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 Study of Copanlisib in Hepatic or Renal Impairment (NCT03172884), a non-randomized phase 1 study. The primary outcome is Maximum Observed Concentration (Cmax) of Copanlisib in Plasma..
| Feature | Registry value |
|---|---|
| ClinicalTrials.gov identifier | NCT03172884 |
| Phase | Phase 1 |
| Condition | Hepatic Insufficiency, Renal Insufficiency |
| Allocation | Non-Randomized |
| Design model | Parallel |
| Masking | None (open label) |
| Enrollment | 30 |
| Arms in the primary outcome | n/a |
| Lead sponsor | Bayer |
| Results posted | Yes |
2. Clinical Question
Population
The study enrolled participants in groups defined by hepatic or renal function, alongside healthy participants. Hepatic impairment groups were classified as moderate, Child-Pugh B (score 7-9), or severe, Child-Pugh C (score 10-15), at screening. Severe renal impairment was defined as eGFR 15-29 mL/min/1.73 m² at screening, based on the MDRD equation. The registry lists an enrollment of 30.
Intervention
All groups received copanlisib, identified in the registry as ALIQOPA or BAY80-6946. The study is described as a single-dose study. The registry record does not report the administered dose in the information available for this analysis.
Comparator
The impaired-function groups were considered in comparison with healthy participants. This was not a randomized comparison: participants were assigned to groups according to their functional status rather than random allocation. The groups therefore should not be treated as interchangeable or as a like-for-like randomized control comparison.
Primary question
The primary endpoint was maximum observed concentration (Cmax) of copanlisib in plasma. The study objective was to evaluate pharmacokinetics and safety in participants with impaired hepatic or renal function in comparison with healthy participants. Numerical group-level Cmax results and the registry’s statistical comparison results are not reported in the registry record.
3. Trial Design
NCT03172884 is a completed phase 1 study titled “Study of Copanlisib in Hepatic or Renal Impairment.” Its official title describes an open-label, non-randomized, single-dose study comparing pharmacokinetics and safety in participants with impaired hepatic or renal function and healthy participants. The design is listed as parallel, with no masking and non-random allocation. The sponsor was Bayer. The registry lists a start date of 2017-06-14 and a primary completion date of 2020-03-13.
The groups were healthy participants, participants with moderate hepatic impairment, participants with severe hepatic impairment, and participants with severe renal impairment. The registry defines the hepatic categories using Child-Pugh classification at screening: Child-Pugh B (score 7-9) for moderate impairment and Child-Pugh C (score 10-15) for severe impairment. Severe renal impairment was defined using eGFR 15-29 mL/min/1.73 m² at screening, calculated with the MDRD equation. The registry record does not report the criteria used to select the healthy participants.
Because allocation was non-randomized, the group comparison is observational within a clinical study rather than a randomized treatment contrast. Differences in participant characteristics may accompany differences in organ function. The record does not report a randomization procedure, masking, or a protocol-level rationale for the group sizes. It lists total enrollment as 30, but the posted information does not give a numerical primary endpoint result for each group.
The primary outcome was plasma Cmax of copanlisib. Secondary outcomes included Cmax and area under the concentration-time curve for metabolite M-1, as well as treatment-emergent adverse events and their severity. The registry lists 7 outcome measures and 9 analyses. The detailed analysis specifications and the numerical pharmacokinetic results 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.
Before assignment: 50 participants were screened in study. 16 were screen failure and 4 withdrew from study. 30 participants were assigned to study arms.
Overall Study
| Stage | Moderate Hepatic Impairment Group | Severe Hepatic Impairment Group | Severe Renal Impairment Group | Healthy Participants |
|---|---|---|---|---|
| STARTED | 8 | 6 | 8 | 8 |
| COMPLETED | 8 | 6 | 8 | 8 |
| NOT COMPLETED | 0 | 0 | 0 | 0 |
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.
| Characteristic | Unit | Moderate Hepatic Impairment Group | Severe Hepatic Impairment Group | Severe Renal Impairment Group | Healthy Participants | Total |
|---|---|---|---|---|---|---|
| Participants analysed | 8 | 6 | 8 | 8 | 30 | |
| Age, Continuous | years | 65.5 (SD 9.4) | 47.5 (SD 11.1) | 65.8 (SD 12.1) | 60.9 (SD 6.6) | 60.7 (SD 11.7) |
| Age, Customized: In utero | Participants | 0 | 0 | 0 | 0 | 0 |
| Age, Customized: Preterm newborn infants (gestational age < 37 wks) | Participants | 0 | 0 | 0 | 0 | 0 |
| Age, Customized: Newborns (0-27 days) | Participants | 0 | 0 | 0 | 0 | 0 |
| Age, Customized: Infants and toddlers (28 days-23 months) | Participants | 0 | 0 | 0 | 0 | 0 |
| Age, Customized: Children (2-11 years) | Participants | 0 | 0 | 0 | 0 | 0 |
| Age, Customized: Adolescents (12-17 years) | Participants | 0 | 0 | 0 | 0 | 0 |
| Age, Customized: Adults (18-64 years) | Participants | 4 | 6 | 3 | 6 | 19 |
| Age, Customized: From 65-84 years | Participants | 4 | 0 | 5 | 2 | 11 |
| Age, Customized: 85 years and over | Participants | 0 | 0 | 0 | 0 | 0 |
| Sex: Female, Male: Female | Participants | 3 | 1 | 2 | 3 | 9 |
| Sex: Female, Male: Male | Participants | 5 | 5 | 6 | 5 | 21 |
| Ethnicity (NIH/OMB): Hispanic or Latino | Participants | 0 | 0 | 0 | 0 | 0 |
| Ethnicity (NIH/OMB): Not Hispanic or Latino | Participants | 8 | 6 | 8 | 8 | 30 |
| Ethnicity (NIH/OMB): Unknown or Not Reported | Participants | 0 | 0 | 0 | 0 | 0 |
| Race (NIH/OMB): American Indian or Alaska Native | Participants | 0 | 0 | 0 | 0 | 0 |
| Race (NIH/OMB): Asian | Participants | 0 | 0 | 0 | 0 | 0 |
| Race (NIH/OMB): Native Hawaiian or Other Pacific Islander | Participants | 0 | 0 | 0 | 0 | 0 |
| Race (NIH/OMB): Black or African American | Participants | 0 | 0 | 0 | 0 | 0 |
| Race (NIH/OMB): White | Participants | 8 | 6 | 8 | 8 | 30 |
| Race (NIH/OMB): More than one race | Participants | 0 | 0 | 0 | 0 | 0 |
| Race (NIH/OMB): Unknown or Not Reported | Participants | 0 | 0 | 0 | 0 | 0 |
| BMI | kg/m^2 | 27.90 (SD 4.68) | 27.12 (SD 4.76) | 26.60 (SD 3.07) | 26.48 (SD 1.64) | 27.02 (SD 3.53) |
6. Primary Endpoint
The registry lists the primary outcome as Maximum Observed Concentration (Cmax) of Copanlisib in Plasma., measured over before copanlisib administration as well as 10 min and 1 h (end of infusion), 1.5, 2, 2.5, 3, 5, 8, 24, 48, 72, 96, 120 and 168 h after start of infusion.
| Element | Registry entry |
|---|---|
| Result type | Geometric Mean |
| Measure of spread | Geometric Coefficient of Variation |
| Unit | μg/L |
| Endpoint classification | not reduced to a single comparison |
The primary endpoint, maximum observed concentration (Cmax) of copanlisib in plasma, is the highest concentration measured among the blood samples collected after administration. The registry describes sampling before copanlisib administration and at 10 min and 1 h (end of infusion), 1.5, 2, 2.5, 3, 5, 8, 24, 48, 72, 96, 120 and 168 h after start of infusion. Cmax is reported as a geometric mean with geometric coefficient of variation as its dispersion measure.
As a general pharmacokinetic concept, Cmax describes the observed peak concentration over the sampled period. It is used alongside other measures, such as area under the concentration-time curve, because the peak and the overall exposure over time describe different features of a concentration profile. The sampled maximum is dependent on the collection schedule: it is the largest measured value, not necessarily a directly observed concentration at the exact time of the true biological peak.
The registry record does not report the numerical Cmax values by group, the associated geometric coefficients of variation, or the estimated differences or ratios between groups. As a result, the endpoint definition and schedule can be described, but the magnitude and precision of the observed group results cannot be evaluated from the registry information.
7. Why No Re-analysis Is Shown
8. Statistical Interpretation
The study’s primary question concerns copanlisib pharmacokinetics across groups defined by hepatic or renal function, with healthy participants serving as a reference group. The primary endpoint is Cmax, and the study also included outcomes for the metabolite M-1 and treatment-emergent adverse events. However, numerical primary endpoint estimates and their uncertainty are not reported in the registry record. The posted information therefore does not support a quantitative account of how Cmax differed between any impaired-function group and healthy participants.
The design matters when interpreting any group contrast. Participants were not randomly allocated, and group membership reflected hepatic or renal status. Randomization can help balance measured and unmeasured characteristics across treatment groups; a non-randomized comparison does not have that protection. A difference between groups, if quantified, would describe the observed groups and would not by itself show that organ impairment caused the difference. This is especially important when the sample is divided among several distinct functional-status groups.
The stated endpoint uses a geometric mean and geometric coefficient of variation. As a general statistical explanation, geometric summaries are often used for positive measurements with a right-skewed distribution, as can occur with concentration data. The geometric coefficient of variation describes relative dispersion on a multiplicative scale. These summaries communicate central tendency and variability but do not replace the need to see group estimates and an uncertainty measure. Those estimates are not reported in the registry record.
The registry lists enrollment of 30, but enrollment alone does not establish the precision of a pharmacokinetic comparison. Precision depends on the observed variability and the number of participants contributing usable measurements to each analysis. The group-specific analysis counts and uncertainty intervals are not reported in the registry record. No conclusion about statistical significance or the size of a group contrast can be drawn from an enrollment total alone.
Safety information is also limited to counts. In the registry’s adverse-event summary, no serious events are listed as affecting participants in any of the four groups. The “other” affected counts are 0 in the moderate hepatic impairment group, 0 in the severe hepatic impairment group, 2 in the severe renal impairment group, and 2 among healthy participants. These counts do not establish comparative risk, and the registry record does not provide inferential estimates for between-group safety differences. In a small, non-randomized study, descriptive counts should be read as a record of observed events rather than as a definitive comparison.
Overall, the record establishes the study question, design, endpoint, assessment schedule, and selected event counts. It does not report the numerical pharmacokinetic results needed to judge the magnitude or precision of the primary comparison. The interpretation must remain correspondingly limited: the objective was to evaluate pharmacokinetics and safety across organ-function groups, but the registry information does not show the primary endpoint estimates or a statistical conclusion about them.
9. Statistical Methods Explained
What does Cmax represent?
Cmax is the highest measured concentration in a participant’s series of blood samples. In this study, the endpoint was the maximum observed plasma concentration of copanlisib. The registry gives a sampling schedule extending from before administration through 168 h after start of infusion, with multiple samples during and after infusion. As a general concept, more frequent sampling near a concentration peak can better characterize its timing and height, but the maximum recorded value remains tied to the actual sampling times. The record does not report the individual concentration profiles or the time at which each participant reached Cmax.
Why report geometric summaries?
The primary endpoint is specified as a geometric mean with a geometric coefficient of variation. As a general statistical explanation, concentration measurements are positive and can have a multiplicative, right-skewed distribution. A geometric mean summarizes measurements on a logarithmic scale and then expresses the result on the original scale. The geometric coefficient of variation describes spread relative to the geometric mean, rather than spread as an additive distance. This approach can be suitable for pharmacokinetic measurements, but the registry record does not provide the values needed to assess the observed distributions or group variability.
What does the design imply for comparisons?
The study was open-label, parallel, and non-randomized. The groups were defined by organ-function status and included healthy participants as a reference. As a general statistical principle, random assignment helps separate treatment-group differences from differences in participant characteristics. Here there was no randomized assignment to impairment categories, and the categories themselves reflect clinical status. Any comparison should therefore be understood as a comparison between the observed groups, not as a randomized causal estimate. The registry record does not report adjustment methods that might account for differences between groups.
The study is described as a single-dose investigation. A single-dose pharmacokinetic assessment can characterize concentrations after that administration under the study conditions. It does not, by itself, describe repeated-dose exposure or outcomes over a longer treatment course. The dose and details of dosing procedures are not reported in the registry record available for this analysis.
How should variability and uncertainty be read?
A confidence interval, as a general statistical concept, gives a range of values compatible with the data under the assumptions of the analysis. It helps readers distinguish a point estimate from its precision. A narrow interval indicates greater precision than a wide interval, while neither an interval nor a point estimate alone establishes clinical importance. The registry information does not report confidence intervals for the primary endpoint or comparisons, so their precision cannot be assessed.
Variability within a group and uncertainty about a group estimate are related but distinct. A geometric coefficient of variation describes the spread of participant measurements on a relative scale. An interval around a group estimate describes uncertainty in estimating that group’s central value or a contrast. The record identifies the dispersion measure for Cmax but does not report its numerical value or an uncertainty interval. It is therefore not possible to characterize the observed variability or the precision of a group contrast.
For general context, over-dispersion occurs when observed variation is greater than a statistical model expects. A model that fails to account for over-dispersion may understate uncertainty. The registry record does not identify a model for the primary comparison, report a dispersion assessment beyond naming the geometric coefficient of variation, or state that over-dispersion was assessed. This concept should not be taken as a description of what occurred in this study.
What can be inferred from the analysis listing?
The registry lists 7 outcome measures and 9 analyses. These counts indicate that several outcomes and analyses were registered, but they do not describe the statistical procedures used for the primary endpoint. The analysis model, transformation details, covariates, handling of outliers, and rules for selecting a comparison are not reported in the registry record. It would be inappropriate to assume a particular test, model, or adjustment strategy from the endpoint summary alone.
Secondary pharmacokinetic outcomes include maximum observed concentration of metabolite M-1 and its area under the concentration-time curve in plasma from 0 to 168 h. As general concepts, Cmax captures a measured peak, while area under the curve summarizes concentration over a specified period. These endpoints provide different descriptions of exposure. The record names them as outcomes but does not provide their numerical results or analysis estimates.
The adverse-event outcomes concern the number of participants with treatment-emergent adverse events and their severity. Counts describe how many participants were recorded in the relevant categories. Statistical comparisons of such outcomes may use methods suited to categorical data, but the registry record does not specify whether any inferential test or adjusted analysis was conducted. The adverse-event summary should consequently be read descriptively.
No sample-size justification, interim analysis plan, or detailed statistical analysis plan is reported in the registry record. Planning illustrations based on an observed effect, when presented, are not observed power and do not establish that the study was designed to detect a particular effect. The record does not include numerical planning results in the information available for this analysis, and no such values can be interpreted.
10. Multiplicity, Missing Data and Analysis Populations
The registry lists 7 outcome measures and 9 analyses, covering the primary Cmax endpoint, metabolite M-1 pharmacokinetic outcomes, and adverse-event outcomes. When multiple outcomes or comparisons are examined, the chance of at least one apparently notable result can increase. As a general statistical concept, multiplicity procedures can control that chance or otherwise clarify which results are confirmatory and which are exploratory.
The registry record does not report a multiplicity adjustment, a hierarchy of endpoints, or a prespecified strategy for interpreting the multiple analyses. It also does not give the detailed analysis plan needed to determine whether the listed analyses were treated as confirmatory or exploratory. No claim about adjustment or control of false-positive findings is therefore supported.
Missing-data handling is not reported in the registry record. The available information does not state how incomplete concentration profiles, missed sample collections, withdrawals, or unavailable outcome measurements were treated. It also does not report imputation methods or sensitivity analyses for missing observations.
The analysis populations are not described in sufficient detail to identify which participants contributed to each endpoint analysis. The registry lists total enrollment as 30, but does not report group-specific numbers with evaluable Cmax measurements or the denominators used for each pharmacokinetic analysis. The record also does not state whether the primary analysis used all enrolled participants or a defined pharmacokinetic population. These omissions limit assessment of missingness, analysis-set selection, and the precision of the reported results.
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 |
|---|---|---|---|
| Moderate Hepatic Impairment Group | 0 | 8 | 0.0% |
| Severe Hepatic Impairment Group | 0 | 6 | 0.0% |
| Severe Renal Impairment Group | 0 | 8 | 0.0% |
| Healthy Participants | 0 | 8 | 0.0% |
Deaths
| Arm | Deaths (participants affected of at risk) |
|---|---|
| Moderate Hepatic Impairment Group | 0 of 8 |
| Severe Hepatic Impairment Group | 0 of 6 |
| Severe Renal Impairment Group | 0 of 8 |
| Healthy Participants | 0 of 8 |
Other (non-serious) adverse events
Participants with at least one non-serious event at or above the registry's 1% reporting threshold.
| Arm | Participants affected of at risk |
|---|---|
| Moderate Hepatic Impairment Group | 0 of 8 |
| Severe Hepatic Impairment Group | 0 of 6 |
| Severe Renal Impairment Group | 2 of 8 |
| Healthy Participants | 2 of 8 |
Most frequent non-serious adverse event terms
| Event term | Organ system | Moderate Hepatic Impairment Group | Severe Hepatic Impairment Group | Severe Renal Impairment Group | Healthy Participants |
|---|---|---|---|---|---|
| Hypertension | Vascular disorders | 0 of 8 | 0 of 6 | 2 of 8 | 1 of 8 |
| Atrial fibrillation | Cardiac disorders | 0 of 8 | 0 of 6 | 0 of 8 | 1 of 8 |
| Diarrhoea | Gastrointestinal disorders | 0 of 8 | 0 of 6 | 1 of 8 | 0 of 8 |
| Headache | Nervous system disorders | 0 of 8 | 0 of 6 | 0 of 8 | 1 of 8 |
The registry’s adverse-event summary distinguishes serious-event counts from other affected counts for each group. The serious-event counts are 0 for the moderate hepatic impairment group, 0 for the severe hepatic impairment group, 0 for the severe renal impairment group, and 0 for healthy participants. The corresponding numbers at risk are 8, 6, 8, and 8. No deaths are listed in any group.
The “other” affected counts are 0 in the moderate hepatic impairment group, 0 in the severe hepatic impairment group, 2 in the severe renal impairment group, and 2 among healthy participants. The numbers at risk for those groups are 8, 6, 8, and 8, respectively. These are descriptive counts, not estimates of comparative safety. No percentages or risk contrasts are reported in the registry record, and none should be inferred from the counts.
A zero count in a small group means no event was recorded among the listed participants in that category; it does not establish that the underlying event risk is zero. The registry also does not provide event narratives or the full detail needed to interpret timing, duration, or relatedness. The counts should therefore be read as a limited description of the posted safety summary rather than a complete characterization of safety.
12. What the Result Does, and Does Not, Mean
The registry record documents a phase 1 investigation of copanlisib pharmacokinetics and safety among participants with hepatic or renal impairment and healthy participants. It identifies Cmax of copanlisib in plasma as the primary endpoint, gives the sampling schedule, describes how the impairment groups were classified, and reports selected adverse-event counts. These registry entries clarify the intended question and the structure of the study.
The record does not report numerical Cmax estimates, geometric coefficients of variation, confidence intervals, or statistical comparisons. It therefore does not establish the observed magnitude, direction, or precision of any pharmacokinetic difference between the impaired-function groups and healthy participants. The study objective should not be mistaken for a result: an evaluation was intended, but the numerical primary endpoint findings are not reported in the registry record.
The non-randomized design also limits interpretation. Participants were grouped according to organ function, so an observed contrast would describe differences between these groups and could reflect differences beyond the impairment classification. Without reported adjustment methods or detailed participant characteristics, the registry information does not allow those influences to be assessed.
The safety summary records no serious events and gives counts for other events, but these counts are descriptive. They do not demonstrate equivalence between groups or establish the absence of risk. The small group counts and lack of comparative uncertainty estimates further limit interpretation.
In short, this record is informative about the study design and outcome definitions but incomplete for judging the primary pharmacokinetic findings. It does not support a conclusion that copanlisib exposure was higher, lower, or similar across the groups, nor does it support a definitive comparative safety conclusion.
13. Why This Trial Matters Statistically
This study illustrates a common pharmacokinetic question: whether drug concentration profiles differ across groups with varying organ function. Such questions require clearly defined participant categories, a specified concentration endpoint, and a sampling schedule capable of measuring the relevant profile. The registry identifies each of these elements for copanlisib, including the hepatic and renal impairment criteria and the Cmax sampling times.
It also highlights why design and analysis details matter. A non-randomized comparison can be useful for describing pharmacokinetics across clinically defined groups, but it does not provide the same protection from group differences as random allocation. Statistical interpretation must account for that design rather than treating the healthy group as a randomized control.
Reporting the geometric mean and geometric coefficient of variation is relevant because pharmacokinetic measurements are often analyzed on a multiplicative scale. The endpoint definition alone, however, cannot establish the size or reliability of a finding. Numerical estimates and uncertainty measures are necessary for judging both the observed contrast and its precision; those results are not reported in the registry record.
The study also demonstrates the distinction between registered outcomes and interpretable findings. Listing the primary and secondary outcomes makes the aims visible, but without endpoint results, analysis methods, and information about the analysis populations, readers cannot determine how the planned questions were answered. The safety counts offer a limited descriptive view, not a complete comparative analysis.
For biostatisticians and clinical researchers, the central lesson is to read study purpose, design, endpoint, analysis, and results as separate pieces of evidence. A clear pharmacokinetic question and a defined collection schedule are important, but conclusions depend on reported estimates and their uncertainty. In this record, the design and measurement framework are described more fully than the numerical findings.
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 principal limitation for interpreting this trial is that numerical results for the primary Cmax endpoint are not reported in the registry record. The group-level geometric means, geometric coefficients of variation, and estimates of between-group contrasts are unavailable in the information summarized. Without those results, neither effect size nor precision can be assessed.
The design was non-randomized and open-label. Group assignment was based on hepatic or renal function, so groups may differ in other characteristics as well. The registry information does not report adjustment methods or enough participant-level detail to evaluate the extent of those differences. The healthy participants are a reference group, but not a randomized control group.
Although total enrollment is listed as 30, evaluable sample sizes for individual pharmacokinetic outcomes are not reported in the registry record. The record also does not specify missing-data handling, the analysis populations, or whether all scheduled samples were available. These gaps make it difficult to judge the contribution of incomplete measurements to the analysis.
The statistical analysis plan, including the model and multiplicity approach, is not reported in the registry record. The analysis listing does not by itself identify which comparisons were planned, how uncertainty was estimated, or whether adjustment was used. The sample-size justification and interim analysis procedures are also not reported.
Finally, the adverse-event summary provides limited counts without event-level descriptions or comparative uncertainty estimates. These data can describe the posted counts but cannot establish a comprehensive safety profile or a precise difference between groups.
15. Related Tutorials
16. Related Statistical Calculators
17. Sources
- ClinicalTrials.gov: Study of Copanlisib in Hepatic or Renal Impairment — NCT03172884.
- Registry record last updated 2021-04-28; status last verified 2021-04.
- Results first posted 2021-04-01.
- 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.
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
NCT03172884 is a completed, open-label, non-randomized, parallel-group phase 1 study sponsored by Bayer. It evaluated single-dose copanlisib in healthy participants and participants with moderate or severe hepatic impairment or severe renal impairment. The registry lists enrollment of 30, a start date of 2017-06-14, and a primary completion date of 2020-03-13.
The primary endpoint was plasma Cmax of copanlisib, summarized as a geometric mean with geometric coefficient of variation. Secondary outcomes included pharmacokinetic measures for metabolite M-1 and treatment-emergent adverse events. Numerical primary pharmacokinetic results and detailed statistical methods are not reported in the registry record. The adverse-event summary lists no serious events in the groups and includes descriptive counts for other events.