Use of Acthar in Rheumatoid Arthritis (RA) Related Flares: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Use of Acthar in Rheumatoid Arthritis (RA) Related Flares (NCT02541955), a randomized phase 4 study. The primary outcome is DAS28.

2. Clinical Question

This is a comparison of two dosing regimens, not a comparison of Acthar with an untreated group or a different drug. The results can therefore describe the observed score changes in each group and the estimated contrast between those groups. They do not, by themselves, establish what would have happened without Acthar.

The registry record reports 40 enrolled participants. The DAS28 model used 20 participants in the 40-unit group and 19 in the 80-unit group; one participant in the latter group had baseline data only and was excluded from that model. Why the modeled groups have these sizes and whether there were other exclusions or missing observations are not reported in the registry record.

3. Trial Design

The registry identifies this as a phase 4, randomized, parallel-group trial. It lists 40 participants as enrolled and rheumatoid arthritis as the condition. The study is marked completed. The recorded start date is 2017-07-20, and the primary completion date is 2025-05-06. These dates describe the registry record and do not, on their own, explain the timing or duration of each participant’s treatment.

The two groups received different Acthar regimens: 40 units per week or 80 units twice per week. The primary outcome was DAS28, assessed over the interval from baseline to 4 weeks. The reported group estimates are least-squares means, with 95% confidence intervals. The registry also lists ultrasound Grey Scale Synovial Hypertrophy Score and HAQ-DI as secondary outcomes. Results for those outcomes are not detailed in the available posted results described in the registry record.

Masking is recorded as none. Thus, the registry does not describe the trial as blinded. How treatment allocation was generated, whether allocation was concealed, and whether outcome assessors were masked are not reported in the registry record. Those details matter when assessing potential sources of bias, but should not be inferred from the randomized designation alone.

The record reports a mixed models analysis for the comparison, with a mean difference in final values, a 95% confidence interval, and a p-value. Details of the model specification, including covariates, repeated-measures structure, and assumptions, are not reported in the registry record. A prospective sample-size justification, planned interim analyses, and a fuller statistical analysis plan are also not reported in the registry record.

The enrolled total and the number contributing to the DAS28 model are not identical. The record specifically notes that one participant in the 80-unit group had baseline data only and was not included in the model. It does not provide enough information to characterize all participant flow or to determine whether the analysis followed an intention-to-treat principle.

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

Analysis population for the primary outcome, as defined in the registry: One patient in the 80 unit group only had baseline data and was not included in the model

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 DAS28, measured over Baseline to 4 Weeks.

DAS28 is a continuous score intended to summarize rheumatoid arthritis disease activity. The registry describes its calculation using tender and swollen joint counts across 28 joints, the participant’s global assessment of disease activity, and the erythrocyte sedimentation rate. The global assessment is recorded on a visual analog scale from 0, meaning no disease activity, to 100, meaning maximum disease activity. The total DAS28 score ranges from 0 to approximately 10, and the registry defines remission as a score <2.6.

The primary outcome is the change in DAS28 from baseline to 4 weeks, reported as a least-squares mean for each group. A continuous measure retains more gradation than a simple category such as remission versus not in remission. It can therefore describe changes across the score range, while a mean summarizes the group’s average modeled result. A mean does not show how every participant changed or how widely individual responses varied.

As a general statistical interpretation, a lower DAS28 represents a lower value on a score designed to measure disease activity. The reported group estimates are negative changes, consistent with lower modeled scores at the end of the stated interval than at baseline. The confidence intervals describe uncertainty around those estimates. The registry does not report the individual participant data or the distribution of changes, so the averages cannot establish the pattern of change for every participant.

The endpoint’s clinical interpretation also depends on the scale’s context and on the model used to estimate change. The registry supplies the score definition and time frame, but does not report a threshold for a clinically important change in this trial. A difference in modeled scores should therefore be read as a statistical contrast on the DAS28 scale, not as a stand-alone judgment about clinical importance.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

What does a least-squares mean represent?

In general, a least-squares mean is a model-based estimate of a group mean. It can account for features included in the statistical model, unlike a simple arithmetic average calculated directly from observed values. Its interpretation therefore depends on the model’s specification and assumptions. The registry identifies the primary outcome estimates as least-squares means but does not report the full model specification, so the adjustments and structure behind these estimates are not reported in the registry record.

The reported estimates are -1.05 for the 40-unit group and -1.4 for the 80-unit group, each for change in DAS28 from baseline to 4 weeks. Their confidence intervals indicate uncertainty around the group estimates. A group mean summarizes the center of the modeled changes; it does not describe the full range of participant responses. Participant-level distributions, standard deviations, and other summaries of variation are not reported in the registry record.

How should the confidence interval be read?

In general, a 95% confidence interval is produced by a procedure that, under its assumptions, would cover the true parameter in 95% of repeated samples. For a particular result, it is best understood as a range of values compatible with the data and model, rather than a probability statement about the fixed true value. The intervals for the group estimates are -1.51 to -0.59 and -1.86 to -0.93. The interval for the reported mean difference in final values is -1.0 to 0.31.

The comparison interval includes 0. This means that a no-difference value is among the values compatible with the reported comparison at this interval level. It also includes contrasts on either side of 0, so the data do not narrowly determine direction or magnitude. Confidence intervals convey precision more directly than a p-value alone, but they do not remedy limitations in design, measurement, or model specification.

What does the mixed models result compare?

The registry labels the analysis “Mixed Models Analysis” and reports a mean difference in final values. In general, mixed models can represent relationships among repeated observations or other grouped data and can estimate differences while accounting for modeled structure. Their properties depend on which observations and variables are included, the covariance structure, and assumptions about missing data. The registry does not report these details, so it is not possible to assess the specific model choices from the record.

The reported contrast is -0.34, with a 95% confidence interval from -1.0 to 0.31 and p = 0.300. The treatment-group ordering and model coding are not explained in enough detail to assign a more specific directional interpretation to the sign of the contrast. The group estimates separately indicate negative changes. The inferential comparison should be interpreted as the registry reports it: a modeled mean difference in final values between groups, with uncertainty that includes 0.

Why do model assumptions matter?

General statistical models require assumptions about the data and the relationship between predictors and outcomes. For continuous outcomes, assumptions may concern the shape of residual variation, the relationship between repeated measurements, and whether missing observations are related to observed or unobserved values. If repeated observations are correlated, a model that accounts for that correlation can give more appropriate uncertainty estimates than one that treats every observation as independent. The registry does not state which assumptions were checked or how departures were handled.

Over-dispersion is most often discussed for count outcomes, where observed variation exceeds what a simple model expects. The primary outcome is continuous, so over-dispersion is not the central issue in interpreting the posted DAS28 result. More generally, when a model fails to represent the variability or dependence in data, standard errors and confidence intervals may be unreliable. The record does not provide diagnostic results with which to evaluate model fit.

How does the p-value relate to the interval?

In general, a p-value summarizes how incompatible observed data are with a specified null hypothesis under an analysis model. It does not give the probability that the null hypothesis is true, and it does not report the size or clinical importance of an effect. The registry reports p = 0.300 for the between-group analysis. The associated 95% confidence interval includes 0, consistent with the result not establishing a difference at the conventional two-sided 0.05 level.

The p-value should not be interpreted as evidence that the groups are identical. A non-significant result can arise when an effect is small, when uncertainty is substantial, or both. The estimate and interval are needed to see which values remain compatible with the data. Here, the interval permits a range of contrasts, and the registry does not report an equivalence or non-inferiority framework.

What can be said about the recalculation?

The posted group summaries do not support a two-arm recalculation for this continuous endpoint, as the registry’s analysis information indicates that values are missing or not estimable for that comparison. No separate recalculated contrast is therefore available to place alongside the sponsor’s mixed models result. This is not evidence that the sponsor analysis is incorrect; it means a simple unadjusted reanalysis cannot be presented from the posted summary statistics. The registry does not flag a discrepancy between a recalculation and the reported analysis.

Sample-size planning illustrations, when available, are hypothetical planning calculations based on stated assumptions and an assumed effect. They are not observed power and do not alter the uncertainty in the actual trial results. The registry does not report the trial’s own sample-size justification or enough information to infer how its enrollment target was chosen.

10. Analyses Reported by the Sponsor

The registry reports the sponsor’s own mixed models analysis as a mean difference in final values of -0.34, with a 95% confidence interval from -1.0 to 0.31 and p = 0.300. That is the posted inferential comparison between the two groups. The registry does not flag a discrepancy between this analysis and a recalculation.

A separate unadjusted comparison cannot be recalculated from the posted summary statistics for this continuous endpoint because the required two-arm values are missing or not estimable. Consequently, there is no independent recalculated estimate to compare numerically with the sponsor’s model result. The arm-specific least-squares mean changes and their intervals are reported, but these alone do not supply the information needed to reproduce the mixed models contrast.

The sponsor’s result should be read with its reported uncertainty, rather than as a definitive ranking of the regimens. The confidence interval includes 0 and p = 0.300; the comparison therefore does not establish a between-group difference at the conventional two-sided 0.05 level. The model details and analysis plan are not reported in the registry record, limiting independent evaluation of the analysis choices.

11. Multiplicity, Missing Data and Analysis Populations

The registry lists four outcome measures and four analyses, while naming two secondary outcomes: Ultrasound Grey Scale Synovial Hypertrophy Score and HAQ-DI. The primary outcome is DAS28. The registry does not report detailed results for the secondary outcomes in the record, and it does not explain how the four analyses map to the outcome measures.

Multiplicity arises when several outcomes, time points, or comparisons are tested. In general, the more tests conducted, the greater the chance of at least one apparently unusual result if all null hypotheses are true. Statistical plans may address this through prespecified hierarchies or adjusted significance thresholds. Whether such a strategy was used, which outcome comparisons were prespecified, and whether any adjustment for multiple testing was applied are not reported in the registry record. The reported p-value should therefore be interpreted as the result of its stated comparison, not as evidence that multiplicity was controlled.

The record notes that one participant in the 80-unit group had baseline data only and was not included in the DAS28 model. This identifies a specific exclusion from that analysis, but does not describe all missing data, the reasons for missingness, or how missing observations were handled in the mixed model. The model’s assumptions about missing data are not reported in the registry record.

The record does not state whether the analysis was intention-to-treat, per-protocol, or based on another defined analysis population. It also does not report the allocation procedure, a protocol-defined analysis population, or participant-level flow through follow-up. With 40 enrolled and modeled group sizes of 20 and 19 for the primary outcome, readers can identify the reported analysis sizes, but cannot infer all reasons for the difference or assess whether exclusions were related to outcomes.

Information about interim analyses, stopping rules, prespecified subgroup analyses, and a full statistical analysis plan is not reported in the registry record. These omissions make it difficult to assess whether the reported analysis was the only planned analysis or how selective reporting may have been addressed.

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 serious adverse event figures list 20 participants at risk in each group and 0 participants with a serious adverse event in either group. Deaths are recorded as 0 in both groups. The registry also reports 20 participants with other adverse events among 20 at risk in each group. These are participant counts in the posted record; the information does not give event counts, severity breakdowns, or descriptions of the other adverse events.

A participant count is not necessarily the same as a count of distinct events: one participant may experience more than one event. The record does not clarify whether the other adverse event counts represent people with at least one event or provide further event-level detail. No serious adverse event terms are listed. The duration of safety observation and the method used to collect or classify adverse events are not reported in the registry record.

These figures should be read as descriptive reports from the trial, not as proof that serious risks are absent. The study enrolled 40 participants, and the registry does not provide enough detail to assess event timing, exposure duration, or the ability to detect uncommon events. The safety numbers do not establish a causal relationship between treatment and an event, and they do not support comparisons beyond the reported counts.

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

The primary result describes modeled DAS28 change from baseline to 4 weeks in two Acthar groups. The 40-unit group estimate was -1.05, with a 95% confidence interval from -1.51 to -0.59. The 80-unit group estimate was -1.4, with a 95% confidence interval from -1.86 to -0.93. Both estimates are changes in a disease-activity score; they do not describe the response of every participant.

The reported mixed models comparison was a mean difference in final values of -0.34, with a 95% confidence interval from -1.0 to 0.31 and p = 0.300. The interval includes 0, so the trial does not establish a difference between the two regimens in the reported analysis. That does not show that the regimens are equivalent, because the record does not report an equivalence design or margin. The confidence interval leaves uncertainty about the size and direction of the contrast.

The trial compares two active regimens and does not list a placebo or untreated group. Accordingly, the changes within the groups cannot establish how much change would have occurred without either regimen. Other influences over time cannot be separated from treatment effects using this comparison alone. The registry’s description of a randomized trial is relevant to the between-group comparison, but details of allocation and model specification are not reported.

The reported endpoint is DAS28 over a short stated interval, and the registry lists ultrasound Grey Scale Synovial Hypertrophy Score and HAQ-DI as secondary outcomes. Detailed secondary results are not reported in the record. No conclusion about longer-term outcomes, other measures, or all people with rheumatoid arthritis follows from the primary result.

Statistical uncertainty is not the same as clinical importance. The record does not state a clinically important difference threshold for DAS28 in this trial. The analysis therefore supports a description of the reported score estimates and their uncertainty, but not a judgment that a particular contrast is clinically meaningful. The results should be understood as limited to the measured outcomes, analyzed participants, and time frame recorded.

14. Why This Trial Matters Statistically

This trial illustrates why a within-group change and a between-group comparison answer different statistical questions. Both groups have negative modeled DAS28 changes, but those changes do not by themselves show whether one regimen differs from the other. The reported mixed models contrast is the relevant inferential result for that question, and its confidence interval includes 0.

It also shows why estimates should be read together with their uncertainty. The group means are single summaries, while the confidence intervals indicate a range of values compatible with each estimate under the model. The comparison interval is broad enough to include no difference and contrasts on either side of it. Reporting the estimate, interval, and p-value together makes the limitations of a binary significant-or-not-significant label more apparent.

The trial has an informative design feature for interpreting the contrast: both groups received Acthar, at different regimens. This makes the central comparison a dose-regimen comparison rather than a comparison with no treatment. It also highlights the importance of not attributing all change over time to the intervention when no untreated comparator is listed.

The registry’s missing model details and incomplete information about missing observations illustrate how reporting affects reproducibility. The primary outcome estimates and sponsor analysis are available, but the record does not specify all model choices or analysis-population rules. Those gaps constrain independent assessment even when a result and its uncertainty are reported.

Finally, the registry distinguishes the primary outcome from listed secondary outcomes, but does not provide detailed secondary results in the record described. That makes it important to avoid treating the primary result as a complete account of every outcome the study set out to examine. The study is a case study in interpreting a small randomized comparison cautiously, with attention to outcome definitions, group contrasts, uncertainty, and reporting completeness.

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 registry reports 40 enrolled participants, with 20 in the 40-unit group and 19 in the 80-unit group contributing to the DAS28 model. One participant in the 80-unit group had baseline data only and was excluded from the model. This leaves limited information for estimating a between-group contrast, and the confidence interval reflects substantial uncertainty. Further participant flow and reasons for any other exclusions are not reported in the registry record.

The registry records no masking. It does not state whether outcome assessment was masked or how random allocation was generated or concealed. These details can affect assessment of bias and cannot be inferred from the randomized designation. Model covariates, covariance structure, missing-data assumptions, diagnostic checks, and the handling of protocol deviations are also not reported in the registry record.

The comparison is between two Acthar regimens, with no placebo or untreated group listed. Changes from baseline therefore cannot separate treatment-associated change from changes that might occur over time for other reasons. The primary outcome is reported from baseline to 4 weeks, and results for longer follow-up are not reported in the registry record.

The record names two secondary outcomes but does not report their results in the information described. It also lists four outcome measures and four analyses without explaining their correspondence or the approach to multiplicity. A prespecified statistical analysis plan, sample-size justification, interim analyses, and a clinically important difference threshold are not reported in the registry record.

Safety reporting gives participant counts for serious and other adverse events, but does not provide event-level descriptions, timing, duration of observation, or severity details for other events. These limitations restrict interpretation of both the effectiveness comparison and the safety summaries. They do not invalidate the reported estimates, but they define what can be concluded from the registry record.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Use of Acthar in Rheumatoid Arthritis (RA) Related Flares — NCT02541955.
• Registry record last updated 2026-08-11; status last verified 2026-07.
• Results first posted 2026-08-11.
• 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

The registry describes NCT02541955 as a completed, randomized, phase 4, parallel-group study of Acthar for rheumatoid arthritis-related flares. It lists 40 enrolled participants and two regimens: 40 units per week and 80 units twice per week. Masking is recorded as none.

The primary outcome was DAS28 change from baseline to 4 weeks. The least-squares mean changes were -1.05 in the 40-unit group and -1.4 in the 80-unit group. The mixed models comparison reported a mean difference in final values of -0.34, with a 95% confidence interval from -1.0 to 0.31 and p = 0.300. The interval includes 0 and does not establish a between-group difference.

One participant in the 80-unit group had baseline data only and was not included in the primary model. The registry lists ultrasound Grey Scale Synovial Hypertrophy Score and HAQ-DI as secondary outcomes. Detailed results for these outcomes and important elements of the analysis plan are not reported in the registry record.