A Randomized, Double-Blind, Placebo-Controlled Study With an Open-Label Period on Efficacy and Safety of Fremanezumab in Chinese Adults With Migraine: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for A Randomized, Double-Blind, Placebo-Controlled Study With an Open-Label Period on Efficacy and Safety of Fremanezumab in Chinese Adults With Migraine (NCT05458011), a randomized phase 3 study. The primary outcome is Double Blind (DB) Period: Mean Change From Baseline in Monthly Average Number of Migraine Days During the 12-Week Period After the First Dose of Fremanezumab.

2. Clinical Question

3. Trial Design

This was a Phase 3, randomized, double-blind, placebo-controlled, parallel-group study with an open-label treatment period. It enrolled adults in China with migraine, and the registry record lists enrollment of 365. The study status is completed. The recorded start date is 2022-09-30, and primary completion is recorded as 2024-01-31.

During the double-blind period, participants were assigned to placebo, monthly fremanezumab, or quarterly fremanezumab. The treatment descriptions use matching placebo injections to maintain masking across the dosing schedules. The primary efficacy comparison combined the monthly and quarterly fremanezumab groups, so the reported primary result does not distinguish between those schedules. The registry record does not report separate primary estimates for each fremanezumab schedule.

An open-label period followed the double-blind period. The arm descriptions indicate that participants received fremanezumab during the open-label period, but the registry record does not provide enough detail to reconstruct every participant's treatment sequence or the full open-label schedule. The primary endpoint described in the record concerns the double-blind period, through Week 12, rather than the open-label period.

Randomization and masking help limit bias in treatment assignment and outcome assessment during the blinded comparison. The placebo group provides a concurrent reference for interpreting changes over the same study period. These design features do not, by themselves, establish that all potential sources of bias or uncertainty were controlled; details such as the randomization procedure and allocation concealment 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: A total of 454 participants were screened; of which 365 participants were randomized and included in the analysis.

DB Period (12 Weeks)

Reasons for not completing this period:

OL Period (12 Weeks)

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: DB mITT analysis set included participants who received at least 1 dose of study drug and had at least 10 days of postbaseline efficacy assessment on the primary endpoint. Efficacy analysis was planned to be evaluated combined for both fremanezumab dose treatment groups.

5. Baseline Characteristics

The table reproduces the baseline characteristics posted in the registry, which describe the participants analysed at baseline and help show whether the randomized groups were comparable.

Population: The intent-to-treat (ITT) analysis set included all randomized participants.

6. Primary Endpoint

The registry lists the primary outcome as Double Blind (DB) Period: Mean Change From Baseline in Monthly Average Number of Migraine Days During the 12-Week Period After the First Dose of Fremanezumab, measured over Baseline (Day -28 to Day -1), up to Week 12.

The primary endpoint is mean change from baseline in monthly average migraine days during the 12-week period after the first dose. Baseline covers Day -28 to Day -1, and the endpoint is assessed through Week 12. The registry defines a migraine day using diary-reported headache duration and migraine criteria, including qualifying migraine or probable migraine headache, or a headache treated with migraine-specific medication. Monthly averages were normalized to a 28-day equivalent using the number of days with recorded assessments.

This endpoint expresses change in a recurring symptom over a treatment period, rather than counting only a single event or measuring a one-time status. The change-from-baseline format compares participants' follow-up experience with their own recorded baseline, while the placebo group helps put that change in context. A negative mean change indicates a decrease from baseline; it does not mean that every participant had a decrease.

The analysis used least-squares means from an analysis of covariance. Such adjusted means are model-based group summaries, not necessarily the raw arithmetic averages. The registry record does not report all details of the model, including the covariates included. The primary population was the double-blind modified intention-to-treat set, defined in the record by receipt of at least one dose and at least 10 days of postbaseline primary endpoint assessment.

7. Results Posted in the Registry

• Fremanezumab Monthly/Quarterly: mean -4.60 versus -2.80 on control; difference -1.80 (95% CI -3.13 to -0.47), standardized effect d = -0.28; z-test p = 0.008.

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.

DB Period: Mean Change From Baseline in the Average Number of Migraine Days During the 4-Week Period After the First Dose of Fremanezumab

• 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:
  • Fremanezumab Monthly/Quarterly: mean -4.50 versus -2.20 on control; difference -2.30 (95% CI -3.74 to -0.86), standardized effect d = -0.33; z-test p = 0.002.
• Interpretation:
  • The 95% confidence interval excludes no difference, so the mean is statistically lower for Fremanezumab Monthly/Quarterly than for the control. This is an unadjusted, secondary comparison, so it is suggestive rather than confirmatory.

DB Period: Mean Change From Baseline in the Monthly Average Number of Days of Use of Any Acute Headache Medications During the 12-Week Period After the First Dose of Fremanezumab

• 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:
  • Fremanezumab Monthly/Quarterly: mean -3.00 versus -1.10 on control; difference -1.90 (95% CI -3.04 to -0.76), standardized effect d = -0.34; z-test p = 0.001.
• Interpretation:
  • The 95% confidence interval excludes no difference, so the mean is statistically lower for Fremanezumab Monthly/Quarterly than for the control. This is an unadjusted, secondary comparison, so it is suggestive rather than confirmatory.

DB Period: Number of Participants Reaching at Least 50% Reduction From Baseline in Monthly Average Number of Migraine Days During the 12-Week Period After the First Dose of Fremanezumab

• Endpoint type: Binary: the number of participants with the event, compared as proportions.
• Test: Unadjusted two-proportion z-test, with a Wald 95% confidence interval for the risk difference.
• Result:
  • Fremanezumab Monthly/Quarterly: 57.5% (103/179) versus 34.6% (63/182) on control; risk difference 22.9 percentage points (95% CI 12.9 to 32.9), risk ratio 1.66 (1.31–2.10); unadjusted two-proportion z-test p = <0.001.
• Interpretation:
  • The 95% confidence interval excludes no difference, so the proportion with the event is statistically higher for Fremanezumab Monthly/Quarterly than for the control. This is an unadjusted, secondary comparison, so it is suggestive rather than confirmatory.

The posted secondary results cover more than one aspect of the double-blind period. They include an early migraine-day change, use of acute headache medication, and the proportion reaching a stated migraine-day reduction threshold. These outcomes broadly complement the primary endpoint by looking at symptom change over an earlier interval, medication use, and a responder definition rather than only the mean change through Week 12.

The reported secondary comparisons follow a direction generally consistent with the primary comparison: the fremanezumab groups combined have more negative mean changes on the continuous outcomes, and the recorded responder comparison favors a larger proportion reaching the specified reduction threshold. These results are supportive context, but they are not independent replications of the primary endpoint. They use related measures from the same study and may be correlated with one another.

The registry lists secondary outcomes including safety and other headache measures, but the record does not provide complete numerical results for every listed outcome in the information summarized by these statistics. Absence of a numerical result from the posted record should not be interpreted as a null finding. The timing and definitions also differ among secondary outcomes, so each addresses a somewhat different question.

Unadjusted secondary p-values carry less weight when many outcomes are tested because the chance of at least one apparently unusual result increases with the number of tests. The registry record does not report a multiplicity-adjustment plan or a hierarchy for secondary testing. Therefore, these outcomes are best viewed as descriptive or supportive evidence rather than as a series of confirmatory claims. Their interpretation should remain anchored to the prespecified primary endpoint and to the fact that the primary analysis combined the monthly and quarterly schedules.

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

• DB Period: Mean Change From Baseline in the Average Number of Migraine Days During the 4-Week Period After the First Dose of Fremanezumab
• DB Period: Mean Change From Baseline in the Monthly Average Number of Days of Use of Any Acute Headache Medications During the 12-Week Period After the First Dose of Fremanezumab
• DB Period: Number of Participants Reaching at Least 50% Reduction From Baseline in Monthly Average Number of Migraine Days During the 12-Week Period After the First Dose of Fremanezumab
• DB Period: Mean Change From Baseline in the Monthly Average Number of Headache Days of at Least Moderate Severity During the 12-Week Period After the First Dose of Fremanezumab
• DB Period: Number of Participants With At Least One Treatment-Emergent Adverse Event (TEAE)
• DB Period: Number of Participants Who Did Not Complete the Study Due to AEs
• OL Period: Number of Participants With at Least One TEAE
• OL Period: Number of Participants Who Did Not Complete the Study Due to AEs

9. Statistical Interpretation

10. Statistical Methods Explained

The primary endpoint is continuous: each participant contributes a measure of change in monthly average migraine days, and the reported group result summarizes those changes. For continuous outcomes, a mean describes the center of the observed values, while a measure of uncertainty describes how precisely that mean or contrast is estimated. The registry reports least-squares means and standard errors for the group summaries.

What does the ANCOVA estimate represent?

Analysis of covariance, or ANCOVA, compares group outcomes while accounting for specified covariates in a statistical model. In a change-from-baseline analysis, the model can estimate adjusted group means and their difference rather than merely subtracting raw group averages. Adjustment can improve precision when the included covariates are informative and the model is appropriate. The registry identifies ANCOVA as the method and reports the LS mean difference, but the covariates, model diagnostics, and other implementation details are not reported in the registry record. No additional model features should be assumed.

The primary LS mean difference is -1.8 days/month, and the sponsor-reported 95% confidence interval is -2.66 to -0.95. The associated p-value is < 0.001. A p-value describes how incompatible the observed data are with a specified null model under the analysis assumptions; it is not the probability that the null hypothesis is true, nor a measure of clinical importance. The registry provides the reported p-value but does not state further details about the testing procedure.

How does the recalculation differ?

The simple recalculation uses posted group summaries to estimate an unadjusted contrast. It gives a mean difference of -1.8 days/month and an unadjusted p-value of 0.008. The recalculation estimates a pooled standard deviation from the posted standard errors and group sizes; the record flags that standard deviation as approximate. This is a summary-statistic calculation, not a reconstruction of the ANCOVA. It does not use unreported participant-level data or unreported model covariates.

Because the calculation is unadjusted and based on approximate dispersion, it is best treated as a complementary check on the scale and direction of the comparison. It is not a replacement for the sponsor's analysis. The primary efficacy outcome's reported analysis is ANCOVA, and the sponsor-reported inferential results should be used when describing that analysis. The trial record marks no discrepancy between the sponsor result and recalculation, but that does not make their methods identical.

What does the standard error describe?

A standard error describes the sampling uncertainty of an estimated mean under the analysis framework. It is not the spread of individual participant outcomes. A confidence interval uses an estimate and its uncertainty to give a range of values compatible with the data and model at the stated confidence level. Wider intervals indicate less precision; narrower intervals indicate greater precision, all else equal. These interpretations are general statistical explanations.

The reported group standard errors are 0.48 days/month for each of the primary groups. The registry does not provide group-specific confidence limits for the primary endpoint, while it does provide a confidence interval for the ANCOVA contrast. The recalculation's estimated pooled standard deviation is 6.449, flagged as approximate. Standard deviations and standard errors answer different questions: the former describes variability among observations, while the latter describes uncertainty in an estimated mean.

Why are the analysis population and endpoint definition important?

The primary efficacy population is the double-blind modified intention-to-treat set. Participants had to receive at least one dose and have at least 10 days of postbaseline efficacy assessment on the primary endpoint. This definition affects which observations contribute to the efficacy analysis. It is not equivalent to a statement that every randomized participant contributed complete data. The registry record does not report the number excluded from this analysis set or the detailed handling of missing diary entries.

The migraine-day definition and normalization also affect interpretation. The endpoint counts qualifying calendar days based on diary information and converts the observed follow-up measure to a 28-day equivalent. Thus, the outcome is a standardized monthly average, not simply a count of all diary entries over the full period. Assessments with missing diary days and the model's approach to them are not described in enough detail to assess their potential influence.

Finally, the primary contrast pools monthly and quarterly schedules. It estimates the result for the combined treatment comparison as analyzed, rather than a separate effect for each schedule. The record's methods description should be followed closely: it supports interpretation of the defined endpoint and population, but not assumptions about unreported statistical procedures, missing-data methods, or separate dose-schedule effects.

11. Confidence Intervals and Precision

The sponsor-reported primary ANCOVA estimate is -1.8 days/month, with a 95% confidence interval from -2.66 to -0.95. The interval lies below zero, indicating that the reported data and model are compatible with a more negative mean change in the combined fremanezumab group than in the placebo group. A confidence interval is a range of values compatible with the observed data under the analysis assumptions; it is not a guarantee that the true effect lies within that particular interval.

The interval communicates precision as well as direction. It shows that the estimate is not exact, while placing the plausible contrast within a range that remains on the negative side of zero. Its interpretation depends on the ANCOVA model and analysis population. The registry record does not provide enough detail to assess every model assumption or the effects of missing outcome data.

The recalculation from summary statistics also estimates a mean difference of -1.8 days/month, but its uncertainty calculation is unadjusted and uses an approximate pooled standard deviation. Its interval has limits of -3.13 and -0.469 in the recalculation; the final limit is not repeated because it exceeds the permitted displayed precision. The recalculated interval should not be substituted for the sponsor's ANCOVA interval.

Confidence intervals do not describe how much participants vary from one another, and they do not establish the importance of the result to individual patients. The registry reports group standard errors of 0.48 days/month. Those values describe uncertainty in group means, not individual outcome variability. The approximate pooled standard deviation is a separate summary and is marked as approximate. Precision is only one part of interpretation, alongside the endpoint, analysis, and population.

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 participants per arm for the continuous primary comparison. They are illustrative calculations based on the observed effect, not the trial's original design specification. For the observed effect, the illustration gives 202 participants per arm for 80% power and 270 participants per arm for 90% power. For planning for 75% of the observed effect, the corresponding figures are 359 and 480 participants per arm. For planning for 50% of the observed effect, they are 807 and 1,080 participants per arm.

The calculation assumes a two-sided significance level of 0.05, equal allocation between the two arms, and a normal approximation. The target effect is the stated fraction of the observed effect. The registry record does not report the trial's own original sample-size assumptions or justification; these planning figures should not be read as that justification.

In plain language, 80% power means that, under the calculation's assumptions and for the effect size being planned for, a study of that size would have an 80% chance of detecting an effect at the specified significance level. The 90% column uses a higher chance of detection under those same assumptions. Smaller effects require more participants to detect with the same power and significance level. These numbers are planning illustrations, not observed power. They do not describe the probability that the completed trial's result is correct or that a treatment effect exists.

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 = -1.800; pooled standard deviation σ = 6.449.
2. n = 2 × (1.96 + 0.842)² × 6.449² / -1.800² = 201.5, rounded up to 202 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 <- -1.8                      # observed difference in means
sigma <- 6.44903775940908                     # 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(5458011)
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 = 202 (80% power), 270 (90% power)
 75% of observed effect: n per arm = 359 (80% power), 480 (90% power)
 50% of observed effect: n per arm = 807 (80% power), 1,080 (90% power)
power.t.test: 202.5 
Simulated power at n = 202 per arm: 0.797 (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. Analyses Reported by the Sponsor

The sponsor-reported primary analysis is an ANCOVA with an LS mean difference of -1.8 days/month, a 95% confidence interval from -2.66 to -0.95, and p < 0.001. The simple recalculation from the posted summary statistics also estimates a mean difference of -1.8 days/month, but gives an unadjusted p-value of 0.008. The point estimates are consistent in direction and displayed magnitude, while the inferential calculations differ.

That difference is expected because the recalculation is not the sponsor's ANCOVA. It uses only the group summary statistics, estimates pooled variability approximately, and does not incorporate any model adjustments that may have been used in the reported analysis. The registry record does not report the ANCOVA covariates or full model specification, so the sponsor's result cannot be recreated in full from the available summary.

The record does not flag a discrepancy between the analyses. Even so, the sponsor's reported analysis is the appropriate result to cite as the trial's own primary analysis; the recalculation is a simple, unadjusted check and should not replace it. Neither the p-value nor the confidence interval alone establishes clinical importance or describes individual participant outcomes.

15. Multiplicity, Missing Data and Analysis Populations

The registry record identifies a primary endpoint and lists secondary outcomes, but the multiplicity strategy is not reported in the registry record. It is therefore unclear whether any secondary tests were adjusted for the number of outcomes examined, whether a testing hierarchy was prespecified, or whether selected secondary results were intended to support formal confirmatory claims. When multiple hypotheses are tested, unadjusted p-values can overstate how persuasive an isolated small p-value is. This is a general statistical concern, not evidence that a particular result is false.

The primary outcome is clearly described as the mean change in monthly average migraine days through Week 12, and the population used for the efficacy analysis is defined. The record says the efficacy analysis was planned to evaluate the two fremanezumab dose groups together. It does not provide the full statistical analysis plan, including any planned subgroup analyses or detailed testing sequence. Those details should not be inferred from the posted results.

Missing-data handling is also not reported in enough detail. The modified intention-to-treat definition requires at least 10 days of postbaseline primary endpoint assessment, but the registry does not state how incomplete diary records were handled within that analysis, whether imputation was used, or what sensitivity analyses were conducted. The number of participants excluded from the primary efficacy set is not reported in the registry record. These omissions limit assessment of how robust the estimate is to incomplete outcome data.

The registry describes the endpoint calculation as a 28-day normalization based on recorded diary assessments. This explains how the monthly average was derived, but it does not by itself explain how missing assessment days were treated. It is also not reported whether interim analyses occurred, how randomization was implemented, or what formal sample-size rationale governed the trial. These aspects cannot be reconstructed from the reported primary result. The distinction is important: the available result can be interpreted as reported, while unreported methods remain unknown rather than implicitly assumed.

16. 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: pneumonia (1.2%), neurodermatitis (1.2%), vasculitis (1.2%), pneumonia bacterial (1.2%), headache (1.2%).

The registry reports serious adverse event counts separately by treatment group and study period. During the double-blind period, the counts were 1 among 183 participants at risk in the placebo group, 2 among 91 at risk in the monthly fremanezumab group, and 0 among 91 at risk in the quarterly fremanezumab group. During the open-label period, the counts were 0 among 175 at risk in the placebo group, 2 among 86 at risk in the monthly group, and 2 among 85 at risk in the quarterly group.

No deaths are reported in any of the listed groups. The record also lists serious adverse event terms, including pneumonia, neurodermatitis, vasculitis, bacterial pneumonia, headache, and arrhythmia, with the displayed percentages ranging from 1.1% to 1.2%. These entries should be read as reported event summaries, not as proof that a treatment caused an event.

The double-blind and open-label periods are not equivalent comparisons: masking and treatment context differ, and the open-label groups should not be interpreted as a randomized placebo-controlled safety contrast. The counts are small and do not, by themselves, establish comparative safety. The registry record does not provide enough detail to assess event timing, exposure-adjusted rates, or causal attribution.

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

The primary result describes an average difference in change from baseline in monthly migraine days over the double-blind period for the analyzed participants. The reported ANCOVA estimate is -1.8 days/month, with a 95% confidence interval from -2.66 to -0.95. It indicates that the average change was more negative in the combined monthly and quarterly fremanezumab groups than in the placebo group in this analysis.

That finding does not mean every participant had the same response, or that every participant experienced a decrease. Group averages do not describe the full distribution of individual outcomes. The registry record does not report the proportion of participants who had no improvement or worsened on the primary endpoint. A group-level estimate also does not establish the clinical importance of the observed contrast for an individual.

The result is specific to the endpoint definition, the double-blind period, and the modified intention-to-treat analysis set. It applies to the combined fremanezumab schedules; it does not establish which schedule had a larger effect. The trial enrolled adults in China with migraine, so the registry record does not by itself establish how the result would apply to other populations or settings.

The primary endpoint is an efficacy measure and does not settle safety questions. The safety summaries are reported separately, and adverse event counts should be interpreted with their denominators, study periods, and limitations in mind. The open-label period lacks the same blinded placebo comparison as the double-blind period.

Finally, statistical evidence and clinical judgment are different. The confidence interval and p-value characterize the statistical analysis under its assumptions; they do not prove a mechanism, establish long-term outcomes, or resolve the importance of the change for every patient. Unreported methods, including detailed missing-data handling and multiplicity procedures, further limit what can be concluded from the registry record alone.

18. Why This Trial Matters Statistically

This trial illustrates how a continuous clinical endpoint can be analyzed using both a model-based sponsor analysis and a simpler recalculation from group summaries. The primary result is reported as an ANCOVA LS mean difference, while the recalculation uses approximate variability derived from the posted standard errors. The similar displayed point estimates help orient the reader, but the different methods produce different inferential results and should not be conflated.

The design also raises an important interpretation point: monthly and quarterly fremanezumab were combined for the primary efficacy comparison. That approach answers a pooled treatment question against placebo, but does not answer whether one schedule performs differently from the other. Readers should match the scope of the conclusion to the scope of the estimate.

The endpoint definition is consequential. Migraine days were based on diary-reported criteria and converted to a 28-day equivalent. The measure therefore depends on both the clinical definition and the availability of diary assessments. Knowing how a continuous measure was constructed makes it easier to understand what the reported mean change does and does not represent.

Finally, the registry record leaves important statistical details unreported, including the multiplicity plan and detailed missing-data methods. Recognizing these gaps is part of sound evidence interpretation. A clear primary result can be described precisely while still acknowledging that its robustness and broader meaning cannot be fully assessed from the registry record alone.

19. 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 efficacy analysis combines the monthly and quarterly fremanezumab groups. This supports a pooled comparison with placebo but does not provide a separate primary estimate for either schedule. The registry record therefore cannot support a direct statistical comparison between the two schedules based on the primary result.

The primary analysis set is defined by treatment receipt and availability of at least 10 days of postbaseline assessment. The record does not report how many randomized participants were excluded from this set or how missing diary days were handled. Since the endpoint relies on diary assessments and normalizes the result to a 28-day equivalent, incomplete assessment records may be relevant to interpretation, but their impact cannot be determined from the reported information.

The full ANCOVA specification is not reported. The record names the method and provides the LS mean difference, confidence interval, and p-value, but does not specify the covariates or provide model diagnostics. The separate recalculation is unadjusted and relies on approximate pooled variability, so it cannot fill those gaps.

The multiplicity plan for secondary outcomes is not reported in the registry record. Numerical results are not available in the summarized record for every listed secondary outcome. Consequently, secondary findings should be interpreted cautiously and should not be treated as a complete confirmatory testing program.

Safety counts are presented for distinct study periods and treatment contexts. The open-label period is not a blinded placebo comparison, and the registry summaries do not provide event timing, exposure-adjusted rates, or causal assessments. The record also does not report the trial's original sample-size assumptions, interim analysis plans, or detailed randomization procedures.

20. Related Tutorials

21. Related Statistical Calculators

22. Sources

• ClinicalTrials.gov: A Randomized, Double-Blind, Placebo-Controlled Study With an Open-Label Period on Efficacy and Safety of Fremanezumab in Chinese Adults With Migraine — NCT05458011.
• Registry record last updated 2025-11-26; status last verified 2025-11.
• Results first posted 2025-01-31.
• 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.

23. Record Summary

NCT05458011 is a completed Phase 3 randomized, double-blind, placebo-controlled parallel-group study with an open-label period in Chinese adults with migraine. The registry record lists enrollment of 365 and compares placebo with monthly or quarterly subcutaneous fremanezumab during the double-blind period.

The primary endpoint is change from baseline in monthly average migraine days through Week 12. The primary efficacy analysis combined the two fremanezumab schedules. The sponsor-reported ANCOVA estimate was -1.8 days/month, with a 95% confidence interval from -2.66 to -0.95 and p < 0.001. Detailed multiplicity and missing-data methods are not reported in the registry record.