Investigation and Modulation of the Mu-Opioid Mechanisms in Migraine (in Vivo): Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Investigation and Modulation of the Mu-Opioid Mechanisms in Migraine (in Vivo) (NCT02964741), a randomized na study. The primary outcome is Days With Moderate-to-severe Headache.

2. Clinical Question

The registry identifies the study as randomized, triple masked, and parallel. It lists the study condition as migraine and records an enrollment of 44. The treatment descriptions and posted outcome groups give the context for interpreting the results: the comparison is between migraine patient groups assigned to active or sham stimulation, while the healthy control description concerns baseline assessments rather than treatment assignment. The posted primary endpoint addresses headache days during follow-up, not every aspect of migraine burden or the imaging measures listed among the secondary outcomes.

3. Trial Design

The registry describes a randomized, triple-masked, parallel-group study of high-definition transcranial direct current stimulation in episodic migraine. The active and sham arms are both described as device interventions. In the active arm, the stated regimen was 20-minute sessions once daily for 10 days, Monday through Friday for 2 weeks. The sham description specifies 30-second administrations at the beginning and end of each 20-minute session on the same stated schedule. The registry says randomization used the Taves method, but does not report further details about allocation concealment or how masking was maintained.

The registry lists enrollment as 44. Its brief summary describes an intended 30 patients receiving active treatment and 30 receiving sham, as well as up to 30 healthy volunteers asked to complete baseline assessments only. These descriptions are not the same as the numbers in the posted primary outcome groups: those results list 13 participants in the active group and 12 in the sham group. The healthy control group is described as receiving no brain stimulation. The record also says healthy volunteer data from a prior study may be used; the posted treatment outcome groups do not include a healthy control arm.

The study began on 2017-02-22, had a primary completion date of 2021-06-01, and is listed as terminated. The reason for termination is not reported in the registry record. The phase is listed as NA. The registry identifies the University of Michigan as sponsor. The information available does not explain the difference between the planned group sizes in the summary and the numbers contributing to the posted primary endpoint, or state whether the posted results include every randomized participant.

Several outcome descriptions refer to the end of treatment and 1 month of follow-up. The PET secondary measure gives a different timing description: the time between PET #1 and PET #2 is typically 21 days, with a stated minimum of 17 days and maximum of 42 days. This timing applies to that outcome description and should not be mistaken for the primary headache follow-up period. The record does not report enough detail to establish how all assessments were scheduled for every participant.

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.

Overall Study

Reasons for not completing this period:

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 Days With Moderate-to-severe Headache, measured over End of treatment - over 1 month follow-up.

The primary endpoint is the mean number of days with moderate-to-severe headache from the end of treatment over 1 month of follow-up. The registry defines moderate-to-severe headache as pain over 3 on a Numeric Rating Scale ranging from 0 to 10 during that period. The outcome therefore turns repeated symptom experience into a count of qualifying headache days for each participant, then summarizes that measure as a group mean.

A headache-day measure is used to describe symptom burden over a defined period, rather than relying on a single pain rating at one moment. The registry's definition gives a threshold for which days count toward this endpoint. In general, a group mean can make average burden easier to compare, while also concealing variation among individual participants: people can have different numbers of headache days even when their group mean is similar. The registry lists a 95% confidence interval for each arm, which conveys uncertainty around each group estimate.

The posted mean is 2.9 days for the active group, with a 95% confidence interval from 2.1 to 3.9. For the sham group, the mean is 3.3 days, with a 95% confidence interval from 2.4 to 4.4. The registry does not report an estimable two-arm comparison for this continuous endpoint. Consequently, these arm estimates alone do not provide a registry-reported estimate and confidence interval for the between-group difference.

The endpoint is specific to moderate-to-severe headache days during the stated follow-up window. It does not, by itself, describe all headache symptoms, rescue medication use, imaging changes, or adverse events. Those are distinct outcomes and should be interpreted on their own terms.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

Statistical methods help distinguish what is directly reported from what readers might infer from arm summaries. For this trial, that distinction is especially important because the registry provides primary arm means and confidence intervals but does not report an estimable two-arm comparison for the continuous primary endpoint. The following concepts explain how to read those summaries without treating them as an unreported analysis.

What does a confidence interval describe?

A confidence interval expresses uncertainty in an estimated quantity under the assumptions of the method used to calculate it. For a group mean, the interval describes uncertainty about that mean, not the spread of individual participant outcomes. A wider interval generally indicates less precision in the estimate; a narrower interval generally indicates greater precision. The intervals posted for the primary outcome are attached to the active and sham means separately. They are not a confidence interval for the difference between the arms.

For the primary endpoint, the active group mean is 2.9 days, with an interval from 2.1 to 3.9, and the sham group mean is 3.3 days, with an interval from 2.4 to 4.4. The registry labels the dispersion as a 95% confidence interval. It does not specify in the available record the exact calculation method used for those primary intervals. Readers should therefore retain the stated interpretation and avoid assuming an unreported model or test.

Why is a direct contrast important?

The trial question concerns the difference between active and sham groups. A direct contrast estimates that difference and quantifies its uncertainty. Separate confidence intervals for each group's mean do not supply the contrast interval. Nor does comparing whether the separate intervals overlap constitute a formal test of the contrast. In general, the contrast's uncertainty depends on the variability and sample sizes in both groups, as well as on the analysis method. Since the registry does not report an estimable primary contrast, readers should not treat a newly calculated difference between the posted means as a sponsor analysis.

The record includes a note that values were missing or not estimable for a two-arm comparison of the continuous endpoint. It does not give a reason for that limitation. Missingness in the reported contrast should not be interpreted as evidence of no difference, and it does not tell readers why an analysis was not estimable. The reasons are not reported in the registry record.

How do the secondary comparisons differ?

The posted binary secondary endpoints include arm percentages and recalculated, unadjusted contrasts. Such a recalculation is a simple comparison from the posted summary counts, not a replacement for a sponsor's prespecified analysis. The record lists no reported analyses for these outcomes. The unadjusted p-values and confidence intervals should consequently be read as exploratory summaries rather than as a full account of the trial's analysis plan.

One secondary outcome is continuous and concerns change in mu-opioid receptor non-displaceable binding potential during a sustained thermal pain threshold stress challenge. Its posted comparison is a recalculated mean difference, with an unadjusted p-value reported as <0.001. The registry gives standard deviations for the group summaries and describes the measurement timing between PET assessments. This is an imaging-related outcome and is not the same measure as headache days. A result on that scale cannot be read as a direct estimate of a change in headache burden.

In general, continuous outcomes summarize measurements on a numerical scale using quantities such as means and standard deviations. Binary outcomes summarize whether an event or condition was recorded, often as a proportion. The interpretation of a difference depends on the outcome's scale and definition. A percentage-point contrast, a mean difference in binding potential, and a mean difference in headache days have different meanings and should not be treated as interchangeable evidence.

What do the planning illustrations mean?

The sample-size illustrations are explicitly described as planning calculations based on observed effects, not as the trial's own design. The stated assumptions include a two-sided significance level of 0.05, equal allocation between the two arms, and a normal approximation. The illustrations consider planning for 100%, 75%, or 50% of the observed effect and give participants per arm for 80% or 90% power. In general, such calculations describe sample sizes under stated assumptions for a future design. They are not observed power, and they do not show that the current study was designed with those assumptions. The registry's own sample-size justification is not reported.

Planning values derived from an observed effect can be sensitive to uncertainty in that observed effect. A small study may produce an unstable estimate, so an illustration based on that estimate can be optimistic or otherwise unrepresentative of a future study. The illustrations are most useful as conditional scenarios, not as a definitive sample-size recommendation. They should not be used to infer the probability that the current trial detected an effect.

Why can multiplicity change interpretation?

When a study examines several outcomes, repeated testing can increase the chance of at least one apparently notable result by chance. A prespecified strategy might prioritize outcomes or adjust inference for multiple comparisons. The registry record does not report a multiplicity plan or a hierarchy among the secondary endpoints. The posted unadjusted results therefore do not account for the possibility of testing several outcomes, and their evidence should be interpreted cautiously.

More broadly, the record does not report the analysis population definition, handling of missing outcome data, or an interim-analysis plan. Those omissions limit what can be established about the methods behind the posted results. General statistical concepts can clarify the summaries, but they cannot fill in unreported trial procedures.

10. Multiplicity, Missing Data and Analysis Populations

The registry record lists several secondary outcomes, including headache intensity, moderate-to-severe headache, rescue medication use, and imaging measures of mu-opioid receptor binding potential. It reports no analyses in its analysis listing. A plan for controlling multiplicity, prioritizing the secondary outcomes, or distinguishing confirmatory from exploratory analyses is not reported in the registry record.

Multiplicity matters because examining several outcomes can increase the chance that at least one result appears notable even when there is no underlying effect. In general, a study can address this through a prespecified hierarchy, adjustment, or another stated strategy. The record does not identify such a strategy. The recalculated secondary comparisons are unadjusted, so their p-values should not be treated as controlling the overall chance of false-positive findings across the outcomes. This does not invalidate the descriptive estimates, but it limits the strength of confirmatory claims that can be drawn from them.

Missing-data handling is also not reported. The available record does not state how participants with incomplete follow-up or missing measurements were treated, whether any imputation was used, or how the analysis population was defined. It is therefore not possible to establish from the registry whether the posted outcome groups represent all randomized participants, participants with available measurements, or another analysis set. The primary outcome group sizes differ from the intended numbers described in the brief summary, but the record does not explain that difference.

The registry does not report an interim-analysis plan, a stopping rule, or a sample-size justification. The status is terminated, but the reason for termination is not reported in the registry record. These omissions should not be filled by assumption: the record does not show whether termination followed a planned decision, operational circumstances, or another reason.

These gaps affect interpretation rather than changing the values that are posted. Readers can describe the reported estimates and their stated uncertainty, while recognizing that the analysis population, missing-data methods, multiplicity approach, and trial-level sample-size rationale remain unspecified. The planning illustrations are explicitly separate from the trial's own design justification.

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 lists no serious adverse events in either treatment group and no deaths in either group. The serious-event figures are reported alongside groups described as having 13 participants at risk in the active group and 12 in the sham group. These are the recorded figures for the posted safety groups. The registry's list of top serious adverse event terms is empty.

The record also lists other adverse events affecting 12 participants in the active group and 12 in the sham group, with the corresponding groups at risk listed as 13 and 12. These figures describe the registry entries; they do not, by themselves, establish the nature, duration, severity, or cause of the other events. The record does not provide event terms in the serious-event list, and the posted summary does not give enough detail to characterize individual events.

Zero recorded serious events does not prove that a treatment has no serious risks. Safety interpretation depends on the amount and duration of observation, event definitions, completeness of reporting, and the size of the groups. The registry record does not report enough detail to assess those elements fully. The observed figures should be read as counts recorded for these groups, not as a guarantee about safety or as a basis for medical advice.

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

The posted results describe outcomes among the participants represented in the registry's active and sham groups. For the primary endpoint, the active group mean was 2.9 days with a 95% confidence interval from 2.1 to 3.9, and the sham group mean was 3.3 days with a 95% confidence interval from 2.4 to 4.4. Those summaries show the estimated group means and their uncertainty. The registry does not report an estimable comparison between the groups for this continuous endpoint.

That distinction sets a boundary on what the primary result means. The arm estimates do not establish the treatment-versus-sham difference with an associated confidence interval or test. Nor does the absence of an estimable comparison mean the groups are identical. The record leaves the primary contrast unresolved. Any interpretation should therefore remain descriptive rather than claiming that active stimulation did or did not change headache days relative to sham.

The trial also includes secondary symptom, medication-use, and imaging measures. These outcomes may describe different aspects of participants' experiences or biological measurements, but they do not convert the primary result into a reported treatment effect. The secondary comparisons are unadjusted and are not listed as reported analyses in the registry. Their role is consequently limited, especially in the absence of a reported multiplicity plan and analysis population definition.

More generally, a trial result depends not only on the direction of an estimate but also on its precision, the analysis used, and how participants and outcomes were handled. The confidence intervals communicate some uncertainty in the group means, but the registry's missing direct comparison, unexplained difference between intended and posted group sizes, and unreported missing-data procedures constrain interpretation. The study's terminated status does not supply an explanation for these limitations.

The findings do not establish that the intervention works or does not work. They do not determine what an individual should do, and they should not be used as medical advice. They provide a limited statistical record: arm-specific primary estimates with confidence intervals, several secondary summaries, and safety counts. A stronger conclusion about comparative effects would require a reported analysis that addresses the primary contrast and makes its methods and uncertainty clear.

13. Why This Trial Matters Statistically

This trial is statistically informative because it illustrates the difference between reporting arm summaries and reporting the comparison that answers a randomized trial's central question. The primary endpoint is available as a mean and confidence interval for each group, but the registry does not report an estimable two-arm comparison. Readers can see the scale of the group estimates while also recognizing that the treatment contrast remains unquantified in the record.

It also shows why a confidence interval must be interpreted in relation to the quantity it accompanies. An interval around a group mean is not an interval around the difference between groups. A direct contrast is needed to quantify uncertainty in that difference. This distinction matters even when the arm means appear close, because descriptive similarity does not substitute for a formal analysis.

The record provides another useful statistical lesson about multiple outcomes. Headache symptoms, rescue medication, and imaging measures address related but distinct questions. When several outcomes are considered without a reported multiplicity plan, apparently notable secondary findings should be treated cautiously. Their different scales also prevent a simple synthesis into a single treatment conclusion.

Finally, the difference between the intended group sizes described in the summary and the posted primary outcome groups underscores the importance of transparent reporting about analysis populations and missing data. The record does not explain that difference or state how missing outcomes were handled. This uncertainty does not erase the posted estimates, but it limits the reader's ability to judge how they relate to the randomized study population.

These points make the study useful for statistical interpretation precisely because the record invites careful distinctions: estimates versus contrasts, primary versus secondary outcomes, descriptive versus inferential findings, and a planning illustration versus the study's design justification. Those distinctions help prevent conclusions that go beyond the available evidence.

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.

Several limitations specific to this record constrain interpretation. First, the posted primary outcome includes arm means and confidence intervals, but no estimable two-arm comparison. The primary question is comparative, so the absence of a reported contrast leaves its size and precision unavailable in the registry record. The arm confidence intervals cannot fill that gap.

Second, the outcome group sizes are smaller than the intended group sizes described in the brief summary. The registry does not explain why the posted primary outcome groups contain 13 participants in the active arm and 12 in the sham arm, while the summary describes 30 in each treatment group. It is not reported whether the difference reflects recruitment, follow-up, missing measurements, analysis eligibility, or another reason. The record also does not define the analysis population or describe missing-data handling.

Third, multiple secondary outcomes are listed, but no analyses are reported in the analysis listing, no multiplicity strategy is reported, and the available secondary comparisons are unadjusted recalculations. These findings may be useful descriptively, but they have limited confirmatory weight. The imaging endpoint also measures a different construct from headache days, so it cannot be assumed to validate the primary outcome.

Fourth, the registry lists the study as terminated without reporting why. It does not report a sample-size justification, interim-analysis plan, or stopping rule. The planning illustrations are based on observed effects and stated assumptions, not on the trial's own design. These omissions make it difficult to assess how the study's conduct and analysis relate to its original plans.

Finally, the safety summaries are brief. The serious-event and death counts are reported, but the registry does not provide serious event terms in its listed terms or enough information to assess observation duration and completeness. The other adverse-event figures do not characterize the events. These limits warrant a cautious reading of safety as well as efficacy-related outcomes.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: Investigation and Modulation of the Mu-Opioid Mechanisms in Migraine (in Vivo) — NCT02964741.
• Registry record last updated 2022-08-26; status last verified 2022-07.
• Results first posted 2022-07-12.
• 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 a randomized, triple-masked, parallel-group study of active versus sham high-definition transcranial direct current stimulation in episodic migraine. Enrollment is listed as 44, and the study is marked terminated. The reason for termination is not reported in the registry record.

The primary endpoint is mean days with moderate-to-severe headache from the end of treatment over 1 month of follow-up. The posted active and sham group means are 2.9 and 3.3 days, respectively, with 95% confidence intervals of 2.1 to 3.9 and 2.4 to 4.4. An estimable two-arm comparison for this continuous endpoint is not reported.

Secondary outcomes include headache symptoms, rescue medication use, and PET binding-potential measures. The registry lists no reported analyses, and it does not report a multiplicity plan, missing-data approach, analysis population, or sample-size justification. Secondary recalculations are unadjusted. The record therefore offers descriptive group results and safety counts, but leaves important aspects of comparative inference and analysis methods unspecified.