Phase 1 TAK-925 Study in Healthy Adult and Elderly Volunteers and Participants With Narcolepsy: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Phase 1 TAK-925 Study in Healthy Adult and Elderly Volunteers and Participants With Narcolepsy (NCT03332784), a randomized phase 1 study. The primary outcome is Number of Participants Reporting One or More Treatment-emergent Adverse Events (TEAEs).

2. Clinical Question

3. Trial Design

This was a phase 1, randomized, double-masked, sequential study sponsored by Takeda. The registry reports total enrollment of 58 and a completed status. The recorded start date is 2017-11-04, and the primary completion date is 2018-09-04. The study examined a single intravenous administration of TAK-925 in healthy adults, healthy elderly participants, and people with narcolepsy.

The design used multiple cohorts and dose levels rather than one simple, parallel comparison of a single TAK-925 dose with placebo. Part 1 included healthy adult cohorts, a healthy elderly cohort, and a cohort described as non-blinded. In several cohorts, the dose level was selected with reference to a targeted plasma level and to safety, tolerability, and pharmacokinetic data from earlier cohorts. Part 2 enrolled participants with narcolepsy. Its cohort doses were described as depending on findings from Part 1 or on safety, tolerability, pharmacokinetic, and Maintenance of Wakefulness Test results from previous cohorts.

Many cohorts were described as double blind. One Part 1 cohort was described as non-blinded, while the Part 2 descriptions say participants were double blind and the sponsor was open. These cohort-specific details matter when interpreting comparisons: the participants were not all drawn from one identical population, and doses and study procedures could vary by cohort. The registry record does not report further detail about the randomization sequence, allocation concealment, or the operational procedures used to maintain masking.

The primary safety analysis set was defined as participants who received at least one dose of study drug. The registry lists 28 outcome measures and three analyses. It identifies average sleep latency in the Maintenance of Wakefulness Test as a secondary outcome. Further details of the statistical plan, including the rationale for the sample size and any planned interim analyses, 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: Healthy adult and elderly participants were enrolled to receive TAK-925 or placebo in Cohorts 1 and 2 under alternating panel design and in Cohorts S1, S2, 3, and 4 under parallel design of Part 1, and participants with type 1 narcolepsy were enrolled to receive TAK-925 or placebo in a 2-period cross-over design in Cohorts 5, 6, and 7 of Part 2.

Only the first 6 of 20 groups are shown.

Parts 1 and 2 - Period 1 (1 Day)

Reasons for not completing this period:

Parts 1 and 2- Period 2 (1 Day)

Part 1- Period 3 (1 Day)

Analysis population for the primary outcome, as defined in the registry: The safety analysis set was defined as all participants who received at least one dose of study drug.

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 analysis set was defined as all participants who received at least one dose of study drug.

Only the first 6 of 21 groups are shown.

6. Primary Endpoint

The registry lists the primary outcome as Number of Participants Reporting One or More Treatment-emergent Adverse Events (TEAEs), measured over Baseline up to Day 7.

The primary endpoint counts participants who reported one or more treatment-emergent adverse events (TEAEs) from baseline up to Day 7. A participant is counted once for this endpoint if at least one qualifying event was reported during the specified period; the measure does not count the total number of individual events. The registry defines the safety analysis set as all participants who received at least one dose of study drug.

This kind of endpoint is used in early-phase safety assessment because it gives a direct description of how many treated participants experienced an event after treatment began. It is a binary participant-level outcome: each person either meets the endpoint or does not. The count is useful for describing event occurrence in each cohort, but it does not tell readers whether participants had one event or several, how intense an event was, how long it lasted, or whether it was judged related to study drug. Those details require other safety summaries, which are not all included in the primary endpoint itself.

The reported timeframe ends at Day 7, so the endpoint addresses short-term event reporting after a single administration. It cannot, on its own, describe adverse events occurring later, establish a causal explanation for an event, or summarize safety across longer exposure. The registry presents results separately by study group and also posts a pooled-placebo comparison. Because the trial used multiple cohorts, the group-specific context is important when reading these counts.

7. Results Posted in the Registry

• Part 2 Cohort 5-7: Pooled Placebo: 0.0% (0/13) versus 9.1% (1/11) on control; risk difference -9.1 percentage points (95% CI -26.1 to 7.9); unadjusted two-proportion z-test p = 0.267.

8. Statistical Interpretation

9. Statistical Methods Explained

The primary outcome is binary at the participant level. Each participant is classified according to whether one or more TEAEs were reported during the endpoint timeframe, baseline up to Day 7. For a binary outcome, a group’s event count and group size describe the observed proportion with the event. The posted arm-level results give counts and denominators; they do not report a separate interval for every group’s proportion.

What does a risk difference represent?

General statistical explanation: a risk difference compares the event proportions in two groups by subtracting one proportion from the other. A value of zero corresponds to equal observed proportions; a negative or positive value indicates which group has the lower or higher observed proportion according to the order used for the contrast. The posted estimate is -0.091. Its interpretation depends on the comparator ordering, so it should be read in the context of the named groups rather than as a dose-versus-placebo treatment effect. Here, the comparison is between two pooled placebo groups from different study parts.

The registry also reports a confidence interval from -0.261 to 0.079 and an unadjusted p-value of 0.267 for that contrast. The confidence interval describes a range of values compatible with the data under the method’s assumptions; it is not a range containing a known true value with certainty. Because its span includes zero, the data are compatible with no difference as well as with differences in either direction. The p-value indicates how unusual results at least this discrepant from the null would be under the null model and the specified test assumptions. It is not the probability that the null hypothesis is true.

Why are the cohorts important?

General statistical explanation: a comparison is most interpretable when the groups have a common design and differ chiefly in the exposure of interest. This study is sequential and cohort-based. The populations include healthy adults, healthy elderly participants, and participants with narcolepsy; the cohort descriptions also vary in dose selection and masking. The specific reported contrast compares pooled placebo groups from different parts of the study. It therefore cannot isolate a TAK-925 effect, and it should not be treated as though it were a randomized within-cohort treatment comparison.

The arm-level outcome counts can still be read descriptively. They show how many participants in each recorded group met the endpoint, with the group size indicating how much information each count represents. A count of events among a small number of participants is inherently imprecise: the experience of one participant can materially change the observed group proportion. The registry does not report adjusted estimates for every dose group or a model accounting for cohort differences.

What do the planning illustrations mean?

General statistical explanation: a sample-size calculation asks how many participants a future study might need under specified assumptions to detect a chosen effect with a stated power and significance level. The planning assumptions recorded for these illustrations use 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 fraction of the observed effect. For time-to-event outcomes the stated convention is total events, while other outcomes are expressed as participants per arm. These are planning illustrations based on the observed effect, not the trial’s original design justification and not observed power. The registry record does not report the original sample-size justification.

Because the observed contrast is between pooled placebo groups, a planning exercise based on that effect should not be interpreted as a recommended sample size for a TAK-925-versus-placebo efficacy or safety comparison. Its meaning depends on the exact endpoint, contrast, target effect, assumptions, and future design. No numerical planning recommendation is stated in this explanation.

What is not established by the statistical output?

The registry lists 28 outcome measures and three analyses, but a complete statistical analysis plan is not reported in the registry record. The analysis population for the primary safety endpoint is described, but details such as how missing endpoint data were handled, whether analyses were adjusted for multiple comparisons, and whether any subgroup analyses were prespecified are not reported in the registry record. No recalculated analysis is needed to interpret the posted comparison, and no discrepancy between the posted and recalculated results is indicated.

General statistical explanation: statistical significance, precision, and clinical importance are different ideas. A p-value addresses compatibility with a specified null model, a confidence interval conveys uncertainty about an estimate, and clinical importance depends on the outcome and context. The registry’s brief safety outcome and small cohort sizes limit what can be inferred about rare events, longer-term risks, or differences between doses. The statistical results should therefore be understood as a description of the observations and the particular posted contrast, not as a definitive ranking of treatment groups.

10. Confidence Intervals and Precision

The posted risk-difference estimate is -0.091, with a confidence interval from -0.261 to 0.079. The interval is wide enough to include zero and values on both sides of zero. It therefore does not pin down the direction of a difference between the two pooled placebo groups with high precision. The corresponding unadjusted p-value is 0.267, which is consistent with the interval’s inclusion of zero; neither statistic establishes a clear difference between the groups.

General statistical explanation: a confidence interval communicates sampling uncertainty around an estimated contrast. If an interval is wide, the data are compatible with a broader range of underlying differences; if it is narrow, the estimate is more precise under the model used. An interval crossing zero for a difference means that no difference is among the values compatible with the data at the interval’s confidence level. It does not prove equality, and it does not rule out differences that may matter.

The small denominators in the cohorts also limit precision. In a group with only a few participants, a single participant’s event status can substantially change the observed proportion. Zero observed events in a group do not establish zero underlying risk, particularly when the group is small. Conversely, an observed event in a small group does not by itself establish a high or persistent risk in a wider population.

The confidence interval pertains to the posted contrast between pooled placebo groups, not to every individual TAK-925 dose or to a pooled treatment effect. The registry record does not report confidence intervals for all arm-specific event counts. The precision of a statistical estimate also does not address possible differences between study parts, population composition, masking, or sequential dose selection. Those design features limit the interpretation of the contrast independently of its numerical uncertainty.

11. Multiplicity, Missing Data and Analysis Populations

The registry record lists 28 outcome measures and three analyses. It does not report a full statistical analysis plan describing how the family of outcomes or comparisons was handled. In particular, whether multiplicity adjustments were planned or applied is not reported in the registry record. The posted p-value of 0.267 is identified as unadjusted, so it should not be treated as an adjustment for testing multiple outcomes or contrasts.

General statistical explanation: when many outcomes or comparisons are examined, the chance of at least one apparently unusual result can increase. Multiplicity procedures can be used to control that issue, but the choice depends on the analysis plan and the purpose of the comparisons. Without a reported plan, it is not possible to determine whether the posted analysis was intended as confirmatory, exploratory, or one of several related tests.

The primary safety analysis population is defined as all participants who received at least one dose of study drug. That definition identifies who could be included in the safety summaries, but it does not explain how missing event information was handled. Whether any participants lacked endpoint data, how such data were treated, or whether additional analysis populations were used is not reported in the registry record.

The study’s multiple cohorts and sequential dose choices also affect interpretability. Some later dose levels were selected using earlier safety, tolerability, and pharmacokinetic information, and some Part 2 cohort decisions also considered Maintenance of Wakefulness Test results. The registry record does not report a statistical adjustment for this sequence or details of how those evolving decisions were incorporated in analysis. These omissions do not invalidate the arm-level counts, but they limit claims that depend on a prespecified, multiplicity-controlled comparison across doses or outcomes.

Accordingly, the event counts and the named placebo-group contrast should be treated as the analyses reported in the registry. Any broader claim about a family of tests, missing observations, or model-based adjustment would require information not reported in the registry record.

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 0% reporting threshold.

Most frequent non-serious adverse event terms

The serious adverse event summaries report zero serious adverse events in every listed group, and deaths are recorded as zero in every group. These are observed counts during the study and should be read as such. They do not prove that the risk of a serious event is absent: the groups are small, and uncommon events may not occur in a study of this size even when an underlying risk exists.

Serious adverse events are distinct from the primary endpoint’s broader count of participants with one or more TEAEs. The posted outcome counts show that some groups had participants reporting TEAEs even though no serious adverse events were recorded. Thus, zero serious events does not mean zero adverse events of all kinds. The serious-event summary also does not provide, in the registry record, a complete narrative of every event or a causal assessment for each event.

General statistical explanation: an observed zero is a sample result, not an estimate of exactly zero risk. The uncertainty around rare events is especially substantial when the number of participants is limited. These data are useful for documenting what was observed in this phase 1 study, but they cannot exclude uncommon harms or characterize safety beyond the recorded follow-up and exposure.

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

The results establish what was recorded in this study: counts of participants with at least one TEAE in each listed group during baseline up to Day 7, together with a specific comparison between two pooled placebo groups. The comparison estimate is -0.091, its confidence interval runs from -0.261 to 0.079, and its unadjusted p-value is 0.267. The interval includes zero, so the posted comparison does not provide clear evidence of a difference between those placebo groups.

These findings do not estimate a TAK-925 treatment effect in a direct, common-cohort randomized comparison. The named contrast compares pooled placebo participants from Part 1 and Part 2. Although the registry reports event counts for multiple TAK-925 dose groups, the posted inferential comparison is not an overall comparison of every dose with placebo. The arm counts alone cannot establish that a dose caused an event or that differences between groups are caused by treatment.

The study’s endpoint is limited to short-term TEAE occurrence following a single dose. It does not characterize longer-term exposure, event duration, event recurrence, severity in detail, or risks that may be uncommon. The absence of recorded serious adverse events and deaths is a description of the observed sample, not proof that such events cannot occur. The small cohort sizes leave considerable uncertainty around group-specific event experience.

The registry record does not report a complete analysis plan, the original sample-size justification, details of missing-data handling, or whether multiplicity was controlled. Nor does the posted contrast resolve potential differences between study parts, including differences in populations and cohort procedures. These limits mean the evidence is best viewed as an early-phase safety description, not a definitive comparative assessment across doses or populations.

General statistical explanation: a nonsignificant result is not proof of equivalence, and an observed difference is not automatically important or causal. Interpretation requires attention to the target comparison, uncertainty, study design, and outcome definition. In this study, the event counts help characterize the recorded experience, while the comparison provides limited evidence about the difference between the two placebo groups specifically.

14. Why This Trial Matters Statistically

This trial illustrates why early-phase safety results are often best interpreted cohort by cohort. The study includes healthy adults, healthy elderly participants, and participants with narcolepsy, with multiple dose levels and a sequential design. A single pooled summary could obscure the fact that participants came from different populations and that later cohort doses were informed by earlier study findings. Keeping the group context visible is important for understanding what each count can and cannot represent.

It also illustrates the distinction between a reported outcome and a reported treatment comparison. The primary endpoint counts participants with one or more TEAEs. The registry provides counts across TAK-925 and placebo groups, but its named statistical contrast is between pooled placebo groups from different study parts. That contrast is not interchangeable with a direct treatment-versus-placebo comparison. Correctly identifying the groups being compared is essential before interpreting an estimate, interval, or p-value.

Small groups make uncertainty especially relevant. A count that appears high or low can be based on only a few participants, and zero observed serious events cannot establish that rare risks are absent. The confidence interval for the posted risk difference spans zero, emphasizing that the available observations do not precisely distinguish the pooled placebo groups.

Finally, the registry record demonstrates the limits of interpreting results when key statistical-plan details are not reported. The listed outcomes and analyses do not reveal how multiplicity, missing data, or the evolving sequential design were handled. For biostatisticians and clinical researchers, the lesson is to separate observed counts, the exact target contrast, statistical uncertainty, and unreported design choices rather than treating them as one conclusion.

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 principal limitation is that the only posted risk-difference comparison is between pooled placebo groups from different study parts. It is not a TAK-925-versus-placebo contrast, so it cannot answer a direct treatment-effect question. The group-specific TAK-925 event counts are descriptive in the material reported, and the registry does not provide a common adjusted comparison across all doses.

The study is small and divided among multiple cohorts. Individual group sizes are limited, which makes event proportions sensitive to the experience of individual participants and limits assessment of uncommon safety events. The total enrollment is 58, but the registry results are presented across numerous separate groups rather than as one homogeneous population.

The design also combines healthy adult participants, healthy elderly participants, and participants with narcolepsy. The cohort descriptions vary in dose selection and masking; one Part 1 cohort is described as non-blinded, and the Part 2 descriptions state that the sponsor was open. These features make cross-cohort comparisons difficult to interpret as though groups differed only by treatment.

The endpoint is confined to TEAEs from baseline up to Day 7 after a single administration. It does not provide a long-term safety assessment. The registry record does not report the original sample-size justification, detailed statistical analysis plan, missing-data procedures, multiplicity approach, or enough information to assess all aspects of randomization and masking. It also does not report event-by-event causal assessments in the safety summary. These limitations restrict both causal conclusions and generalization beyond the recorded study groups and follow-up.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Phase 1 TAK-925 Study in Healthy Adult and Elderly Volunteers and Participants With Narcolepsy — NCT03332784.
• Registry record last updated 2021-03-30; status last verified 2021-03.
• Results first posted 2020-11-18.
• 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

NCT03332784 is a completed phase 1, randomized, double-masked, sequential study sponsored by Takeda, with total enrollment of 58. It assessed single intravenous doses of TAK-925 in healthy adults, healthy elderly participants, and participants with narcolepsy. The primary safety endpoint was the number of participants reporting one or more TEAEs from baseline up to Day 7, in a safety analysis set defined by receipt of at least one dose.

The posted comparison is between the Part 2 Cohort 5-7 pooled placebo group and the Part 1 Cohort 1-2 pooled placebo group. The risk difference is -0.091, with a confidence interval from -0.261 to 0.079 and an unadjusted p-value of 0.267. Serious adverse events and deaths are recorded as zero in each listed group. The results describe small, cohort-specific groups and do not constitute a direct treatment-versus-placebo estimate across TAK-925 doses. Important details about the full statistical plan, missing data, multiplicity, and original sample-size justification are not reported in the registry record.