A Study to Determine the Bioavailability of Lanadelumab (SHP643) Administered Subcutaneously With the Prefilled Syringe and the Autoinjector in Healthy Adult Volunteer Participants.: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for A Study to Determine the Bioavailability of Lanadelumab (SHP643) Administered Subcutaneously With the Prefilled Syringe and the Autoinjector in Healthy Adult Volunteer Participants. (NCT03918239), a randomized phase 1 study. The primary outcome is Area Under the Concentration Versus Time Curve From Time Zero to the Last Quantifiable Concentration (AUC0-last) of SHP643 in Plasma.

2. Clinical Question

3. Trial Design

This was a randomized, open-label, parallel-arm, single-center phase 1 study in healthy adult volunteers. The stated purpose was to evaluate the bioavailability of lanadelumab after one subcutaneous dose delivered by either a prefilled syringe or an autoinjector. The registry lists enrollment as 190. Participants were assigned to one of the two delivery-method groups, and the design did not involve each participant receiving both methods.

Both groups were scheduled to receive 300 mg of SHP643 by subcutaneous injection into the abdomen on Day 1. The in-house period was Day 1 to Day 5. The study was open-label, meaning masking was not used according to the registry. The registry lists the study as completed, with a start date of 2019-05-14 and primary completion date of 2019-11-13.

The primary endpoint was a pharmacokinetic measure of plasma lanadelumab exposure: area under the concentration-versus-time curve from time zero to the last quantifiable concentration. Sampling was scheduled from pre-dose through 2664 hours post dose at the listed time points. The primary endpoint population was defined using receipt of the complete dose and availability of sufficient data for at least one primary pharmacokinetic endpoint. The registry reports 89 participants analyzed in each group for this outcome.

The registry also lists treatment-emergent adverse events and development of positive antidrug antibodies at specified time points as secondary outcomes. It records 10 outcome measures and 3 analyses. Further details on randomization procedures, allocation concealment, the statistical analysis plan, and the rationale for the planned enrollment 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: A total of 190 participants were enrolled and received the treatment. Out of which, 173 participants completed this study.

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: Pharmacokinetic (PK) set was defined as all randomized participants who received the complete dose of SHP643 and had sufficient data to calculate at least one primary PK endpoint. Here, the number of participants analyzed signifies participants who were evaluable for this outcome measure.

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 set consisted of all randomized participants who received the dose of SHP643.

6. Primary Endpoint

The registry lists the primary outcome as Area Under the Concentration Versus Time Curve From Time Zero to the Last Quantifiable Concentration (AUC0-last) of SHP643 in Plasma, measured over Pre-dose, 8, 24, 48, 72, 96, 168, 336, 504, 672, 1008, 1344, 2016, 2664 hours post dose.

The primary endpoint, AUC0-last, measures plasma exposure to lanadelumab over time, from the start of measurement through the last concentration that could be quantified. It combines concentration information across the scheduled sampling period, rather than describing the concentration at only one time point. The registry reports this endpoint in day*microgram per milliliter and summarizes each group using a geometric mean and geometric coefficient of variation.

Pharmacokinetic exposure measures are used in studies of delivery methods because they describe how much drug is present in the body across the observed concentration-time profile. Comparing exposure after administration by prefilled syringe and autoinjector can help characterize whether the delivery methods produce different measured plasma exposure in the study population. This is a pharmacokinetic comparison; it does not, by itself, establish a difference in clinical outcomes.

The registry reports the ratio of geometric least-squares means as the primary comparison. A ratio expresses the exposure estimate for one group relative to the other, with 1 representing equal estimated group means. The reported 90% confidence interval provides a range of uncertainty around the estimate under the analysis model. The registry does not report a prespecified equivalence or acceptance margin, so the estimate and interval alone do not establish whether a formal equivalence criterion was met.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The registry reports an analysis of variance (ANOVA) for the primary comparison, with the result expressed as a ratio of geometric least-squares means. The two groups were the SHP643 prefilled syringe and SHP643 autoinjector arms. The analysis estimate was 1.079, and the reported 90% confidence interval was 0.986 to 1.181. No p-value is reported for this analysis in the registry record.

What the ratio represents

In general, a ratio compares one group estimate with another on a relative scale. A ratio of 1 represents equal estimates; a ratio above 1 indicates that the numerator estimate is larger, and a ratio below 1 indicates that it is smaller. Here, the registry's analysis lists the prefilled syringe group first and the autoinjector group second, and the reported comparison is interpreted as autoinjector relative to prefilled syringe. The registry labels the parameter as a ratio of geometric least-squares means.

Geometric means are used for data that are analyzed on a multiplicative or logarithmic scale. In general, transforming positive measurements to a logarithmic scale can make relative differences easier to model and compare. A least-squares mean is a model-based group estimate; it can reflect the fitted analysis rather than simply being the arithmetic average of the raw observations. The registry does not provide the detailed model specification, covariates, or transformation details, so those aspects are not reported in the registry record.

How to read the confidence interval

In general, a confidence interval expresses the uncertainty around an estimate under the statistical model and its assumptions. The reported interval, 0.986 to 1.181, includes 1, the value representing equal estimated geometric means. This indicates that the reported interval encompasses equality, while also allowing relative values below and above equality. It does not say that every value in the range is equally likely, and it does not establish a particular probability that the true ratio lies within the interval.

The interval is 90%, as reported by the registry. It should be read as an interval accompanying the estimate, not as an equivalence test by itself. In general, a formal equivalence assessment requires prespecified limits defining what differences are acceptable and an analysis that evaluates the estimate against those limits. Those limits and the associated decision rule are not reported in the registry record.

Geometric variation and dispersion

The registry reports geometric coefficients of variation of 33.4% for the prefilled syringe group and 41.3% for the autoinjector group. In general, a coefficient of variation describes variability relative to a measure of the center. The geometric coefficient of variation is a dispersion summary on a relative scale, appropriate to data summarized geometrically. It is not a confidence interval and does not quantify the precision of the between-group ratio. The registry does not report individual participant measurements or additional distribution summaries that would permit a fuller assessment of the shape of the data.

In general, over-dispersion means that observed variability is greater than a statistical model expects. When present, it can make standard errors and confidence intervals too small if the model does not account for it. The posted geometric coefficients of variation describe dispersion, but the registry does not report an over-dispersion assessment or a specific adjustment for it. It would therefore be inappropriate to infer that over-dispersion was present or absent from those summaries alone.

Analysis population and outcome availability

The registry defines the pharmacokinetic set as randomized participants who received the complete dose and had sufficient data to calculate at least one primary pharmacokinetic endpoint. For the AUC0-last outcome, 89 participants were analyzed in each group. This endpoint-specific population is not necessarily identical to the full randomized population. In general, restricting an analysis to participants with usable outcome data can affect the comparison if data availability is related to participant characteristics or outcomes. The registry does not report detailed reasons for non-inclusion, missing-data methods, or a comparison of included and excluded participants.

The primary endpoint used concentration measurements collected at multiple scheduled post-dose times. In general, an AUC measure summarizes exposure across time using the available concentration profile, while the last quantifiable concentration sets the endpoint's final observation point. The registry lists sampling from pre-dose through 2664 hours post dose. Details on the calculation method, handling of values below quantification limits, and any interpolation or extrapolation are not reported in the registry record.

Analysis plan and interpretation

The registry identifies ANOVA and the ratio of geometric least-squares means, but it does not report a full statistical analysis plan. The model's specific terms, any covariate adjustment, assumptions checks, and rules for handling protocol deviations are not reported in the registry record. A reported confidence interval reflects the analysis as performed, but readers cannot reconstruct every modeling choice from the registry summary alone.

In general, multiple outcomes or repeated statistical tests can raise multiplicity concerns because the chance of at least one chance finding may increase as the number of tests grows. The registry lists 10 outcome measures and 3 analyses, but does not report whether or how multiplicity was controlled. It also does not report interim analyses. These omissions limit what can be concluded about the broader testing strategy; they do not change the numerical estimate and confidence interval reported for this primary comparison.

10. Analyses Reported by the Sponsor

The registry reports the sponsor's primary comparison as an ANOVA ratio of geometric least-squares means: 1.079, with a 90% confidence interval from 0.986 to 1.181. This is the inferential result available for the primary AUC0-last comparison. The registry does not report a p-value for that analysis.

A separate unadjusted recalculation from posted summary statistics is not reported in the registry record, so there is no second estimate or interval to compare with the sponsor's analysis. The geometric mean and dispersion summaries for each group are descriptive values and should not be mistaken for a recalculated between-group analysis. The registry does not flag a discrepancy between analyses.

In general, an unadjusted recalculation based on group summaries would not necessarily reproduce an analysis that uses a model and participant-level information. The methods can differ in the scale of analysis, assumptions, and treatment of available data. The reported ANOVA estimate and confidence interval should therefore be interpreted as the registry's sponsor-reported analysis, not as a calculation reconstructed from the displayed group summaries.

11. Multiplicity, Missing Data and Analysis Populations

The registry identifies AUC0-last as the primary endpoint and lists treatment-emergent adverse events and development of positive antidrug antibodies at specified time points as secondary outcomes. It also records 10 outcome measures and 3 analyses. The record does not describe a multiplicity adjustment, a hierarchy of hypotheses, or another strategy for controlling the interpretation of results across outcomes. Whether any such strategy was specified elsewhere is not reported in the registry record.

In general, testing several outcomes can increase the chance of observing at least one apparently notable result by chance. This does not mean that any particular reported result is invalid; it means the analysis plan and the number of planned comparisons matter when interpreting a collection of results. The registry information does not establish how the secondary outcomes were handled statistically or whether their results were intended as confirmatory or descriptive.

Missing-data handling for the primary endpoint is also not described in detail. The registry defines the pharmacokinetic set as randomized participants who received the complete dose and had sufficient information to calculate at least one primary pharmacokinetic endpoint. It reports 89 analyzed participants in each group for AUC0-last. The criteria define who could contribute to the endpoint analysis, but the record does not give the number or reasons for exclusions, the amount of missing concentration data, or the method used when some scheduled measurements were unavailable.

The registry does not report whether missingness was assessed as potentially related to participant characteristics or outcome values. It also does not describe sensitivity analyses for missing observations or alternative analysis populations. These details matter because an endpoint analysis based on participants with sufficient data may differ from an analysis that includes all randomized participants under a specified missing-data approach.

The statistical analysis plan, including any interim analyses or multiplicity procedures, is not reported in the registry record. The available summary therefore supports interpretation of the reported primary estimate and interval, but not a full evaluation of all planned testing and missing-data decisions.

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 5% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: appendicitis (1.1%), abortion induced (1.1%), anaemia (1.0%), abortion spontaneous (1.0%), nephrolithiasis (1.0%).

The registry reports serious adverse events for participants at risk in each group. In the prefilled syringe group, 2 participants were recorded as affected among 94 at risk; in the autoinjector group, 2 participants were recorded as affected among 96 at risk. No deaths were reported in either group. These are participant counts, not a comparison adjusted for differences between groups.

For other adverse events, the registry reports 0 affected among 94 at risk in the prefilled syringe group and 9 affected among 96 at risk in the autoinjector group. The record also lists serious-event terms with percentages, including Appendicitis and Abortion induced at 1.1%, and Anaemia, Abortion spontaneous, and Nephrolithiasis at 1.0%. The listed percentages should not be assigned to a particular group unless the registry explicitly identifies that attribution.

These figures describe events recorded in this study; they do not establish that the delivery method caused an event or explain why the event occurred. The registry summary does not provide the timing, duration, clinical course, or detailed attribution for each event. Nor does it provide enough information to make a precise comparative safety estimate. The study involved healthy volunteers and a single dose, so its adverse-event summaries should be understood within that study setting.

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

The results describe a comparison of plasma lanadelumab exposure after one subcutaneous dose delivered by prefilled syringe or autoinjector in healthy adult participants. The registry's primary estimate is a ratio of geometric least-squares means of 1.079, with a 90% confidence interval from 0.986 to 1.181. The interval includes 1, so the estimate is not precise enough to rule out equality on the basis of the reported interval alone. It also permits values above 1. The result is best read as an estimate with uncertainty, not as a definitive statement that exposure is identical or different.

The finding concerns AUC0-last, a pharmacokinetic endpoint summarizing plasma exposure over the observed concentration-time profile. It is not a direct measure of clinical benefit, long-term outcomes, or the experience of people with a health condition. Participants were healthy volunteers, and the study used a single dose. The registry does not report clinical efficacy outcomes in the listed primary endpoint information.

The confidence interval does not, by itself, show that formal equivalence was established. A formal equivalence conclusion depends on margins specified before analysis and a method that tests the estimate against those margins. Such margins are not reported in the registry record. Similarly, the reported point estimate should not be presented as proof that one device delivers more drug in a clinically meaningful way: the interval represents statistical uncertainty and the registry does not provide a threshold for clinical importance.

Safety counts are also descriptive in this setting. The registry reports 2 participants with serious adverse events in each group, with different numbers at risk, and no deaths. The record's adverse-event summaries do not establish causation or provide a comprehensive estimate of comparative safety across broader populations or longer exposure.

Overall, the posted result addresses a focused phase 1 bioavailability question. The extent to which it generalizes beyond the study's healthy adult volunteers, single-center setting, and single-dose administration is not established by the registry summary. Additional design and analysis details that could refine interpretation are not reported in the registry record.

14. Why This Trial Matters Statistically

Comparisons of delivery methods raise a statistical question distinct from whether a medicine has a clinical effect: do the methods produce sufficiently similar or different measured exposure under the study conditions? This trial uses a pharmacokinetic endpoint to frame that question. AUC0-last draws on concentrations measured at multiple times and provides a summary of exposure across the observed profile, rather than relying on a single concentration measurement.

The ratio scale is useful for this type of comparison because it expresses one group’s geometric mean relative to the other. The estimate of 1.079 is accompanied by a 90% confidence interval from 0.986 to 1.181. That interval makes uncertainty visible and discourages interpretation based only on the point estimate. Because it includes 1, the registry result does not, by itself, resolve whether the true relative exposure is exactly equal or differs from equality.

The study also illustrates why equivalence claims require more than a ratio near 1. In general, a formal equivalence assessment needs an explicit range of differences that would count as acceptably small, as well as an analysis designed to assess that range. The registry does not report such margins. Without them, the result can be described as an exposure estimate with a confidence interval, but a formal equivalence conclusion cannot be established from the reported summary alone.

Finally, the endpoint population and the safety population are not described in the same way: the pharmacokinetic analysis requires complete dosing and sufficient endpoint data, while the adverse-event summaries use their own at-risk counts. Keeping those denominators and definitions distinct is important when reading a trial record. The study offers a focused example of how endpoint choice, analysis population, uncertainty, and design features shape the interpretation of a clinical comparison.

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 registry describes a randomized, open-label, single-center, parallel-arm study. Randomization can support a balanced comparison, but the record does not report the randomization method or allocation concealment. Because the study was open-label, participants and study personnel were not masked according to the registry. The record does not report whether outcome assessment or laboratory analysis was masked.

The study enrolled healthy adult volunteers and evaluated one 300 mg dose. Its primary result therefore concerns pharmacokinetic exposure in this study setting. The registry does not establish how the comparison generalizes to other populations, repeated dosing, or clinical outcomes. The record also does not report a planned enrollment justification or a formal equivalence margin, which limits interpretation of the study's precision relative to any target range.

The primary endpoint analysis included 89 participants in each group, under a definition requiring complete dose receipt and sufficient data for at least one primary pharmacokinetic endpoint. Enrollment was 190, but the registry does not report a participant flow accounting for the difference between enrollment and endpoint analysis. Reasons for non-inclusion, missing concentration measurements, and methods for handling incomplete profiles are not reported in the registry record.

The registry provides the endpoint summaries and ANOVA ratio but not the full model specification, covariates, assumption checks, or detailed AUC calculation procedures. It also does not report a multiplicity strategy, interim analyses, or detailed missing-data sensitivity analyses. These omissions constrain the ability to independently assess the analysis choices and the robustness of the result.

The safety summary gives counts and selected serious-event terms, but does not provide detailed timing, duration, attribution, or clinical course for each event. The reported counts are not adjusted comparative estimates. These limitations do not alter the reported results, but they restrict the conclusions that can be drawn from the registry summary.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: A Study to Determine the Bioavailability of Lanadelumab (SHP643) Administered Subcutaneously With the Prefilled Syringe and the Autoinjector in Healthy Adult Volunteer Participants. — NCT03918239.
• Registry record last updated 2020-12-08; status last verified 2020-11.
• Results first posted 2020-12-08.
• 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

NCT03918239 is a completed, randomized, open-label, parallel-arm, single-center phase 1 study sponsored by Shire. It enrolled healthy adult volunteers and compared a single 300 mg subcutaneous dose of lanadelumab delivered by prefilled syringe or autoinjector. Both injections were administered into the abdomen on Day 1.

The primary outcome was plasma AUC0-last. The registry reports geometric mean values of 348.9 day*microgram per milliliter for the prefilled syringe and 376.5 day*microgram per milliliter for the autoinjector, with 89 participants analyzed in each group. The reported ratio of geometric least-squares means was 1.079, with a 90% confidence interval from 0.986 to 1.181.

The interval includes 1 and does not establish formal equivalence, for which the registry does not report prespecified margins. The record also lists adverse-event and antidrug-antibody outcomes. Further detail on the statistical plan, missing-data handling, and equivalence criteria is not reported in the registry record.