A Study to Evaluate the Effect of Genotype on LY2216684: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for A Study to Evaluate the Effect of Genotype on LY2216684 (NCT01460381), a non-randomized phase 1 study. The primary outcome is Pharmacokinetics: Area Under the Plasma Concentration-time Curve From Time 0 to Infinity [AUC(0-∞)] of LY2216684 in Cytochrome P450 (CYP)2C19 Extensive Metabolizers (EM) Versus Poor Metabolizers (PM).

2. Clinical Question

3. Trial Design

This was a completed phase 1 study with non-randomized allocation, no masking, and a parallel model. The registry record gives enrollment as 18 and lists the study start as 2011-10 and primary completion as 2012-08. It describes the official study purpose as investigating the effect of CYP2C19 phenotype on LY2216684 pharmacokinetics in healthy subjects. The listed condition is depressive disorder, major; the record does not explain the relationship between that listing and the healthy-subject description.

The arm descriptions distinguish participants predicted by genotyping analysis to be CYP2C19 poor metabolizers from those predicted to be extensive metabolizers. In Period 1, the descriptions state that participants received a single oral dose of 18 mg LY2216684 on Day 1. For poor metabolizers, the record describes 300 mg quinidine sulfate controlled release in Period 2, which began on Days 8-15. The text describing both arms is truncated, so additional details about the treatment schedule cannot be established. The extensive-metabolizer description says they did not participate in the quinidine period.

Because allocation was non-randomized, the phenotype groups were not formed by random assignment. The primary contrast therefore describes pharmacokinetic measurements across groups defined by predicted metabolic phenotype; it does not isolate a randomized treatment effect. The record also lists pharmacokinetic outcomes for LY2216684 plus quinidine in poor metabolizers, including AUC, maximum observed concentration (Cmax), and time to maximum concentration (Tmax). It lists a quinidine-only group in the safety information.

The record marks the study completed, but does not report the primary endpoint estimate or an analysis result. It also does not report the rationale for the enrollment target or a statistical design plan.

4. Participant Flow and Accounting

The registry reports how participants moved through each stage of the study. All counts below are exactly as posted; missing counts are not inferred from other stages.

Period 1 (Days 1-7)

Period 2 (Days 8-15)

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: Participants who received at least 1 dose of LY2216684 and had evaluable LY2216684 plasma concentration data were included in the analysis. Participants who vomited within twice the median time to maximum observed drug concentration (tmax) following dosing of LY2216684 were excluded from the analysis.

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: All enrolled participants.

6. Primary Endpoint

The registry lists the primary outcome as Pharmacokinetics: Area Under the Plasma Concentration-time Curve From Time 0 to Infinity [AUC(0-∞)] of LY2216684 in Cytochrome P450 (CYP)2C19 Extensive Metabolizers (EM) Versus Poor Metabolizers (PM), measured over Predose up to 120 hours post administration of LY2216684.

The primary endpoint was LY2216684 AUC(0-∞), reported in nanograms*hours per milliliter (ng*h/mL), with a geometric mean as the summary measure and geometric coefficient of variation as the dispersion measure. The endpoint was defined over plasma concentrations from predose up to 120 hours after LY2216684 administration. Blood samples were collected before dosing and at times up to 120 hours after the Day 1 dose in Period 1.

AUC represents the area under a concentration-time curve. As a general statistical concept, it captures exposure across the measurement interval rather than describing concentration at only one sampling time. Extending the area to infinity aims to represent total exposure beyond the observed sampling period, although the registry record does not explain the extrapolation method used. The endpoint was selected to compare exposure between participants classified as CYP2C19 extensive and poor metabolizers.

Geometric means are commonly used for positive pharmacokinetic measures that may be right-skewed: taking logarithms can make analysis more suitable for methods based on a roughly symmetric distribution, after which results can be expressed on the original scale. The geometric coefficient of variation describes relative spread on a multiplicative scale; it is not the same as an arithmetic standard deviation. The registry record names these summaries but does not report their values, a between-group estimate, or a confidence interval. Consequently, the magnitude and precision of the primary comparison cannot be interpreted from the record.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The primary endpoint is a pharmacokinetic measure, not a clinical symptom or functional outcome. A concentration-time profile records the amount of drug measured in plasma at different times after dosing. AUC compresses that profile into an exposure measure. The primary endpoint, AUC(0-∞), denotes area from time zero through the period represented by the curve extended to infinity. The stated sampling timeframe was predose up to 120 hours after administration of LY2216684. The registry record does not describe how the unobserved portion after the sampling window was handled when estimating the infinite-time area.

Why use a geometric mean?

As a general statistical explanation, pharmacokinetic measures are often positive and can have a skewed distribution, with some values much larger than others. An arithmetic mean can be strongly influenced by high observations. A geometric mean is calculated using logarithms and then transformed back to the original scale; it is often a useful summary when ratios and multiplicative variation are natural ways to compare values. The primary endpoint specifies a geometric mean. The record does not report the actual geometric means or say which inferential procedure was applied to compare groups.

The geometric coefficient of variation is a measure of relative dispersion suited to a multiplicative scale. Unlike an ordinary standard deviation, it describes spread relative to the scale of the measurement. The record names it as the dispersion measure, but supplies no numerical value. It is therefore not possible to judge how variable the observed AUC values were or how much distributions overlapped.

What does the group comparison estimate?

The primary question compares extensive metabolizers with poor metabolizers after LY2216684 dosing. Because participants were assigned by predicted phenotype rather than randomized, the contrast is an association between phenotype group and measured exposure in this study. General statistical reasoning cautions that non-randomized groups may differ in characteristics other than the classification being studied. The registry record does not report covariate adjustment or enough detail to determine how such differences were addressed.

A confidence interval, when reported, describes a range of values compatible with the data and the statistical model at a stated confidence level. It conveys uncertainty around an estimate and is distinct from the spread of individual observations. The registry record does not report a confidence interval or a primary effect estimate. No p-value for the primary comparison is reported either. Therefore, statistical significance and estimation precision cannot be assessed from the record.

How should the quinidine outcomes be distinguished?

The registry record lists secondary pharmacokinetic outcomes for LY2216684 plus quinidine in poor metabolizers: AUC(0-∞), Cmax, and Tmax. AUC summarizes overall exposure, Cmax is the maximum observed plasma concentration, and Tmax is the time at which that maximum is observed. These measures answer related but distinct questions: total exposure, peak concentration, and timing of the peak. The record also lists quinidine as an intervention and a quinidine-only safety group. It does not report numerical results for the secondary pharmacokinetic measures or a statistical comparison for them.

The arm descriptions state that the poor-metabolizer group received LY2216684 in Period 1 and describe quinidine sulfate controlled release in Period 2. The text is truncated, so the full schedule and other procedural details are not established. The record says extensive metabolizers did not participate in the quinidine period. This means the quinidine-related measures should not be read as a randomized comparison between phenotype groups. The arm structure and allocation method matter when interpreting any contrast.

What can planning calculations say?

As a general concept, a sample-size calculation estimates how many participants might be needed under specified assumptions to detect an effect at a chosen significance level and power. The registry's planning assumptions describe an illustration based on the observed effect, a two-sided significance level of 0.05, equal allocation, and a normal approximation. It states that the effect to detect is a stated fraction of the observed effect. These calculations are planning illustrations, not evidence of the study's original design or observed power. The registry record does not report the numerical primary effect needed to assess the assumptions or reproduce such a calculation. No numerical planning results are available in the record.

Finally, the primary analysis population was not simply all enrolled participants by definition. It included participants with at least 1 dose of LY2216684 and evaluable plasma concentration data. Participants who vomited within twice the median time to maximum observed concentration after dosing were excluded from the analysis. This rule identifies a potential source of selection in the analyzed data. The record does not report how many participants were excluded, whether any other missing measurements occurred, or how missing concentrations were handled.

10. Multiplicity, Missing Data and Analysis Populations

The registry lists a primary pharmacokinetic endpoint and secondary pharmacokinetic measures, but it does not report a statistical analysis plan or any outcome analyses. In particular, there is no description of how the primary comparison was tested, whether confidence intervals were planned, or how multiple outcomes or comparisons were handled. Multiplicity arises when several hypotheses are evaluated: without an appropriate strategy, the chance of at least one false-positive finding can increase. That is a general concern, not a claim that a particular method was or was not used in this study. The method is not reported in the registry record.

The primary analysis population is described as participants who received at least 1 dose of LY2216684 and had evaluable plasma concentration data. The record also states that participants who vomited within twice the median time to Tmax after LY2216684 dosing were excluded. It does not report how many participants met the analysis criteria, how many were excluded for vomiting, or whether missing samples affected the endpoint. The handling of other missing data, protocol deviations, and any sensitivity analyses is not reported in the registry record.

The record does not state whether the primary analysis followed a prespecified statistical plan, how covariates were selected, or whether adjustments were made for the non-randomized phenotype groups. No interim analyses are reported. The record lists no outcome analyses, so it cannot establish whether the methods described in the record were the methods ultimately used. These absences limit assessment of multiplicity control, missing-data consequences, and the robustness of the primary comparison.

11. Safety Results

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

Other (non-serious) adverse events

Participants with at least one non-serious event at or above the registry's 5% reporting threshold.

Most frequent non-serious adverse event terms

The registry safety information separates events into serious adverse events and other adverse events for each listed group. It reports zero participants with serious adverse events among the 18 at risk in the LY2216684 extensive- and poor-metabolizer group, zero among the 7 at risk in the quinidine poor-metabolizer group, and zero among the 7 at risk in the LY2216684 plus quinidine poor-metabolizer group. These are recorded counts for the groups, not estimates of comparative risk.

For other adverse events, the record reports 10 of 18 participants affected in the LY2216684 group, 1 of 7 in the quinidine group, and 3 of 7 in the LY2216684 plus quinidine group. The event terms are not listed in the registry record for these groups, so the types, timing, severity, and overlap of events cannot be described. The record lists no top serious-event terms. Death counts are null, which means a death count is not reported in the registry record; it should not be interpreted as a reported zero.

These groups are not a like-for-like randomized safety comparison: allocation was non-randomized, and the groups differ in phenotype and treatment. The counts are descriptive and do not establish that one treatment caused more or fewer events. They also do not replace the missing pharmacokinetic outcome results.

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

The registry record establishes the study's purpose and measurement framework: it examined LY2216684 pharmacokinetics by predicted CYP2C19 phenotype and listed additional pharmacokinetic outcomes involving quinidine in poor metabolizers. Its primary measure was AUC(0-∞), with plasma sampling described through 120 hours after dosing. This makes the intended question about drug exposure clear.

What the record does not establish is the primary result. It gives no group estimates, contrast, confidence interval, or test result for the primary endpoint. As a result, it is not possible to state whether measured exposure was higher or lower in either phenotype group, how large any difference was, or how precisely it was estimated. The secondary pharmacokinetic outcomes likewise have no numerical results reported in the registry record.

The non-randomized design is also important. The groups were classified by predicted CYP2C19 phenotype, not created by random assignment. A group difference, if reported, would describe the observed association in this study and would not by itself demonstrate a causal effect of phenotype. The record does not provide enough statistical detail to assess adjustment for differences between groups.

The safety information reports counts of participants affected by other adverse events and zero serious adverse events in each listed group. It does not provide event terms or a reported death count. Those details do not permit a comprehensive comparison of safety, and the non-randomized group structure further limits causal conclusions.

Thus, this record can be used to understand the study question, endpoint definition, design, and some event counts. It cannot establish the magnitude or precision of the primary pharmacokinetic comparison, the results for secondary pharmacokinetic measures, or a causal treatment effect. The absence of a reported result should not be interpreted as evidence that groups had equal exposure or that no difference existed.

13. Why This Trial Matters Statistically

This study illustrates why endpoint definitions and outcome results must be read separately. The registry specifies a biologically relevant pharmacokinetic measure, AUC(0-∞), along with its unit, summary scale, dispersion measure, sampling timeframe, and analysis-population description. Those details show what the investigators intended to measure and how the result was to be summarized. Without the actual estimates, however, the scientific question remains unanswered by the registry record.

It also highlights the interpretive consequences of a non-randomized design. A comparison based on predicted metabolic phenotype can describe how exposure varies across the observed groups, but it does not have the protection against confounding that random allocation can offer. Statistical adjustment may sometimes address measured differences, but the registry record does not report whether adjustment was performed. Readers therefore need to distinguish a group association from a randomized causal contrast.

The record also separates the phenotype comparison from the quinidine-related outcomes. AUC, Cmax, and Tmax capture different parts of a concentration-time profile. Keeping those measures distinct helps prevent a peak concentration or timing result from being mistaken for an overall exposure result. Here, the listed secondary outcomes have no numerical results in the record.

Finally, the described analysis-population exclusions and absent statistical details matter for transparency. The vomiting-related exclusion could affect which concentration data contributed to analysis, while the number excluded and handling of other missing measurements are not reported. Similarly, no analysis plan or multiplicity approach is reported. These omissions do not prove that a particular method was inappropriate; they limit the ability to evaluate the analysis and its uncertainty.

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 most consequential limitation of the registry information is that it does not report the primary endpoint estimate. The group-specific geometric means, geometric coefficients of variation, between-group comparison, confidence interval, and test result are not reported in the registry record. The record also lists no outcome analyses. Therefore, readers cannot assess the magnitude, direction, precision, or statistical evidence for the primary comparison.

Study design and reporting create additional limits. Allocation was non-randomized, and participants were classified by predicted CYP2C19 phenotype. The record does not describe adjustment for potential differences between groups or provide a statistical plan. The arm descriptions are truncated, limiting understanding of the complete schedule. The listed condition, depressive disorder, major, sits alongside an official title describing healthy subjects; the record does not clarify this discrepancy.

The analysis population excluded participants who vomited within twice the median Tmax after dosing and required evaluable plasma concentration data. The number excluded, missing-data handling, and sensitivity analyses are not reported. The record does not give enough information to evaluate how exclusions or incomplete sampling may have affected the endpoint.

Safety reporting is also limited: non-serious event terms are not available, serious-event terms are not listed, and death counts are not reported. These gaps preclude a detailed description of the event profile. Finally, the registry's planning assumptions describe an illustration, not the trial's own design, and no numerical primary result is reported for assessing the observed effect on which that illustration depends.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: A Study to Evaluate the Effect of Genotype on LY2216684 — NCT01460381.
• Registry record last updated 2018-10-26; status last verified 2018-03.
• Results first posted 2018-10-26.
• 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

The completed phase 1 study examined LY2216684 pharmacokinetics in CYP2C19 extensive and poor metabolizers, with additional quinidine-related outcomes in poor metabolizers. It used non-randomized allocation, no masking, and a parallel model; enrollment was 18. The primary endpoint was AUC(0-∞) from predose up to 120 hours after dosing, summarized by a geometric mean with geometric coefficient of variation.

The registry record does not report the primary estimate, secondary pharmacokinetic results, confidence intervals, or statistical tests. The primary analysis population required at least 1 LY2216684 dose and evaluable concentration data, with a stated vomiting-related exclusion. Serious adverse-event counts were zero in the listed groups; counts for other adverse events were reported, but event terms were not. The record does not report a death count or statistical analysis plan.