Drug-Drug Interaction Study of TAK-788 and Midazolam in Participants With Advanced Non-small Cell Lung Cancer (NSCLC): Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Drug-Drug Interaction Study of TAK-788 and Midazolam in Participants With Advanced Non-small Cell Lung Cancer (NSCLC) (NCT04051827), a non-randomized phase 1 study. The primary outcome is Part A, Cmax: Geometric Mean Maximum Observed Plasma Concentration (Cmax) for Midazolam Administered Orally With Mobocertinib (Cycle 1 Day 24) and Without Mobocertinib (Cycle 1 Day 1).

2. Clinical Question

3. Trial Design

This was a phase 1, open-label, multicenter, nonrandomized study with a sequential model. The registry record lists 26 participants as enrolled. The study is marked completed, with a start date of 2019-12-23 and primary completion date of 2020-12-17. No random allocation or masking is reported.

Part A focused on the midazolam pharmacokinetic assessment. Participants received oral midazolam 3 mg once on Days 1 and 24, and intravenous midazolam 1 mg once on Days 2 and 25. TAK-788 160 mg was given orally once daily from Day 3 through Day 30 of Cycle 1. This sequence allowed the Day 1 oral midazolam assessment without TAK-788 to be compared with the Day 24 assessment during TAK-788 administration. The primary pharmacokinetic outcome was planned for Part A only.

Part B was described as continued TAK-788 treatment, with eligible participants from Part A potentially entering this part. The record describes daily oral TAK-788 160 mg in 28-day treatment cycles from Cycle 2 through Cycle 24, or until progressive disease, intolerable toxicity, or another discontinuation criterion, whichever occurred sooner. The Part B description ends mid-sentence, so any further details are not reported in the registry record.

The comparison is within a sequential treatment schedule rather than between randomized groups. Such a design can characterize pharmacokinetic measurements at different study times, but the record does not describe randomization, blinding, or a concurrent untreated control. It also does not report the protocol’s rationale for the enrollment target or further details of the analysis 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.

Before assignment: Participants with a historical diagnosis of locally advanced or metastatic non-small cell lung cancer (NSCLC) were enrolled in this 2-part study to receive midazolam oral solution along with mobocertinib (formerly TAK-788) capsule in Part A (Cycle 1) and mobocertinib capsule only in Part B (Cycle 2 to 19). After completion of Part A, eligible participants entered Part B to continue treatment with mobocertinib. As planned, combined safety data for Parts A and B was collected and reported.

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: Pharmacokinetic (PK) evaluable population (Part A, Cycle 1) received protocol-specified dosing regimen without dose reductions prior to Day 26; had no dose interruptions within 1 week prior to Day 24; experienced no more than 1 day of dose interruption within first 14 days of mobocertinib; did not receive excluded concomitant medications through Day 26; and had sufficient midazolam concentration-time data to permit reliable estimation of PK parameters by noncompartmental analysis methods.

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: The safety population was defined as all participants who received at least 1 dose of any study drug (mobocertinib or midazolam).

6. Primary Endpoint

The registry lists the primary outcome as Part A, Cmax: Geometric Mean Maximum Observed Plasma Concentration (Cmax) for Midazolam Administered Orally With Mobocertinib (Cycle 1 Day 24) and Without Mobocertinib (Cycle 1 Day 1), measured over Cycle 1: Days 1 and 24 pre-dose and at multiple time points (up to 24 hours) post-dose (Cycle length is equal to [=] 30 days).

The primary endpoint is the geometric mean maximum observed plasma concentration, or Cmax, of midazolam. Cmax is the highest measured plasma concentration after a dose within the sampling period. The listed unit is nanogram per milliliter (ng/mL), and the stated sampling period includes pre-dose and multiple post-dose time points up to 24 hours on Cycle 1 Days 1 and 24.

The endpoint compares oral midazolam administered without TAK-788 on Day 1 with oral midazolam administered with TAK-788 on Day 24. The study’s broader pharmacokinetic purpose also included single intravenous midazolam doses, but the primary endpoint named in the registry record is specifically the oral midazolam Cmax comparison. The registry record says this outcome was assessed only in Part A.

As general statistical context, a geometric mean is often used for positive measurements that vary multiplicatively or have a right-skewed distribution. It summarizes the central level on a multiplicative scale rather than by adding measurements and dividing by their count. The listed dispersion measure is the geometric coefficient of variation, which describes relative variability on a multiplicative scale.

The registry record does not report the endpoint’s numerical estimates, the geometric coefficient of variation values, or an interval estimate. Without those results, the magnitude and precision of the comparison cannot be assessed from the record.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The trial used a phase 1, open-label, multicenter, nonrandomized, sequential design. In general, phase 1 studies can be used to characterize early clinical pharmacology and safety. The record’s stated objective was to characterize the effect of repeated oral TAK-788 on single-dose oral and intravenous midazolam pharmacokinetics. It does not report a detailed statistical analysis plan, so the exact inferential methods used for the endpoint are not reported in the registry record.

What does a sequential pharmacokinetic comparison mean?

In Part A, oral midazolam was measured before TAK-788 administration and again after TAK-788 had been given on the specified schedule. The comparison therefore follows measurements at different times within the study sequence. This can be useful for characterizing pharmacokinetics under the planned dosing conditions. As a general design consideration, however, a sequential comparison is not the same as random allocation to concurrent treatment groups. The registry record does not report a randomized control group for this endpoint, and the order of the conditions is built into the schedule.

Intravenous midazolam was also administered on Days 2 and 25. The study purpose includes both oral and intravenous midazolam pharmacokinetics, but the primary endpoint named in the record is oral Cmax. Specific endpoint definitions and numerical results for the intravenous assessments are not reported in the registry record.

Why use a geometric mean?

Cmax is a positive concentration measurement. As general statistical background, pharmacokinetic measurements may be analyzed on a multiplicative scale when proportional differences are more meaningful than fixed additive differences. A geometric mean summarizes measurements on that scale. It is different from an arithmetic mean, which summarizes values by addition. The registry record identifies the geometric mean as the parameter for the primary endpoint but does not explain the choice in a statistical analysis plan.

The record lists geometric coefficient of variation as the dispersion measure. In general, this describes variability relative to the scale of the measurements and is compatible with multiplicative summaries. It does not replace an effect estimate or confidence interval. The numerical geometric means and dispersion values are not reported in the registry record.

What do sampling times contribute?

The endpoint description states that sampling took place pre-dose and at multiple time points up to 24 hours after dosing on Days 1 and 24. Repeated concentration measurements over time support characterization of a concentration-time profile, including identification of the maximum observed concentration within the sampling window. The record does not specify the individual sampling times, the approach for handling values below quantification limits, or the method used to derive the reported endpoint.

In general, observed Cmax depends on the sampling schedule: the highest measured value is not necessarily identical to the true peak between measurements. The schedule is described only as multiple time points up to 24 hours, so its finer detail is not reported in the registry record. No numerical concentration-time results are reported.

How should uncertainty and significance be read?

A point estimate describes the estimated value or contrast, while a confidence interval gives a range of values compatible with the data under the interval’s statistical assumptions. A p-value, when used, summarizes how unusual the observed data would be under a specified null hypothesis and model. These are general concepts; the registry record does not report a confidence interval or p-value for the primary endpoint. It also does not report the statistical model, transformation details, or testing procedure used for the primary comparison. Consequently, neither statistical significance nor precision can be assessed from the information recorded.

What are the planning illustrations?

The planning illustrations are described as calculations based on an observed effect, with a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation. The assumed effect to detect is a stated fraction of the observed effect. For time-to-event outcomes, the illustration uses a total number of events; other illustrations use participants per arm. These are planning assumptions, not observed trial results and not observed power.

The registry record does not report a sample-size justification from the original trial design. Nor does it report a numerical observed effect in the information available for this explanation. Therefore, no conclusion about the original enrollment target’s adequacy or the numerical planning estimates can be made from the record. Planning illustrations answer a hypothetical design question under stated assumptions; they do not establish the certainty of a completed trial’s findings.

Finally, the record identifies nine outcome measures and four analyses, but does not describe the statistical methods for those analyses in detail. The endpoint name also uses Mobocertinib, whereas the study title and dosing descriptions use TAK-788. The registry record does not explain this naming difference, so its interpretation should not be guessed.

10. Multiplicity, Missing Data and Analysis Populations

The registry record identifies a primary pharmacokinetic endpoint and lists secondary outcomes covering treatment-emergent adverse events, clinically significant changes from baseline in laboratory values, and clinically significant changes from baseline in vital signs. It also reports nine outcome measures and four analyses. The statistical approach to multiple comparisons is not reported in the registry record.

Multiplicity is a general concern when many outcomes, time points, or comparisons are examined. Testing several hypotheses can increase the chance of obtaining at least one apparently notable result by chance. Common approaches include identifying a primary endpoint in advance, adjusting significance thresholds, or treating secondary analyses as exploratory. The record names the primary endpoint, but does not report whether any multiplicity adjustment or testing hierarchy was used. No adjustment should be assumed.

Missing-data procedures are also not reported in the registry record. The primary pharmacokinetic population is described as participants meeting specified dosing and interruption conditions, but the full population criteria are truncated in the record. The record does not explain how missing concentration samples, incomplete profiles, withdrawals, or other unavailable measurements were handled. It does not report imputation methods or sensitivity analyses.

Analysis populations are not fully described. The primary endpoint was planned for the Part A pharmacokinetic-evaluable population in Cycle 1, but complete eligibility details are not reported. The record also does not provide the number of participants included in the primary analysis or explain whether any participants were excluded from it. Enrollment of 26 should not be treated as the analysis denominator without those details.

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 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 (23.1%), dyspnoea (11.5%), dehydration (7.7%), pyrexia (7.7%), vomiting (7.7%).

The registry record lists an adverse-event group covering Parts A and B. It reports 26 participants at risk for serious adverse events, 20 affected by serious adverse events, 26 at risk for other adverse events, and four deaths. These are recorded counts; they do not by themselves describe the timing, duration, severity distribution, or causal relationship of individual events to study treatment.

The serious-event terms listed with percentages are diarrhoea at 23.1%, dyspnoea at 11.5%, dehydration at 7.7%, pyrexia at 7.7%, vomiting at 7.7%, and arrhythmia at 3.8%. These percentages are registry-listed values and should be read as event-term summaries, not as measures of comparative risk against a control group. The study was nonrandomized and the record does not report a like-for-like control comparison.

The four deaths are reported as a count. The registry record does not state in this information whether they were considered related to treatment, nor does it provide their causes or timing. A count of events alone cannot establish causation. The listed secondary safety outcomes include treatment-emergent adverse events and clinically significant changes in laboratory values and vital signs, but the numerical results for those outcomes are not reported in the registry record.

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

This trial was designed to characterize whether repeated TAK-788 administration was associated with a change in the pharmacokinetics of midazolam, including oral and intravenous dosing. The named primary endpoint focuses on oral midazolam Cmax before and during TAK-788 administration. The sequential schedule makes that pharmacokinetic question explicit, but the registry record does not report the numerical endpoint results.

Accordingly, the record as described does not show the size or direction of the primary comparison, its variability, or its uncertainty. It does not provide a confidence interval or p-value for the primary endpoint. The study’s objective and design should not be mistaken for an observed result: the fact that an endpoint was planned does not reveal what its measured value was.

The study also does not supply a randomized comparison between TAK-788 and an alternative treatment. It was open-label and nonrandomized, and the primary comparison was scheduled within Part A at different study times. That design information is important when interpreting any results that may be available elsewhere, but no additional result should be inferred from the registry record.

The safety record gives selected counts and serious-event terms. Those entries describe events reported during the study; they do not alone establish that TAK-788 or midazolam caused the events. The record’s four deaths likewise cannot be attributed to treatment from the count alone.

In short, the registry information describes the clinical question, treatment sequence, endpoint definition, and selected safety data. It does not report the primary pharmacokinetic estimate or enough detail to assess its precision, statistical significance, or missing-data handling. Any interpretation of the treatment effect beyond those recorded design details would go beyond what the registry record reports.

13. Why This Trial Matters Statistically

This study illustrates how a clinical pharmacology question can be framed around a defined exposure and a measurable concentration endpoint. The primary endpoint is oral midazolam Cmax, compared before and during repeated TAK-788 administration. The listed geometric mean and geometric coefficient of variation reflect a multiplicative approach to summarizing pharmacokinetic measurements, a common statistical framework for positive concentration data.

It also highlights why design structure matters. The study is sequential and nonrandomized, so the comparison is tied to different scheduled study days. It is not a randomized comparison between concurrent groups. A careful statistical reading distinguishes the intended pharmacokinetic comparison from evidence that would support a causal conclusion, and notes which design and analysis details are not reported.

The record further separates endpoint definition from endpoint result. A clearly named measure and sampling window tell readers what investigators intended to quantify, but without numerical estimates and uncertainty measures, readers cannot assess the magnitude or precision of the observed comparison. This is an important distinction for registry-based interpretation.

Finally, safety counts and planning illustrations answer different questions from the primary pharmacokinetic endpoint. Event counts describe recorded safety outcomes; planning calculations illustrate hypothetical assumptions for study design. Neither substitutes for a reported primary estimate. The record’s incomplete analysis details and the naming difference between TAK-788 and Mobocertinib also show why registry descriptions should be read closely and without filling gaps by assumption.

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 primary limitation for statistical interpretation is that the numerical primary endpoint results are not reported in the registry record. There is no stated geometric mean Cmax for either condition, no reported geometric coefficient of variation, and no confidence interval or p-value. The effect’s magnitude, direction, and precision therefore cannot be assessed from this information.

The study was open-label, nonrandomized, and sequential. Its primary comparison contrasts measurements on different study days, before and during TAK-788 administration. The registry record does not describe a concurrent control group for that endpoint. This design context should be retained when interpreting any results, and the record does not provide enough information to determine how other time-related influences were handled.

The primary pharmacokinetic population description is truncated. The record states that participants had to meet dosing and interruption conditions but does not give the full criteria or the number analyzed. The handling of missing samples, incomplete concentration profiles, and participants outside the evaluable population is not reported in the registry record.

The statistical analysis plan, model details, multiplicity procedures, and sample-size justification are also not reported. The planning illustrations are based on an observed effect and specified assumptions, but numerical illustration results are not included in the record. The primary endpoint title refers to Mobocertinib, while the study title and dosing descriptions refer to TAK-788; the registry record does not explain this naming difference.

Lastly, the Part B arm description is incomplete. These omissions constrain interpretation of study conduct, analysis populations, and results, but do not change the stated design details or the safety counts recorded.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: Drug-Drug Interaction Study of TAK-788 and Midazolam in Participants With Advanced Non-small Cell Lung Cancer (NSCLC) — NCT04051827.
• Registry record last updated 2025-07-28; status last verified 2025-07.
• Results first posted 2024-04-12.
• 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 registry record describes NCT04051827, a completed phase 1, open-label, multicenter, nonrandomized, sequential study in participants with advanced non-small cell lung cancer. Enrollment was 26. The study started on 2019-12-23 and reached primary completion on 2020-12-17.

Its purpose was to characterize the effect of repeated oral TAK-788 160 mg once daily on single-dose oral and intravenous midazolam pharmacokinetics. The primary outcome was geometric mean oral midazolam Cmax in Part A, comparing Cycle 1 Day 1 without TAK-788 with Day 24 during TAK-788 administration. Numerical primary results and detailed analysis methods are not reported in the registry record.

The record lists 20 participants with serious adverse events among 26 at risk and four deaths. It provides several serious-event terms and percentages but does not establish causality. The record also identifies secondary safety outcomes, while their numerical results are not reported.