Comparison of Two Formulations of AZD5363 and the Effect of Food on Pharmacokinetic Exposure, Safety and Tolerability: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Comparison of Two Formulations of AZD5363 and the Effect of Food on Pharmacokinetic Exposure, Safety and Tolerability (NCT01895946), a non-randomized phase 1 study. The primary outcome is Ratio of Css,Max for Day 4 to Day 11.

2. Clinical Question

This was not a randomized comparison between treatment groups. The study instead addresses pharmacokinetic questions across formulation and food conditions, alongside safety and tolerability in patients with advanced disease. Part A evaluates a formulation switch from tablet to capsule. Part B evaluates food effect with the tablet formulation. The registry describes patients who contributed data under both relevant conditions as the population for pharmacokinetic analysis. That design can make each patient's measurements informative for comparing conditions, but the record does not specify the exact statistical model or test used for the endpoint.

The primary question is about drug exposure, not a clinical efficacy contrast. Secondary outcomes include best objective response, disease control at Week 12, target lesion size changes and progression-free survival. The registry lists those outcomes but does not report their results. The available record therefore supports a description of the questions and study structure, not conclusions about comparative clinical benefit.

3. Trial Design

The registry identifies NCT01895946 as a completed Phase I, open-label, multicentre study sponsored by AstraZeneca. The study began in 2013-12, and primary completion was recorded in 2015-02. Enrollment was 33. The official title describes two dosage formulations of AZD5363 and an assessment of food effects on pharmacokinetic exposure, safety and tolerability in patients with advanced solid malignancies.

The study had two parts. In Part A, AZD5363 tablet twice daily was followed by AZD5363 capsule twice daily, using an intermittent schedule of 4 days on and 3 days off. In Part B, AZD5363 tablet was taken twice daily on the same intermittent schedule, with and without food on one occasion. The registry lists allocation as non-randomized, masking as none and the model as parallel. Thus, the record does not describe a blinded or randomized allocation to a like-for-like control comparison.

The primary outcome concerns the ratio of maximum plasma concentration at steady state for Day 4 to Day 11. The specified timeframe is Day 4 and Day 11. The PK analysis population was defined by providing concentration-time data for both capsule and tablet administration in Part A, or both fed and fasted treatments in Part B, while meeting dietary and evaluability requirements. The registry does not report how many participants met these criteria or provide the primary endpoint result.

Secondary outcomes address tumour response and progression, including best objective response, disease control at Week 12, target lesion size changes and progression-free survival. Results for these outcomes are not reported in the registry record. The non-randomized structure means that any observed differences should be interpreted as comparisons across the study's treatment conditions, not as randomized evidence between independent treatment groups.

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: Note, Part A involved a cross over between tablet and capsule formulations A total of 33 patients were enrolled. 30 of these patients passed screening assessments and were dosed

Overall Study

Analysis population for the primary outcome, as defined in the registry: All patients who provided concentration-time data for AZD5363 for both capsule and tablet administration (Part A) or for both fed and fasted treatments and who were compliant with the standard dietary and evaluability requirements (Part B) were included in PK analysis set.

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 Ratio of Css,Max for Day 4 to Day 11, measured over Day 4 and Day 11.

The primary endpoint is the ratio of AZD5363 maximum plasma concentration at steady state, or Css,max, on Day 4 to Css,max on Day 11. Css,max represents the highest measured plasma concentration at steady state during the dosing interval. The ratio expresses the concentration on one specified day relative to the concentration on the other specified day; it does not by itself describe all aspects of drug exposure.

The registry specifies a geometric mean parameter and a 90% confidence interval. The endpoint is based on pharmacokinetic concentration-time data, with actual sampling times used in parameter calculations. The study also determined time to Css,max, minimum steady-state concentration, area under the plasma concentration-time curve over the dosing interval, and apparent clearance. Css,max and time to Css,max were determined by inspection of concentration-time profiles. AUCss used the linear up / log down trapezoidal rule, and CLss/F was determined from dose divided by AUCss.

General: Pharmacokinetic endpoints help characterize how drug concentrations vary under different dosing conditions. Maximum concentration is one aspect of exposure, while AUC reflects exposure across the dosing interval. A confidence interval communicates the precision of an estimate under the analysis assumptions; it does not establish that the observed contrast is clinically important.

The registry record does not report the ratio estimate or its confidence limits. It therefore does not establish the magnitude or precision of the Day 4 to Day 11 comparison.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

What does a geometric mean ratio represent?

The primary parameter is identified as a geometric mean, and the outcome is a ratio of Css,max on Day 4 to Css,max on Day 11. General: Geometric means are useful for measurements such as drug concentrations that may be skewed rather than symmetrically distributed. A ratio puts the compared values on a relative scale. Its interpretation depends on which condition or time point is placed in the numerator and which is placed in the denominator. Here the registry names Day 4 first and Day 11 second.

The record does not report the numerical ratio. Without the estimate, it is not possible to state whether the measured concentration was higher on one day, or how large any relative difference was. The record also does not report the confidence interval limits. The interval is therefore part of the specified method, not a result that can be interpreted from the available record.

What does the confidence interval communicate?

The dispersion measure is a 90% confidence interval. General: A confidence interval describes the uncertainty around an estimate under the assumptions of the statistical method. It is not a guarantee that the true value lies within a particular interval, and it does not directly indicate whether a difference matters clinically. Narrower intervals generally indicate greater precision, while wider intervals indicate less precision. No conclusion about precision is possible without the interval limits.

The registry does not report a hypothesis test, a p-value or a decision threshold for the primary endpoint. Whether such elements were part of the full analysis plan is not reported in the registry record. The stated confidence interval should not be treated as a substitute for unreported results or analysis details.

How were the pharmacokinetic parameters derived?

The record says actual sampling times were used and that pharmacokinetic parameters were derived using standard non-compartmental methods. Css,max and time to Css,max were determined by inspection of the concentration-time profiles. AUCss, the area under the plasma concentration-time curve from zero to the end of the dosing interval, was calculated using the linear up / log down trapezoidal rule. Apparent clearance, CLss/F, was determined from dose divided by AUCss.

General: Non-compartmental analysis estimates pharmacokinetic quantities from observed concentration-time data without requiring the investigator to specify a particular compartment model for the body. The trapezoidal rule approximates the area under a curve between observed measurements. A linear up / log down approach uses different interpolation conventions depending on whether concentrations are rising or falling. These choices describe how calculations are made; they do not supply missing concentration data or endpoint estimates.

What is important about the analysis population?

The PK analysis set included patients with concentration-time data for both capsule and tablet administration in Part A, or both fed and fasted treatment in Part B, who complied with standard dietary and evaluability requirements. This definition makes clear that inclusion depended on having the required data under both relevant conditions. The record does not report the number included in the PK analysis set, the number excluded, or the reasons for any exclusions.

General: When a comparison uses data from the same participant under multiple conditions, accounting for that within-participant structure can be important because measurements from one participant may be related. The registry description indicates that participants contributed data for both conditions to be included, but the statistical model or method used to handle this structure is not reported in the registry record. It should not be assumed that a particular paired test or model was used.

How should planning illustrations be understood?

The registry record describes sample-size planning illustrations based on the observed effect, with a two-sided significance level of 0.05, equal allocation between two arms and a normal approximation. The effect to detect is expressed as a stated fraction of the observed effect. For time-to-event calculations, the planning quantity is the total number of events; other calculations describe participants per arm. These are planning illustrations, not observed power and not the original trial's design justification.

General: Planning calculations ask how much information a future study might need under stated assumptions. They do not change the precision of the completed trial, and they do not show that a completed study had a particular probability of detecting an effect. The registry record does not report the trial's own sample-size justification or establish that these planning assumptions were used to design the study.

10. Multiplicity, Missing Data and Analysis Populations

The registry lists a primary pharmacokinetic endpoint and secondary outcomes covering best objective response, disease control at Week 12, target lesion size changes and progression-free survival. It also describes several pharmacokinetic parameters. The registry record does not report how statistical testing across these outcomes was organized or whether any adjustment for multiple comparisons was planned. The multiplicity strategy is not reported in the registry record.

General: When several outcomes or comparisons are tested, the chance of finding an apparently unusual result by chance can increase. Methods for controlling that risk depend on the analysis plan and the intended claims. In the absence of a reported strategy, individual results should not be treated as if the handling of multiple testing were known. No outcome estimates or p-values for the secondary efficacy outcomes are reported in the registry record.

The PK analysis population required data for both conditions within the relevant study part and compliance with dietary and evaluability requirements. The number included in that population, the extent of missing concentration-time data, and the reasons for missingness or exclusion are not reported in the registry record. The record also does not describe imputation or other missing-data methods.

The allocation is non-randomized and the study is open-label. The registry does not report an analysis plan describing adjustment for potential differences between participants or conditions. It also does not report interim analyses or a statistical plan. These omissions limit assessment of how prespecified analyses, missing data and multiple outcomes were handled.

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 serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: diarrhoea (25.0%), rash maculo-papular (16.7%), pneumonia mycoplasmal (8.3%), hyperglycaemia (8.3%), vomiting (8.3%).

The registry reports serious adverse event counts separately for Part A and Part B. Part A lists 5 serious adverse events among 18 participants at risk; Part B lists 6 among 12 participants at risk. The registry also lists other adverse events for 18 participants at risk in Part A and 12 in Part B. These are the posted group counts and should be read within their respective study parts, not as a randomized comparison between equivalent groups.

The listed serious adverse event terms and percentages are diarrhoea, 25.0%; rash maculo-papular, 16.7%; pneumonia mycoplasmal, 8.3%; hyperglycaemia, 8.3%; vomiting, 8.3%; and stomatitis, 8.3%. The registry presents these as serious adverse event terms. The percentages should not be reinterpreted as comparative risks between formulations or food conditions, because the record does not provide a randomized control comparison or a causal analysis.

General: Serious adverse events are distinct from all adverse events, and event counts do not by themselves establish causation. The registry record does not report deaths. It also does not provide additional detail in the listed details on timing, recurrence, severity grading beyond the serious classification, or attribution to study treatment. Those details are not reported in the registry record.

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

The record establishes that this was a Phase I, open-label, non-randomized study of AZD5363 formulation and food conditions in patients with advanced solid malignancies. It defines a primary pharmacokinetic endpoint: the ratio of Css,max on Day 4 to that on Day 11, with a 90% confidence interval. It also describes the methods used to derive pharmacokinetic parameters and gives serious adverse event counts by study part.

The primary endpoint estimate and confidence limits are not reported in the registry record. As a result, the posted information does not show the size or precision of the Day 4 to Day 11 ratio. Numerical findings for the secondary efficacy outcomes are also not reported. Without those results, the record does not support a conclusion about the direction or magnitude of exposure differences, tumour outcomes or comparative effects of food.

The study was not randomized and was open-label. It should not be read as a randomized comparison of treatment groups or as evidence that observed differences were caused by formulation or food condition. Its primary focus is pharmacokinetic exposure, with safety and tolerability also assessed. The listed safety counts describe events recorded in each part, but they do not establish causation or comparative safety.

General: Pharmacokinetic measurements can characterize drug exposure under specified conditions, but exposure measures are not interchangeable with clinical benefit or harm. A confidence interval, when available, would help describe the precision of an estimate; it would not alone determine clinical importance. Here, the endpoint definition and methods are reported, but the numerical result needed to assess the estimated contrast is not.

The registry record also does not report the full statistical plan, multiplicity handling, missing-data methods or the size of the analysis population. Those omissions limit assessment of the statistical evidence. The appropriate interpretation is therefore descriptive: the record identifies what the study set out to measure and reports selected safety counts, while leaving the main pharmacokinetic result unreported.

13. Why This Trial Matters Statistically

This study raises a useful statistical distinction between measuring drug exposure and evaluating clinical outcomes. Its primary endpoint is a pharmacokinetic ratio based on maximum plasma concentration at steady state on specified study days. Such a measure focuses on concentration under dosing conditions. The record also identifies AUCss and apparent clearance as pharmacokinetic parameters, while separately listing tumour response and progression outcomes.

The design has two different condition comparisons: a tablet-to-capsule switch in Part A and fed versus fasted tablet dosing in Part B. The registry describes data from both conditions as a requirement for inclusion in the PK analysis set. That structure makes it important to understand which participants contributed paired condition data and how the statistical analysis handled those measurements. The exact model or test is not reported in the registry record.

The record is also a reminder that endpoint definitions and analysis methods do not substitute for numerical results. It explains how concentration-time measures were obtained, including the use of actual sampling times and non-compartmental methods, but does not report the primary estimate or its confidence limits. Readers can identify the planned statistical target without being able to assess the observed effect or its precision.

Finally, non-randomized, open-label studies answer different questions from randomized control comparisons. The design and the reported safety counts should be interpreted descriptively, with no causal comparison inferred from the separate study parts. The case illustrates why statistical interpretation depends on both the estimand and the information actually reported.

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 the primary endpoint is that its estimate and 90% confidence interval are not reported in the registry record. The endpoint definition is available, but not the numerical result needed to assess its direction, size or precision. Results for the listed secondary efficacy outcomes are also not reported.

The study was open-label and non-randomized. The registry explicitly indicates that its arms are not a like-for-like control comparison. Comparisons across the formulation switch and food conditions therefore should not be treated as randomized estimates of causal effects. The record does not report details of allocation procedures beyond the non-randomized classification.

The registry defines the PK analysis population by availability of data for both conditions and compliance with dietary and evaluability requirements. It does not report the number included, missing-data methods, exclusions, or reasons for missing measurements. The precise statistical model used for within-participant condition data is not reported in the registry record.

The record does not describe adjustment for multiple outcomes, an interim analysis plan, or the trial's statistical plan and sample-size justification. It does not provide numerical results for the other pharmacokinetic parameters or the secondary efficacy outcomes. Deaths are not reported in the registry record. The listed serious adverse event counts and terms provide limited safety information and do not establish attribution to treatment or differences between conditions.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: Comparison of Two Formulations of AZD5363 and the Effect of Food on Pharmacokinetic Exposure, Safety and Tolerability — NCT01895946.
• Registry record last updated 2016-05-25; status last verified 2016-04.
• Results first posted 2016-05-25.
• 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

NCT01895946 is a completed Phase I, open-label, multicentre study sponsored by AstraZeneca. It enrolled 33 patients with advanced solid malignancies and compared two AZD5363 formulations while assessing food effects on pharmacokinetic exposure, safety and tolerability. The study began in 2013-12, with primary completion in 2015-02.

Part A switched participants from AZD5363 tablet to capsule dosing; Part B assessed tablet dosing with and without food on one occasion. Both used twice-daily dosing on an intermittent schedule of 4 days on and 3 days off. The primary endpoint was the ratio of Css,max on Day 4 to Day 11, with a 90% confidence interval. The registry describes non-compartmental pharmacokinetic methods but does not report the primary estimate or its interval. It lists serious adverse event counts by part and secondary efficacy outcomes, whose results are not reported in the registry record.