefiderocol pharmacokinetic measures among the secondary outcomes. The record does not report a multiplicity strategy, such as a hierarchy of tests, adjustment method, or rationale for interpreting several outcomes together. It also does not report whether the listed analyses were prespecified in a statistical analysis plan.
Multiplicity is a general concern when several hypotheses are evaluated because repeated testing can increase the chance of at least one result appearing statistically notable by chance. Whether and how to address that concern depends on the study’s objectives and analysis plan. The registry’s count of outcomes and analyses is not enough to determine what approach was appropriate or used. The adjustment method, if any, is not reported in the registry record.
The pharmacokinetics population is defined as participants with at least one parameter appropriately estimated, and the record states that participants in the Midazolam plus Cefiderocol population with available data were analyzed. It does not report how many participants had an evaluable primary endpoint at each time, how missing Cmax measurements were handled, or why any observations may have been unavailable. The method for handling missing or unevaluable data is not reported in the registry record.
The record also does not describe imputation, sensitivity analyses, or an intention-to-treat analysis. These approaches should not be assumed. In a within-participant comparison, incomplete measurements can affect which participants contribute to the contrast; without the analysis counts and missing-data methods, the impact cannot be assessed.
11. Safety Results
The registry reports serious adverse events as affected participants divided by participants at risk.
| Arm | Participants with serious adverse events | Participants at risk | Percentage |
|---|---|---|---|
| Cefiderocol Plus Midazolam | 0 | 14 | 0.0% |
Deaths
| Arm | Deaths (participants affected of at risk) |
|---|---|
| Cefiderocol Plus Midazolam | 0 of 14 |
Other (non-serious) adverse events
Participants with at least one non-serious event at or above the registry's 0% reporting threshold.
| Arm | Participants affected of at risk |
|---|---|
| Cefiderocol Plus Midazolam | 11 of 14 |
Most frequent non-serious adverse event terms
| Event term | Organ system | Cefiderocol Plus Midazolam |
|---|---|---|
| Infusion site extravasation | General disorders | 7 of 14 |
| Infusion site pain | General disorders | 4 of 14 |
| Infusion site phlebitis | General disorders | 4 of 14 |
| Abdominal pain | Gastrointestinal disorders | 2 of 14 |
| Diarrhoea | Gastrointestinal disorders | 2 of 14 |
| Nausea | Gastrointestinal disorders | 2 of 14 |
| Catheter site pain | General disorders | 2 of 14 |
| Headache | Nervous system disorders | 2 of 14 |
| Somnolence | Nervous system disorders | 2 of 14 |
| Chills | General disorders | 1 of 14 |
The registry reports 0 participants with a serious adverse event among 14 at risk in the Cefiderocol Plus Midazolam group. It reports 11 participants with other adverse events among 14 at risk. The record lists 0 deaths and no serious adverse event terms. These are counts of participants, not event rates calculated for different exposure periods.
The categories distinguish serious adverse events from other adverse events; they should not be combined or treated as interchangeable. The serious-event count describes what was recorded in this study group. It does not establish that the risk of a serious event is absent. A study with 14 participants has limited ability to characterize uncommon events, and the registry record does not provide detailed event descriptions, timing, severity breakdowns, or attribution to a study drug.
The other adverse-event count is also descriptive. The registry does not give event types or indicate whether a participant could contribute more than one event, so the count should not be read as a count of distinct event episodes. There is no separate control group listed for a like-for-like safety comparison. These figures therefore do not establish whether events were caused by cefiderocol, midazolam, their combination, or other factors.
12. What the Result Does, and Does Not, Mean
The registry record describes a small, open-label Phase 1 study in healthy adult participants that compares midazolam pharmacokinetics at baseline with midazolam on Day 15 after repeated cefiderocol dosing. Its primary endpoint is clearly defined as midazolam Cmax over the stated postdose sampling interval. The record also states the summary format and identifies the pharmacokinetics analysis population.
What the record does not report is the numerical primary outcome result. It gives no baseline or Day 15 Cmax estimate, no GCV values, no treatment comparison estimate, and no confidence interval. The direction, magnitude, and precision of any difference are therefore not reported in the registry record. The study question cannot be answered from the endpoint description alone.
The design supports a within-participant comparison in principle, but the registry does not describe the statistical model or how it handled repeated observations, missing data, period effects, or potential carryover. It also does not report a detailed statistical analysis plan or multiplicity approach. These omissions limit assessment of how the primary comparison was estimated and how it should be interpreted alongside other outcomes.
The adverse-event counts describe events recorded among the study participants. They do not establish causality, and the absence of reported serious events in this group does not establish an absence of risk. The healthy-participant setting and enrollment of 14 also limit how broadly the safety observations can be interpreted.
More generally, a pharmacokinetic endpoint is not itself a clinical outcome. Cmax describes a concentration peak, not whether a participant experienced a clinical benefit or harm. The registry record concerns the measured pharmacokinetics of midazolam under the study conditions; it does not report clinical outcome comparisons or establish implications beyond those conditions.
13. Why This Trial Matters Statistically
This trial is statistically interesting because its main question is framed as a within-participant pharmacokinetic comparison. Each participant’s baseline midazolam assessment is contrasted with a later assessment after repeated cefiderocol dosing. Such designs can use each participant as their own reference, making the relationship between repeated measurements central to the analysis rather than treating the observations as independent groups.
The record also illustrates why a well-defined endpoint is not enough for interpreting a study result. Cmax, its measurement window, and its geometric summary are specified, but the numerical estimates and uncertainty around the comparison are not reported in the registry record. Without those results, readers cannot judge either the estimated change or how precisely it was measured. A design description and an outcome definition cannot substitute for an effect estimate.
The contrast between the actual design and the planning assumptions is another useful statistical distinction. The registry describes hypothetical sample-size illustrations using equal allocation between two arms and a normal approximation, while the study itself is listed as a one-sequence crossover. Planning illustrations can help explore assumptions, but they do not show that the trial was designed with those assumptions, and they are not observed power.
Finally, this record shows why population definitions and missing-data reporting matter. The analysis population is described in terms of appropriately estimated pharmacokinetic parameters and available data, but the number contributing to the primary comparison and the handling of unavailable measurements are not reported. Those details are necessary for understanding what data informed the estimate and how representative the analyzed set was of the enrolled participants.
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 statistical interpretation is that the registry record does not report numerical results for the primary endpoint. Without the midazolam Cmax estimates, a treatment comparison, or an uncertainty interval, the size and precision of the primary effect cannot be assessed. The stated geometric mean and GCV describe the intended summary format, not the observed result.
The study enrolled 14 participants and involved healthy adults. That setting and enrollment size limit the scope of inference, particularly for characterizing variability or uncommon safety events. The registry does not report the number of participants with evaluable paired Cmax measurements, so the analysis sample for the primary comparison cannot be established from the enrollment count.
The record describes an open-label, one-sequence crossover comparison without a randomized parallel control group. It does not report washout details, a model for repeated measurements, or methods for evaluating period or carryover effects. These are important design and analysis considerations for a sequential comparison, but their handling cannot be inferred from the design label.
Missing-data methods, exclusions, sensitivity analyses, and the detailed statistical analysis plan are not reported in the registry record. The record lists multiple outcomes and analyses, but does not state how multiplicity was handled. These gaps prevent a full assessment of robustness and selective interpretation. Dose amounts and further schedule details are also not reported in the registry record beyond the stated dose counts and assessment periods.
15. Related Tutorials
16. Related Statistical Calculators
17. Sources
- ClinicalTrials.gov: A Study to Assess the Effect of Cefiderocol on the Pharmacokinetics (PK) of Midazolam in Healthy Participants — NCT05395104.
- Registry record last updated 2023-12-14; status last verified 2023-03.
- Results first posted 2023-12-14.
- 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.
Continue through the Clinical Biostats statistical pathway
Use this trial's endpoint as a starting point for deeper study of effect measures, confidence intervals, and sample-size planning.
18. Record Summary
NCT05395104 is a completed Phase 1, open-label, one-sequence crossover study sponsored by Shionogi. It enrolled 14 healthy participants and assessed the effect of repeated cefiderocol dosing on midazolam pharmacokinetics. Each participant was described as receiving 2 doses of midazolam and 45 doses of cefiderocol according to the dosing schedule.
The primary outcome was midazolam Cmax from predose through 24 hours postdose on Day -1, when midazolam was given alone at baseline, and Day 15. It was specified as a geometric mean with geometric coefficient of variation. The registry record does not report numerical primary endpoint results or a comparison estimate. It lists 13 outcome measures and 3 analyses. Safety figures include 0 participants with serious adverse events, 11 with other adverse events, and 0 deaths in the reported group.