CGRP, Estrogen, Cortisol, VIP, α-Amylase, PGE2, PGI2 and ß-Endorphin Levels in Menstrual Migraine Before and After Treximet: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for CGRP, Estrogen, Cortisol, VIP, α-Amylase, PGE2, PGI2 and ß-Endorphin Levels in Menstrual Migraine Before and After Treximet (NCT01329562), a randomized phase 4 study. The primary outcome is Migraine Recurrence.

2. Clinical Question

The trial’s broader aims included assessing pain-free efficacy and changes in saliva biomarkers before and after treatment. The listed biomarkers include CGRP, estrogen, cortisol, VIP, α-amylase, PGE2, PGI2 and ß-Endorphin. The registry also describes an aim to compare salivary estrogen with urinary estradiol at specified stages around a menstrual migraine episode and treatment. Those aims provide context, but the primary endpoint is recurrence rather than a biomarker measurement.

The trial asks a focused short-term question about whether pain returns or worsens within 24 hours among participants initially pain free or with mild pain at 2 hours. The posted primary results do not show an outcome for every enrolled participant: they report results for 11 placebo participants and 14 Treximet participants. The record does not explain the difference between those denominators and the enrollment total.

3. Trial Design

The registry describes a randomized, double-masked, parallel-group phase 4 trial. Participants were assigned to Treximet or placebo for treatment at the onset of a menstrual migraine headache. The registry lists 41 participants enrolled and records the study as completed. The recorded start was 2011-05 and primary completion was 2012-06.

The Treximet arm description specifies one tablet at headache-pain onset. It also states that all participants would receive one tablet of Treximet for persistent or recurring headache between 2 and 24 hours following study medication. The placebo arm description specifies a placebo tablet at headache-pain onset and includes the same statement about a Treximet tablet for persistent or recurring headache. More detailed instructions, including the exact circumstances governing additional treatment, are not reported in the registry record.

Randomization indicates that treatment allocation was assigned by chance, while double masking indicates that the trial was described as masked for two groups of people. The identities of those groups and the procedures used to maintain masking are not reported in the registry record. The record identifies a parallel design, in which the listed arms are distinct treatment groups; it does not describe a crossover comparison.

The primary endpoint uses results from 11 participants in the placebo arm and 14 in the Treximet arm. The safety results use 20 and 21 participants, respectively. The record does not explain why these outcome-specific denominators differ, or whether the difference reflects eligibility, missing measurements, exclusions, or another reason. The analysis populations and handling of missing observations are not reported in the registry record.

The registry lists 18 outcome measures, including the primary recurrence outcome and secondary outcomes concerning recurrence responders, time to pain free, and biomarker measurements at several stages. Nine secondary outcomes are listed as posted, but numerical results for them are not included in the available trial details. The protocol, allocation ratio, sample-size justification, interim analyses and detailed statistical plan 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: Subjects were enrolled and randomized at Visit 1. There were no significant events between enrollment and assignment.

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 Migraine Recurrence, measured over From onset of a single menstrual migraine episode to 24 hours post menstrual migraine treatment..

The primary endpoint is migraine recurrence, expressed as a number of participants. It counts participants who were pain free or had mild pain at 2 hours and whose pain level increased within 24 hours after treatment for one menstrual migraine. Pain was described on a scale from 0 to 3, with 0 meaning no pain, 1 mild, 2 moderate and 3 severe. The endpoint therefore concerns a change in pain status after an initial response, rather than pain at a single time alone.

This type of endpoint is useful for describing how often an initially improved headache worsens during a defined follow-up period. A participant count is directly interpretable as the number of people meeting the recurrence definition. Comparing the counts between randomized arms can describe whether recurrence was more or less frequent in the groups under the study conditions.

The registry reports 0 participants with recurrence among 11 in the placebo arm and 2 among 14 in the Treximet arm. The posted definition conditions recurrence on being pain free or mildly affected at 2 hours. The record does not separately provide the number of participants who met that initial-response condition in each arm, nor does it explain how participants who did not meet it were handled in the primary analysis. Therefore, the endpoint counts should be read according to the posted definition and outcome denominators rather than as a complete account of every participant’s pain course.

The endpoint is distinct from the trial’s other aims concerning pain-free efficacy and biomarker levels. Those outcomes may address different aspects of response, but their detailed numerical results are not reported in the registry record.

7. Results Posted in the Registry

• Treximet: 14.3% (2/14) versus 0.0% (0/11) on control; risk difference 14.3 percentage points (95% CI -4.0 to 32.6); unadjusted two-proportion z-test p = 0.191.

8. Statistical Interpretation

9. Statistical Methods Explained

General: what a randomized comparison describes. Random assignment is intended to make treatment groups comparable, on average, with respect to factors that could influence outcomes. It supports a comparison between the assigned groups, but it does not guarantee that the groups will be identical, particularly when the numbers contributing to an outcome are limited. The registry identifies randomization, double masking and a parallel design. It does not report the randomization method, allocation concealment procedures, or which people were masked.

The outcome as a binary event. The primary measure is a count of participants who meet a defined recurrence condition. For a binary outcome, each participant is classified as either having or not having the event for the analysis. The registry reports 0 events among 11 participants in the placebo arm and 2 among 14 in the Treximet arm. The risk difference expresses the contrast in event risks between arms on an absolute scale. The posted estimate is 0.143 for Treximet relative to placebo. An absolute difference is not the same as a relative comparison; it describes the separation between the two event risks rather than their ratio.

General: confidence intervals. A confidence interval gives a range of values compatible with the observed data under the method used to calculate it. It conveys uncertainty around an estimate and is not a range containing every participant’s outcome. The posted 95% confidence interval for the risk difference runs from -0.040 to 0.326. Because it includes zero, the interval includes no between-arm difference as well as differences in either direction. The width also signals that the estimate is imprecise. Confidence intervals are affected by the amount of information in the data and by the analysis method.

General: p-values. A p-value describes how unusual data at least as incompatible with a specified null hypothesis would be if that null hypothesis and the test’s assumptions were true. It is not the probability that the null hypothesis is true, and it does not communicate the magnitude of an effect. The registry reports a p-value of 0.191. The record does not identify the specific test or state whether the analysis accounted for any design or baseline variables. The result should therefore be read as the posted test statistic rather than as a complete account of the analysis procedure.

Why sparse events matter. With few events, estimates of event risk and the difference between groups can be unstable. A small change in the event count could have a noticeable influence on a comparison. This is a general property of sparse binary data, not evidence of a particular unreported event. Here, the primary outcome includes two events in one arm and none in the other, so the numerical estimate is based on a limited number of observed recurrences. The confidence interval makes the uncertainty explicit. It is more informative to consider the event counts, effect estimate and interval together than to focus on the p-value alone.

General: over-dispersion. Over-dispersion is a concern when observed variability exceeds what a statistical model expects. It can make standard errors too small and confidence intervals too narrow if the model does not account for that extra variation. It is more often relevant to outcomes such as counts or clustered observations than to a simple participant-level binary outcome. The primary endpoint is reported as participant counts, but the registry does not give enough detail about the analysis model to assess whether any adjustment or alternative variance method was used. No over-dispersion assessment is reported in the registry record.

What the record does not establish. The registry lists 18 outcome measures and nine secondary outcomes, but numerical results for those secondary measures are not reported in the registry record. The statistical analysis plan, model specification, analysis population, treatment of missing data, and any adjustment for multiple comparisons are also not reported in the registry record. The trial’s sample-size justification and any interim analyses are not reported in the registry record. Without those details, the posted primary contrast can be described, but its relationship to a prespecified analysis plan cannot be evaluated.

The sample-size assumptions described for planning illustrations are not the same as the trial’s own design justification or an observed-power analysis. Such illustrations use a stated effect and assumptions to show what a future study might require. They do not change the uncertainty in the trial’s observed result, and they do not determine whether the observed comparison is conclusive. Any sample-size figures should be understood as planning illustrations rather than as evidence about the probability that this trial detected an effect.

In summary, the posted primary analysis is a comparison of binary recurrence outcomes expressed as a risk difference, accompanied by a confidence interval and p-value. The counts give the observed event pattern; the risk difference gives its absolute comparative scale; and the interval communicates uncertainty. Important procedural details needed for a fuller appraisal are not reported in the registry record.

10. Confidence Intervals and Precision

The primary risk-difference estimate is 0.143, and its 95% confidence interval extends from -0.040 to 0.326. The interval includes zero, so the posted data do not rule out no difference between the arms under the interval method used. It also includes estimates on either side of zero, so the direction of the underlying difference remains uncertain. The interval is broad, indicating limited precision rather than a narrowly determined effect.

Precision depends in part on how much information contributes to the estimate. The primary comparison includes 11 placebo participants and 14 Treximet participants, with 0 and 2 recurrence events, respectively. These small event counts provide limited information about the underlying event risks. The estimate should not be treated as a stable prediction of the recurrence pattern that would necessarily occur in another group of participants.

A confidence interval is not a guarantee that the true value lies within its endpoints, and it does not show the range of individual responses. It is a statistical range generated by a method and its assumptions. The registry does not report the confidence-interval method, so its particular assumptions cannot be assessed from the record.

The interval should be read alongside the event counts and the p-value of 0.191. A p-value alone does not show the size or precision of a difference; the estimate and interval provide that context. The observed direction is not enough to resolve the uncertainty, and the interval should not be interpreted as evidence that the treatments are equivalent. The registry record does not report an equivalence or non-inferiority design or margin.

Finally, the primary outcome denominators differ from enrollment and from the safety denominators. Because the record does not explain those differences, the precision figures apply to the reported primary comparison and should not be assumed to summarize all enrolled participants.

11. Multiplicity, Missing Data and Analysis Populations

The registry lists 18 outcome measures, including a primary endpoint and secondary outcomes related to migraine recurrence, time to pain free and biomarker levels at multiple time points. Nine secondary outcomes are listed as posted, but their numerical results are not reported in the registry record. The number and variety of outcomes make it important to know which analyses were prespecified and whether statistical adjustment was planned when interpreting a collection of findings.

Whether the trial adjusted for multiple comparisons is not reported in the registry record. When many hypotheses are tested, the chance of observing at least one apparently unusual result can increase. General methods for addressing this issue include prespecifying a primary outcome, using a testing hierarchy, or adjusting the interpretation of secondary analyses. The record does not state whether any such approach was used, so no claim about multiplicity control is warranted.

Missing-data handling and analysis populations are also not reported in the registry record. The primary results use 11 placebo participants and 14 Treximet participants, whereas enrollment is 41 and the safety outcomes use 20 and 21. The record does not explain these denominator differences. It does not state whether participants were excluded, lacked an assessable primary outcome, did not meet the endpoint’s initial-response condition, or were handled in another way. These possibilities should not be assumed.

The record also does not describe whether the primary analysis followed randomized assignment regardless of treatment received, or whether a different analysis population was used. It does not report imputation, sensitivity analyses or procedures for incomplete follow-up. Such details matter because conclusions can depend on who is included and how unavailable outcomes are treated.

The registry record does not report a statistical analysis plan, sample-size justification, interim analyses, or the methods used for the posted p-value and confidence interval. Consequently, the available results support a description of the reported counts and comparison, but not a determination that all analyses followed a prespecified plan or that missing outcomes and multiple testing were adequately addressed.

12. Safety Results

The registry reports serious adverse events as affected participants divided by participants at risk.

Other (non-serious) adverse events

Participants with at least one non-serious event at or above the registry's 3.2% reporting threshold.

Most frequent non-serious adverse event terms

The safety results list serious adverse events for 20 participants in the placebo arm and 21 in the Treximet arm. No serious adverse events are reported in either group: 0 of 20 in the placebo arm and 0 of 21 in the Treximet arm. This describes the registry’s recorded serious-event counts for those safety denominators. It does not establish that the risks are identical or that an event could not occur.

Other adverse events are reported for 6 of 20 participants in the placebo arm and 7 of 21 in the Treximet arm. These are participant counts, not counts of individual event episodes, unless otherwise specified; the registry record does not clarify how multiple events in one participant were handled. The record lists no serious adverse-event terms. Death counts are not reported in the registry record.

Safety denominators differ from the primary endpoint denominators, and the record does not explain why. These safety figures should therefore be interpreted separately from the primary migraine recurrence comparison. With no serious events recorded in either group, the data are limited in their ability to characterize uncommon harms or to establish a precise difference in serious-event risk. The posted figures describe what was recorded, not a complete assessment of safety beyond the registry information.

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

The primary result describes a small number of migraine recurrence events under the endpoint definition: 0 among 11 participants assigned to placebo and 2 among 14 assigned to Treximet. The posted risk difference is 0.143, with a 95% confidence interval from -0.040 to 0.326 and a p-value of 0.191. Together, these statistics show a positive point estimate but substantial uncertainty about the direction and size of the underlying difference.

The result does not establish that Treximet increases recurrence, nor does it establish that the arms are equivalent. The confidence interval includes no difference and estimates in both directions. The p-value does not represent the probability that one treatment is superior, and it is not a measure of clinical importance. No equivalence or non-inferiority framework is reported in the registry record.

The endpoint is limited to participants who were pain free or had mild pain at 2 hours and whose pain level then increased within 24 hours. The record does not state how many participants in each arm met the initial condition, or explain the primary outcome denominators in relation to enrollment. The result should not be generalized to all enrolled participants or to other definitions of headache response without additional information.

The record includes broader aims involving pain-free efficacy and salivary biomarkers, as well as listed secondary outcomes. Numerical results for those outcomes are not reported in the registry record. They therefore cannot be used to draw conclusions about biomarker changes, response timing, or other aspects of treatment.

These findings are a description of the posted trial results, not medical advice. The information does not determine what treatment is appropriate for an individual. It also does not answer questions beyond the recorded outcome definitions, follow-up period, participants and analyses.

14. Why This Trial Matters Statistically

This trial is statistically instructive because its primary endpoint has a clear event definition and a direct between-arm comparison, yet the observed number of recurrence events is small. The combination highlights why an effect estimate should be considered together with its confidence interval and the underlying counts. A point estimate alone can make a result appear more definite than the data warrant.

The posted risk difference gives an absolute comparison that can be interpreted alongside the event counts. Its confidence interval extends across zero and is broad, emphasizing that the estimate is imprecise. The p-value of 0.191 is not a substitute for that uncertainty assessment. Looking at all three elements—the event counts, estimated difference and interval—gives a more complete account of the primary result.

The record also illustrates the importance of denominators. Enrollment is 41, while the primary outcome reports 11 placebo participants and 14 Treximet participants, and safety results use 20 and 21. Without an explanation, readers cannot determine why the analyzed numbers vary or how the outcome populations relate to the enrolled group. Such context is essential for judging representativeness and potential missing-data concerns.

Finally, the trial lists multiple biomarker and clinical outcomes, but their numerical results and the multiplicity approach are not reported in the registry record. The primary comparison can be described, but the broader set of objectives cannot be evaluated from numerical results. This distinction between stated objectives and available results is central to careful registry-based interpretation.

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 primary comparison rests on 11 participants in the placebo arm and 14 in the Treximet arm, with only 0 and 2 recurrence events. The resulting estimate is imprecise, as reflected by the 95% confidence interval from -0.040 to 0.326. The registry does not report a sample-size justification, so it is not possible to assess the planned ability to estimate the primary outcome with a desired precision.

Enrollment is listed as 41, but the primary outcome denominators account for fewer participants. Safety results use 20 and 21 participants instead. Reasons for these differences, the analysis populations, and the handling of missing outcome data are not reported in the registry record. The number of participants eligible for the recurrence definition at 2 hours is also not stated, limiting interpretation of the event counts.

The record identifies randomization, double masking and a parallel design, but does not report allocation procedures, masking details, or the statistical methods used to produce the comparison. It does not report a statistical analysis plan, interim analyses, multiplicity procedures, or whether any covariates were included. These omissions limit assessment of how the posted result relates to prespecified methods.

The registry lists biomarker and other secondary outcomes, but numerical results for them are not reported in the registry record. Consequently, the broader aims cannot be assessed alongside the primary result. The available safety figures also do not establish risks for uncommon events, and death counts are not reported in the registry record. These limitations restrict conclusions to the particular outcomes and denominators that are posted.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: CGRP, Estrogen, Cortisol, VIP, α-Amylase, PGE2, PGI2 and ß-Endorphin Levels in Menstrual Migraine Before and After Treximet — NCT01329562.
• Registry record last updated 2014-04-09; status last verified 2014-03.
• Results first posted 2014-04-09.
• 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

The registry describes a completed randomized, double-masked, parallel phase 4 trial of Treximet and placebo in menstrual migraine, with 41 participants enrolled. The primary outcome is recurrence within 24 hours among participants pain free or mildly affected at 2 hours.

The primary results report 0 recurrence participants among 11 in the placebo arm and 2 among 14 in the Treximet arm. The risk difference is 0.143, with a 95% confidence interval from -0.040 to 0.326 and a p-value of 0.191. The interval includes zero and indicates an uncertain comparison.

Safety results report no serious adverse events among 20 placebo participants or 21 Treximet participants; other adverse events are reported for 6 and 7 participants, respectively. The record lists biomarker and additional clinical outcomes, but their numerical results, the analysis populations, missing-data methods, sample-size justification and multiplicity approach are not reported in the registry record.