Efficacy of Methotrexate in Myasthenia Gravis: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Efficacy of Methotrexate in Myasthenia Gravis (NCT00814138), a randomized phase 2 study. The primary outcome is Total Prednisone Dose Area Under the Curve.

2. Clinical Question

The study’s stated aim was to assess whether methotrexate could reduce reliance on prednisone in people with myasthenia gravis while clinical measures improved. The primary endpoint focuses on prednisone use rather than a direct measure of disease severity. That distinction matters: the primary comparison addresses prednisone exposure during the stated period, while the secondary outcomes were intended to describe daily prednisone dose and several measures of myasthenia gravis status and quality of life.

The registry lists an enrollment of 50 and two groups of 25. Those figures describe the registered enrollment and group sizes; they do not, by themselves, establish how many participants contributed complete data to the primary analysis. The analysis population and the handling of missing outcome measurements are not reported in the registry record.

3. Trial Design

This was a phase II, randomized, double-masked, parallel-group trial of methotrexate versus placebo for myasthenia gravis. The sponsor was the University of Kansas Medical Center. The registry lists the study as completed, with a start date of 2009-04 and a primary completion date of 2014-01. The enrollment was 50, and the listed group sizes were 25 for methotrexate and 25 for placebo.

The study summary describes participants as having symptoms and signs of myasthenia gravis while taking prednisone, and identifies the intended population as prednisone-dependent patients. The primary-outcome population description further specifies adults aged 18 and older who were acetylcholine antibody positive and had a Myasthenia Gravis Foundation score of Grade II, III or IV. These eligibility features limit how directly the results apply to people outside the described population.

The intervention arms were methotrexate and placebo. The study summary says participants were randomized to one of these options and describes methotrexate as oral. The registry does not report the medication dose, treatment schedule, details of allocation concealment, or the specific parties who were masked. Those details should not be inferred from the labels “randomized” and “double” in the design record.

The primary endpoint was prednisone dose area under the curve during months 4-12, a nine-month period. Secondary outcomes listed in the registry include average daily prednisone dose, Quantitative Myasthenia Gravis score, manual muscle testing, MGQOL, MG-ADL and MG Composite change over 12 months. Numerical results for those secondary outcomes are not reported in the registry record. The record does not describe the sample-size justification, the statistical analysis plan, or whether interim analyses were conducted.

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: Myasthenia Gravis patients aged 18 and older that were acetylcholine antibody positive with a myasthenia gravis foundation score of Grade II, III or IV.

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: Eligible participatns were aged at least 18 years; had a diagnosis of generalized Myasthenia Gravis Foundation of America class II, III or IV; positive acetylcholine receptor antibodies; stable dose of greater than or equal to 10 mg/day of prednisone.

6. Primary Endpoint

The registry lists the primary outcome as Total Prednisone Dose Area Under the Curve, measured over 9 months.

The primary endpoint was total prednisone dose area under the curve, expressed in mg*Months, over a nine-month timeframe. The description identifies the period as months 4-12. In general, an area-under-the-curve measure combines the level of a quantity with the time over which it is observed. For a dose-time measure, it represents accumulated prednisone exposure during the specified period rather than a single dose measurement.

The registry says this endpoint was chosen because prednisone doses could change frequently during a month. A measure accumulated across time can reflect those changes more fully than a single dose reading, which captures only one point. The endpoint therefore focuses on overall prednisone exposure during the stated period. It does not, by itself, measure disease severity or establish why a dose changed.

The registry reports mean endpoint values of 2997.0 for the methotrexate group and 3485.0 for the placebo group, each with a 95% confidence interval. The reported analysis describes a mean difference in final values and gives a separate confidence interval for that contrast. The registry does not explain the precise calculation used to produce the interval alongside the stated Wilcoxon (Mann-Whitney) method. The reported result should therefore be read as the registry presents it, without assuming unreported details about the calculation.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The registry reports a randomized, double-masked, parallel design. In general, random assignment is intended to make treatment groups comparable, on average, with respect to measured and unmeasured characteristics at the start of a trial. Masking is intended to reduce the influence of treatment knowledge on care, outcome assessment or reporting. The registry does not report the detailed procedures used for allocation or masking, so those protections cannot be assessed beyond the design labels.

What does the primary endpoint represent?

The primary endpoint is prednisone dose area under the curve during months 4-12, reported in mg*Months. In general, an area-under-the-curve outcome represents accumulated exposure over a period by combining measurements over time. The registry says this measure was selected because prednisone doses could change frequently during a month. It is therefore designed to represent dose exposure across the period rather than relying on a dose recorded at one isolated time.

The area-under-the-curve value does not say whether a dose changed because symptoms improved, worsened, or for another reason. It is an outcome measure of prednisone exposure. The study hypothesis links reduced prednisone dose with improvement in clinical measures, but the primary endpoint is not itself a clinical severity scale. The registry lists those clinical measures separately among secondary outcomes.

What does the confidence interval communicate?

A confidence interval expresses statistical uncertainty around an estimate under the assumptions of the method used. In general, a 95% confidence interval is generated by a procedure that, over repeated studies under the same conditions, would cover the target quantity at the stated rate. It is not a probability statement that the particular interval contains a fixed true value, nor is it a prediction range for individual participants.

For each group, the registry reports an endpoint estimate and a 95% confidence interval. It also reports a confidence interval for the group contrast. The contrast interval ranges from -2443.4 to 1467.3, so it includes zero and values on either side. This indicates that the estimate is not precise enough to isolate a single direction of difference under the reported interval. The interval should be considered alongside the magnitude and meaning of the endpoint, not treated as a binary label.

What does the reported p-value mean?

The reported p-value is 0.26. In general, a p-value measures how compatible the observed data are with a specified null model, given the statistical method and its assumptions. A larger p-value does not prove that there is no difference, and a smaller p-value does not measure the size or clinical importance of a difference. It is not the probability that the null hypothesis is true.

Here, the p-value does not provide a substitute for the confidence interval. The confidence interval displays a range of contrasts consistent with the estimate and method, while the p-value summarizes evidence against a null comparison under that method. The registry does not report an equivalence or noninferiority framework, so neither the p-value nor the interval can be used to claim equivalence.

Why is the Wilcoxon method relevant?

The registry names the Wilcoxon (Mann-Whitney) method for the primary comparison. In general, this is a rank-based method that compares the distributions of observations between groups rather than relying directly on a comparison of group means in the same way as a conventional mean-based test. Rank methods can be useful when the assumptions of a mean-based model are not appropriate, but their interpretation depends on the shape and distribution of the data.

The registry labels the comparison parameter as a mean difference in final values while naming a rank-based test. It does not state how the mean-difference confidence interval was calculated, whether the test and interval use the same estimand, or how the analysis handles ties or other features of the outcome data. It is therefore appropriate to report both labels as registered and avoid assuming additional statistical details. The record does not provide raw participant-level data with which to verify the computation independently.

How should the secondary outcomes be understood?

The registry lists six secondary outcomes: average daily prednisone dose, Quantitative Myasthenia Gravis score, manual muscle testing change, MGQOL change, MG-ADL change and MG Composite change over 12 months. These outcomes address related but distinct aspects of treatment exposure, symptoms, function and quality of life. In general, multiple outcomes create multiple opportunities to observe an apparently notable result by chance, particularly when many comparisons are considered together.

The registry record does not report whether a multiplicity adjustment or a hierarchy among outcomes was used. It also does not include numerical results for the listed secondary outcomes in the available record. Their names alone do not show the direction, magnitude or uncertainty of any result. The primary finding should not be extended to those outcomes without their analyses.

What is not described about the analysis?

The registry record does not report the primary analysis population, the number of participants contributing data to the primary endpoint, or how missing measurements were handled. In general, missing outcomes can affect precision and may introduce bias if their absence is related to treatment or outcome. Whether that concern is material depends on the amount and pattern of missingness, which are not reported in the registry record.

The record also does not report a detailed statistical analysis plan, interim-analysis procedures, or the rationale used to choose the enrollment target. Without those details, it is not possible to assess whether the final analysis followed a prespecified plan or how decisions about endpoints and analyses were made. The registered enrollment is not a measure of statistical power, and it does not reveal the design assumptions used when planning the trial.

10. Analyses Reported by the Sponsor

The sponsor listed for the trial is the University of Kansas Medical Center. The registry reports the primary comparison as a Wilcoxon (Mann-Whitney) analysis, with a mean difference in final values of -488.0, a 95% confidence interval from -2443.4 to 1467.3, and p = 0.26. These are the registry’s reported analysis results.

No separate recalculated contrast or recalculated p-value is reported in the registry record, so there is no additional numerical estimate to compare with the reported analysis. The registry record does not flag a discrepancy between a reported result and a recalculation. The reported sponsor-side analysis therefore remains the result to interpret; there is no competing recalculated result in the record.

The record does not describe the full calculation underlying the contrast interval or explain in detail how the mean-difference parameter relates to the named rank-based test. That limitation concerns the available methodological description, not evidence that the reported result is incorrect. The interval and p-value should be interpreted as reported, with the stated uncertainty and the analysis details that remain unavailable.

11. Multiplicity, Missing Data and Analysis Populations

The registry lists six secondary outcomes in addition to the primary prednisone area-under-the-curve outcome. They include average daily prednisone dose, Quantitative Myasthenia Gravis score, manual muscle testing, MGQOL, MG-ADL and MG Composite change. Considering several outcomes can increase the chance of at least one apparently notable result arising by chance. In general, a prespecified hierarchy or multiplicity adjustment can address that issue, but the registry record does not report whether either was used.

The record indicates seven analyses, but the numerical results for the secondary outcomes are not reported in the registry record. Without those estimates, uncertainty intervals and p-values, their findings cannot be evaluated or compared with the primary endpoint. It is also not possible to establish whether all planned analyses were posted or whether any outcome definitions changed.

The registry record does not report the primary analysis population, the number with evaluable primary endpoint data, or an approach to missing outcomes. It does not say whether participants were analyzed according to randomized assignment, whether a per-protocol population was used, or how withdrawals and incomplete follow-up were treated. Those details matter because an analysis restricted to participants with observed outcomes can differ from an analysis that preserves the randomized comparison.

In general, missing data can reduce precision and can bias an estimate when the likelihood of missingness is related to treatment assignment or outcome. The available record does not provide the missingness pattern or information that would support an assessment of those possibilities. The fact that group sizes are listed does not establish the analysis denominators for each outcome.

The record also does not report interim analyses, a statistical analysis plan, or sample-size justification. These omissions leave uncertainty about planning and analysis decisions, but they do not establish that a particular procedure was or was not used. Interpretation should remain limited to the primary estimate and the information explicitly recorded.

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 0% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: stroke (4.0%), pancreatitis (4.0%), thrombosis (4.0%), dyspnea (4.0%).

The registry records serious adverse events affecting 2 participants in the methotrexate group and 1 in the placebo group. For other adverse events, it records 23 participants in each group as affected. These counts describe the registry’s adverse-event categories; they do not establish that every event was caused by the assigned intervention. The record does not report death counts.

The registry lists Stroke, Pancreatitis, Thrombosis and Dyspnea among the top serious adverse-event terms, each with a reported frequency of 4.0%. The record does not give enough detail in this summary to assign each listed term to a particular group or to determine whether the listed terms refer to unique participants or events. The terms should therefore be read as reported, without treating them as comparative group-specific risks.

In general, adverse-event counts are descriptive unless the reporting method and analysis support a formal comparison. The registry record does not provide event timing, severity grading beyond the serious-event category, exposure duration by participant, attribution judgments, or confidence intervals for the counts. These figures alone cannot establish a difference in safety between the groups, nor can they exclude risks that were not observed or reported.

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

The posted primary result describes prednisone exposure over months 4-12 in a randomized comparison of methotrexate and placebo among the population specified by the registry. The methotrexate group’s reported endpoint estimate was 2997.0 mg*Months, and the placebo group’s estimate was 3485.0 mg*Months. The reported mean difference was -488.0, with a 95% confidence interval from -2443.4 to 1467.3 and p = 0.26.

The interval spans zero and values in both directions. The result is therefore uncertain about the direction and size of the contrast under the reported analysis. It does not demonstrate that the groups are equal: the registry gives no equivalence margin or equivalence analysis. It also does not establish that one treatment is superior. A p-value of 0.26 should not be read as the probability that there is no effect, and the estimate should not be interpreted without its interval.

The primary measure is accumulated prednisone exposure, not a direct measure of myasthenia gravis severity. The registry’s study hypothesis also concerned clinical improvement and the possibility of reducing prednisone, but the listed clinical outcomes are secondary. Their numerical results are not reported in the registry record, so the primary result cannot answer whether clinical status, muscle testing, daily dose or quality of life changed.

The record also does not provide the analysis population, missing-data handling, multiplicity approach or detailed statistical plan. These omissions limit assessment of how robustly the posted estimate represents the randomized groups and how secondary findings should be interpreted. The adverse-event counts are descriptive and do not establish comparative safety.

In short, the registry records a primary comparison with substantial uncertainty and does not provide enough information to make broader claims about other outcomes, equivalence, or safety. The interpretation is specific to the trial population, treatment comparison, and prednisone-exposure period described in the record.

14. Why This Trial Matters Statistically

This trial raises a useful statistical question because the treatment hypothesis involves both medication exposure and disease status. The primary endpoint is prednisone area under the dose-time curve, which aims to capture dose changes over time rather than rely on a single measurement. The registry explicitly says this was chosen because prednisone doses could change frequently during a month. That makes the choice of estimand central to interpretation: cumulative exposure and clinical severity are related questions, but they are not interchangeable outcomes.

The analysis also illustrates why an estimate, its uncertainty interval and the test result need to be read together. The reported contrast is -488.0, but its 95% confidence interval extends from -2443.4 to 1467.3. The interval includes zero and values on both sides, so the direction and magnitude remain uncertain under the reported analysis. A p-value of 0.26 does not resolve that uncertainty or establish equivalence.

There is also a methodological interpretation issue: the registry names a Wilcoxon (Mann-Whitney) comparison while labeling the parameter as a mean difference. Those methods can summarize group data differently, and the record does not explain the construction of the reported interval. Explicitly defining the estimand and the method used for its interval would make the result easier to assess.

Finally, the trial record lists several clinical and quality-of-life outcomes but does not report their numerical results or explain multiplicity handling. This illustrates why outcome definitions, analysis populations, missing-data procedures and planned comparisons are important parts of a complete statistical account. Without those details, readers should keep the interpretation focused on the primary result that is actually reported.

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 record provides limited detail about the analysis. It does not report the statistical analysis plan, the primary analysis population, the number contributing evaluable data, or the handling of missing measurements. These details are needed to assess how the randomized comparison was preserved and how incomplete follow-up may have affected precision or potential bias.

The reported method is Wilcoxon (Mann-Whitney), while the stated parameter is a mean difference in final values. The record does not explain how the confidence interval was calculated or how the effect estimate and test relate. This makes it difficult to reproduce or fully assess the statistical procedure from the registry entry alone.

The registry lists six secondary outcomes, but their numerical results are not reported in the registry record. It also does not report multiplicity procedures or a hierarchy among the outcomes. As a result, the available primary comparison cannot be interpreted alongside the secondary findings, and the risk of chance findings across multiple outcomes cannot be assessed.

The stated population is specific: adults aged 18 and older who were acetylcholine antibody positive and had a Myasthenia Gravis Foundation score of Grade II, III or IV; the study summary also identifies prednisone-dependent patients with symptoms while receiving prednisone. The findings should not automatically be extended to people who differ from that population.

The adverse-event record is descriptive and lacks several details needed for comparative interpretation, including event timing, attribution, group assignment for the listed serious-event terms and death counts. The record also does not report a sample-size justification, interim-analysis procedures, medication dosing details or full masking procedures. These are limitations of the registry description and should not be treated as evidence that a particular procedure was absent.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Efficacy of Methotrexate in Myasthenia Gravis — NCT00814138.
• Registry record last updated 2016-05-26; status last verified 2016-04.
• Results first posted 2015-12-23.
• Data retrieved from ClinicalTrials.gov on 2026-11-09.
• Group sizes, means, event counts and sponsor-reported p-values are reproduced as posted. Effect estimates, confidence intervals and p-values not attributed to the sponsor are independently calculated from the posted summary statistics.

19. Record Summary

NCT00814138 is a completed, randomized, double-masked, parallel-group phase II trial sponsored by the University of Kansas Medical Center. It compared methotrexate with placebo in patients with myasthenia gravis who were prednisone-dependent. Enrollment was 50, with 25 participants listed in each group.

The primary outcome was prednisone dose area under the curve during months 4-12, expressed in mg*Months. The reported mean difference in final values was -488.0, with a 95% confidence interval from -2443.4 to 1467.3 and p = 0.26. The interval includes zero and values in both directions, indicating uncertainty about the contrast.

The registry lists six secondary outcomes, but their numerical results are not reported in the registry record. The record also does not report the analysis population, missing-data handling, multiplicity procedures or detailed statistical plan. Serious adverse events were recorded for 2 participants in the methotrexate group and 1 in the placebo group; deaths are not reported in the record.