Efficacy and Safety of Subcutaneous Administration of TEV-48125 for the Preventive Treatment of Episodic Migraine: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Efficacy and Safety of Subcutaneous Administration of TEV-48125 for the Preventive Treatment of Episodic Migraine (NCT03303092), a randomized phase 2, phase 3 study. The primary outcome is Mean Change From Baseline in the Monthly (28 Days) Average Number of Migraine Days During the 12-week Period After the First Dose of Investigational Medicinal Product (IMP).

2. Clinical Question

The primary measure is a change score: it describes the difference between participants’ baseline monthly average migraine days and their average during the post-dose period. A more negative change represents a larger reduction from baseline. The central statistical question is not simply whether each group’s average changed, but whether the changes differed between randomized groups. The posted comparisons show an estimated mean difference of 3.0 days/month for the 675 mg/placebo/placebo regimen versus placebo, with a 95% confidence interval from 1.947 to 4.053. For the 225/225/225 mg regimen versus the 675 mg/placebo/placebo regimen, the estimated mean difference was 0.02 days/month, with a 95% confidence interval from -1.02 to 1.06. These are unadjusted recalculations from the posted group summaries, rather than reported registry analyses.

3. Trial Design

The record describes a randomized, quadruple-masked, parallel-group, placebo-controlled trial with Phase 2 and Phase 3 classification. It was multicenter. The trial enrolled 357 participants and is marked completed. The registry dates are 2017-12-19 for the start and 2019-11-22 for primary completion. The sponsor is Otsuka Pharmaceutical Co., Ltd.

Participants were assigned to one of three subcutaneous regimens administered once monthly for 3 months: TEV-48125 225 mg at each dose; TEV-48125 675 mg at the first dose followed by placebo; or placebo at each dose. The record describes masking as quadruple, but does not specify in the registry record which roles were masked or how masking was maintained.

The primary endpoint population was the Full Analysis set, defined as participants who received the investigational medicinal product at least once and had baseline and Week 12 data for monthly average migraine days. The posted endpoint summaries include 121 participants in the 225/225/225 mg group, 117 in the 675 mg/placebo/placebo group, and 116 in the placebo group. The adverse-event risk groups have different counts: 121, 118, and 117, respectively. These are endpoint-specific reported populations and should not be treated as interchangeable denominators.

The record lists five outcome measures in total and four secondary outcomes. The registry record does not report the original sample-size justification, allocation ratio details beyond the parallel randomized design, or further operational details about the study procedures. Those features should not be inferred from the posted outcome summaries.

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:

Analysis population for the primary outcome, as defined in the registry: Full Analysis set (FAS): Subjects who received the IMP at least once and had baseline and Week 12 data on monthly average number of migraine days.

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 Mean Change From Baseline in the Monthly (28 Days) Average Number of Migraine Days During the 12-week Period After the First Dose of Investigational Medicinal Product (IMP), measured over Baseline, 12 weeks.

The primary endpoint is mean change from baseline in the monthly average number of migraine days during the 12-week period after the first dose of investigational medicinal product. Its unit is days/month, with baseline and 12-week time points. The reported group summaries give a mean change and standard error.

A change-from-baseline measure expresses how much the endpoint moved relative to each participant’s starting value, then summarizes those changes across the analysis population. Negative values indicate fewer monthly average migraine days relative to baseline. Comparing the group-level changes helps distinguish a shared change over time from a difference between randomized regimens. The comparison with placebo is particularly relevant because the placebo group provides a concurrent reference under the same trial setting.

The endpoint was derived from headache variables collected using an electronic diary. Participants entered headache data for the previous 24-hour period each day. When headache was reported, the diary collected information including occurrence, duration, maximum severity, associated symptoms, and acute headache medication use. Severity was subjectively recorded as mild, moderate, or severe; photophobia, phonophobia, nausea, vomiting, and use of acute headache medication were also recorded.

General: repeated diary collection can capture day-to-day variation more directly than a single retrospective assessment, but it depends on diary completion and the endpoint’s definitions. The registry record does not report a detailed missing-diary rule or the statistical model used for the primary endpoint.

7. Results Posted in the Registry

• TEV-48125 (225/225/225 mg) Group: mean -4.00 versus -4.02 on control; difference 0.02 (95% CI -1.02 to 1.06), standardized effect d = 0.00; z-test p = 0.970.
• Placebo Group: mean -1.02 versus -4.02 on control; difference 3.00 (95% CI 1.95 to 4.05), standardized effect d = 0.73; z-test p = <0.001.

8. Secondary Efficacy Endpoints

The registry also posts results for secondary outcomes. For each outcome below, the endpoint type, the test applied to the posted summary statistics, the result and its interpretation are given in turn. Secondary endpoints are usually not adjusted for multiple testing, so they support rather than confirm the primary finding.

Proportion of Subjects Reaching at Least 50% Reduction in the Monthly Average Number of Migraine Days During the 12-week Period After the First Dose of IMP

• Endpoint type: Binary: the percentage of participants with the event (counts rebuilt from the posted percentages and group sizes).
• Test: Unadjusted two-proportion z-test, with a Wald 95% confidence interval for the risk difference.
• Result:
  • TEV-48125 (225/225/225 mg) Group: 42.0% (21/50) versus 45.3% (24/53) on control; risk difference -3.3 percentage points (95% CI -22.4 to 15.9), risk ratio 0.93 (0.60–1.44); unadjusted two-proportion z-test p = 0.737.
  • Placebo Group: 7.7% (1/13) versus 45.3% (24/53) on control; risk difference -37.6 percentage points (95% CI -57.3 to -17.9), risk ratio 0.17 (0.03–1.14); unadjusted two-proportion z-test p = 0.012.
• Interpretation:
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between TEV-48125 (225/225/225 mg) Group and the control. The interval gives the range of effects that remain compatible with the data.
  • The 95% confidence interval excludes no difference, so the proportion with the event is statistically lower for Placebo Group than for the control. This is an unadjusted, secondary comparison, so it is suggestive rather than confirmatory.

Mean Change From Baseline in the Monthly Average Number of Days With Use of Any Acute Headache Medications During the 12-week Period After the First Dose of IMP

• Endpoint type: Continuous: a mean value per participant, compared as a difference in means.
• Test: Unadjusted two-sample z-test for the difference in means, using the posted standard errors.
• Result:
  • TEV-48125 (225/225/225 mg) Group: mean -3.30 versus -3.29 on control; difference -0.01 (95% CI -0.98 to 0.96), standardized effect d = -0.00; z-test p = 0.984.
  • Placebo Group: mean -0.46 versus -3.29 on control; difference 2.83 (95% CI 1.85 to 3.81), standardized effect d = 0.74; z-test p = <0.001.
• Interpretation:
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between TEV-48125 (225/225/225 mg) Group and the control. The interval gives the range of effects that remain compatible with the data.
  • The 95% confidence interval excludes no difference, so the mean is statistically higher for Placebo Group than for the control. This is an unadjusted, secondary comparison, so it is suggestive rather than confirmatory.

Mean Change From Baseline in the Monthly Average Number of Migraine Days During the 12-week Period After the First Dose of IMP in Patients Not Receiving Concomitant Preventive Migraine Medications

• Endpoint type: Continuous: a mean value per participant, compared as a difference in means.
• Test: Unadjusted two-sample z-test for the difference in means, using the posted standard errors.
• Result:
  • TEV-48125 (225/225/225 mg) Group: mean -4.42 versus -4.21 on control; difference -0.21 (95% CI -1.22 to 0.80), standardized effect d = -0.06; z-test p = 0.684.
  • Placebo Group: mean -1.40 versus -4.21 on control; difference 2.81 (95% CI 1.78 to 3.84), standardized effect d = 0.78; z-test p = <0.001.
• Interpretation:
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between TEV-48125 (225/225/225 mg) Group and the control. The interval gives the range of effects that remain compatible with the data.
  • The 95% confidence interval excludes no difference, so the mean is statistically higher for Placebo Group than for the control. This is an unadjusted, secondary comparison, so it is suggestive rather than confirmatory.

The secondary outcomes cover several related aspects of migraine during the 12-week period after the first dose: reaching at least a 50% reduction in monthly average migraine days, change in days with acute headache medication use, and change in migraine days among participants not receiving concomitant preventive migraine medications. Another listed secondary outcome concerns change in MIDAS disability score after the final dose, but a corresponding result is not included among the posted secondary summaries.

Across the posted summaries, the active regimen groups generally have more favorable mean changes or a higher proportion reaching the stated reduction threshold than placebo. Comparisons between the two active regimens are much closer in the posted calculations. This broad pattern is consistent with the primary endpoint comparisons, but it does not independently confirm them: the outcomes are related, their participant groups and denominators can differ, and several analyses are considered.

The posted secondary summaries do not include reported registry analyses. The pairwise comparisons and p-values described from them are unadjusted recalculations, so they should be treated as exploratory descriptions rather than as a family of confirmatory tests. When multiple outcomes and contrasts are examined, chance alone can produce seemingly notable results. Without a reported multiplicity strategy or prespecified hierarchy, the secondary results carry less inferential weight than a clearly specified primary analysis would.

The secondary outcomes also measure different constructs. Migraine-day counts, medication-use days, a response threshold, and disability scores are not interchangeable. A pattern that points in a similar direction across related measures can be informative, but it does not eliminate the limitations of missing analysis details or establish that all outcomes were handled consistently. The registry record does not report results for the disability outcome in the posted secondary summaries, so its result cannot be inferred from the other measures.

Secondary outcomes registered for this trial, for reference (only those above were recalculated):

• Proportion of Subjects Reaching at Least 50% Reduction in the Monthly Average Number of Migraine Days During the 12-week Period After the First Dose of IMP
• Mean Change From Baseline in the Monthly Average Number of Days With Use of Any Acute Headache Medications During the 12-week Period After the First Dose of IMP
• Mean Change From Baseline in the Monthly Average Number of Migraine Days During the 12-week Period After the First Dose of IMP in Patients Not Receiving Concomitant Preventive Migraine Medications
• Mean Change From Baseline in Disability Score, as Measured by Migraine Disability Assessment (MIDAS) Questionnaire at 4 Weeks After the Final (Third) Dose of IMP

9. Statistical Interpretation

10. Statistical Methods Explained

General: a continuous endpoint is measured on a numeric scale, and a group mean summarizes the values in that group. Here, the endpoint is change in monthly average migraine days, measured in days/month. A negative group mean indicates a reduction from baseline on average. The standard error describes the statistical uncertainty around an estimated mean; it is not the spread of individual participants’ outcomes. The registry reports standard errors for the primary endpoint but does not report standard deviations for those endpoint groups.

What does a mean difference compare?

A mean difference compares the group averages for the same outcome. In the posted recalculations, the comparison estimate is formed from the summarized group means. Its sign depends on the order of the groups in that comparison. For the placebo comparison, the reported estimate of 3.0 corresponds to the difference between the 675 mg/placebo/placebo group mean of -4.02 and the placebo group mean of -1.02, expressed in the comparison direction. For the active-regimen comparison, the estimate of 0.02 reflects the close means of -4.02 and -4.0. These comparisons are unadjusted recalculations from the posted summaries; the registry record does not report a fitted model or adjusted estimates.

What does a confidence interval contribute?

General: a confidence interval gives a range of values compatible with the data and the calculation method at a stated confidence level. It communicates precision as well as the point estimate. A narrow interval indicates greater precision than a wide interval, all else equal. If a confidence interval for a difference includes zero, the posted interval does not rule out no difference under that calculation. If it excludes zero, the estimate is less compatible with zero under that calculation, but that does not address every concern about study design, data completeness, or multiple comparisons.

The registry record does not include confidence limits for the individual arm means. The comparison intervals are recalculated from the posted summary information. The comparison p-values are unadjusted and are not presented as sponsor-reported analysis results. A p-value measures how unusual data at least as incompatible with a null hypothesis would be under the assumptions of a particular test; it does not give the probability that the null hypothesis is true, nor does it measure the size or importance of an effect.

Why does the analysis population matter?

The primary outcome population includes participants who received the investigational medicinal product at least once and had both baseline and Week 12 data. That definition makes endpoint availability part of inclusion in the reported summary. Participants without the required endpoint data are not represented in these group means. The registry record does not report the number excluded for missing endpoint information, the reasons for missingness, or an imputation method. General: if missing outcomes are related to participants’ underlying outcomes or treatment experience, a complete-case summary may differ from the result that would have been observed with complete follow-up for everyone.

Denominators also vary by outcome. The primary summaries report 121, 117, and 116 participants in the three groups. The serious and other adverse-event summaries use 121, 118, and 117 at-risk participants. Secondary outcomes have their own reported denominators. Interpret each result against its own analysis population rather than assuming every outcome has the same participants.

What can be concluded from unadjusted recalculations?

General: simple summary-statistic comparisons can help readers understand the direction, size, and rough precision of differences. They do not substitute for a prespecified analysis plan. A trial’s formal analysis might account for baseline values, repeated measurements, stratification, or other design features, but which methods were planned or used is not reported in the registry record. No reported analysis rows are posted. The comparison estimates and p-values discussed in these explanations are therefore unadjusted recalculations, not verified outputs of the sponsor’s formal analysis.

The record also does not report a multiplicity adjustment. When several outcomes or comparisons are examined, the chance of at least one apparently notable result can increase. General: interpreting each unadjusted p-value as if it were the only planned test can overstate the strength of evidence. This issue is relevant when reading both the primary comparisons and the secondary outcomes, particularly because the complete analysis plan is not available in the registry record.

The posted endpoint is a mean, which can be useful for estimating an average group-level change. General: means can be influenced by unusually large or small individual values, and the record does not report distributional diagnostics or an alternative robust summary. The registry record also does not report whether the calculations account for clustering by site, the use of rescue medication, or other covariates. Those details should not be assumed.

11. Confidence Intervals and Precision

The primary comparison intervals convey appreciable uncertainty around the point estimates. For the 225/225/225 mg regimen versus the 675 mg/placebo/placebo regimen, the estimated mean difference is 0.02 days/month and the 95% confidence interval is -1.02 to 1.06. The interval includes zero and extends to values on either side of it. Thus, the point estimate alone should not be read as an exact or certain difference between the regimens.

For the 675 mg/placebo/placebo regimen versus placebo, the estimated mean difference is 3.0 days/month, with a 95% confidence interval from 1.947 to 4.053. For the 225/225/225 mg regimen versus placebo, the same estimated mean difference and interval are posted. Both intervals lie above zero in the reported comparison direction. The p-values for these comparisons are reported as < 0.001 in the unadjusted recalculations.

General: the confidence interval reflects sampling uncertainty under its calculation assumptions; it does not account automatically for possible bias from missing data, outcome selection, or unreported analytical choices. The registry record does not provide sponsor-reported confidence intervals or a formal analysis model to compare with the simple recalculations. It also does not report confidence intervals for the arm-specific means.

Precision is not the same as clinical importance. The interval describes a range for the estimated group difference under a statistical procedure; it does not establish whether every value in that range would matter to patients. The registry record does not provide a threshold for a clinically important difference. Interpretation therefore requires attention to both the estimate and its interval, as well as the endpoint definition and analysis limitations.

12. Planning a Similar Trial: Sample Size

This is a planning illustration, not a re-evaluation of the original trial. It asks: if a new study wanted to detect a difference like the one observed, or a smaller one, how large would it need to be? It is deliberately not “observed power” of the finished trial, which is not a meaningful quantity.

The planning figures are illustrations based on the observed effect, not the trial’s original design justification. For these non-time-to-event outcomes, the figures are participants per arm, not total events. The stated assumptions are a two-sided significance level of 0.05, equal allocation between the two arms, and a normal approximation. The assumed effect to detect is the stated fraction of the observed effect.

The 80% power column gives the planned number of participants per arm that the calculation estimates would be needed to have an 80% chance of detecting the specified effect, under those assumptions, if that effect were the true one. The 90% power column uses a higher target chance of detection, so it generally requires more participants per arm for the same assumed effect. For example, the placebo comparison for the primary outcome lists 30 participants per arm for 80% power and 40 participants per arm for 90% power when planning for 100% of the observed effect. When planning for 75% of the observed effect, the corresponding figures are 53 and 70 participants per arm; for 50%, they are 118 and 158.

Smaller effects are harder to distinguish from random variation, so the planning illustration requires more participants per arm when the assumed effect is reduced. For the active-regimen comparison, the observed mean difference is very close to zero, and the corresponding planning figures are extremely large: 656,444 participants per arm for 80% power when planning for 100% of that observed effect. Such figures reflect the calculation’s dependence on the observed estimate and should not be mistaken for the trial’s actual enrollment target or its original sample-size rationale.

These figures are planning illustrations, not observed power. The original sample-size assumptions and justification are not reported in the registry record.

13. How the Sample Size Is Derived

Power is the probability that a study of a given size rejects the null hypothesis when a specific true effect exists. It depends on four things: the effect to detect, the variability of the outcome, the significance level (here a two-sided α of 0.05, so z_1−α/2 = 1.960) and the desired power (z_1−β = 0.842 for 80% and 1.282 for 90%).

Formula

n is the number of participants in each arm, Δ is the difference in means to detect and σ is the common standard deviation.

Worked calculation for this trial

1. Observed difference Δ = 0.020; pooled standard deviation σ = 4.090.
2. n = 2 × (1.96 + 0.842)² × 4.090² / 0.020² = 656,443.2, rounded up to 656,444 participants per arm for 80% power.

The smaller-effect rows in the table above repeat the same calculation with the effect multiplied by 0.75 and 0.5 (for ratios, applied to the logarithm of the ratio).

R code

alpha <- 0.05
z_a   <- qnorm(1 - alpha / 2)          # two-sided
delta <- 0.0199999999999996                      # observed difference in means
sigma <- 4.08987215414958                     # pooled standard deviation
n_per_arm <- function(power, frac = 1) {
  ceiling(round(2 * (z_a + qnorm(power))^2 * sigma^2 / (delta * frac)^2, 6))
}
for (f in c(1, 0.75, 0.5))
  cat(sprintf("%3.0f%% of observed effect: n per arm = %s (80%% power), %s (90%% power)\n", 100 * f,
              format(n_per_arm(0.80, f), big.mark = ","), format(n_per_arm(0.90, f), big.mark = ",")))

# Check against R's built-in function (t-based, so very slightly larger)
cat("power.t.test:", round(power.t.test(delta = delta, sd = sigma, power = 0.80)$n, 1), "\n")

# Simulation: exact two-sample t-test using simulated means and variances
set.seed(3303092)
n    <- n_per_arm(0.80)
reps <- 20000
m_diff <- rnorm(reps, delta, sigma * sqrt(2 / n))             # difference in sample means
s2     <- sigma^2 * rchisq(reps, 2 * (n - 1)) / (2 * (n - 1))   # pooled sample variance
tstat  <- m_diff / sqrt(s2 * 2 / n)
cat(sprintf("Simulated power at n = %s per arm: %.3f (%d replicates)\n", format(n, big.mark = ","), mean(abs(tstat) > qt(0.975, 2 * (n - 1))), reps))

Output from running the code

100% of observed effect: n per arm = 656,444 (80% power), 878,792 (90% power)
 75% of observed effect: n per arm = 1,167,011 (80% power), 1,562,296 (90% power)
 50% of observed effect: n per arm = 2,625,773 (80% power), 3,515,165 (90% power)
power.t.test: 656444.1 
Simulated power at n = 656,444 per arm: 0.801 (20000 replicates)

The simulation draws many sets of group means and variances at the planned sample size and counts how often the two-sample t-test rejects the null. It should land close to the target power; at very small required sample sizes it can fall below it, because the normal approximation is rough there.

14. Multiplicity, Missing Data and Analysis Populations

The registry record lists five outcome measures, with four secondary outcomes, but no reported analysis rows are posted. It does not report a multiplicity adjustment, a testing hierarchy, or which comparisons were prespecified for formal hypothesis testing. The unadjusted p-values from summary-statistic recalculations therefore do not describe a documented familywise testing procedure. General: when several outcomes and contrasts are tested, the chance of finding one result that appears statistically notable can be greater than for a single isolated test.

The primary endpoint population includes participants who received the investigational medicinal product at least once and had baseline and Week 12 data. The record does not report the number of participants with missing primary endpoint data, the reasons for missingness, how missing diary days were handled, or whether any imputation was performed. It also does not report sensitivity analyses assessing the effect of missing data. These omissions limit assessment of whether the posted means represent all randomized participants or only those with the required endpoint observations.

The registry record does not report the statistical model, covariate adjustments, handling of repeated measurements, or the planned method for comparing groups. The intervals and p-values described in the interpretation are simple unadjusted recalculations from the posted summaries, not sponsor-reported analyses. The original sample-size justification and interim-analysis plan are not reported in the registry record.

Analysis populations differ by endpoint. The primary outcome group counts are 121, 117, and 116; the adverse-event at-risk counts are 121, 118, and 117. Secondary outcomes also list outcome-specific denominators. This variation is important when assessing which participants contributed to each result, but the registry record does not explain every denominator difference. No conclusion about exclusions or missingness mechanisms should be drawn beyond the population definitions stated in the record.

15. 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 posted serious adverse-event summaries report 0 affected participants in each group. The at-risk counts are 121 for TEV-48125 225/225/225 mg, 118 for TEV-48125 675 mg/placebo/placebo, and 117 for placebo. The record lists no top serious-event terms. Deaths are reported as 0 in each group.

Other adverse events were reported for 69 participants in the 225/225/225 mg group, 74 in the 675 mg/placebo/placebo group, and 77 in the placebo group. Their at-risk counts are the same group-specific denominators. These are counts of affected participants as posted, not measures of event severity or duration.

General: zero observed serious adverse events in a group does not establish that the risk is zero, especially when the number of participants observed is limited. The registry record does not provide event-level details, exposure-adjusted rates, or a fuller safety analysis. The counts describe the reported safety summaries and do not establish a comparative safety conclusion.

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

The posted primary summaries show mean reductions from baseline in monthly migraine days in all three groups. The two TEV-48125 regimen means are close to one another, while each active-regimen mean is more negative than the placebo mean. The unadjusted recalculated comparisons estimate a difference of 0.02 days/month between active regimens and 3.0 days/month for each active regimen compared with placebo. The confidence interval for the active-regimen comparison includes zero; the placebo comparisons have intervals above zero in the stated comparison direction.

These findings describe group averages during the measured 12-week period after the first dose. They do not tell whether any individual participant experienced a reduction, nor do they capture outcomes beyond the stated timeframe. A mean change can conceal variation in responses across participants. The registry record does not provide a clinically important difference threshold, so the posted mean differences alone cannot establish clinical importance.

The recalculated comparisons are unadjusted and are not sponsor-reported analyses. The registry record does not report the original statistical analysis plan, the formal model, multiplicity handling, or missing-data methods. Those gaps matter when judging how confirmatory the p-values and intervals are. The secondary results provide related outcome descriptions, but they do not replace a complete prespecified analysis and should be read with additional caution because multiple outcomes are involved.

The safety summaries report no serious adverse events or deaths in the listed groups, alongside nonzero counts of other adverse events. These observations should not be generalized beyond the participants and follow-up represented in the record, and they do not show that serious risks are absent. Overall, the posted data offer a statistical description of group outcomes in this completed trial; they do not by themselves establish an individual outcome, a long-term result, or a treatment recommendation.

17. Why This Trial Matters Statistically

This trial is statistically informative because it includes a concurrent placebo group and two distinct TEV-48125 dosing regimens in a randomized, masked, parallel-group design. Randomization provides a framework for comparing group outcomes, while the placebo group helps place changes over time in context. The endpoint was based on repeated electronic diary entries and summarized as change in monthly average migraine days, a directly interpretable count-based measure.

The comparison between the two active regimens is also distinct from the comparisons against placebo. The posted means for the active groups are close, and the recalculated interval is broad enough to include differences in either direction. The placebo comparisons have larger estimated differences and intervals above zero in the stated comparison direction. Separating these contrasts prevents the overall pattern from being reduced to a single claim about all regimens.

The record also illustrates why statistical interpretation requires more than looking at a p-value. Estimates, confidence intervals, analysis populations, and outcome definitions all shape what can be concluded. The primary endpoint has standard errors and comparison intervals, while secondary measures cover response, medication use, and a subgroup not receiving concomitant preventive medication. Their related but different scopes make it important to keep each measure’s population and meaning in view.

Finally, the registry entry illustrates the limits of public outcome summaries when the formal statistical plan and reported analyses are absent. Simple recalculations can help describe the posted data, but they cannot establish which analyses were prespecified or how missingness and multiple testing were handled. Recognizing that distinction is part of responsible interpretation of clinical trial results.

18. 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 are specific to the information recorded for this trial. The registry record does not report the original sample-size justification, so the planning illustrations derived from observed effects cannot be taken as evidence of the assumptions used to design the trial. It also does not report the statistical analysis plan, formal model, or sponsor-reported analysis results. The comparison estimates and p-values discussed in the statistical interpretation are unadjusted recalculations from posted summaries.

The primary endpoint population requires both baseline and Week 12 data. The record does not describe the amount or pattern of missing diary data, exclusions from this population, imputation, or sensitivity analyses. That makes it difficult to assess how missing observations may have affected the estimated means. The registry record also does not explain all differences between outcome-specific denominators.

The record lists multiple secondary outcomes, but does not report a multiplicity procedure or analysis hierarchy. The posted secondary comparisons therefore have limited confirmatory interpretation. One listed secondary outcome, disability score measured by MIDAS, has no corresponding result in the posted secondary summaries. A result for that outcome cannot be inferred from the other endpoints.

The primary endpoint covers the 12-week period after the first dose, and the listed secondary outcomes also focus on this period or a time point after the final dose. Longer-term outcomes are not reported in the registry record. General: trial averages also do not describe the full range of individual responses. The summaries do not provide participant-level distributions or subgroup results beyond the stated secondary population. The safety summaries provide event counts but not event-level descriptions or exposure-adjusted rates.

19. Related Tutorials

20. Related Statistical Calculators

21. Sources

• ClinicalTrials.gov: Efficacy and Safety of Subcutaneous Administration of TEV-48125 for the Preventive Treatment of Episodic Migraine — NCT03303092.
• Registry record last updated 2021-07-29; status last verified 2021-07.
• Results first posted 2021-07-08.
• 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.

22. Record Summary

The completed randomized, quadruple-masked, parallel-group, placebo-controlled trial enrolled 357 participants and evaluated subcutaneous TEV-48125 regimens for episodic migraine prevention. Participants received TEV-48125 225 mg monthly for 3 months, TEV-48125 675 mg followed by placebo doses, or placebo monthly for 3 months.

The primary endpoint was mean change from baseline in monthly average migraine days during the 12-week period after the first dose. The posted group means were -4.0, -4.02, and -1.02 days/month, respectively, for the two TEV-48125 regimens and placebo. Unadjusted recalculations show an estimated mean difference of 0.02 days/month between the active regimens and 3.0 days/month for each active regimen versus placebo.

The registry record does not report sponsor analyses, the original sample-size justification, multiplicity handling, or missing-data methods. Secondary outcome and safety summaries are available, but they require interpretation within their outcome-specific populations and the analytical limitations.