A Study to Assess the Pharmacokinetics and Safety of Different Forms and Formulations of AZD9496 in Healthy Subjects: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for A Study to Assess the Pharmacokinetics and Safety of Different Forms and Formulations of AZD9496 in Healthy Subjects (NCT02780713), a na phase 1 study. The primary outcome is Pharmacokinetics: Maximum Plasma Concentration (Cmax) for AZD9496 and Its Metabolites at Each Treatment Period..

2. Clinical Question

3. Trial Design

This was a phase 1, open-label, single-centre study of AZD9496 in healthy volunteers. The registry records a single-group design, no masking and no randomized allocation. Its description states that each volunteer would receive five single doses across five sequential treatment periods. The periods were intended to assess different forms, formulations and doses of AZD9496. This is a within-participant sequence rather than a trial with separate randomized treatment arms.

The listed interventions are AZD9496 Reference and Variants A, B, C and D. The arm description specifies that Treatment period 1 assessed Variant A at 100mg and that Treatment period 2 assessed the Reference. It does not give a complete account of the formulations, doses or assignment of variants for the remaining periods. The full schedule, including any rules for moving between periods, is not reported in the registry record.

The registry records enrollment of 14 and study status as completed. The recorded study dates are 2016-06-02 for start and 2016-09-20 for primary completion. These details describe the registered study, but do not establish how many participants contributed evaluable data to each pharmacokinetic analysis. The record identifies a safety set and gives a specific description of the primary pharmacokinetic population, but a complete participant flow and reasons for any missing period-specific data are not reported.

A fixed sequence can make each participant’s measurements across formulations useful for describing pharmacokinetic profiles. At the same time, treatment-period comparisons can be affected by factors associated with order or time, and the open-label design does not conceal which formulation is administered. The record does not report a randomized order or a separate concurrent control group. Consequently, the design should not be read as a randomized, parallel-group efficacy trial.

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 screening period of maximum of -28 days.

Period 1: Variant A (100mg)

Period 2: Reference (100mg)

Period 3: Variant B (100mg)

Reasons for not completing this period:

Period 4: Variant C (100mg)

Analysis population for the primary outcome, as defined in the registry: Safety set with 1 primary PK parameter for AZD9496 calculable for Treatment Period 2 and 1 other period. For AUC 0-inf, a predefined R2adj \>0.8 (the goodness of fit parameter for regression estimate of elimination rate constant lambda z used in the AUC 0-inf calculation) was used to determine if the individual AUC estimate was reportable.

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 Pharmacokinetics: Maximum Plasma Concentration (Cmax) for AZD9496 and Its Metabolites at Each Treatment Period., measured over Regular Pharmacokinetic measurement Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 7, 8, 12, hours post-dose on Day 1, 24 and 36 hours post-dose (Day 2), 48 hours post-dose (Day 3), 72 hours post-dose (Day 4) of each treatment period.

The primary endpoint is maximum observed plasma concentration, or Cmax, for AZD9496 and its metabolites M3 and M5 at each treatment period. Cmax is the highest concentration measured in the scheduled blood samples after a dose. It describes the peak observed exposure over the sampling period; it does not by itself describe total exposure, the time taken to reach the peak, or the duration of drug presence.

The registry specifies Cmax in ng/mL and identifies the summary parameter as a geometric mean with geometric coefficient of variation. Pharmacokinetic concentrations are often summarized on a logarithmic scale because concentration values can be right-skewed and because ratios between formulations may be informative. A geometric mean represents a central value on that scale, while geometric coefficient of variation describes relative dispersion. These are general interpretations of the named statistics; the numerical Cmax estimates and their uncertainty are not reported in the registry record.

Comparing Cmax across formulations can help characterize whether peak concentration profiles differ after single-dose administration. It is one component of pharmacokinetic assessment, not a direct measure of clinical benefit or long-term safety. The registry describes measurements from pre-dose through 72 hours post-dose across each treatment period.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The primary outcome is a pharmacokinetic measure, not a clinical event. Cmax means the maximum observed plasma concentration after administration. It is identified for AZD9496 and the metabolites M3 and M5. The registry lists a series of collection times from pre-dose through 72 hours post-dose on specified days of each treatment period. The maximum is selected from the observed concentrations; it is therefore tied to the sampling schedule and is not necessarily a measurement of the exact biological peak between samples. This is a general feature of sampled concentration data.

The registry names the geometric mean as the summary parameter and the geometric coefficient of variation as the measure of dispersion. In general, a geometric mean is calculated on a logarithmic scale and then expressed on the original scale. It is useful when positive measurements are skewed or when proportional changes are more relevant than absolute changes. The geometric coefficient of variation expresses variability relative to the geometric mean rather than as an absolute spread. Neither statistic, by itself, provides a confidence interval for a comparison or a test of whether formulations differ. Numerical estimates and uncertainty intervals for the primary outcome are not reported in the registry record.

The study uses a fixed sequence of treatment periods. In a within-participant design, measurements from different periods can be compared while holding many stable participant characteristics constant. In general, this can make a participant’s own measurements useful comparators. However, sequential data can also reflect period effects, carryover, changes in measurement conditions or other time-related influences. These possibilities need consideration in design and analysis. The registry does not report a washout description, a model for period effects, or a statistical method for estimating formulation contrasts. The details needed to assess these features are not reported in the registry record.

The record describes the primary pharmacokinetic analysis population as the safety set with one primary PK parameter for AZD9496 calculable for Treatment period 2 and one other period. It also notes a predefined R2adj >0.8 criterion for AUC 0-inf, relating to the goodness of fit for the regression estimate of the elimination rate constant used in that calculation. The description does not fully specify how this criterion was applied, and it concerns the AUC calculation rather than the Cmax definition. The complete analysis population rules and handling of unusable measurements are not reported.

Several secondary outcomes are listed. They include Tmax, the time to reach maximum observed concentration; effective and terminal elimination half-lives; metabolite-to-parent ratios; AUC over stated post-dose intervals; apparent volume of distribution; apparent oral clearance; and the apparent terminal elimination rate constant. In general, AUC summarizes concentration over time, Tmax describes when the observed peak occurs, and elimination measures characterize the decline in concentration. These measures address different aspects of pharmacokinetics and should not be treated as interchangeable. The registry lists these outcomes but does not report their numerical findings.

Multiplicity arises when several outcomes, metabolites, treatment periods or formulation contrasts are examined. In general, testing many contrasts can increase the chance of at least one apparently notable result unless the analysis plan accounts for the number and structure of comparisons. The record lists 15 outcome measures and 6 analyses, but it does not report whether a formal multiplicity procedure, a hierarchy of outcomes or a prespecified contrast set was used. The number of listed outcomes alone does not establish how many statistical tests were conducted.

For uncertainty, a confidence interval would ordinarily show a range of values compatible with the data under the specified analysis and assumptions. For formulation comparisons, the contrast may be expressed in a form suited to the analysis, but the registry does not state the chosen contrast scale or report confidence intervals. A p-value, if reported, would address compatibility with a null hypothesis under a statistical model; it would not quantify clinical importance. No numerical p-values or comparison estimates for Cmax are reported in the registry record.

Sample-size calculations used for planning are distinct from observed power. In general, planning illustrations depend on assumptions about the effect to detect, variability, significance level, allocation and analysis method. The registry does not report the study’s original sample-size justification or a full statistical analysis plan. Any planning illustration based on an observed effect should be interpreted as an illustration rather than as observed power, and it cannot substitute for estimates and uncertainty from the trial itself.

10. Multiplicity, Missing Data and Analysis Populations

The registry lists multiple pharmacokinetic outcomes, including Cmax, Tmax, AUC measures, elimination parameters, distribution, clearance and metabolite-to-parent ratios. It also describes evaluations across treatment periods and for AZD9496 and its metabolites. When many outcomes or contrasts are examined, multiplicity is relevant: in general, the chance of a false-positive finding can increase across repeated tests. The registry does not report a multiplicity adjustment, a testing hierarchy, or which comparisons were designated as confirmatory. The number of listed outcomes and analyses does not, on its own, identify the number of tests performed.

Missing-data handling is also not reported in sufficient detail. The primary population description requires a calculable primary PK parameter for Treatment period 2 and one other period, but the record does not give the number with evaluable measurements at each period, reasons for missing or excluded data, or rules for imputation. These details matter because the available data may differ across periods, and the analysis set can affect both estimates and precision.

The registry names the safety set in describing the primary pharmacokinetic population. A complete definition of that set, other analysis populations and their use is not reported. The record does not provide the full statistical analysis plan, including model specification, treatment of period effects, assumptions, or sensitivity analyses. The original sample-size justification is not reported in the registry record. These omissions limit assessment of whether the analyses followed a prespecified strategy and how robust any comparison would be to alternative analytic choices.

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 non-serious adverse event terms

The registry reports no serious adverse events in any treatment-period group and records zero deaths in each group and in the all-participants grouping. For other adverse events, it lists 2 affected participants in Treatment period 1, 1 in Treatment period 2, 1 in Treatment period 3, 0 in Treatment period 4 and 1 in Treatment period 5. The all-participants grouping lists 5 affected participants. The record gives the number at risk for each period, but these are period-specific counts in a sequential study; they should not be treated as separate randomized treatment arms.

These counts describe what the registry records, not comparative event rates or evidence about causation. The registry does not list serious adverse-event terms, and no serious events are recorded. It does not provide a detailed breakdown of the other adverse events, their severity, timing, relatedness to AZD9496, or whether an individual could contribute events in more than one period. The all-participants entry is a registry grouping, not a basis for adding period counts together. The counts should therefore be read as descriptive safety information for this study, not as proof that a formulation is safer or riskier than another.

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

The study is relevant as a description of how a phase 1 investigation can compare pharmacokinetic profiles across formulations using sequential single-dose periods. Its primary endpoint, Cmax, concerns peak plasma concentration for AZD9496 and its metabolites. The registry also identifies a broader set of pharmacokinetic measures that address timing, exposure and disposition. This gives readers a clear sense of the scientific questions the study was designed to examine.

What the registry record does not establish is the direction or size of any Cmax difference, the precision of a comparison, or whether formulations met a prespecified similarity or difference criterion. Numerical primary and secondary pharmacokinetic results are not reported in the registry record. Without estimates and uncertainty, the stated objective cannot be translated into a conclusion about the observed relationship between the formulations.

The study’s single-group, open-label fixed-sequence design is also distinct from a randomized comparison between independent groups. Each participant was intended to receive multiple single doses, which can support within-participant comparisons, but order and period effects remain relevant considerations. The registry does not report the methods used to address them. The results, even if available elsewhere, would need to be interpreted in light of the enrolled healthy-volunteer population and single-dose setting. The record does not describe outcomes in people with breast cancer or long-term treatment.

The safety counts are descriptive. The registry records no serious adverse events or deaths and reports counts for other adverse events, but it does not give event details or attribution. These data do not establish a comparative safety profile. Nor does the study answer questions about clinical effectiveness: the listed outcomes are pharmacokinetic and safety measures, not measures of cancer response or patient benefit.

Accordingly, the registry supports an account of the trial’s purpose and design, but not a conclusion that one formulation produced higher, lower, equivalent or clinically preferable exposure. It also does not support claims about efficacy or long-term safety.

13. Why This Trial Matters Statistically

This trial illustrates why the design context matters when reading pharmacokinetic comparisons. A fixed sequence in which participants receive several formulations differs from a parallel-group comparison. Within-participant measurements may reduce the influence of stable differences between participants, but the order of treatment periods and changes over time can complicate interpretation. Knowing which design was used is essential before treating a period contrast as a direct formulation effect.

The endpoint choice is also statistically meaningful. Cmax captures the observed peak concentration, while AUC, Tmax, half-life, clearance and distribution describe other features of the concentration-time profile. A single endpoint cannot stand in for all of these dimensions. The registry’s broad outcome list reflects that pharmacokinetic characterization is multidimensional, while also raising questions about how comparisons and multiplicity were handled. Those analysis details are not reported in the registry record.

The use of geometric summaries is common for positive concentration data, where proportional variation may be more informative than absolute variation. But a geometric mean and coefficient of variation do not reveal the uncertainty of a between-formulation contrast by themselves. Estimates, confidence intervals and a clearly stated analysis are needed for readers to judge precision and compatibility with relevant criteria. Those numerical results are not reported in the registry record.

Finally, this record demonstrates the distinction between trial registration details and a complete results report. It identifies the intervention sequence, endpoints and some safety counts, but it does not provide the primary pharmacokinetic estimates or a full account of analysis decisions. Statistical interpretation must therefore stay within what is documented rather than infer conclusions from the study objective or its completion status.

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 central limitation for interpreting the primary question is the absence of numerical Cmax results in the registry record. No geometric means, geometric coefficients of variation, formulation contrasts or uncertainty estimates are reported. As a result, the direction, magnitude and precision of differences among the formulations cannot be evaluated from this record.

The design is open-label, single-group and fixed-sequence, without randomized allocation. The reference formulation is included in the sequence rather than assigned as a concurrent parallel control. Treatment period, sequence and formulation may therefore be difficult to separate unless the analysis addresses these features; the statistical approach is not reported. The registry also does not give a complete period-by-period account of the formulations and doses. Only Variant A at 100mg in Treatment period 1 and the Reference in Treatment period 2 are specified in the available arm description.

The participant population is described as healthy volunteers, limiting direct interpretation for people with breast cancer or other clinical populations. The registry lists 14 enrolled participants, but does not report period-specific numbers with evaluable primary endpoint data or a complete account of missing observations and exclusions. The safety information is limited to counts and does not provide event descriptions, severity or relatedness.

Finally, the record does not report the full statistical analysis plan, multiplicity strategy, original sample-size justification, or sensitivity analyses. These omissions restrict assessment of prespecification, analytic robustness and the intended scope of inference. They do not demonstrate that particular methods were or were not used; those details are not reported in the registry record.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: A Study to Assess the Pharmacokinetics and Safety of Different Forms and Formulations of AZD9496 in Healthy Subjects — NCT02780713.
• Registry record last updated 2021-08-25; status last verified 2021-08.
• Results first posted 2021-08-25.
• 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

NCT02780713 is a completed phase 1, open-label, single-centre study of single-dose AZD9496 formulations in healthy subjects. The registry describes a fixed sequence of five treatment periods, with each volunteer intended to receive five single doses. The listed interventions are AZD9496 Reference and Variants A, B, C and D. The primary outcome is Cmax for AZD9496 and its metabolites M3 and M5, summarized as a geometric mean with geometric coefficient of variation.

The registry records enrollment of 14 and lists 15 outcome measures and 6 analyses. It reports no serious adverse events or deaths and provides period-specific counts for other adverse events. Numerical primary pharmacokinetic results, detailed treatment-period assignments, the full statistical analysis plan, missing-data methods and multiplicity procedures are not reported in the registry record. The record therefore describes the study’s design and objectives but does not establish the size or precision of differences between formulations.