A 3-arm Proof of Concept Study of AIN457, ACZ885 or Corticosteroids in Patients With Polymyalgia Rheumatica: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for A 3-arm Proof of Concept Study of AIN457, ACZ885 or Corticosteroids in Patients With Polymyalgia Rheumatica (NCT01364389), a randomized phase 2 study. The primary outcome is Polymyalgia Rheumatica Activity Score (PMR-AS).

2. Clinical Question

3. Trial Design

This was a phase 2, randomized, parallel-group proof-of-concept study of AIN457, ACZ885, and corticosteroids in people with polymyalgia rheumatica. The registry reports enrollment of 16 and a terminated status. The brief summary describes a planned total of 30 participants, randomized among the three arms at a ratio of 1:1:1. The reason for termination is not reported in the registry record.

The initial treatment period was two weeks. The brief summary describes dosing over 15 days, followed by a non-randomized, open-label follow-up period intended to bring total study duration to six months. It describes follow-up for 154 days, or 4 months after the last biologic dose, whichever was greater, and unblinded redosing in the event of a flare. The official title also describes an open-label phase to assess safety and longer-term efficacy. These later-phase activities should be distinguished from the primary Day 15 outcome.

The registry’s masking entry says double, while the brief summary describes the initial study as single-blinded and double-dummy. The arm descriptions also state that placebo was used to maintain the blind. The registry record does not clarify the difference between its masking label and the wording of the summary.

The primary outcome was measured at baseline and Day 15. The posted primary analysis population was the Pharmacodynamic Analysis Set, which excluded participants with major protocol deviations that could affect pharmacodynamic data. The registry lists 17 outcome measures and 16 posted secondary outcomes. It does not report a statistical analysis plan, a sample-size justification, or the reason the study stopped at its reported enrollment.

4. Participant Flow and Accounting

The registry reports how participants moved through each stage of the study. All counts below are exactly as posted; missing counts are not inferred from other stages.

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: Pharmacodynamic (PD) Analysis Set: This set included participants who received at least one dose of study medication and had no major protocol deviation that may impact the PD data.

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 Polymyalgia Rheumatica Activity Score (PMR-AS), measured over Baseline, Day 15.

The primary endpoint was percent reduction in the Polymyalgia Rheumatica Activity Score (PMR-AS) from baseline to Day 15. PMR-AS combines several aspects of disease activity: C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), early morning stiffness, the patient’s ability to elevate the upper limbs, the patient’s pain assessment, and the physician’s global assessment of disease activity. The composite is intended to represent activity across laboratory measures, symptoms, function, and clinician assessment rather than relying on a single measure.

A percent reduction expresses change relative to the baseline score. As a general statistical point, a composite outcome can capture multiple dimensions of a condition, but its interpretation depends on the components being measured consistently and on the composite being appropriate for the study question. The registry identifies PMR-AS as the measure used to assess the effect of a single dose of AIN457 and ACZ885, and reports the endpoint as a least-squares mean with a standard error.

The time point is important: the primary outcome concerns the short initial treatment period and does not, on its own, describe later flares, redosing, longer-term activity, or safety during follow-up. Those topics appear among the secondary outcomes. The registry record does not report a clinically important threshold for interpreting a particular size of PMR-AS reduction.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

What does a least-squares mean represent?

A least-squares mean is an estimated mean from a statistical model. In general, model-based means can account for variables included in that model, whereas a raw arithmetic mean is calculated directly from observed values. The registry labels the primary parameter as a least-squares mean, but does not report the model specification, the covariates included, or the estimation details. The posted values should therefore be described using the registry’s label, without assuming how the model was constructed.

How should the standard errors be read?

A standard error quantifies the sampling uncertainty of an estimated statistic. In general, smaller standard errors indicate more precise estimates, while larger ones indicate less precision. A standard error is not the same as the spread of individual participant outcomes, and it is not a confidence interval. The reported standard errors are 0.68 for ACZ885, 0.47 for AIN457, and 86.2 for prednisone. The registry does not post confidence limits for these estimates, so confidence intervals should not be inferred from the standard errors.

Why are arm estimates not the same as a treatment comparison?

Each arm mean describes an estimated outcome within that arm. A comparative effect asks how outcomes differ between arms and requires an estimate of that contrast, together with uncertainty and an appropriate inferential analysis. The registry lists ACZ885 as the control for the primary outcome, but no comparative analyses are posted. It also records that a two-arm comparison for the continuous endpoint had values missing or not estimable. Thus, the arm summaries cannot be substituted for a reported between-arm test.

In general, comparing the numerical sizes of two separate means does not account for uncertainty in either estimate or uncertainty in their difference. A valid comparison also depends on the analysis model and the data available for the arms being compared. The model and the comparative estimates are not reported in the registry record.

What does the analysis population mean?

The Pharmacodynamic Analysis Set included participants who received at least one dose and had no major protocol deviation that might affect pharmacodynamic data. This is a defined analysis population rather than necessarily everyone enrolled or randomized. Such population definitions can be important because exclusions may affect which participants contribute to an outcome estimate. The registry gives the definition but does not report a participant-level account of all exclusions or deviations.

The primary outcome description specifically states that the ACZ885 estimate is based on N=3 because CRP values at Day 15 were missing for 2 participants. CRP is one of the PMR-AS components, so its absence affects the availability of the composite outcome as described in the record. The registry does not report how missing CRP values were handled beyond giving the resulting analysis count. It does not report an imputation method, sensitivity analysis, or other assessment of how missing data might affect the result.

What can a planning calculation tell a reader?

In general, a sample-size planning calculation illustrates how many participants might be needed under specified assumptions to detect a chosen effect with a chosen statistical design. The planning assumptions described for this study use a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation; the targeted effect is described as a fraction of the observed effect. For time-to-event outcomes, the planning convention is based on total events, while other outcomes are expressed as participants per arm.

Such calculations are planning illustrations, not observed evidence about the trial’s power and not a substitute for a prospective sample-size justification. The registry record does not report that these assumptions formed the original trial design. It also does not report the trial’s own sample-size justification, so the planning framework should not be attributed to the original protocol.

Why does multiplicity matter?

When a study examines several outcomes or makes several comparisons, the chance of at least one false-positive finding can increase if each is tested independently without an appropriate strategy. In general, a prespecified hierarchy, adjustment, or other multiplicity plan can address that issue. The registry lists 17 outcome measures and 16 posted secondary outcomes, but does not report a multiplicity strategy or a hierarchy for interpreting them. No confirmatory interpretation across multiple outcomes can be reconstructed from the posted record.

The registry also does not report interim analyses, a detailed statistical analysis plan, or the model used for the primary outcome. These absences limit the ability to evaluate whether the posted analyses followed a prespecified plan. No recalculated comparative effect is presented in the record, and no sponsor analysis takes precedence over a recalculation because no such discrepancy is reported.

10. Confidence Intervals for Each Arm

No two-arm comparison is shown for this trial, but each arm's mean can be given with a t-based 95% confidence interval computed from the posted mean, spread and number of participants.

R code and output

arm <- c("ACZ885", "AIN457", "Prednisone")
n   <- c(3, 6, 4)
m   <- c(64.5, 51.7, 91.9)
sp  <- c(0.68, 0.47, 86.2)
sd  <- sp * sqrt(n)      # standard errors converted to SDs
for (i in seq_along(n)) {
  se <- sd[i] / sqrt(n[i]); h <- qt(0.975, n[i] - 1) * se
  cat(sprintf("CARM|%s|%d|%.3f|%.3f|%.3f|%.3f\n", arm[i], n[i], m[i], sd[i], m[i] - h, m[i] + h))
}

CARM  ACZ885  3  64.500  1.178  61.574  67.426
CARM  AIN457  6  51.700  1.151  50.492  52.908
CARM  Prednisone  4  91.900  172.400  -182.427  366.227

11. Multiplicity, Missing Data and Analysis Populations

The registry lists 17 outcome measures and 16 posted secondary outcomes. The secondary outcomes include time to partial and complete clinical response, time to first flare, number of flares over a six-month period, mean steroid dose over a six-month period, adverse events, serious adverse events and deaths, response after redosing, and health-related quality of life measured with the Short Form-36 questionnaire. This breadth means that outcome selection and multiplicity are relevant when interpreting a collection of results.

In general, testing many outcomes or comparisons can increase the chance of a positive result arising by chance. A prespecified multiplicity strategy can control or describe that risk. The registry record does not report such a strategy, an outcome hierarchy, or which outcomes were designated for formal hypothesis testing. It also does not report interim analyses or the complete statistical analysis plan. The absence of these details does not establish that no plan existed; it means the plan is not reported in the registry record.

Missing data are directly noted for the primary endpoint. The ACZ885 analysis has N=3 because CRP at Day 15 was missing for 2 participants. Since CRP is a component of PMR-AS, this missingness affects the endpoint’s available analysis population. The registry does not report imputation, sensitivity analyses, or the reason those CRP values were missing. Other missing-data details for the primary endpoint are not reported in the registry record.

The stated Pharmacodynamic Analysis Set includes participants who received at least one dose and had no major protocol deviation that could impact pharmacodynamic data. The record does not give a complete account of deviations or exclusions from that set. Nor does it describe how all secondary outcomes handled missing observations. These limitations make it difficult to assess the robustness of estimates to incomplete data or to determine how the posted outcome population relates to every randomized participant.

12. Safety Results

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

Deaths

Other (non-serious) adverse events

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

Most frequent non-serious adverse event terms

The registry reports serious adverse events for three safety groups: ACZ885 3mg/kg, AIN457 3mg/kg, and prednisone 20mg. The numbers at risk were 5, 6, and 5, respectively. The reported serious adverse event counts were 0 in each group, and deaths were also reported as 0 in each group.

These counts mean that the registry records no serious adverse events or deaths among the participants included in those safety groups. They do not establish that the risk is absent. In general, zero observed events in a small group still leaves uncertainty about the frequency of an event outside the observed participants. The registry does not provide confidence intervals for these safety counts or a detailed account of event definitions and exposure time.

The record also reports other adverse events: 3 in the ACZ885 group, 2 in the AIN457 group, and 5 in the prednisone group. These are separate from the serious adverse event counts in the registry presentation. The registry’s listed safety outcomes include adverse events, serious adverse events, and deaths; detailed event terms and severity summaries are not reported in the listed serious-event terms. Safety counts should be read descriptively and in light of the small numbers at risk and the study’s terminated status. They do not establish comparative safety between treatments.

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

The primary result describes estimated reductions in PMR-AS at Day 15 in the participants included in the Pharmacodynamic Analysis Set. The arm-level estimates were 64.5 percent for ACZ885, 51.7 percent for AIN457, and 91.9 percent for prednisone. These summaries address the short-term endpoint defined in the record, not the full follow-up period or every outcome listed for the trial.

The result does not establish that the arms differed. The registry posts no comparative tests or confidence intervals for the primary endpoint, and records that values for a two-arm comparison were missing or not estimable. The standard errors also show differing precision, with the prednisone estimate particularly imprecise. A ranking of the arm-level point estimates alone cannot determine whether the underlying treatment effects differ.

The findings do not establish longer-term response, flare prevention, the effect of redosing, or comparative safety. Those subjects appear in the secondary outcomes and follow-up description, but their detailed results are not included in the registry record described by the registry record. The brief summary describes an open-label follow-up phase, which is distinct from the randomized initial treatment period and would not have the same comparative design.

The total enrollment was 16, while the brief summary describes a planned total of 30. The study is listed as terminated, and the reason is not reported in the registry record. The endpoint analysis counts are smaller than total enrollment and vary by arm, including the noted missing CRP values for ACZ885. The results therefore characterize a limited set of posted observations; they do not provide a precise or definitive estimate of comparative treatment effects.

In general, proof-of-concept studies can describe whether an approach merits further investigation, but their estimates may be uncertain, especially when the number of participants contributing to an outcome is small. That general point does not imply any particular conclusion about this trial’s treatments. The registry record supports a descriptive reading of the reported outcome and safety counts, while leaving comparative efficacy and longer-term outcomes unresolved.

14. Why This Trial Matters Statistically

This trial is statistically notable because it places three active treatment arms in a randomized, parallel design while focusing its primary assessment on a short-term change in a composite disease-activity score. The PMR-AS combines laboratory measures, symptoms, function, and clinician assessment. That gives the endpoint a broader scope than a single component, while also making complete component data important for producing the composite.

The registry’s note about missing Day 15 CRP values makes that data-completeness issue concrete: the ACZ885 primary analysis has N=3 because CRP was missing for 2 participants. The resulting estimates are not accompanied by posted comparative tests or confidence intervals. This highlights a basic distinction in clinical-trial reporting: descriptive arm summaries can communicate observed patterns, but they do not answer whether the treatment groups differ with known precision.

The study also illustrates the importance of separating randomized treatment-period evidence from later open-label follow-up. Randomization applies to the initial three-arm comparison, while the described follow-up was non-randomized and open label. Outcomes such as later flares, redosing, steroid use, and quality of life address different questions and require interpretation in light of that design.

Finally, the enrollment and status information matters to the precision and scope of the evidence. The registry reports enrollment of 16, a planned total of 30 in the brief summary, and a terminated status, without reporting the reason for termination. These details do not explain the results, but they frame the limited amount of information available for evaluating estimates and comparisons. The study is therefore a useful example of why outcome definition, analysis population, missing data, uncertainty, and design phase all matter when reading a small proof-of-concept trial.

15. Limitations

• The posted summary statistics are the only data these results rest on; patient-level data, full protocols and statistical analysis plans are not available.
• Recalculated results are simple, unadjusted calculations from posted summaries. They do not replace the sponsor's prespecified analysis.

The primary endpoint has limited available data, and the ACZ885 analysis is specifically based on N=3 because of missing Day 15 CRP values. The record does not explain why those measurements were missing or report an imputation approach or sensitivity analysis. Since CRP contributes to PMR-AS, the missing measurements matter to the endpoint’s availability.

The posted primary outcome consists of arm-level least-squares means and standard errors. Comparative estimates, confidence intervals, and inferential tests are not reported. The registry says values were missing or not estimable for a two-arm comparison of the continuous endpoint. This prevents assessment of the precision of treatment contrasts or a statistical test of between-arm differences from the registry record.

The total enrollment was 16, while the brief summary describes a planned total of 30. The study is listed as terminated, but the reason for termination is not reported in the registry record. A trial-specific sample-size justification is also not reported. The record does not establish whether the planned sample was intended to support the posted outcome analysis or what assumptions informed the plan.

There is a difference in the masking descriptions: the registry entry labels masking as double, while the brief summary calls the initial design single-blinded and double-dummy. The record does not clarify this discrepancy. It also does not report the detailed statistical analysis plan, model specification, multiplicity handling, interim analyses, or complete missing-data procedures. These gaps limit assessment of prespecification and analytic choices.

The initial randomized period was short, and the later phase was described as open label and non-randomized. Results from those phases would answer different questions. Detailed results for longer-term efficacy and several secondary outcomes are not included in the registry entries considered for this analysis, so conclusions about those outcomes cannot be drawn.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: A 3-arm Proof of Concept Study of AIN457, ACZ885 or Corticosteroids in Patients With Polymyalgia Rheumatica — NCT01364389.
• Registry record last updated 2021-09-17; status last verified 2021-08.
• Results first posted 2015-03-04.
• 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.

19. Record Summary

NCT01364389 is a phase 2, randomized, parallel, three-arm proof-of-concept study of AIN457, ACZ885, and prednisone in polymyalgia rheumatica. The registry reports enrollment of 16 and terminated status. The brief summary describes a planned total of 30 and a two-week initial treatment period followed by non-randomized, open-label follow-up.

The primary outcome was percent reduction in PMR-AS from baseline to Day 15. The posted least-squares mean reductions were 64.5 for ACZ885, 51.7 for AIN457, and 91.9 for prednisone, with standard errors of 0.68, 0.47, and 86.2. The ACZ885 endpoint analysis includes N=3 because Day 15 CRP values were missing for 2 participants. No comparative analyses or confidence intervals are reported.

The safety record reports 0 serious adverse events and 0 deaths in each listed group. The reason for termination, trial-specific sample-size justification, detailed analysis plan, and reason for missing CRP values are not reported in the registry record.