A Randomized, Double-Blind, Parallel Group, Placebo-Controlled Study to Assess STS101 in the Acute Treatment of Migraine: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for A Randomized, Double-Blind, Parallel Group, Placebo-Controlled Study to Assess STS101 in the Acute Treatment of Migraine (NCT04940390), a randomized phase 3 study. The primary outcome is Percentage of Subjects With Freedom From Migraine Headache Pain at 2 Hours Post Dose.

2. Clinical Question

The endpoint was defined using a four-point pain scale, from no pain (0) to severe pain (3). Pain freedom meant that a participant who rated pain as moderate (2) or severe (3) reached no pain (0). This is a specific, time-limited question about the response after a dose; it is not a measure of all symptoms, longer-term migraine patterns, or outcomes beyond the posted follow-up point.

3. Trial Design

The registry describes a completed phase 3, randomized, double-blind, parallel-group, placebo-controlled, multicenter study. It evaluated the efficacy, safety, and tolerability of single doses of STS101, a dihydroergotamine nasal powder, in the acute treatment of migraine. The sponsor was Satsuma Pharmaceuticals, Inc. The registry lists 1591 participants enrolled.

The trial record lists triple masking. The exact roles covered by masking are not reported in the registry record, so the term should not be expanded into assumptions about which individuals were unaware of treatment assignment. Random allocation and a parallel-group design mean that participants were assigned to one of the study groups and remained in that group for the comparison described in the record. The comparator group received STS101 placebo.

The registry records a start date of 2021-06-30 and a primary completion date of 2022-10-13; the overall status is completed. The posted primary comparison includes 716 participants in the STS101 5.2 mg group and 708 in the placebo group. These are the denominators reported for the primary endpoint and should not be assumed to describe every safety or analysis population in the study.

The trial is identified as a multicenter study, but the number and locations of centers are not reported in the registry record. Detailed eligibility criteria, the original sample-size justification, and the full analysis plan are also not reported in the registry record. The posted primary endpoint is pain freedom at 2 hours after dosing. A secondary endpoint addresses relief from migraine headache pain at the same general post-dose time point.

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 1591 participants were randomized in the study, of which 1424 reported a qualifying migraine attack, received study drug, and reported efficacy data in at least one post-treatment e-diary (modified intent to treat population).

Overall Study

Analysis population for the primary outcome, as defined in the registry: The analysis was performed on the mITT population.

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: Patient demographics are presented for the mITT population.

6. Primary Endpoint

The registry lists the primary outcome as Percentage of Subjects With Freedom From Migraine Headache Pain at 2 Hours Post Dose, measured over 2 Hours Post-Dose.

The primary endpoint is the percentage of participants with freedom from migraine headache pain 2 hours after dosing. Pain was rated on a four-point scale: no pain (0), mild pain (1), moderate pain (2), and severe pain (3). For this endpoint, pain freedom means a change from moderate or severe pain to no pain. The endpoint therefore captures a defined state at a specified assessment time, rather than any reduction in pain or a general improvement across migraine symptoms.

A binary endpoint such as pain freedom allows the trial to compare the proportion meeting a clearly stated response definition in each group. The posted counts are 146 of 716 participants for STS101 5.2 mg and 124 of 708 for placebo. The corresponding posted proportions are 0.204 and 0.175. These summaries describe the endpoint among the analyzed participants; they do not by themselves explain how missing assessments were handled or whether any additional analysis rules were applied.

As a general statistical point, a fixed-time binary outcome can be straightforward to interpret because it distinguishes participants who met the endpoint definition from those who did not. It also discards detail: a participant with mild pain and one with severe pain are both outside the pain-freedom category unless the endpoint definition says otherwise. Pain relief is a separate secondary endpoint and should not be treated as interchangeable with complete pain freedom.

7. Results Posted in the Registry

• STS101 5.2 mg: 20.4% (146/716) versus 17.5% (124/708) on control; risk difference 2.9 percentage points (95% CI -1.2 to 6.9), risk ratio 1.16 (0.94–1.44); unadjusted two-proportion z-test p = 0.166.

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.

Percentage of Subjects With Relief From Migraine Headache Pain at 2 Hours Post Dose

• 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:
  • STS101 5.2 mg: 52.9% (379/716) versus 44.6% (316/708) on control; risk difference 8.3 percentage points (95% CI 3.1 to 13.5), risk ratio 1.19 (1.07–1.32); unadjusted two-proportion z-test p = 0.002.
• Interpretation:
  • The 95% confidence interval excludes no difference, so the proportion with the event is statistically higher for STS101 5.2 mg than for the control. This is an unadjusted, secondary comparison, so it is suggestive rather than confirmatory.

The registry posts one secondary endpoint: relief from migraine headache pain at 2 hours after dosing. Its estimated risk difference is 0.083, with a 95% confidence interval from 0.031 to 0.135 and an unadjusted p value of 0.002. This is a more inclusive response concept than the primary endpoint’s requirement for no pain, so the two outcomes address related but distinct questions.

The overall pattern is that the posted secondary comparison has a positive estimated difference and an interval that does not include zero, while the primary pain-freedom comparison has an interval that includes zero. This contrast does not make the endpoints interchangeable or mean that the secondary outcome answers the primary question. It indicates that the observed pattern depends on the particular outcome definition being assessed.

The secondary p value is unadjusted. When multiple outcomes or hypotheses are examined, the chance of obtaining at least one apparently notable result can increase. General statistical practice therefore treats unadjusted secondary findings as less conclusive unless the testing plan, hierarchy, or multiplicity procedure is known. The registry record does not report such a procedure or a prespecified order of testing, and it lists no reported analyses for the secondary endpoint. The posted secondary comparison can be described, but its inferential weight is limited by the missing information about how it fits into the full analysis plan.

The secondary result should be considered alongside the primary result, endpoint definitions, and analysis limitations rather than used to substitute for the primary finding. The registry record does not report additional secondary outcomes with posted estimates in the information summarized for this trial.

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

• Percentage of Subjects With Relief From Migraine Headache Pain at 2 Hours Post Dose

9. Statistical Interpretation

10. Statistical Methods Explained

The primary outcome is binary: each participant either met the stated pain-freedom definition at 2 hours or did not. The posted counts are 146 participants meeting the endpoint among 716 in the STS101 5.2 mg group, and 124 among 708 in the placebo group. The registry presents the comparison as a risk difference, which expresses the difference between the two group proportions. In the posted comparison, the estimated risk difference is 0.029.

What does the risk difference convey?

A risk difference is an absolute comparison between proportions. Its sign indicates which group had the larger observed proportion under the order used in the comparison, while its magnitude describes the separation on the proportion scale. Unlike a relative measure, it does not express the difference as a multiple of the comparator rate. The posted estimate of 0.029 should be interpreted with its confidence interval, from -0.012 to 0.069, because the point estimate alone does not show the range of uncertainty compatible with the data and method.

How should the confidence interval be read?

A confidence interval gives a range of estimates compatible with the observed data under the statistical procedure used. It reflects sampling uncertainty, not every possible source of uncertainty in a trial. The primary interval extends across zero, so the posted data are compatible with a small difference in either direction as well as a positive difference. A confidence interval is not a guarantee that the true value lies within its endpoints, nor does it assess potential bias from missing data, outcome measurement, or analysis choices.

What does the p value add?

The primary unadjusted p value is 0.166. In general, a p value describes how unusual data at least as inconsistent with a specified null model would be if that model and the test assumptions were correct. It is not the probability that the null hypothesis is true, nor does it measure the size or practical importance of an effect. The unadjusted label matters: the registry record does not report a multiplicity adjustment for this comparison. The estimate, interval, endpoint definition, and analysis population all remain important to interpretation.

What are relative measures?

The posted comparison also includes a risk ratio of 1.164, with an interval from 0.938 to 1.444, and an odds ratio of 1.206, with an interval from 0.925 to 1.574. A risk ratio compares the two proportions as a ratio; an odds ratio compares the odds of meeting the endpoint. These measures use different scales from the risk difference and are not interchangeable. Their intervals also include the null value for a ratio measure. The registry record does not report an adjusted analysis that would account for other participant characteristics.

Why distinguish pain freedom from pain relief?

The secondary endpoint measures relief from migraine headache pain, whereas the primary endpoint requires reaching no pain from moderate or severe pain. The definitions capture different degrees of response. For binary outcomes, changing the response threshold can change how many participants qualify and can alter the estimated comparison. The secondary result must therefore be read as evidence about its own outcome definition, not as another version of the primary endpoint.

What does an unadjusted comparison imply?

An unadjusted comparison uses the posted group summaries without accounting for additional covariates in the comparison. This does not establish that the original trial analysis used no adjustments: the registry record does not report enough detail to determine the full statistical procedure. The simple recalculated comparison is useful for understanding the posted counts, but the primary analysis plan and any sponsor analysis are not described in detail in the registry record. The discrepancy indicator is false, and no conflict between the posted count-based calculation and the listed comparison is flagged.

General statistical considerations also apply to binary outcomes. Precision depends on the number of participants and the frequency of the event, and the method used to calculate an interval or test can affect its value. The exact inferential procedure used for the registry’s displayed comparisons is not reported in the registry record. Accordingly, the numerical estimates are best read alongside the explicit endpoint definition, group counts, interval, and limits of the analysis information available.

11. Confidence Intervals and Precision

The primary estimate is a risk difference of 0.029, with a 95% confidence interval from -0.012 to 0.069. This interval spans zero. In practical statistical terms, the posted estimate is not very precise about the direction of the difference: values on either side of zero remain compatible with the interval. The interval also spans effects of differing size, so the point estimate should not be treated as a fixed or exact measure of the group contrast.

Confidence intervals quantify sampling uncertainty under the method used. They do not account automatically for uncertainty about the trial’s analysis choices, possible missing outcome data, or the broader applicability of the study population. The registry record identifies an mITT population for the primary analysis but does not report the detailed population definition or missing-data procedures. Those omissions limit what can be concluded about sources of uncertainty beyond the interval itself.

The posted risk-ratio interval is 0.938 to 1.444, and the odds-ratio interval is 0.925 to 1.574. Each includes its ratio-scale null value. These relative measures offer another description of the same binary outcome, but they do not make the estimate more certain than the underlying data support. The absolute risk difference remains useful because it expresses the observed contrast directly on the proportion scale.

General interpretation: a narrow interval indicates greater statistical precision than a wide interval, provided the same type of method and outcome are being compared. Precision is distinct from importance and from whether a result passes a significance threshold. For this primary comparison, the interval’s inclusion of zero and its breadth should be considered alongside the group counts and the unadjusted p value of 0.166.

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 calculations. For these binary outcomes, the figures are participants per arm; they are not total events. The stated assumptions are a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation. Each planning scenario targets a stated fraction of the observed effect, with separate columns for participants per arm for 80% power and participants per arm for 90% power.

Power describes the probability that a planned study would detect an effect of the specified size under the planning assumptions if that effect were the true one. The 80% column gives the per-arm sample size associated with an 80% chance of detection under those assumptions; the 90% column gives the per-arm size associated with a 90% chance. A higher target probability generally requires more participants. Planning for 75% or 50% of the observed effect represents a smaller effect than planning for 100% of the observed effect, and smaller effects need more participants to detect with the same power target.

For the primary endpoint, the planning illustrations use the observed risk difference of 0.029 and display scenarios for 100%, 75%, and 50% of that effect. The corresponding per-arm figures are listed in the planning display. They are not evidence that the trial had a particular probability of success after it was completed: this is not observed power. The registry record does not report the original sample-size justification or its planning assumptions.

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, p₀ and p₁ are the control and treatment proportions, and p̄ is their average.

Worked calculation for this trial

1. Control proportion p₀ = 0.175; treatment proportion p₁ = 0.204; average p̄ = 0.190.
2. First term: z_1−α/2 × √[2p̄(1−p̄)] = 1.96 × 0.5543 = 1.0863.
3. Second term: z_1−β × √[p₀(1−p₀) + p₁(1−p₁)] = 0.842 × 0.5539 = 0.4662.
4. n = (1.0863 + 0.4662)² / (0.0288)² = 2,912.1, rounded up to 2,913 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
p0 <- 0.175141242937853                          # control proportion
p1 <- 0.20391061452514                          # treatment proportion
n_per_arm <- function(power, frac = 1) {
  q1 <- p0 + (p1 - p0) * frac               # smaller effect = fraction of the observed difference
  pbar <- (p0 + q1) / 2
  z_b <- qnorm(power)
  ceiling(round((z_a * sqrt(2 * pbar * (1 - pbar)) + z_b * sqrt(p0 * (1 - p0) + q1 * (1 - q1)))^2 / (q1 - p0)^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 (unrounded n per arm)
cat("power.prop.test:", round(power.prop.test(p1 = p0, p2 = p1, power = 0.80)$n, 1), "\n")

# Simulation: how often does the z-test reject at the 80%-power sample size?
set.seed(4940390)
n    <- n_per_arm(0.80)
reps <- 20000
x0 <- rbinom(reps, n, p0); x1 <- rbinom(reps, n, p1)
ph <- (x0 + x1) / (2 * n)
z  <- ((x1 - x0) / n) / sqrt(ph * (1 - ph) * 2 / n)
cat(sprintf("Simulated power at n = %s per arm: %.3f (%d replicates)\n", format(n, big.mark = ","), mean(abs(z) > z_a, na.rm = TRUE), reps))

Output from running the code

100% of observed effect: n per arm = 2,913 (80% power), 3,898 (90% power)
 75% of observed effect: n per arm = 5,103 (80% power), 6,831 (90% power)
 50% of observed effect: n per arm = 11,310 (80% power), 15,140 (90% power)
power.prop.test: 2912.1 
Simulated power at n = 2,913 per arm: 0.802 (20000 replicates)

The simulation draws many pairs of event counts at the planned sample size and counts how often the two-proportion z-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

Multiplicity arises when a study evaluates more than one outcome, comparison, time point, or analysis. If each is tested separately without accounting for the collection of tests, the overall chance of a false-positive finding can be higher than for a single prespecified test. General approaches include a testing hierarchy or a statistical adjustment, but the registry record does not report whether either was used for this trial.

The record posts one secondary endpoint, relief from migraine headache pain at 2 hours, and its comparison is labelled unadjusted. It does not report a multiplicity correction, a confirmatory testing sequence, or the planned relationship between the primary and secondary endpoints. Consequently, the secondary p value should not be interpreted as though the registry had established it as a multiplicity-controlled confirmatory result.

The primary analysis population is identified as mITT. The meaning of that population, the exact inclusion rules for the analysis, and how participants with missing endpoint assessments were handled are not reported in the registry record. The record also does not report imputation methods, sensitivity analyses, or assumptions about missing outcomes. These details matter because the observed proportions depend on which participants contribute outcome data and how unavailable measurements are treated.

The registry record does not report the full statistical analysis plan, covariate adjustment, interim analyses, or the original sample-size justification. These absences do not establish that such procedures were not used; they mean their use and details cannot be evaluated from the registry record. Interpretation should therefore stay close to the posted counts and comparisons, while recognizing that the full handling of multiplicity, missingness, and analysis populations is not documented 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 2% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: suicide attempt (0.1%), procedural abdominal pain post-hysterectomy (0.1%), asthma exacerbation/pneumonia (0.1%).

The posted serious adverse event figures list 3 affected participants among 731 at risk in the STS101 5.2 mg group and 0 among 729 at risk in the placebo group. No deaths are listed in either group. The registry lists Suicide Attempt, Procedural Abdominal Pain Post-hysterectomy, and Asthma Exacerbation/Pneumonia among the top serious terms, each with a reported value of 0.1%.

These are descriptive counts. They do not establish that an event was caused by study treatment, and the registry record does not provide individual case details or an attribution assessment for these events. The safety denominators differ from the primary endpoint denominators: the reported serious-event risk groups are 731 and 729, while the primary analysis groups are 716 and 708. The registry record does not explain the difference.

The separate other-adverse-event counts are 111 of 731 in the STS101 5.2 mg group and 14 of 729 in the placebo group. These figures should be read as registry-reported counts, not as evidence that every event had the same severity, duration, or relationship to treatment. Small event counts and the absence of detailed case information limit comparisons, especially for rare serious events.

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

The primary result describes a higher observed proportion meeting the pain-freedom definition in the STS101 5.2 mg group than in the placebo group: 0.204 compared with 0.175. The estimated risk difference is 0.029. Its 95% confidence interval, from -0.012 to 0.069, includes zero, and the unadjusted p value is 0.166. Taken together, these statistics show a positive point estimate but substantial uncertainty about the direction and size of the difference.

This result does not establish that the groups differ on the primary endpoint, nor does it prove that they are equivalent. A confidence interval crossing zero is compatible with a range of possible differences; it is not evidence that the true difference is exactly zero. The registry record also does not report enough detail about missing data, the full analysis plan, or the mITT definition to assess every potential influence on the estimate.

The secondary pain-relief result has a positive estimated difference and an interval that does not include zero, but it concerns a different endpoint and is unadjusted. Without reported information on multiplicity or the testing hierarchy, it should be interpreted cautiously and should not be treated as overriding the primary result.

More generally, registry results address the outcomes, populations, and time points that are reported. They do not establish effects on unreported outcomes, longer-term patterns, or populations not described by the record. The safety counts are also descriptive and do not establish causation. Statistical interpretation concerns the strength and limits of the posted evidence; it is not medical advice or a recommendation about treatment.

17. Why This Trial Matters Statistically

This trial is statistically informative because it reports a randomized, placebo-controlled comparison with explicit group counts for a binary primary endpoint. The endpoint definition is specific: pain freedom means a participant moves from moderate or severe pain to no pain at 2 hours after dosing. That clarity makes it possible to distinguish complete pain freedom from the separate secondary concept of pain relief.

The primary estimate illustrates why an effect estimate should be read together with its precision. The point estimate is positive, but the confidence interval includes zero and the unadjusted p value is 0.166. Looking only at the point estimate would understate uncertainty; looking only at a thresholded p value would discard the estimated direction and range of plausible values. The counts and interval together support a more measured reading of the evidence.

The secondary endpoint also illustrates the importance of prespecification and multiplicity. Its result differs in inferential appearance from the primary comparison, but the registry record does not explain whether it was part of a hierarchy or whether any adjustment was used. Reporting the outcome is useful, while the missing testing-plan details constrain how strongly it can be interpreted.

Finally, the record distinguishes outcome-analysis denominators from safety denominators and identifies the primary population as mITT without defining it further. Those details remind readers that results depend not only on the randomized groups but also on which participants and events enter each analysis. Clear reporting of population definitions, missing-data procedures, and statistical plans is important for evaluating how robust a trial’s estimates are.

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 trial-specific limitations of interpretation arise from details not reported in the registry record. The exact eligibility criteria are not included in the available record summary, so the characteristics of the study population and the boundaries of generalizability cannot be assessed in detail. Although the trial is described as multicenter, the number and locations of centers are not reported.

The primary endpoint analysis is identified as mITT, but the record does not define that population or explain how participants with missing 2-hour assessments were handled. The primary endpoint denominators are 716 and 708, while the safety risk groups are 731 and 729; the registry record does not explain these differences. No missing-data sensitivity analyses are reported in the record.

The record also does not report the original sample-size justification, the complete statistical analysis plan, covariate adjustments, or interim analyses. The posted planning illustrations are based on the observed effect and stated generic assumptions, so they do not replace the trial’s original design rationale. The secondary endpoint has an unadjusted comparison, but the record does not report a multiplicity strategy or testing hierarchy. These omissions limit assessment of confirmatory status and the role of the secondary finding.

Safety information is presented as counts and selected serious event terms. The record does not provide case narratives, event timing, or causal attribution details, so the counts should not be used to infer that treatment caused an event or to characterize individual event courses. The registry status is completed, but the information summarized in the record does not supply a detailed account of all outcomes or analyses.

19. Related Tutorials

20. Related Statistical Calculators

21. Sources

• ClinicalTrials.gov: A Randomized, Double-Blind, Parallel Group, Placebo-Controlled Study to Assess STS101 in the Acute Treatment of Migraine — NCT04940390.
• Registry record last updated 2023-11-27; status last verified 2023-11.
• Results first posted 2023-07-24.
• 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 registry record describes NCT04940390, a completed phase 3 randomized, triple-masked, parallel-group, placebo-controlled, multicenter study sponsored by Satsuma Pharmaceuticals, Inc. It evaluated single doses of STS101, a dihydroergotamine nasal powder, for acute migraine. The record lists 1591 participants enrolled.

The primary endpoint was freedom from migraine headache pain 2 hours after dosing in the mITT population. The posted comparison was 146 of 716 participants for STS101 5.2 mg and 124 of 708 for placebo. The risk difference was 0.029, with a 95% confidence interval from -0.012 to 0.069 and an unadjusted p value of 0.166. One secondary pain-relief endpoint is posted. The registry record does not report the full analysis plan, original sample-size justification, detailed missing-data procedures, or multiplicity approach.