Methotrexate (Rheumatrex) High Dose Special Investigation (Regulatory Post Marketing Commitment Plan): Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Methotrexate (Rheumatrex) High Dose Special Investigation (Regulatory Post Marketing Commitment Plan) (NCT01414257), a registered phase not stated study. The primary outcome is Number of Participants With Treatment-Related Adverse Events.

2. Clinical Question

This is a safety-focused question about methotrexate use in daily medical practice, rather than a question about the difference between two assigned treatments. The record describes enrollment of 2860 participants and identifies rheumatoid arthritis and high-dose use among its conditions. The methotrexate group description specifies treatment at a dose higher than 8 mg/week. The primary outcome is defined as a treatment-related adverse event: an untoward medical occurrence attributed to methotrexate in a participant who received it.

The registry lists secondary outcomes that include treatment-related serious adverse events, treatment-related pre-specified important serious adverse events, and clinical efficacy rate. However, it does not report results for those secondary outcomes as outcome estimates. The posted safety figures include counts for serious and other adverse events, but these do not supply a complete result for the primary endpoint as defined. Consequently, the central question can be described, but its primary outcome result cannot be quantified from the registry record.

3. Trial Design

This is a completed, single-group, post-marketing investigation of methotrexate use for rheumatoid arthritis at a dose higher than 8 mg/week. The record gives enrollment as 2860 and lists methotrexate as the intervention. It describes the purpose as assessing safety-related information and verifying efficacy in long-term daily medical practice among patients receiving the specified preparation and dose. The record does not state an allocation method. Its single listed group and the absence of a comparator mean it is not a randomized comparison between treatments.

The start date is 2011-05, and primary completion is listed as 2014-03. The primary outcome is the number of participants with treatment-related adverse events, with a timeframe of 24 Weeks. The safety analysis set is described as participants who satisfied the inclusion criteria and received methotrexate at least once. The adverse-event record gives 2838 as the number at risk for both serious and other adverse-event counts. That figure is the reported risk-set size for those entries; it should not be substituted for the overall enrollment figure.

The registry lists 8 outcome measures and 0 analyses. It names three secondary outcomes: treatment-related serious adverse events, treatment-related pre-specified important serious adverse events, and clinical efficacy rate. The record does not include a control arm, treatment allocation details, or enough information to reconstruct a comparative treatment effect. It also does not describe the protocol’s sample-size justification, interim analyses, or a statistical analysis plan. Those details are not reported in the registry record.

The post-marketing setting is relevant to interpretation: the stated aim concerns use in medical practice, while the outcome definitions and analysis population determine which participants contribute to particular results. The registry record should therefore be read as a description of a safety investigation and its posted counts, not as evidence from a controlled treatment comparison. The completion status indicates the investigation is marked completed in the record; it does not, by itself, fill gaps in the posted outcome results or analysis methods.

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: The safety analysis set comprised of participants who satisfied the inclusion criteria and had received methotrexate at least once.

5. Baseline Characteristics

The table reproduces the baseline characteristics posted in the registry, which describe the participants analysed at baseline and help show whether the randomized groups were comparable.

Population: Not in particular

6. Primary Endpoint

The registry lists the primary outcome as Number of Participants With Treatment-Related Adverse Events, measured over 24 Weeks.

The primary endpoint is the number of participants with treatment-related adverse events. The registry defines a treatment-related adverse event as an untoward medical occurrence attributed to methotrexate in a participant who received methotrexate. Its stated timeframe is 24 Weeks. The safety analysis population includes participants who met the inclusion criteria and received methotrexate at least once.

A participant count is a binary-outcome summary: each person is categorized according to whether the specified event occurred within the endpoint definition and timeframe. This kind of endpoint is used to describe how many participants experienced an event, rather than how many events each participant experienced or how long it took for an event to occur. As a general statistical point, a count is most interpretable alongside the number of participants assessed and clear definitions of the event, timeframe, and analysis population.

The registry record does not give a primary endpoint result under this exact definition. It does report serious and other adverse-event counts, but those entries do not establish the total number of participants with any treatment-related adverse event as defined for the primary endpoint. They should not be combined or treated as a substitute for that result. The registry also lists clinical efficacy rate as a secondary outcome, but its result is not reported in the registry record.

This endpoint is relevant to the stated safety purpose because it counts participants with an event attributed to methotrexate. Attribution is part of the definition, not proof of causation. The registry’s result cannot establish that methotrexate caused every reported event, and without a comparator it cannot quantify how event occurrence differs from another treatment or from no treatment.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The registry identifies the primary outcome as a count of participants with treatment-related adverse events, with a binary meaning: participants with an event. In general, a binary outcome classifies each participant into an event or no-event category according to a prespecified definition. The result may be expressed as a count, a proportion, or a treatment contrast, but only the count and risk-set details actually posted can be described as registry results. No primary endpoint estimate in the registry is reported under the stated definition.

What does a participant count represent?

A participant count differs from a count of event episodes. If a participant experiences more than one event, an event-count measure may count each episode, while a participant measure generally counts that person once for the specified outcome. The registry names the outcome in terms of participants, and the safety entries likewise present affected-participant counts. The record does not provide additional detail about how repeat events, overlapping event categories, or event timing were handled. Those rules are not reported in the registry record.

The primary event definition includes attribution to methotrexate and a timeframe of 24 Weeks. These details matter because a result depends on which events qualify, the period in which they are observed, and who enters the analysis population. The stated safety population consists of participants who satisfied the inclusion criteria and received methotrexate at least once. The adverse-event entries give a risk-set count of 2838. The record also reports overall enrollment of 2860, but does not explain the relationship between that enrollment figure and the safety risk set.

Why does the design matter?

A single treatment group supports descriptive reporting of outcomes among participants receiving that treatment. A comparison between treatments generally requires comparable groups and a defined contrast. Here, only methotrexate is listed, allocation is not stated, and the record flags that this is not a randomized comparison. As a general statistical point, a control group can help distinguish an outcome pattern associated with one treatment from background risks and other influences, but the registry does not provide such a group. The posted counts therefore do not estimate a relative treatment effect.

Randomization, when used, is a way to assign participants to groups so that known and unknown characteristics are balanced on average. That general explanation does not describe this investigation: its allocation is not stated, and the record does not list a comparator. It would be inappropriate to infer that randomization or a particular assignment process occurred. Likewise, the record does not report adjustment methods for differences between participants or other potential influences on the observed counts.

What can uncertainty measures add?

In general, a confidence interval conveys uncertainty around an estimate under a statistical model and method. A p-value addresses compatibility of observed data with a specified null hypothesis under an analysis plan. Neither measure independently establishes clinical importance or causation. The registry record lists 0 analyses and does not post confidence intervals, p-values, or an adjusted model for the outcomes described. Therefore, the precision of the posted counts cannot be judged using inferential statistics from this record. No significance claim can be made from counts alone.

Over-dispersion is a general issue for some count models when variability exceeds what a simple model assumes. It is not a central feature of a participant-level binary endpoint, which records event status rather than a number of recurrent events. The registry does not report a model for recurrent event counts or a model-based analysis. It would therefore be speculative to describe an over-dispersion adjustment as part of the investigation’s methods.

How should planning illustrations be read?

The record describes sample-size planning illustrations based on the observed effect, with a two-sided significance level of 0.05, equal allocation between two hypothetical arms, and a normal approximation. It says the effect to detect is a stated fraction of the observed effect. These are planning assumptions, not evidence that the investigation itself used two arms or those design settings. Since this investigation lists one group and no comparator, the hypothetical equal-allocation framework does not describe its recorded design. The illustrations are not observed power, and they do not establish that the study was designed with a particular sample-size justification. That justification is not reported in the registry record.

Sample-size planning asks how many participants may be needed under chosen assumptions to detect a specified effect with a selected error rate and power. Such calculations depend on the endpoint, the assumed effect, variability or event frequency, allocation, and analysis method. In general, changing an assumption can change the planning estimate. The registry’s stated planning framework can be explained, but no additional values should be inferred from it, and it does not supply a retrospective measure of the investigation’s evidential strength.

Finally, missing-data handling, censoring rules, subgroup analyses, and multiplicity procedures are not described in the registry record. These choices can affect an analysis and its uncertainty. Without the relevant methods, the posted event counts remain descriptive registry results rather than a full statistical analysis.

10. Exact Estimates for Each Arm

No two-arm comparison is shown for this trial, but each arm's result can still be summarized with exact interval estimates computed from the posted counts. The Clopper-Pearson interval is exact and conservative; the Wilson interval is a common closer-to-nominal alternative; the Bayesian credible interval uses a uniform Beta(1, 1) prior. For small groups the three can differ noticeably.

R code and output

arm    <- c("Methotrexate")
n      <- c(2838)
events <- c(608)
for (i in seq_along(n)) {
  ci <- binom.test(events[i], n[i])$conf.int          # Clopper-Pearson exact interval
  cr <- qbeta(c(0.025, 0.975), 1 + events[i], 1 + n[i] - events[i])   # Bayesian, uniform Beta(1,1) prior
  wi <- (function(x, n) { p <- x / n; z <- qnorm(0.975); d <- 1 + z^2 / n
    c((p + z^2 / (2 * n) - z * sqrt(p * (1 - p) / n + z^2 / (4 * n^2))) / d, (p + z^2 / (2 * n) + z * sqrt(p * (1 - p) / n + z^2 / (4 * n^2))) / d) })(events[i], n[i])
  cat(sprintf("ARM|%s|%d|%d|%.1f|%.1f|%.1f|%.1f|%.1f|%.1f|%.1f\n", arm[i], n[i], events[i], 100 * events[i] / n[i],
              100 * ci[1], 100 * ci[2], 100 * wi[1], 100 * wi[2], 100 * cr[1], 100 * cr[2]))
}

ARM  Methotrexate  2838  608  21.4  19.9  23.0  20.0  23.0  20.0  23.0

11. Multiplicity, Missing Data and Analysis Populations

The registry lists 8 outcome measures and 0 analyses. It names the primary outcome and lists secondary outcomes that include treatment-related serious adverse events, treatment-related pre-specified important serious adverse events, and clinical efficacy rate. The registry record does not describe a statistical analysis plan for these outcomes or explain how multiple outcome tests were handled.

Multiplicity arises when several outcomes or hypotheses are examined. As a general statistical point, testing many hypotheses can increase the chance of finding at least one apparently unusual result by chance, depending on the testing strategy. Methods such as adjusting significance thresholds or identifying a primary hypothesis in advance can address particular multiplicity concerns. The record does not report whether such methods were planned or used. No multiplicity adjustment should be assumed.

The safety population is described as participants who met the inclusion criteria and received methotrexate at least once. The registry does not explain how missing outcome data were handled, whether participants were excluded for incomplete follow-up, or how the analysis treated participants without endpoint information. Those details are not reported in the registry record. The record also does not give a participant flow accounting for the difference between enrollment of 2860 and the adverse-event risk-set size of 2838.

These omissions matter because analysis populations and missing-data methods determine which observations contribute to estimates. The reported risk-set counts provide context for the posted adverse-event figures, but they do not answer whether all enrolled participants had complete outcome assessment. Nor do they reveal the assumptions used for any unobserved outcomes. Consequently, the available record does not support conclusions about the extent or impact of missing data or the control of multiplicity.

12. 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 1.0% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: pneumonia (0.4%), interstitial lung disease (0.2%), pneumocystis jirovecii pneumonia (0.2%), lymphoma (0.1%), urinary tract infection (0.1%).

The registry reports an at-risk count of 2838 for the serious and other adverse-event entries. It records 69 participants in the serious-event affected count and 340 in the other-event affected count. These figures should be kept in their separate categories. The record does not state that the two counts are mutually exclusive, so they should not be added to create a total number of participants with adverse events.

The listed serious-event terms have registry percentages: Pneumonia, 0.4%; Interstitial lung disease, 0.2%; Pneumocystis jirovecii pneumonia, 0.2%; Lymphoma, 0.1%; Urinary tract infection, 0.1%; and Gastric cancer, 0.1%. These terms and percentages describe the posted serious-event entries; they are not a complete account of every possible event. The registry record does not report a deaths count.

As a general point, an adverse-event count describes observations under the outcome definition and the population assessed. A serious-event count is not automatically a count of events caused by treatment, and attribution is distinct from proof of causation. These safety figures also do not replace the primary endpoint result, which is not reported in the registry record under its stated definition.

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

The posted results establish that the registry includes safety counts for a methotrexate group in a post-marketing investigation of rheumatoid arthritis treatment at a dose higher than 8 mg/week. The adverse-event entries use an at-risk count of 2838 and report 69 participants in the serious-event affected count and 340 in the other-event affected count. The registry also lists several serious-event terms with percentages. These findings are descriptive of the entries recorded; the available record does not provide a comparative estimate.

They do not establish the treatment-related adverse-event result for the primary endpoint. Although the primary outcome is defined as participants with an adverse event attributed to methotrexate during 24 Weeks, a result under that exact definition is not reported in the registry record. The listed counts should not be reinterpreted as a complete primary result. The clinical efficacy rate is named as a secondary outcome, but no efficacy result is posted.

The investigation is not a randomized comparison: the record lists one intervention group, no comparator, and allocation is not stated. Therefore, the event counts cannot show whether risk is greater or lower than it would be with another treatment or in another group. They also cannot establish causation. The event definition includes attribution to methotrexate, but an attribution judgment is not equivalent to a controlled causal estimate.

There are no reported confidence intervals, p-values, or adjusted analyses in the registry record. In general, statistical estimates need both an outcome definition and a method for quantifying uncertainty; a count alone does not show how precisely an underlying event frequency is estimated. The record also does not explain missing-data handling, participant exclusions, or the relationship between enrollment and the adverse-event risk set.

The appropriate conclusion is limited to the registry’s descriptive information: it documents a completed post-marketing investigation and posts adverse-event counts and term percentages. It does not report enough primary outcome, efficacy, or inferential information to support broader comparative conclusions.

14. Why This Trial Matters Statistically

This investigation is statistically relevant because it shows the difference between documenting events in a post-marketing setting and estimating a comparative treatment effect. The record’s stated purpose is to assess adverse reactions, factors considered to affect safety, and efficacy during daily medical practice. Its posted adverse-event counts can contribute descriptive safety information, but the single listed group cannot answer how those outcomes compare with a control group.

Outcome definitions and analysis populations are central to interpreting even straightforward counts. The primary outcome is defined as participants with treatment-related adverse events during 24 Weeks, while the safety population is restricted to participants meeting inclusion criteria who received methotrexate at least once. The adverse-event entries identify a risk set of 2838. Because the registry does not report a result for the primary endpoint under its stated definition, the available counts cannot simply be treated as that endpoint’s result.

The record also demonstrates why completion status and enrollment alone do not establish the strength or precision of evidence. Enrollment is listed as 2860, but there is no reported participant flow, uncertainty interval, p-value, or adjusted analysis. A completed investigation may still have gaps in the posted results. The record lists 8 outcome measures and 0 analyses, and it does not describe multiplicity or missing-data methods.

Finally, the stated planning illustrations use hypothetical assumptions that differ from the one-group design recorded for the investigation. Separating planning exercises from actual design prevents a hypothetical two-arm framework from being mistaken for the study that was conducted. Together, these points make the record a useful example of why outcome reporting, design details, and analysis methods are all needed to move from descriptive counts toward well-supported statistical conclusions.

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 main limitation is that the registry does not report a result for the primary endpoint as defined: the number of participants with treatment-related adverse events during 24 Weeks. Although it posts serious and other adverse-event counts, those entries are not identified as a complete primary endpoint result. The clinical efficacy rate is listed as a secondary outcome, but its result is not reported in the registry record.

The record contains one methotrexate group and no comparator. Allocation is not stated, and the investigation is not a randomized comparison. This limits interpretation to the group described and prevents a controlled comparison of event occurrence. The registry does not report an adjusted analysis that might address differences among participants or other influences on observed outcomes.

The relationship between overall enrollment of 2860 and the adverse-event risk-set size of 2838 is not explained. No participant flow or detailed accounting of exclusions is reported. The registry does not describe missing-data handling, follow-up completeness, or how events and overlapping event categories were counted. The listed serious-event terms and percentages should therefore be treated as the reported entries, not a complete safety profile.

There are no reported confidence intervals, p-values, or model-based estimates, and the record lists 0 analyses. The statistical analysis plan, sample-size justification, interim analyses, and multiplicity methods are not reported in the registry record. The sample-size planning assumptions describe an illustration rather than the actual one-group design. Finally, the record does not report a deaths count. These gaps constrain both precision assessment and interpretation beyond descriptive reporting.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Methotrexate (Rheumatrex) High Dose Special Investigation (Regulatory Post Marketing Commitment Plan) — NCT01414257.
• Registry record last updated 2018-08-06; status last verified 2017-11.
• Results first posted 2018-08-06.
• 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

This completed registry record concerns methotrexate use for rheumatoid arthritis at a dose higher than 8 mg/week in daily medical practice. Enrollment is listed as 2860; the start date is 2011-05, and primary completion is 2014-03. The primary outcome is the number of participants with treatment-related adverse events during 24 Weeks. The safety analysis set is described as participants meeting the inclusion criteria who received methotrexate at least once.

The adverse-event entries report 2838 at risk, 69 in the serious-event affected count, and 340 in the other-event affected count. Several serious-event terms are listed with percentages. The registry does not report the primary endpoint result under its stated definition or a clinical efficacy rate result. It lists 8 outcome measures and 0 analyses. One intervention group is recorded, no comparator is listed, and allocation is not stated. Missing-data methods, multiplicity methods, and inferential analyses are not reported in the registry record.