Study to Demonstrate the Efficacy, Safety and Tolerability of an Intravenous Regimen of Secukinumab Compared to Placebo in Subjects With Active axSpA: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Study to Demonstrate the Efficacy, Safety and Tolerability of an Intravenous Regimen of Secukinumab Compared to Placebo in Subjects With Active axSpA (NCT04156620), a randomized phase 3 study. The primary outcome is Percentage of Participants Who Achieved an ASAS40 (Assessment of SpondyloArthritis International Society Criteria).

2. Clinical Question

The trial asked whether an intravenous secukinumab regimen produced a different Week 16 ASAS40 response proportion from an intravenous placebo regimen among participants with active ankylosing spondylitis or non-radiographic axial spondyloarthritis. The study description concerns participants whose disease remained active despite current or previous NSAID, DMARD and/or anti-TNF therapy. The primary endpoint assessed change from baseline to Week 16.

ASAS40 is a composite responder definition. A participant must achieve at least a 40% improvement and an absolute improvement of at least 20 units in at least three of four domains: back pain, patient global assessment of disease activity, physical function and inflammation. The remaining domain must not worsen. The endpoint therefore asks whether improvement is broad across several aspects of disease assessment, rather than reflecting a change in only one measure.

The comparison is between assigned treatment groups, not a comparison of each group with its own baseline alone. The central statistical question is the difference between the observed response proportions, together with the uncertainty around that difference. The registry reports the sponsor’s logistic-regression analysis as a marginal difference and also gives group response proportions with confidence intervals.

The registry describes missing responses for any reason in the primary full analysis set as non-responses. This makes the primary question one of response under that stated classification rule. The endpoint does not by itself address every possible measure of disease activity, function, quality of life, longer-term outcomes, or safety.

3. Trial Design

NCT04156620 is a completed Phase III study sponsored by Novartis Pharmaceuticals. The registry describes a randomized, parallel-group, placebo-controlled, multicenter study. Its official title calls it double-blind, while the registry’s masking classification is quadruple. Both descriptions are recorded, but the specific roles covered by the masking classification are not reported in the registry record.

The registry records an enrollment of 527. The primary endpoint arm summaries include 264 participants in the secukinumab arm and 262 in the placebo arm. The study population was described as people with active ankylosing spondylitis or non-radiographic axial spondyloarthritis. The condition field lists ankylosing spondylitis, while the study summary and official title also include non-radiographic axial spondyloarthritis.

The primary comparison was scheduled from baseline to Week 16. The study description says data were collected for up to 52 weeks to further support assessment of efficacy and safety. The registry lists the primary endpoint as the percentage of participants achieving ASAS40 and identifies the full analysis set, with missing responses for any reason imputed as non-responders.

The registry records the study start as 2019-12-11, primary completion as 2022-02-17, and status as completed. The original sample-size justification, the assumptions used in the trial’s design, details of any interim analyses, and the complete statistical analysis plan are not reported in the registry record. The planning illustrations associated with the posted results are separate from the trial’s original design calculations.

The posted arm labels include AIN457, while the intervention descriptions identify secukinumab and placebo intravenous regimens. The record lists 12 outcome measures and 12 analyses, with 11 secondary outcomes posted. These registry totals do not establish that every outcome was measured or analyzed in an identical way at every 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: 769 participants were screened for the study and 527 participants were randomized. However, one participant was mis-randomized and discontinued prior to dosing and is not included in the table below.

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: Full analysis set with missing responses for any reason imputed as non-responders.

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 Percentage of Participants Who Achieved an ASAS40 (Assessment of SpondyloArthritis International Society Criteria), measured over Baseline to Week 16.

The primary endpoint is the percentage of participants achieving ASAS40 from baseline to Week 16. ASAS40 requires at least a 40% improvement and at least a 20-unit absolute improvement, on the specified 0–100 ranges, in at least three of four domains: back pain, patient global assessment of disease activity, physical function measured by BASFI, and inflammation based on BASDAI items. There must be no worsening in the remaining domain.

This is a composite response definition: success depends on improvement across multiple domains and on the absence of worsening in the fourth. Such a definition can summarize several aspects of a condition in one endpoint, but the resulting percentage does not show the size of change in each domain separately. Nor does it describe participants who improved without meeting the full responder rule.

The registry also describes six ASAS domains, including two additional domains concerning spinal mobility and C-reactive protein. The primary ASAS40 definition itself is based on the four main domains. The primary population is the full analysis set, with missing responses for any reason counted as non-responses. The endpoint is therefore interpreted as a group-level comparison of the proportions meeting this specific rule by Week 16, not as a complete account of every clinical outcome or the course of each participant.

ASAS40 is used to represent a meaningful response across several assessed areas rather than a single isolated measurement. The registry record does not report the rationale used to select this endpoint or its role in the trial’s original sample-size justification.

7. Results Posted in the Registry

• AIN457 6 mg/kg - 3 mg/kg i.v.: 40.9% (108/264) versus 22.9% (60/262) on control; risk difference 18.0 percentage points (95% CI 10.2 to 25.8), risk ratio 1.79 (1.37–2.33); unadjusted two-proportion 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.

Percentage of Participants Who Achieved Ankylosing Spondylitis Disease Activity Score (ASDAS)-C-Reactive Protein (CRP) Major Improvement

• 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:
  • AIN457 6 mg/kg - 3 mg/kg i.v.: 28.0% (74/264) versus 7.6% (20/262) on control; risk difference 20.4 percentage points (95% CI 14.1 to 26.7), risk ratio 3.67 (2.31–5.84); 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 AIN457 6 mg/kg - 3 mg/kg i.v. than for the control. This is an unadjusted, secondary comparison, so it is suggestive rather than confirmatory.

The Change From Baseline in Total Bath Ankylosing Spondylitis Disease Activity Index (BASDAI)

• 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:
  • AIN457 6 mg/kg - 3 mg/kg i.v.: mean -2.70 versus -1.69 on control; difference -1.01 (95% CI -1.41 to -0.61), standardized effect d = -0.44; z-test p = <0.001.
• Interpretation:
  • The 95% confidence interval excludes no difference, so the mean is statistically lower for AIN457 6 mg/kg - 3 mg/kg i.v. than for the control. This is an unadjusted, secondary comparison, so it is suggestive rather than confirmatory.

The Change From Baseline in Total Bath Ankylosing Spondylitis Functional Index (BASFI)

• 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:
  • AIN457 6 mg/kg - 3 mg/kg i.v.: mean -2.33 versus -1.39 on control; difference -0.94 (95% CI -1.35 to -0.53), standardized effect d = -0.40; z-test p = <0.001.
• Interpretation:
  • The 95% confidence interval excludes no difference, so the mean is statistically lower for AIN457 6 mg/kg - 3 mg/kg i.v. than for the control. This is an unadjusted, secondary comparison, so it is suggestive rather than confirmatory.

The numerical secondary results posted for Week 16 point in a direction consistent with the primary comparison. The secukinumab group has a higher reported percentage achieving ASDAS-CRP major improvement, while the reported mean changes for BASDAI and BASFI are more negative in that group than in the placebo group. The sponsor-reported secondary analyses identify superiority for these outcomes.

These results add information about disease activity and function beyond the ASAS40 responder definition. They do not simply repeat the same outcome: ASDAS-CRP major improvement is another responder measure, while BASDAI and BASFI are continuous change-from-baseline measures. Their agreement in direction provides context for the primary finding, but does not establish that every outcome domain or every participant changed similarly.

The registry lists additional secondary outcomes, including ASAS 5/6, SF-36 PCS, ASQol, hsCRP and ASAS20. Numerical findings for all of those outcomes are not reported in the information available in the registry record. The record lists 11 secondary outcomes posted; that count does not mean all listed outcomes have detailed numerical results in the record.

Unadjusted secondary p-values carry less weight when several outcomes are examined because the chance of finding at least one apparently notable result can increase with multiple testing. Whether and how the trial controlled multiplicity across secondary outcomes is not reported in the registry record. Secondary findings are therefore best treated as supportive context rather than independent confirmation on the same footing as the primary endpoint.

The secondary outcomes also differ in scale and analysis method. Percentages of responders, score changes and laboratory measurements answer related but distinct questions. The results should not be combined into a single effect estimate or treated as interchangeable measures of one underlying response.

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

• Percentage of Participants Who Achieved Ankylosing Spondylitis Disease Activity Score (ASDAS)-C-Reactive Protein (CRP) Major Improvement
• The Change From Baseline in Total Bath Ankylosing Spondylitis Disease Activity Index (BASDAI)
• Percentage of Participants Who Achieved an ASAS 5/6 (Assessment of Spondylarthritis International Society Criteria)
• The Change From Baseline in Total Bath Ankylosing Spondylitis Functional Index (BASFI)
• The Change From Baseline in Short Form-36 Physical Component Summary (SF-36 PCS)
• The Change From Baseline in Ankylosing Spondylitis Quality of Life (ASQol)
• The Change From Baseline in High Sensitivity C-Reactive Protein (hsCRP)
• Percentage of Participants Who Achieved an ASAS20 (Assessment of SpondyloArthritis International Society Criteria)

9. Statistical Interpretation

10. Statistical Methods Explained

The primary endpoint is binary: each participant either meets the ASAS40 responder definition or does not. The group summaries are percentages, and the primary comparison is a difference in response proportions. This makes the result interpretable as a contrast in the fraction of participants meeting the composite response rule, rather than a comparison of average scores.

What the primary comparison estimates

The registry-reported method is logistic regression, with the reported parameter described as a marginal difference. Logistic regression models the probability of a binary outcome using the log odds scale, then can express a group contrast on the probability scale as a marginal difference. The registry gives the resulting estimate as 17.91, with a 95% confidence interval from 10.12 to 25.71 and p < 0.001. Details of model covariates, any stratification factors, and the precise marginalization procedure are not reported in the registry record.

The unadjusted recalculation uses posted event counts and group sizes to estimate a risk difference directly from the observed summaries. It does not reproduce a model-adjusted analysis. The recalculated estimate is 0.180, with a 95% confidence interval from 0.102 to 0.258 and p < 0.001. This is a simple comparison based on the posted summaries, not a substitute for the sponsor’s stated regression analysis.

How to read the p-value

General explanation: a p-value describes how compatible the observed data, or data more extreme, are with a specified null model and its assumptions. It is not the probability that the null hypothesis is true, nor does it measure the magnitude or clinical importance of an effect. The sponsor-reported p-value is tied to its logistic-regression analysis; the recalculated p-value is tied to the unadjusted comparison. Their numerical thresholds should therefore be understood in the context of their respective methods.

The registry classifies the primary analysis as a superiority analysis. That label describes the direction of the statistical question in the reported analysis, not a complete interpretation of the endpoint, the uncertainty, or the practical meaning of the observed result. A confidence interval alongside the point estimate supplies information about the range of effects compatible with the analysis at its stated confidence level.

Why a binary endpoint matters

General explanation: binary responder outcomes make a threshold-based question easy to state, but they discard some information about how far individual participants are from the threshold. Two participants with different degrees of improvement may both count as responders, while a participant just short of the rule counts as a non-responder. The reported percentage therefore describes how often the full rule was met, not the distribution of every underlying measurement.

ASAS40 itself combines several domains and requires no worsening in the remaining domain. That construction reflects a multi-domain response, but it also means that the responder proportion can be affected by any one component’s measurement or missingness. In this trial, the primary analysis specifies that missing responses for any reason are imputed as non-responders. Details of the imputation implementation beyond that rule are not reported in the registry record.

Meaning of the secondary continuous analyses

The posted BASDAI and BASFI results are changes from baseline summarized as least-squares means, with standard errors for the arm estimates. Their sponsor-reported comparisons use mixed models analysis and report LS mean change, confidence intervals and p-values. General explanation: a least-squares mean is a model-based mean, rather than necessarily the raw arithmetic average. A mixed model can account for the structure of repeated measurements, but the specific model structure, covariance assumptions, covariates and handling of missing continuous outcomes are not reported in the registry record.

The unadjusted recalculations for those outcomes are based on posted summaries. The record marks the pooled standard deviation as approximate, so standardized summaries derived from it are approximate as well. Such recalculations are useful for context, but they should not be treated as a reproduction of the sponsor’s mixed-model analysis.

Over-dispersion and count models

General explanation: over-dispersion occurs when count data vary more than a simple model assumes. In a count endpoint, this can make standard errors too small if the model does not allow for that extra variation. The primary endpoint in this trial is a binary percentage, not a count-rate endpoint, and the posted primary analysis is logistic regression. The registry does not report an over-dispersion model for the primary endpoint.

Finally, the registry record does not report the complete prespecified statistical analysis plan, whether interim analyses were conducted, the original sample-size calculation, or the adjustment strategy for all secondary outcomes. These omissions limit how completely the posted analyses can be situated within the trial’s initial design decisions.

11. Confidence Intervals and Precision

The sponsor-reported primary marginal difference is 17.91, with a 95% confidence interval from 10.12 to 25.71. The interval gives a range of values reasonably compatible with the model and data under the analysis assumptions. Because the interval is entirely above zero, the reported comparison supports a positive difference in the response proportions for the secukinumab group relative to placebo under that analysis.

The unadjusted recalculation gives a risk difference of 0.180, with a 95% confidence interval from 0.102 to 0.258. This interval also excludes zero. The sponsor and recalculated intervals arise from different methods, so the difference between their endpoints should not be interpreted as an inconsistency in the posted record. The registry does not identify a discrepancy.

The individual response-proportion intervals are 34.94 to 46.76 for secukinumab and 17.86 to 28.02 for placebo. These intervals describe uncertainty for each arm separately. For inference about the contrast, the confidence interval for the marginal difference or risk difference is the appropriate direct summary, rather than a visual comparison of the two arm intervals.

General explanation: a confidence interval is not a guarantee that the true value lies in the particular interval, nor does a 95% interval mean that 95% of participants’ outcomes fall within its limits. Its interpretation depends on the statistical procedure and its assumptions. Precision concerns how narrowly the effect is estimated; it does not establish clinical importance or eliminate bias, measurement limitations or uncertainty from unreported analysis details.

The Week 16 endpoint and its responder definition also constrain what these intervals mean. They quantify uncertainty about a group-level response contrast for this endpoint and time frame, not all possible effects across the full 52-week data collection period or every secondary outcome.

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 calculation. For the binary primary endpoint, the figures refer to participants per arm, not total events. The listed assumptions are a two-sided significance level of 0.05, equal allocation between the two arms, a normal approximation, and an effect to detect equal to the stated fraction of the observed effect. The trial’s own original sample-size assumptions are not reported in the registry record.

The 80% power column means the illustrated number of participants per arm for a design that would have an 80% probability of detecting the specified effect under the planning assumptions, if that effect and those assumptions held. The 90% column uses a higher target probability of detecting that effect. These are design-planning concepts; they are not probabilities that the trial’s conclusion is correct.

The illustrations use 100%, 75% and 50% of the observed effect. As the assumed effect becomes smaller, more participants are needed to detect it at the same target power and significance level. For example, the primary endpoint illustration lists 104 participants per arm for 80% power at 100% of the observed effect, 179 for planning for 75% of the observed effect, and 385 for planning for 50% of the observed effect. For 90% power, the corresponding figures are 139, 239 and 514 participants per arm.

These calculations are sensitive to the planning assumptions, including the target effect and the analysis approximation. They do not account for unreported details of the trial’s original design, and should not be read as a reconstruction of that design. This is not observed power.

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 = 0.229; treatment proportion p₁ = 0.409; average p̄ = 0.319.
2. First term: z_1−α/2 × √[2p̄(1−p̄)] = 1.96 × 0.6592 = 1.2920.
3. Second term: z_1−β × √[p₀(1−p₀) + p₁(1−p₁)] = 0.842 × 0.6468 = 0.5443.
4. n = (1.2920 + 0.5443)² / (0.1801)² = 104.0, rounded up to 104 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 <- 0.229007633587786                          # control proportion
p1 <- 0.409090909090909                          # 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(4156620)
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 = 104 (80% power), 139 (90% power)
 75% of observed effect: n per arm = 179 (80% power), 239 (90% power)
 50% of observed effect: n per arm = 385 (80% power), 514 (90% power)
power.prop.test: 104 
Simulated power at n = 104 per arm: 0.797 (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. Analyses Reported by the Sponsor

The sponsor’s reported primary analysis uses logistic regression and gives a marginal difference of 17.91, with a 95% confidence interval from 10.12 to 25.71 and p < 0.001. The posted analysis is classified as superiority. This is the sponsor-reported model-based comparison in the registry record.

The recalculation uses the posted group summaries and gives an unadjusted risk difference of 0.180, with a 95% confidence interval from 0.102 to 0.258 and p < 0.001. It is a simple re-analysis of summary statistics and does not reproduce the logistic-regression model or any adjustments included in it. The estimates are close in scale, but the methods and reported quantities are not identical.

The registry does not flag a discrepancy between the sponsor analysis and the recalculation. The sponsor’s result should therefore be understood as the reported inferential analysis, while the recalculation offers a transparent unadjusted check based on the posted summaries. Neither result should be interpreted without its endpoint definition, analysis population and confidence interval.

15. Multiplicity, Missing Data and Analysis Populations

The primary endpoint is clearly identified as Week 16 ASAS40, and its primary population and missing-response rule are described. The registry does not report a complete statistical analysis plan, the planned hierarchy among primary and secondary tests, or a multiplicity adjustment strategy for secondary outcomes. It is therefore not possible to establish from the registry record whether the reported secondary p-values were adjusted for the number of outcomes or comparisons.

General explanation: when several hypotheses are tested, the chance of at least one small p-value under a collection of null hypotheses can be greater than for a single test. Prespecified testing hierarchies or other multiplicity procedures can address that issue. Without reported details, secondary p-values should be read as nominal evidence and interpreted cautiously, not as if they were necessarily protected from multiplicity.

For the primary endpoint, the record states that participants in the full analysis set with missing responses for any reason were imputed as non-responders. This is a specific rule for the primary binary outcome. The registry does not report further implementation details, such as the number of missing responses or sensitivity analyses testing alternative assumptions.

The registry does not describe missing-data handling for the secondary outcomes in the details available for this analysis. In particular, the primary non-responder imputation rule should not be assumed to apply to the continuous BASDAI and BASFI analyses or every other secondary measure. The mixed models analysis is named for those continuous outcomes, but model specification and missing-data assumptions are not reported in the registry record.

The analysis populations for secondary outcomes, the use of covariate adjustment, any interim analyses, and the original sample-size justification are also not reported in the registry record. These gaps limit assessment of how closely posted analyses follow the full prespecified plan and whether the inferential evidence across outcomes was controlled as intended.

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 2% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: myocardial infarction (0.4%), abdominal pain (0.4%), colitis ulcerative (0.4%), cellulitis (0.4%), cholecystitis (0.4%).

The registry reports serious adverse event counts for Any AIN457 and Placebo Until Week 16 groups. In the Any AIN457 group, 32 serious adverse events are recorded among 517 participants at risk; in the Placebo Until Week 16 group, 3 are recorded among 261 at risk. The other adverse event counts are 172 among 517 and 35 among 261, respectively. Deaths are recorded as 1 and 0.

These are group-level counts with the listed denominators. The group labels distinguish Any AIN457 from placebo through Week 16, so the figures should not be treated as if they necessarily represent identical exposure periods. The registry also lists six serious-event terms at 0.4% each: myocardial infarction, abdominal pain, ulcerative colitis, cellulitis, cholecystitis and tonsillitis.

These summaries do not show event timing, duration, severity beyond the serious classification, whether events were judged treatment-related, or whether one participant could contribute more than one event. Those details are not reported in the registry record. The counts are descriptive safety information and do not by themselves establish cause or permit a complete comparison of risk.

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

The posted primary result describes the proportion of participants meeting the ASAS40 composite response rule at Week 16. The secukinumab arm’s reported percentage is 40.85, compared with 22.94 in the placebo arm. The sponsor’s logistic-regression analysis reports a marginal difference of 17.91, with a 95% confidence interval from 10.12 to 25.71 and p < 0.001. The unadjusted recalculation also yields a confidence interval above zero.

This is evidence about a group-level difference for this specific endpoint, population, treatment regimen and time point. It does not show that every participant in the secukinumab group met the response definition, or that no participant in the placebo group did. Nor does the responder proportion describe the full range of changes among people who did not meet the threshold.

The result does not by itself establish the size of change in each ASAS domain, explain which components drove the composite response, or answer questions about every secondary outcome. The primary endpoint’s missing-response rule counts missing responses as non-responses, and the record does not provide the number missing or sensitivity analyses that might show how alternative assumptions affect the result.

The study collected data for up to 52 weeks, but the primary comparison is baseline to Week 16. The result should not be extended to later time points based only on the primary endpoint. Similarly, the registry’s safety counts are descriptive summaries and do not establish whether an event was caused by a treatment.

Statistical evidence and clinical importance are related but distinct. The confidence interval conveys uncertainty about the estimated group contrast under the analysis assumptions; it does not determine whether the magnitude is important to patients or how it compares with other evidence. The registry record does not provide a threshold for clinical importance or the full contextual information needed to resolve that question.

18. Why This Trial Matters Statistically

This study illustrates how a clinical trial can pair a threshold-based composite endpoint with both model-based and unadjusted summaries. ASAS40 asks whether a participant improves across several domains without worsening in the remaining domain, while the group comparison estimates how frequently that full response rule was met in each randomized arm.

The primary result also demonstrates why the comparison estimate and its confidence interval matter alongside the individual arm percentages. The sponsor reports a marginal difference with an interval that excludes zero, while the unadjusted recalculation provides a related but methodologically distinct contrast. Reading both clarifies what is directly reported and what can be checked from the posted summaries.

The trial’s secondary results show how different outcome types can provide complementary context: responder proportions, disease activity scores and functional scores are not interchangeable, even when their directions align. They also highlight the importance of multiplicity reporting when multiple outcomes are tested. Without the full plan, secondary results should not be treated as equivalent to a multiplicity-controlled primary finding.

Finally, planning illustrations based on observed effects are not the same as a prospective sample-size justification. Showing how assumed smaller effects require more participants helps explain design sensitivity, but the original design assumptions are not reported in the registry record. Separating design planning, observed results and post hoc illustrations is important for sound statistical interpretation.

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.
• Participant counts were reconstructed from posted percentages and arm sizes, so small rounding differences are possible.

The registry record does not report the complete statistical analysis plan, including model covariates, the precise marginalization procedure for logistic regression, or the planned approach to multiplicity across secondary outcomes. It also does not report the original sample-size justification or whether interim analyses were conducted. These omissions limit assessment of the full prespecified analysis strategy.

The primary endpoint has a specific threshold-based composite definition. It summarizes response across four domains but does not show the separate contribution of each domain or the distribution of improvements among non-responders. Missing responses in the primary full analysis set are classified as non-responses, but the number of missing values and sensitivity analyses are not reported in the registry record.

The posted secondary results do not provide numerical findings for every listed secondary outcome in the available record. Secondary outcome populations and missing-data procedures are not fully described. Multiplicity handling is also not reported, so the secondary p-values should not be treated as necessarily adjusted for multiple testing.

The primary endpoint is at Week 16, although the study collected data for up to 52 weeks. A Week 16 comparison does not itself characterize later outcomes. The serious-event summary lacks details about timing, event-level exposure, treatment attribution and whether individual participants experienced multiple events. Those counts therefore provide only limited safety context.

The registry title describes the study as double-blind, while its masking classification is quadruple. The record does not explain the roles covered by that classification. This is a reporting detail that cannot be resolved from the available registry information.

20. Related Tutorials

21. Related Statistical Calculators

22. Sources

• ClinicalTrials.gov: Study to Demonstrate the Efficacy, Safety and Tolerability of an Intravenous Regimen of Secukinumab Compared to Placebo in Subjects With Active axSpA — NCT04156620.
• Registry record last updated 2024-06-18; status last verified 2024-06.
• Results first posted 2024-01-23.
• 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

NCT04156620 is a completed, randomized, parallel-group, placebo-controlled Phase III study of intravenous secukinumab in participants with active ankylosing spondylitis or non-radiographic axial spondyloarthritis. The registry records 527 enrolled participants and identifies Novartis Pharmaceuticals as sponsor.

The primary endpoint was the Week 16 percentage achieving ASAS40 in the full analysis set, with missing responses for any reason imputed as non-responders. The sponsor-reported logistic-regression marginal difference was 17.91, with a 95% confidence interval from 10.12 to 25.71 and p < 0.001. The unadjusted recalculation gives a risk difference of 0.180, with a 95% confidence interval from 0.102 to 0.258 and p < 0.001.

Posted secondary results for ASDAS-CRP major improvement, BASDAI and BASFI have directions consistent with the primary comparison. The registry also reports serious adverse event and other adverse event counts, but the safety summaries do not establish causality. Full details of the original sample-size rationale, multiplicity plan and several analysis procedures are not reported in the registry record.