Relative Exposure and Safety Study of Kimyrsa in ABSSSI Patients: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Relative Exposure and Safety Study of Kimyrsa in ABSSSI Patients (NCT03873987), a randomized phase 1 study. The primary outcome is Relative Exposure of AUC of the New Formulation to the Approved Formulation.

2. Clinical Question

3. Trial Design

This was a phase 1, randomized, open-label, parallel-group study of Kimyrsa and the approved oritavancin formulation. The registry lists an enrollment of 102 and a completed study status. The study start date is 2019-07-16, and primary completion was 2019-08-27. The registry identifies Melinta Therapeutics, Inc. as the sponsor.

Participants were being treated for acute bacterial skin and skin structure infection. The two interventions were single 1200 mg intravenous doses of oritavancin, delivered in different formulations and infusion preparations. The current formulation used three 400 mg vials, reconstituted with SWFI and diluted in D5W to a total volume of 1000 mL for infusion over 3 hours. Kimyrsa used a single 1200 mg vial, reconstituted with SWFI and diluted with 0.9% sodium chloride to 250 mL for infusion over 1 hour.

Randomization means assignment to the study arms was intended to occur by chance. The parallel design means participants were assigned to one formulation rather than receiving both formulations in a crossover sequence. The study was open label, with no masking reported. These design features describe how treatment was assigned and delivered; they do not by themselves establish that the groups were comparable on every characteristic or that an outcome difference was caused by formulation.

The primary endpoint was relative exposure based on AUC0-72, and the registry states that it was measured over 72 hours. The pharmacokinetic population required receipt of the full dose and at least one valid drug-level sample. The registry reports 50 participants per arm for the primary endpoint. The detailed randomization procedure, eligibility criteria, participant flow, and protocol deviations 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.

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: PK Population: all subjects who have received the full dose of oritavancin and have any valid samples measured for study drug levels

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 Relative Exposure of AUC of the New Formulation to the Approved Formulation, measured over 72 hours.

The primary endpoint is relative exposure based on the area under the plasma concentration-time curve from time zero to 72 hours (AUC0-72). AUC summarizes drug concentration across a defined period: it reflects both the concentration reached and how concentrations change over time. Pharmacokinetic studies use AUC to characterize systemic exposure after a dose. Because the formulations use different concentrations, diluents, volumes, and infusion times, comparing AUC is relevant to describing whether the resulting measured exposure is similar or different.

The registry presents a geometric least-squares mean for each arm, expressed in h*µg/mL, together with a geometric coefficient of variation. The reported values are 1470.0 for Orbactiv and 1460.0 for Kimyrsa; the corresponding geometric coefficients of variation are 39.7 and 35.1. These are arm-level summaries, not a reported ratio or direct estimate of the relative exposure contrast. A confidence interval, hypothesis test, or prespecified acceptance range for the relative comparison is not reported in the registry record.

AUC is a pharmacokinetic endpoint, not a direct measure of symptom improvement or infection resolution. The registry identifies safety as another study focus and lists a treatment-emergent adverse event outcome, but the primary endpoint itself concerns measured drug exposure. The results therefore describe pharmacokinetics over the stated observation period, not the overall clinical benefit of either formulation.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The registry reports geometric least-squares means and geometric coefficients of variation for the primary pharmacokinetic endpoint. These statistics summarize drug exposure in each arm, but the record does not give the model, the treatment contrast, or an inferential analysis. The explanations below describe the general statistical concepts; they do not establish which specific model or procedures were used in this study.

What does AUC measure?

Area under the concentration-time curve combines drug concentrations observed across a defined time interval. AUC0-72 refers to the interval from time zero to 72 hours after dosing. In general, this type of endpoint is used in pharmacokinetic research to summarize exposure rather than focusing on a single concentration measurement. It does not directly measure a clinical outcome such as symptom change or infection resolution.

The registry gives the endpoint unit as h*µg/mL and identifies the primary measure as a geometric least-squares mean. It reports 1470.0 for Orbactiv and 1460.0 for Kimyrsa. These separate arm summaries do not themselves give the relative exposure estimate named in the endpoint title. To interpret a relative comparison inferentially, readers would generally need the treatment contrast on the relevant scale and a measure of uncertainty, such as a confidence interval. Those results are not reported in the registry record.

What is a geometric least-squares mean?

In general, a geometric mean summarizes measurements on a multiplicative scale and is often useful for positive, right-skewed pharmacokinetic outcomes. A least-squares mean is typically a model-based mean adjusted for terms included in a statistical model. The exact model and any adjustment variables used for this study are not reported in the registry record, so the displayed values should not be assumed to reflect particular covariate adjustments.

Geometric means are often used when the scientific question concerns proportional differences. A comparison may be expressed as a ratio, and uncertainty around that ratio can help show which relative effects are compatible with the data. However, no ratio, confidence interval, or test result for the primary relative exposure comparison is posted. It would not be appropriate to reconstruct that inferential result from the arm means alone.

How should variability be read?

The registry identifies the spread measure as a geometric coefficient of variation and reports 39.7 for Orbactiv and 35.1 for Kimyrsa. In general, a coefficient of variation expresses dispersion relative to the scale of the measurements; the geometric version is suited to data analyzed on a multiplicative scale. It helps describe how much participant-level measurements vary in relation to their typical level. It is not a confidence interval, and it does not show how precisely the arm means or the comparison have been estimated.

Over-dispersion is a general concern when observed outcome variability is greater than a statistical model expects. If a model fails to account for such variability, standard errors and uncertainty intervals can be too small. The registry does not report a model diagnostic or an over-dispersion assessment, so no conclusion about this issue can be drawn for the study. The posted coefficients of variation provide descriptive information but do not substitute for model checks or participant-level data.

What would a confidence interval add?

In general, a confidence interval gives a range of effect estimates compatible with the data under the assumptions of the analysis. For a relative-exposure comparison, an interval for the ratio could show both the direction and precision of the estimate. A sufficiently narrow interval may support a more definite interpretation than two arm means alone, while a wide interval indicates greater uncertainty. No confidence interval for the primary comparison is reported in the registry record. The record also does not report a prespecified margin or decision rule for declaring exposure sufficiently similar.

What can planning illustrations tell readers?

Sample-size planning calculations are not observed results and do not measure the power actually achieved in a completed trial. The planning assumptions described for this analysis use a two-sided significance level of 0.05, equal allocation, a normal approximation, and an effect defined as a stated proportion of the observed effect. The record characterizes those calculations as planning illustrations rather than the trial's own design justification. The registry does not report the trial's sample-size justification. Any such illustration should be read as conditional on its assumptions, not as evidence that the trial was adequately powered or that a null result proves no difference.

10. Multiplicity, Missing Data and Analysis Populations

The registry lists one primary outcome and one secondary outcome: the number of subjects with at least one treatment-emergent adverse event (TEAE). It reports three outcome measures in total, but does not provide a complete account of all comparisons, endpoint-specific analysis populations, or the relationship among those measures. The number of listed outcomes does not establish how many statistical tests were planned or performed.

Multiplicity arises when several outcomes, comparisons, or interim looks are tested. In general, repeated testing can increase the chance of obtaining at least one apparently notable result by chance, so a statistical plan may specify how to address it. Adjustment methods, a testing hierarchy, and interim analyses are not reported in the registry record. No formal analyses are listed, so the record does not establish whether multiplicity procedures were needed or applied.

The primary pharmacokinetic population is defined as subjects who received the full dose and had any valid samples measured for study drug levels. The posted endpoint summaries include 50 participants in each arm. The safety counts use different group sizes: 52 for Orbactiv and 50 for Kimyrsa for serious and other adverse events. These population definitions should not be conflated. The registry does not give a full participant disposition or explain why the primary endpoint population differs from the safety group counts.

Missing-data methods, the number and pattern of missing samples, and any sensitivity analyses are not reported in the registry record. The record also does not report an intention-to-treat analysis or a per-protocol analysis for the primary endpoint. Because the primary population requires a full dose and valid samples, the results apply to the participants meeting that definition; the extent to which they represent all randomized participants cannot be assessed from the posted information.

11. Safety Results

The registry reports serious adverse events as affected participants divided by participants at risk.

Deaths

Other (non-serious) adverse events

Participants with at least one non-serious event at or above the registry's 0% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: worsening of left leg cellulitis (2.0%), pyelonephritis (2.0%).

The registry reports serious adverse events for 1 of 52 participants in the Orbactiv group and 2 of 50 participants in the Kimyrsa group. It reports other adverse events for 31 of 52 and 24 of 50 participants, respectively. Deaths were 0 in each group. These are counts of participants with events, not counts of all event episodes, and the record presents them separately from the primary pharmacokinetic endpoint.

The serious adverse event terms listed are “worsening of left leg cellulitis” and “Pyelonephritis,” each shown as 2.0%. The registry does not specify in this summary which group each listed term belongs to, how many event episodes occurred for each term, or whether investigators considered the events related to study treatment. No cause should be inferred from the listed terms alone.

Safety counts are descriptive. A difference in counts is not by itself proof of a treatment-related difference, and the registry does not report a statistical comparison, confidence interval, or detailed safety analysis. The record also does not provide event timing, duration, severity categories beyond the serious-event classification, or completeness of follow-up. The figures should therefore be read as the reported counts within the stated safety groups, not as a full assessment of comparative safety.

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

The posted results describe measured AUC0-72 in the pharmacokinetic population and report geometric least-squares means of 1470.0 h*µg/mL for Orbactiv and 1460.0 h*µg/mL for Kimyrsa. The geometric coefficients of variation are 39.7 and 35.1. The study therefore contributes arm-specific summaries of plasma exposure after administration of the two formulations under the study conditions.

Those summaries do not, on their own, establish whether relative exposure was equivalent, noninferior, or different. The registry record does not report a relative estimate, confidence interval, statistical test, or prespecified margin. Without these elements, the precision of the relative comparison and the range of plausible treatment effects cannot be assessed from the posted endpoint values.

The findings also do not establish differences in clinical effectiveness. The primary endpoint is a pharmacokinetic measure, not a direct measure of infection outcomes. Although the study enrolled people being treated for ABSSSI, no clinical efficacy outcome result is described in the posted primary results. A pharmacokinetic summary should not be substituted for evidence about patient symptoms, recovery, or other clinical outcomes.

The safety counts are similarly limited. The registry reports serious adverse events in 1 of 52 Orbactiv participants and 2 of 50 Kimyrsa participants, other adverse events in 31 and 24 participants, and 0 deaths in each group. These counts do not establish whether an event was caused by treatment or whether one formulation has a safer overall profile. Details needed for a full comparative safety interpretation are not reported in the registry record.

Overall, the record supports a descriptive account of exposure and reported adverse events in this phase 1 randomized study. It does not provide enough inferential detail to make a definitive claim about relative exposure or clinical outcomes. The results should be interpreted within the stated population, endpoint, and available registry information.

13. Why This Trial Matters Statistically

This study is statistically relevant because it compares two formulations of the same drug using a pharmacokinetic endpoint, while changing several features of preparation and administration. The approved formulation was diluted to a total volume of 1000 mL and infused over 3 hours; Kimyrsa was diluted to 250 mL and infused over 1 hour. AUC0-72 provides a summary of measured plasma exposure across the stated period, allowing the formulations to be described on a common pharmacokinetic endpoint.

It also illustrates why arm-level values and a treatment contrast are not interchangeable. Geometric least-squares means are reported for each arm, but the registry does not report a relative estimate or uncertainty interval. For a question framed around relative exposure, a ratio or other clearly defined contrast and its precision are important to interpretation. Similar-looking arm summaries alone cannot establish the strength of evidence for similarity or difference.

The registry also makes the distinction between study populations important. The primary endpoint includes participants who received the full dose and had valid drug-level samples, with 50 participants per arm reported for that endpoint. Safety results use group sizes of 52 and 50. Those differing counts underline that the population contributing to a pharmacokinetic analysis need not be the same as the population contributing to safety summaries.

Finally, the study provides a reminder that statistical interpretation depends on more than a point estimate. The model, uncertainty, missing-data handling, analysis plan, and criteria for interpreting relative exposure are not reported in the registry record. Without those details, the posted results remain useful descriptive evidence but cannot answer every inferential question raised by the study objective.

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 registry record does not report the relative exposure contrast, confidence interval, hypothesis test, or a prespecified criterion for interpreting the comparison. Although the endpoint is described as relative exposure, the posted primary results are separate arm-level geometric least-squares means. The uncertainty around the relative comparison is therefore not available in the record.

The statistical model, model covariates, diagnostic checks, and handling of influential observations are not reported. The method used to construct the geometric least-squares means is therefore not fully described. The registry also does not provide participant-level pharmacokinetic measurements or the distribution of observed AUC values, limiting independent assessment of variability and precision.

The primary population excludes people who did not receive the full dose or did not have any valid study-drug samples, according to its registry definition. A complete account of randomized participants, exclusions from the pharmacokinetic analysis, missing samples, and reasons for missingness is not reported in the registry record. It is therefore not possible to assess whether missing measurements could affect the reported summaries.

The record does not report baseline characteristics, eligibility details, the randomization procedure, allocation concealment, or protocol deviations. The study was open label, and blinding of sample processing or outcome analysis is not described. No clinical efficacy results are reported in the primary outcome information. The safety record is limited to event counts and selected serious-event terms; detailed timing, attribution, severity, and follow-up are not reported. These omissions constrain interpretation of both the pharmacokinetic comparison and the safety summaries.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: Relative Exposure and Safety Study of Kimyrsa in ABSSSI Patients — NCT03873987.
• Registry record last updated 2021-04-13; status last verified 2021-03.
• Results first posted 2021-04-13.
• 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

This completed phase 1, randomized, open-label, parallel-group study compared Kimyrsa with the approved oritavancin formulation in people being treated for acute bacterial skin and skin structure infection. The registry reports enrollment of 102, a start date of 2019-07-16, and primary completion on 2019-08-27.

The primary endpoint was relative exposure based on AUC0-72 over 72 hours. Geometric least-squares means were 1470.0 h*µg/mL for Orbactiv and 1460.0 h*µg/mL for Kimyrsa; geometric coefficients of variation were 39.7 and 35.1. The registry does not report an inferential relative comparison or its uncertainty.

Serious adverse events affected 1 of 52 Orbactiv participants and 2 of 50 Kimyrsa participants; other adverse events affected 31 and 24 participants, respectively. Deaths were 0 in both groups. The record provides descriptive pharmacokinetic and safety summaries, but does not report a full statistical analysis plan, missing-data methods, or detailed safety analyses.