A Study Evaluating Oral Atogepant for the Prevention of Migraine in Japanese Participants With Chronic or Episodic Migraine: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for A Study Evaluating Oral Atogepant for the Prevention of Migraine in Japanese Participants With Chronic or Episodic Migraine (NCT04437433), a non-randomized phase 3 study. The primary outcome is Percentage of Participants With at Least 1 Treatment-Emergent Adverse Event and Treatment-Emergent Serious Adverse Event (TEAEs/TESAEs).

2. Clinical Question

The central question is about longer-term safety and tolerability during atogepant use, rather than a randomized comparison of treatment effects. A treatment-emergent adverse event is an untoward medical occurrence that began or worsened on or after the first dose; the definition does not require the event to have been caused by the study drug. Serious adverse events are identified using specified consequences, including death, a life-threatening event, hospitalization, persistent or significant disability, or an important medical event requiring intervention or medical judgment.

The registry record describes two cohorts: participants with chronic migraine who completed a lead-in study and newly recruited participants with episodic migraine. Since allocation was not randomized and the cohorts were assembled differently, their outcomes should not be treated as a controlled comparison. The record reports the number of participants with events in each group and in total. It does not report a comparative efficacy result or a causal estimate of atogepant's effect on migraine outcomes.

3. Trial Design

This was a phase 3, multicenter, open-label, nonrandomized, parallel-group extension study. The study evaluated oral atogepant 60 mg once daily over 52 weeks in Japanese participants with chronic or episodic migraine. Enrollment was 186, and the registry status is completed. The recorded start date is 2020-06-18, and the primary completion date is 2024-06-11.

The chronic migraine cohort consisted of participants who completed lead-in Study 3101-303-002 (NCT03855137). The episodic migraine cohort consisted of newly recruited participants who met the study entry criteria. Both cohorts received the same listed atogepant dose and schedule. However, shared treatment does not make the cohorts randomized arms: participants were not allocated by random assignment, and the groups differed in how they entered the study.

There was no masking, so participants and investigators knew the treatment being given. That matters particularly for outcomes involving symptom reporting or investigator assessment. The registry describes assessment of laboratory values, electrocardiograms, vital signs, and suicidal ideation and behavior as secondary safety outcomes, alongside the primary adverse-event outcome.

The primary safety timeframe ran from the first dose through 4 weeks after the last dose, up to 56 weeks. This is broader than the 52-week treatment period because it includes follow-up after treatment ends. The registry record does not report a control arm, randomization procedure, masking procedure, sample-size justification, interim-analysis plan, or detailed statistical analysis plan. These features should not be inferred from the phase label or the study's stated objectives.

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: The study consisted of a 52-week open-label treatment period and a 4-week safety follow-up period for all participants.

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: Safety population: all participants who received at least 1 dose of study intervention (atogepant) in this extension study

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: Safety population: all participants who received at least 1 dose of study intervention (atogepant) in this extension study

6. Primary Endpoint

The registry lists the primary outcome as Percentage of Participants With at Least 1 Treatment-Emergent Adverse Event and Treatment-Emergent Serious Adverse Event (TEAEs/TESAEs), measured over From first dose of study drug until 4 weeks following the last dose of study drug (up to 56 weeks).

The primary endpoint is the percentage of participants with at least one treatment-emergent adverse event or treatment-emergent serious adverse event. The registry defines a treatment-emergent event as one that began or worsened in severity on or after the first dose. An adverse event is an untoward medical occurrence; it need not have a causal relationship to atogepant. The investigator assesses the relationship to study drug separately.

A serious adverse event is classified by its seriousness, such as being life-threatening, resulting in death or hospitalization, or meeting other specified medical criteria. Seriousness is distinct from whether an event is judged related to treatment. The primary endpoint therefore describes the occurrence of events during the defined observation period; it does not by itself establish their cause.

This type of endpoint is used in safety monitoring because it captures whether participants experienced events during exposure and follow-up. Counting participants with at least one event focuses on the proportion affected, rather than the total number of event episodes. The registry record defines the safety population as participants who received at least one dose of study intervention. The posted results report participant counts for serious events and other events. They do not report an efficacy endpoint or an estimate comparing atogepant with a control treatment.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The posted primary results are participant-level event counts from an open-label, nonrandomized extension. Their interpretation depends on the endpoint definition, the population included, the follow-up window, and the study's lack of a randomized control group. The registry record does not report inferential analyses for these outcomes.

What does a participant-level event measure?

For a binary safety outcome, each participant is classified according to whether the event occurred at least once during the specified period. The result is commonly expressed as a percentage of participants, with the number of participants who experienced the event as the numerator and the relevant population at risk as the denominator. The posted results give counts and denominators for serious events and other events. No new percentages are needed to read those counts, and the registry does not provide confidence intervals for them.

This participant-level measure differs from counting every event episode. A participant with repeated events can still contribute only once to a measure of whether at least one event occurred. The endpoint therefore describes how many participants were affected, not the total burden, duration, recurrence, or severity of every event. Separate summaries would be needed to describe those features.

How should serious events be distinguished from treatment-related events?

Seriousness is determined by the event's consequences or medical significance under the registry definition. Causality is a separate judgment about whether the event is related to study drug. An event can meet the definition of serious without being judged drug-related, and a non-serious event can still be judged related. The primary endpoint's treatment-emergent timing rule concerns when an event began or worsened; it does not, by itself, establish causation.

General statistical context: reporting the number of participants with at least one event is useful for a broad safety description, while event-level summaries can show repeated occurrences and detail. Neither form alone can determine causality. That determination requires appropriate comparisons and clinical assessment, neither of which is replaced by a simple count.

Why does study design affect interpretation?

Random allocation is used in controlled trials to make treatment groups comparable on average with respect to both measured and unmeasured characteristics. This study was nonrandomized and open-label, and its chronic and episodic migraine groups were recruited differently. General statistical context: when groups differ at baseline or in how participants enter a study, observed outcome differences can reflect those differences as well as treatment exposure. Therefore, comparing the two cohorts as if one were a control group would not provide a reliable treatment contrast.

Open-label conduct also means that treatment identity was known. General statistical context: awareness can influence reporting, follow-up, or investigator assessment, especially for outcomes that involve judgment. The extent of any such influence in this study is not reported in the registry record.

What does a confidence interval ordinarily add?

General statistical context: a confidence interval communicates the statistical uncertainty around an estimate, showing a range of values compatible with the data under the method's assumptions. Its width depends in part on the amount of information available and the variability of the outcome. A point estimate alone does not communicate that uncertainty. No confidence intervals are reported for the posted adverse-event counts, so their precision cannot be evaluated using that measure.

General statistical context: over-dispersion matters for count outcomes when observed variability exceeds what a simple count model expects, because a model that understates variability can produce overly narrow uncertainty estimates. The primary outcome is described as the percentage of participants with at least one event, not as a modeled event count, and the registry record does not report an over-dispersion assessment or a model for these results.

What analysis details are available?

The registry identifies the safety population as all participants who received at least one dose of atogepant in the extension. The primary timeframe begins at first dose and continues through 4 weeks after the last dose, up to 56 weeks. The listed measure is a percentage of participants, while the posted results include counts in the chronic migraine, episodic migraine, and total groups.

The registry record does not report a statistical model, confidence intervals, hypothesis tests, covariate adjustments, a missing-data method, or a planned analysis population for the secondary outcomes. It also does not report a sample-size justification or interim analyses. Without those details, the counts should be read as descriptive results, not as evidence from a prespecified comparative statistical test.

10. Multiplicity, Missing Data and Analysis Populations

The registry lists one primary safety outcome and secondary outcomes covering potentially clinically significant laboratory values, electrocardiogram findings, vital sign measurements, and Columbia-Suicide Severity Rating Scale assessments during the open-label treatment period and the safety follow-up period. Multiple outcomes create a general statistical issue: when many hypotheses are tested, the chance of at least one apparently notable result can increase. Methods such as prespecifying a hierarchy or adjusting inference can address that issue, but the registry record does not report a multiplicity strategy or a set of inferential tests for these outcomes.

The registry record does not report how missing outcome data were handled, how participants who discontinued treatment were followed, or whether analyses used any imputation or sensitivity methods. These details matter because the interpretation of a percentage depends on which participants contributed data and how unavailable assessments were treated. The primary endpoint's safety population is defined as participants who received at least one dose, but further outcome-specific analysis-population details are not reported in the registry record.

The record describes a safety follow-up window after the last dose, but it does not state how incomplete follow-up affected the reported counts. It also does not report a sample-size justification, interim analyses, or a statistical analysis plan. In the absence of these details and of reported inferential analyses, the posted results are best understood as descriptive event counts within the stated safety population and follow-up period, rather than as tests of a treatment hypothesis.

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: vertigo (0.6%), cholelithiasis (0.6%), appendicitis (0.6%), alanine aminotransferase increased (0.6%), aspartate aminotransferase increased (0.6%).

The registry reports serious adverse events for 7 of 155 participants with chronic migraine and 0 of 31 participants with episodic migraine; the total is 7 of 186. Other adverse events are reported for 108 of 155, 24 of 31, and 132 of 186 participants, respectively. No deaths were reported. These are counts of participants, not counts of every event episode.

The terms listed as serious events—vertigo, cholelithiasis, appendicitis, alanine aminotransferase increased, aspartate aminotransferase increased, and uterine leiomyoma—are each reported at 0.6%. These listings should be read as recorded serious-event terms, not as proof that the study drug caused them.

Seriousness and causality are separate concepts. The registry defines adverse events without requiring a causal link to treatment, and the investigator assesses that relationship separately. The record does not provide a controlled safety comparison, confidence intervals, or a treatment-related analysis alongside these counts. The observed zero serious events in the episodic migraine group does not establish zero underlying risk; it describes the events recorded among that group during the reported observation period.

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

The registry results describe adverse events recorded during an open-label extension in which Japanese participants with chronic or episodic migraine received atogepant 60 mg once daily. The safety population comprised participants who received at least one dose. The primary outcome covered events beginning or worsening after the first dose through 4 weeks after the last dose, up to 56 weeks.

The posted counts show that serious and other adverse events were recorded, and no deaths were reported. They offer a descriptive account of what occurred in the study population. They do not establish that atogepant caused the events, because the adverse-event definition does not require causation and the investigator's relationship assessment is distinct from event reporting.

The design does not support a controlled comparison of treatment safety: there was no randomized control group, and the chronic and episodic migraine cohorts were recruited differently. Differences in their event counts cannot be attributed to treatment effects or used as a like-for-like comparison. The results also do not establish how these counts compare with another therapy, placebo, or no treatment.

The registry record does not report comparative efficacy results, confidence intervals, hypothesis tests, missing-data methods, or a multiplicity approach. It therefore does not establish the statistical precision of the observed event counts or support conclusions about migraine prevention efficacy. General statistical context: a descriptive result can summarize observed experience while leaving uncertainty about its precision and about how it would compare under a different study design.

The findings are specific to this extension's participants, recruitment pathways, treatment schedule, and follow-up period. They should be interpreted as a record of observed safety events in that setting, rather than as a definitive causal estimate or a basis for generalizing to populations or settings not described in the registry.

13. Why This Trial Matters Statistically

This trial is statistically informative as a long-term, open-label safety description in Japanese participants with chronic or episodic migraine. Its 52-week treatment period and follow-up of up to 56 weeks define the context in which the registry recorded adverse events. The study also reports distinct chronic and episodic migraine cohorts, making clear that results come from two groups with different entry routes.

For biostatistical interpretation, the key issue is not only the number of events but the design behind those numbers. A nonrandomized extension without a control arm can describe event occurrence among treated participants, but it cannot isolate the treatment's contribution to that occurrence. Differences between cohorts do not supply the missing control because their recruitment pathways differed and allocation was not randomized.

The registry's distinction between treatment-emergent timing, seriousness, and investigator-assessed relationship is also important. These classifications answer different questions: when an event occurred, whether it met seriousness criteria, and whether it was judged related to study drug. Keeping those concepts separate prevents descriptive safety counts from being mistaken for causal findings.

The record also illustrates the limits of registry result interpretation when inferential details are absent. No confidence intervals, tests, missing-data methods, or multiplicity strategy are reported. Readers can identify the event counts and denominators, but cannot use the record to assess statistical precision or a prespecified treatment comparison. This makes the design and reporting context essential to interpreting the observed safety experience.

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 is the absence of a randomized control group. Since every reported cohort received atogepant and the study was nonrandomized, the posted event counts cannot distinguish events associated with treatment from events that might have occurred otherwise. The chronic and episodic migraine cohorts were not recruited in the same way, so their counts should not be treated as comparative treatment results.

The study was open-label, and the registry does not report masking. General statistical context: knowledge of treatment can affect the reporting or assessment of some outcomes. The registry record does not quantify whether or how this may have influenced event ascertainment. The broad adverse-event definition also includes events that are not necessarily related to the study drug.

The registry record does not report confidence intervals or other inferential analyses for the posted event counts, limiting assessment of their precision. It also does not report missing-data handling, outcome-specific analysis populations beyond the stated safety population, a multiplicity strategy, sample-size justification, or interim analyses. These omissions prevent a fuller assessment of the analysis plan and the impact of incomplete follow-up.

The reported experience concerns Japanese participants meeting the study's entry criteria and receiving the stated dose and schedule in an extension setting. The registry record does not provide enough detail to determine how representative the participants were of other populations or care settings. It also does not report comparative efficacy outcomes in the posted results. These limitations constrain interpretation to a descriptive safety account in the study population and observation period.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: A Study Evaluating Oral Atogepant for the Prevention of Migraine in Japanese Participants With Chronic or Episodic Migraine — NCT04437433.
• Registry record last updated 2025-07-22; status last verified 2025-07.
• Results first posted 2025-07-22.
• 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

NCT04437433 is a completed phase 3, multicenter, open-label, nonrandomized, parallel extension study of oral atogepant 60 mg once daily for 52 weeks in Japanese participants with chronic or episodic migraine. Enrollment was 186. The chronic migraine cohort had completed a lead-in study; the episodic migraine cohort was newly recruited. The primary safety outcome was the percentage of participants with at least one treatment-emergent adverse event or serious adverse event, assessed from first dose through 4 weeks after the last dose, up to 56 weeks.

The registry reports 7 of 155 participants with chronic migraine and 0 of 31 with episodic migraine experiencing a serious adverse event; the total was 7 of 186. Other adverse events were reported for 108 of 155, 24 of 31, and 132 of 186 participants, respectively. No deaths were reported. These are descriptive results, not a randomized comparison or proof of causation. Comparative efficacy results and detailed inferential analysis methods are not reported in the registry record.