Dose Ranging Study to Evaluate the Efficacy and Safety of SAR153191 (REGN88) in Patients With Ankylosing Spondylitis: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Dose Ranging Study to Evaluate the Efficacy and Safety of SAR153191 (REGN88) in Patients With Ankylosing Spondylitis (NCT01061723), a randomized phase 2 study. The primary outcome is Percentage of Participants Who Achieved 20% Response According to the Assessment in Ankylosing Spondylitis (AS) Working Group Criteria for Response (ASAS20) at Week 12.

2. Clinical Question

The comparison is between each sarilumab regimen and placebo, rather than a direct comparison among doses. The study was designed as a dose-ranging evaluation of efficacy and safety. The primary endpoint was a binary response: each participant either met the registry’s ASAS20 definition or did not. The reported percentages describe the proportion meeting that definition in each group; they do not capture the size of improvement beyond the threshold.

The registry record also lists secondary measures of higher-level response, partial remission, disease activity, range of motion, chest expansion, and spinal MRI. These broaden the outcomes assessed, but the primary question remains whether the percentage meeting the ASAS20 response definition differed between each regimen and placebo at Week 12.

3. Trial Design

The registry describes a Phase 2, randomized, triple-masked, parallel-group, placebo-controlled dose-ranging study. It lists an enrollment of 301 participants with ankylosing spondylitis and Sanofi as the sponsor. The study status is completed; the recorded start is 2010-02 and the primary completion is 2011-06.

Participants were assigned to placebo or one of five sarilumab regimens. The active regimens varied by dose and schedule: 100 mg every other week, 150 mg every other week, 100 mg weekly, 200 mg every other week, or 150 mg weekly. The regimen descriptions specify subcutaneous injection for active treatment and placebo injections on alternating weeks for every-other-week regimens. Each regimen was scheduled for 12 weeks.

The primary outcome was the percentage achieving ASAS20 at Week 12, assessed from baseline to Week 12 with last observation carried forward for missing data. The primary analysis population was the intent-to-treat population, described as including all randomized participants. Group sizes in the posted primary outcome range from 49 to 52; the outcome-specific denominators are not identical across all measures.

The registry record does not report the original sample-size justification, the assumptions used to plan the study, or a fuller statistical analysis plan. It also does not report whether interim analyses were conducted. The study’s recorded design and outcome results can be described, but these missing design details should not be inferred from the results or from illustrative sample-size calculations.

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: Participants were randomized in 1:1:1:1:1:1 ratio for Placebo and Sarilumab (100 mg weekly \[qw\]; 150 mg qw; 100 mg every other week \[q2w\]; 150 mg q2w and 200 mg q2w) with screening high-sensitivity C-Reactive Protein (hs-CRP) (≤1.5 mg/L or \>1.5 mg/L) and region as stratification factors.

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: Intent-to-treat (ITT) population included all randomized participants. Missing data was imputed using LOCF.

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.

Only the first 6 of 7 groups are shown.

6. Primary Endpoint

The registry lists the primary outcome as Percentage of Participants Who Achieved 20% Response According to the Assessment in Ankylosing Spondylitis (AS) Working Group Criteria for Response (ASAS20) at Week 12, measured over Baseline to Week 12 (Last Observation Carried Forward [LOCF]).

The primary endpoint is the percentage of participants who achieved an ASAS20 response at Week 12. The registry defines response as an improvement of at least 20% and at least 1 unit in at least three of four Assessment in Ankylosing Spondylitis working group improvement-criteria domains, with no qualifying worsening in the remaining domain.

The domains cover physical function, back pain, participant global assessment, and inflammation. Physical function is measured by the Bath Ankylosing Spondylitis Functional Index; pain, global assessment, and the specified inflammation measure use 0-to-10 numerical rating scales, with inflammation based on the mean of the last two Bath Ankylosing Spondylitis Disease Activity Index questions. The response definition therefore combines several dimensions rather than relying on a single symptom or measurement.

A threshold-based response endpoint is useful for expressing how many participants reached a prespecified level of improvement. It is straightforward to interpret as a percentage, but it also simplifies the underlying data: participants just meeting the threshold and participants improving more substantially are both counted as responders. The endpoint does not, by itself, describe the full distribution of changes in each domain or establish how durable any response may be beyond the reported assessment period.

The registry specifies the intent-to-treat population and last-observation-carried-forward imputation for missing data. Those choices are part of how the reported percentage should be understood, not an indication that every participant had an observed Week 12 measurement.

7. Results Posted in the Registry

• Sarilumab 100 mg q2w: 24.5% (12/49) versus 24.0% (12/50) on control; risk difference 0.5 percentage points (95% CI -16.4 to 17.4), risk ratio 1.02 (0.51–2.05); unadjusted two-proportion z-test p = 0.955.
• Sarilumab 150 mg q2w: 30.0% (15/50) versus 24.0% (12/50) on control; risk difference 6.0 percentage points (95% CI -11.4 to 23.4), risk ratio 1.25 (0.65–2.39); unadjusted two-proportion z-test p = 0.499.
• Sarilumab 100 mg qw: 19.2% (10/52) versus 24.0% (12/50) on control; risk difference -4.8 percentage points (95% CI -20.7 to 11.2), risk ratio 0.80 (0.38–1.69); unadjusted two-proportion z-test p = 0.558.
• Sarilumab 200 mg q2w: 30.0% (15/50) versus 24.0% (12/50) on control; risk difference 6.0 percentage points (95% CI -11.4 to 23.4), risk ratio 1.25 (0.65–2.39); unadjusted two-proportion z-test p = 0.499.

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 40% Response According to the Assessment in AS Working Group Criteria for Response (ASAS40) at Week 12

• 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:
  • Sarilumab 100 mg q2w: 14.3% (7/49) versus 8.0% (4/50) on control; risk difference 6.3 percentage points (95% CI -6.1 to 18.6), risk ratio 1.79 (0.56–5.72); unadjusted two-proportion z-test p = 0.320.
  • Sarilumab 150 mg q2w: 16.0% (8/50) versus 8.0% (4/50) on control; risk difference 8.0 percentage points (95% CI -4.6 to 20.6), risk ratio 2.00 (0.64–6.22); unadjusted two-proportion z-test p = 0.218.
• Interpretation:
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between Sarilumab 100 mg q2w and the control. The interval gives the range of effects that remain compatible with the data.
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between Sarilumab 150 mg q2w and the control. The interval gives the range of effects that remain compatible with the data.

Percentage of Participants Who Achieved Partial Remission According to the Assessment in AS Working Group Criteria for Response (ASAS) at Week 12

• 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:
  • Sarilumab 100 mg q2w: 8.2% (4/49) versus 2.0% (1/50) on control; risk difference 6.2 percentage points (95% CI -2.4 to 14.8), risk ratio 4.08 (0.47–35.24); unadjusted two-proportion z-test p = 0.161.
  • Sarilumab 150 mg q2w: 2.0% (1/50) versus 2.0% (1/50) on control; risk difference 0.0 percentage points (95% CI -5.5 to 5.5), risk ratio 1.00 (0.06–15.55); unadjusted two-proportion z-test p = 1.000.
• Interpretation:
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between Sarilumab 100 mg q2w and the control. The interval gives the range of effects that remain compatible with the data.
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between Sarilumab 150 mg q2w and the control. The interval gives the range of effects that remain compatible with the data.

Change From Baseline in Ankylosing Spondylitis Disease Activity Score (ASDAS) at Week 12

• 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 deviations.
• Result:
  • Sarilumab 100 mg q2w: mean -0.50 versus -0.40 on control; difference -0.10 (95% CI -0.42 to 0.22), standardized effect d = -0.12; z-test p = 0.545.
  • Sarilumab 150 mg q2w: mean -0.80 versus -0.40 on control; difference -0.40 (95% CI -0.79 to -0.01), standardized effect d = -0.41; z-test p = 0.042.
• Interpretation:
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between Sarilumab 100 mg q2w and the control. The interval gives the range of effects that remain compatible with the data.
  • The 95% confidence interval excludes no difference, so the mean is statistically lower for Sarilumab 150 mg q2w than for the control. This is an unadjusted, secondary comparison, so it is suggestive rather than confirmatory.

The registry lists secondary outcomes spanning higher-level ASAS response, partial remission, disease activity, functional and mobility-related measures, and imaging. Across these different kinds of measures, the posted results do not form a single uniformly favorable pattern across every outcome and regimen. Some group estimates move in a direction that could be read as improvement relative to placebo, while other estimates are close to placebo or move in the opposite direction. The secondary outcomes therefore provide context, but do not resolve the uncertainty in the primary comparison.

Secondary outcomes can help show whether the primary endpoint is accompanied by changes in related clinical or measurement domains. They are not interchangeable with ASAS20: continuous disease-activity measures describe mean change, while responder outcomes describe the share crossing a threshold. Imaging and range-of-motion outcomes address still other aspects. A consistent pattern across prespecified, adequately powered measures might add context, but the registry record does not establish that condition.

Unadjusted secondary findings carry less weight because the record does not report how multiplicity was handled. When many outcomes and treatment comparisons are examined, some apparently notable results may occur by chance. The registry also does not provide a complete analysis plan or a hierarchy indicating which secondary tests, if any, were confirmatory. Secondary estimates should consequently be treated as exploratory context rather than independent proof of a treatment effect.

The Week 12 secondary outcomes are reported with last observation carried forward where specified. That approach and the differing outcome-specific denominators matter when comparing results across measures. The secondary results should be interpreted alongside their own uncertainty and definitions, not as a substitute for the primary endpoint or as evidence of a dose-response relationship.

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

• Percentage of Participants Who Achieved 40% Response According to the Assessment in AS Working Group Criteria for Response (ASAS40) at Week 12
• Percentage of Participants Who Achieved Partial Remission According to the Assessment in AS Working Group Criteria for Response (ASAS) at Week 12
• Change From Baseline in Ankylosing Spondylitis Disease Activity Score (ASDAS) at Week 12
• Change From Baseline in BASDAI Score at Week 12
• Change From Baseline in Range of Motion Assessed by the Bath AS Metrology Index (BASMI) at Week 12
• Change From Baseline in Magnetic Resonance Imaging (MRI) Score of the Spine Assessed by the Berlin Modification of the AS Spine MRI-active (ASspiMRI-a) Score at Week 12
• Percentage of Participants Who Achieved ASAS 5/6 Improvement Criteria at Week 12
• Change From Baseline in Chest Expansion at Week 12

9. Statistical Interpretation

10. Statistical Methods Explained

What is a binary response outcome?

The primary endpoint records whether each participant met the ASAS20 response definition by Week 12. A binary outcome has two possible participant-level states: response or no response. The group percentage expresses the share meeting the definition. It is accessible to readers, but it does not preserve all the detail in continuous measurements such as pain or disease-activity scores.

The ASAS20 rule combines a relative improvement threshold with an absolute change threshold in at least three domains and a restriction on worsening in the remaining domain. A participant who satisfies the full rule counts as a responder. A participant who improves in some domains but fails one part of the rule does not. Consequently, modest changes in measurement or in the location of participants near the threshold can affect the percentage classified as responders.

What does a risk difference describe?

The recalculated risk difference is the active-group response proportion minus the placebo response proportion. A positive estimate means the posted response proportion was higher in the active group; a negative estimate means it was lower. Zero corresponds to equal proportions. The intervals and p-values attached to these estimates are simple, unadjusted recalculations from the posted summary statistics. They are not the sponsor’s reported analyses.

Risk difference is an absolute contrast in proportions, while an odds ratio compares the odds of response between groups. These measures answer related but not identical questions, and their numerical scales differ. The registry’s reported analyses use Cochran-Mantel-Haenszel odds ratios. The recalculated risk differences should therefore be understood as a complementary, unadjusted summary rather than a reproduction of the sponsor’s analysis.

Why are confidence intervals useful?

A confidence interval gives a range of values compatible with the data under the method used to calculate it. A wide interval indicates that the estimate is uncertain; a narrow interval indicates greater precision. For a risk difference, an interval including zero does not rule out equal response proportions. For an odds ratio, an interval including 1 does not rule out equal odds. Neither interval alone determines whether a result is important in a clinical context.

These general interpretations depend on the analysis being appropriate for the data and design. The registry record identifies the sponsor’s method for the reported odds ratios, but it does not provide a full statistical analysis plan. The simple recalculations are unadjusted and should not be mistaken for the registry’s full inferential procedure.

What does the reported analysis add?

The sponsor reports a Cochran-Mantel-Haenszel odds ratio for each active regimen versus placebo, along with a 95% confidence interval and p-value. These are the registry’s own analyses of the primary endpoint. A stratified method such as Cochran-Mantel-Haenszel can combine comparisons across strata when the analysis is structured that way, but the registry record does not specify the strata or additional details of implementation. They should not be guessed.

The sponsor-reported estimates and the simple risk-difference recalculations are not interchangeable. They use different effect measures and may use different analytical procedures. Since the discrepancy indicator is false, the registry-reported analyses are not flagged as discrepant from the recalculations; still, each set of results should be identified by its method. The sponsor’s own analysis is the appropriate source for the trial’s reported inferential result, while recalculated contrasts can help readers understand the absolute difference in posted response percentages.

How should missing outcomes be understood?

The primary outcome description says that missing data were imputed using last observation carried forward. This approach uses a participant’s last recorded observation as the imputed value for a later missing assessment. In general, that method can make assumptions about how outcomes evolve after the last observation, and those assumptions may not fit every participant. The registry record does not report sensitivity analyses or additional missing-data methods, so the effect of this choice on the estimates cannot be established from the record.

The primary population is described as intent-to-treat and includes all randomized participants. The outcome description also identifies last-observation-carried-forward imputation. These details clarify the stated analysis population and missing-data handling, but do not answer whether every randomized participant contributed an observed Week 12 measurement.

What should be made of multiple comparisons?

The primary result includes comparisons of multiple sarilumab regimens against placebo. The registry record does not report whether the p-values or confidence intervals were adjusted for these comparisons. In general, making multiple statistical comparisons creates more opportunities for an apparently notable result to arise by chance. Adjustment methods, prespecified testing sequences, or a clear hierarchy can address this concern, but none is described in the record. Unadjusted findings should therefore be treated cautiously, especially when interpreting secondary outcomes or comparing apparent patterns across regimens.

11. Confidence Intervals and Precision

The primary outcome percentages are estimates from groups with outcome denominators around 50 participants. The recalculated risk-difference confidence intervals are broad relative to many of the point estimates. For 100 mg every other week, the estimate is 0.005 with a confidence interval from -0.164 to 0.174. For 150 mg every other week and 200 mg every other week, the estimate is 0.06 with an interval from -0.114 to 0.234. For 100 mg weekly, the estimate is -0.048 with an interval from -0.207 to 0.112. For 150 mg weekly, the estimate is 0.14 with an interval from -0.039 to 0.319.

Each interval includes zero, so the unadjusted risk-difference estimates do not exclude equal response proportions. The intervals also encompass differences in both directions. The observed percentages alone are therefore not precise enough to establish a clear separation between any one regimen and placebo. Similarity or overlap between intervals is not, by itself, a formal test comparing active regimens with one another.

The sponsor-reported odds-ratio intervals are also wide: each reported 95% interval includes 1. In general, an odds-ratio interval including 1 is compatible with equal odds, while an interval extending substantially to either side indicates uncertainty about the size and direction of the contrast. The registry’s reported intervals should be interpreted with their corresponding odds-ratio estimates and analyses.

Confidence intervals do not cover every source of uncertainty. They do not account automatically for unreported analytical choices, missing-data assumptions, or multiplicity. The registry record identifies the primary analysis population and imputation approach, but does not report sensitivity analyses or a detailed multiplicity strategy. Precision should consequently be considered both statistically and in light of these limits in the record.

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 sample-size figures are planning illustrations based on observed effects, not the trial’s original design calculations. For these non-time-to-event outcomes, the figures are participants per arm, not total participants. The listed assumptions are a two-sided significance level of 0.05, equal allocation between the two arms, and a normal approximation. Each planning scenario targets the stated fraction of the observed effect.

The column for 80% power gives the estimated participants per arm for a future study to have an 80% chance of detecting the selected effect under the listed assumptions, if that effect is real and the assumptions hold. The 90% power column describes the corresponding planning target for a 90% chance. Higher planned power generally requires a larger study. These are design calculations, not observed power, and they do not describe the probability that the trial’s findings are true.

The table distinguishes planning for 100%, 75%, or 50% of the observed effect. Smaller effects are harder to distinguish from random variation and therefore require more participants. The resulting figures can change markedly when the target effect is smaller, which is why planning based only on a trial’s observed estimate can be unstable. An observed effect may be unusually large or small because of sampling variability, especially in a small study.

The registry record does not report the assumptions behind the original sample-size calculation. The planning illustrations do not fill that gap and should not be read as evidence that the completed trial was designed using these assumptions. Nor do they establish that a future study of the illustrated size would reproduce the observed result.

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 = 0.240; treatment proportion p₁ = 0.245; average p̄ = 0.242.
2. First term: z_1−α/2 × √[2p̄(1−p̄)] = 1.96 × 0.6061 = 1.1879.
3. Second term: z_1−β × √[p₀(1−p₀) + p₁(1−p₁)] = 0.842 × 0.6061 = 0.5101.
4. n = (1.1879 + 0.5101)² / (0.0049)² = 120,180.9, rounded up to 120,181 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 <- 0.24                          # control proportion
p1 <- 0.244897959183673                          # 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(1061723)
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 = 120,181 (80% power), 160,888 (90% power)
 75% of observed effect: n per arm = 213,289 (80% power), 285,533 (90% power)
 50% of observed effect: n per arm = 479,073 (80% power), 641,342 (90% power)
power.prop.test: 120180.9 
Simulated power at n = 120,181 per arm: 0.796 (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 registry’s own primary analyses compare each sarilumab group with placebo using Cochran-Mantel-Haenszel odds ratios. The reported odds ratios range from 0.8 to 1.8, and every reported 95% confidence interval includes 1. The sponsor-reported p-values range from 0.143 to 0.966. These are the trial’s posted inferential results for the primary endpoint.

The recalculated results instead express unadjusted risk differences, with confidence intervals and p-values calculated from the posted summary statistics. They describe the absolute difference between the response proportions and are not a substitute for the sponsor’s odds-ratio analysis. The risk-difference intervals also include zero.

The record does not flag a discrepancy between the posted analyses and the recalculations. Because the methods and effect measures differ, the numerical values should not be compared as though they were estimates on the same scale. The sponsor’s analysis is the appropriate reference for what the registry reports as its formal analysis; the recalculation adds an unadjusted absolute-scale perspective.

15. Multiplicity, Missing Data and Analysis Populations

The registry record reports comparisons of each sarilumab regimen with placebo for the primary outcome and lists numerous secondary outcomes. It does not report whether a multiplicity adjustment was applied, whether tests followed a prespecified hierarchy, or whether a particular endpoint was designated as confirmatory beyond the stated primary endpoint. The statistical plan for handling multiple comparisons is not reported in the registry record.

This matters because repeated testing increases the chance that at least one result will appear noteworthy even if there is no underlying difference. In general, adjustment procedures or a planned testing sequence can control how evidence is interpreted across multiple comparisons. Without a reported strategy, individual unadjusted p-values should not be treated as if they were the only test conducted. This caution is especially relevant to the secondary outcomes.

The primary outcome description defines the analysis population as intent-to-treat, including all randomized participants. It also says missing data were imputed using last observation carried forward. The registry record does not report sensitivity analyses that test whether the primary findings change under different missing-data assumptions, nor does it describe other imputation approaches. In general, carrying the last observed value forward can be problematic if a participant’s outcome would have changed after the last measurement; the record does not establish the direction or size of any impact.

The original sample-size justification and the trial’s own design assumptions are not reported in the registry record. The separate planning illustrations use specified assumptions but cannot be used to reconstruct the original design rationale. Interim analyses are also not reported in the registry record. These gaps limit the ability to assess the full prespecification and operating characteristics of the trial from registry information alone.

16. Safety Results

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

Other (non-serious) adverse events

Participants with at least one non-serious event at or above the registry's 5% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: epilepsy (2.0%), false positive tuberculosis test (2.0%), neutropenia (2.0%), myocardial ischemia (2.0%), pain (2.0%).

The registry lists serious adverse events by treatment group. The recorded counts are 0 for placebo; 1 for sarilumab 100 mg every other week; 4 for sarilumab 150 mg every other week; 1 for sarilumab 100 mg weekly; 0 for sarilumab 200 mg every other week; and 1 for sarilumab 150 mg weekly. The corresponding numbers at risk listed for these safety groups are 50, 49, 51, 52, 49, and 49.

The registry also lists serious-event terms with a reported frequency of 2.0% each: epilepsy, false positive tuberculosis test, neutropenia, myocardial ischemia, pain, and alanine aminotransferase increased. The record does not map those listed terms to particular treatment groups in the information presented, so group attribution should not be inferred.

These figures describe reported events during the registry’s safety reporting period; they do not establish that treatment caused an event or that unlisted events did not occur. Death counts are not reported in the registry record. The safety figures alone do not provide a complete comparison of risks, and they should be read with the trial’s duration and reporting limitations in mind.

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

The posted data describe ASAS20 response percentages at Week 12 for placebo and five sarilumab regimens. The percentages vary across regimens, with the highest posted percentage in the 150 mg weekly group. However, the unadjusted risk-difference intervals include zero for every active-versus-placebo comparison, and the sponsor-reported odds-ratio intervals include 1. These estimates are imprecise and do not establish a clear difference from placebo in this registry record.

This interpretation is limited to the endpoint definition, analysis population, missing-data approach, and assessment period reported. ASAS20 is a composite threshold: it classifies participants according to whether they meet the response rule, rather than describing the complete range of change in each component. A percentage meeting the threshold does not indicate the size or durability of improvement for individuals.

The results do not establish that one sarilumab regimen is superior to another, because the reported primary analyses compare each regimen with placebo. They do not establish a dose-response relationship, nor do they answer questions about outcomes beyond Week 12. The secondary outcomes offer additional measures, but their multiplicity handling and full statistical plan are not reported.

These registry results also do not provide medical advice or determine what treatment is appropriate for an individual. They describe the posted group-level findings and their statistical uncertainty. Interpretation of safety is similarly limited: the registry lists serious adverse event counts and selected terms, but those figures alone do not demonstrate causality or provide a complete assessment of comparative risk.

18. Why This Trial Matters Statistically

This trial illustrates why dose-ranging results should be read through both effect estimates and their uncertainty. Several sarilumab regimens have response percentages above the placebo percentage, while one is below it. But the active-versus-placebo contrasts are not precise: the reported intervals include the null values for both the unadjusted risk differences and the sponsor-reported odds ratios. A visual ordering of percentages is not equivalent to evidence that the regimens differ.

The study also highlights the distinction between absolute and relative effect measures. The recalculated risk differences describe changes in response proportion on an absolute scale, while the sponsor reports odds ratios. Readers need to know which measure is being interpreted and which analysis produced it; numbers on different scales are not directly interchangeable.

Multiplicity is another central statistical issue. A dose-ranging trial can generate several treatment comparisons and outcome measures. Without a reported testing hierarchy or adjustment strategy, isolated secondary findings deserve caution. Prespecification and transparent reporting help distinguish planned confirmatory tests from exploratory analyses.

Finally, missing-data handling and sample-size planning affect interpretation. The primary outcome used last observation carried forward, while the registry does not report the original sample-size justification or sensitivity analyses. The posted planning illustrations are not evidence about the trial’s original design. Together, these features show why a complete reading considers design, endpoint definition, analysis method, precision, and reporting gaps rather than relying on a single percentage or p-value.

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 gives a short primary endpoint description and reports the intent-to-treat population with last-observation-carried-forward imputation. It does not provide a full statistical analysis plan, the original sample-size rationale, or sensitivity analyses for missing data. Consequently, the robustness of the results to alternative assumptions cannot be assessed from the record.

The primary comparisons involve multiple sarilumab regimens against a shared placebo group, but multiplicity handling is not reported. The record also does not specify whether the sponsor’s Cochran-Mantel-Haenszel analysis used strata, or give further implementation details. These omissions limit the ability to reconstruct the reported analyses independently.

The primary endpoint is assessed at Week 12, so the reported results do not describe longer-term response. The threshold-based ASAS20 measure also reduces multidimensional changes to responder status. Secondary outcomes cover several domains, but the registry record does not report a confirmatory hierarchy or multiplicity strategy for interpreting them.

Safety reporting includes serious adverse event counts and selected serious-event terms, but deaths are not reported in the registry record. The listed terms are not mapped to treatment groups in the available record. These data therefore do not support a complete causal or comparative safety assessment. The sample-size illustrations are based on observed effects and specified planning assumptions; they do not explain the original trial’s design or remove uncertainty in the observed estimates.

20. Related Tutorials

21. Related Statistical Calculators

22. Sources

• ClinicalTrials.gov: Dose Ranging Study to Evaluate the Efficacy and Safety of SAR153191 (REGN88) in Patients With Ankylosing Spondylitis — NCT01061723.
• Registry record last updated 2017-08-08; status last verified 2017-07.
• Results first posted 2017-08-08.
• Data retrieved from ClinicalTrials.gov on 2026-11-09.
• Group sizes, means, event counts and sponsor-reported p-values are reproduced as posted. Effect estimates, confidence intervals and p-values not attributed to the sponsor are independently calculated from the posted summary statistics.

23. Record Summary

The registry describes a completed Phase 2 randomized, triple-masked, parallel-group, placebo-controlled dose-ranging study of sarilumab in participants with ankylosing spondylitis. Sanofi is listed as sponsor, enrollment is 301, and the recorded study dates are 2010-02 to primary completion in 2011-06.

The primary outcome was the percentage achieving ASAS20 at Week 12, analyzed in the intent-to-treat population with missing data imputed using last observation carried forward. Posted response percentages varied across placebo and the sarilumab regimens. The recalculated risk-difference intervals and sponsor-reported odds-ratio intervals include their respective null values, leaving the primary comparisons uncertain.

The registry also reports secondary outcomes and serious adverse event counts. Multiplicity handling, the original sample-size justification, interim analyses, and several details of the statistical plan are not reported in the registry record.