Combined Treatment of Methotrexate + Glucocorticoids Versus Glucocorticoids Alone in Patients With PM and DM: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Combined Treatment of Methotrexate + Glucocorticoids Versus Glucocorticoids Alone in Patients With PM and DM (NCT00651040), a randomized phase 3 study. The primary outcome is The Primary Endpoint is the Total Dose of Glucocorticoids Administered Between Baseline and the End of Treatment..

2. Clinical Question

The trial’s central statistical question concerns the average cumulative glucocorticoid dose, reported in mg/kg, in the two randomized groups. The registry describes a prospective, randomized, assessor-blind comparison and identifies the primary endpoint as total glucocorticoid dose between baseline and the end of treatment. Its stated comparison is not simply whether glucocorticoids were used: both groups received glucocorticoid treatment, while methotrexate was added in one group.

The posted arm summaries report a mean of 124.0 mg/kg for the Prednison group and 135.0 mg/kg for the Prednison Methotrexate group. The reported mean difference is 11.0 mg/kg, with an interval from -28.49 to 50.49. These figures describe the observed group summaries and the estimated difference; they do not by themselves establish a precise or definitive contrast. The reported unadjusted p-value is 0.585.

The trial also lists secondary areas including disease activity and damage, muscle strength and endurance, enzyme levels, glucocorticoid side effects, functional ability, quality of life, and treatment failures. The registry record does not report a detailed result for each of those areas. The primary question should therefore be kept distinct from broader questions about symptoms, function, safety, or longer-term outcomes.

3. Trial Design

The registry identifies this as a Phase 3, randomized, parallel-group study with single masking. Its study description calls the design open-label and assessor-blind: treatment was not described as masked to participants and treating teams, while outcome assessment was intended to be blinded. The record describes an international multicenter study, but the number and locations of participating centers are not reported in the registry record.

The comparison was between prednisone alone and prednisone with methotrexate. The arm descriptions say prednisone was administered orally, initially at 1.0 mg/kg/day and then tapered gradually and equally in both arms. In the combination group, methotrexate was administered once weekly for 48 weeks, with a clinically oriented dose escalation from 10 up to 20-25 mg. The record also describes folic acid administration after each methotrexate dose. These are registry descriptions of the intended regimens, not evidence that every participant received the same doses or completed treatment as planned.

The brief study summary describes a planned total of 50 patients, with 25 per arm and equal allocation. The actual enrollment field reports 31 participants. The posted primary endpoint summaries include 16 participants in the Prednison group and 15 in the Prednison Methotrexate group. The study is marked completed, with a start in 2008-05 and primary completion in 2014-11.

The described treatment period was 12 months, followed by a 12-month follow-up period. The primary endpoint timeframe is reported as 1 year. The registry record does not report the achieved follow-up duration by participant, the number who completed follow-up, or details of withdrawals. The original sample-size justification and the trial’s statistical analysis plan are not reported in the registry record.

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

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 The Primary Endpoint is the Total Dose of Glucocorticoids Administered Between Baseline and the End of Treatment., measured over 1 year.

The primary endpoint is the total dose of glucocorticoids administered between baseline and the end of treatment. It is reported as a mean continuous measure in mg/kg, with a standard deviation for each group, over a timeframe of 1 year. In practical terms, the endpoint summarizes cumulative glucocorticoid exposure during the defined treatment period rather than a single dose at one visit.

This measure is relevant to the randomized comparison because both groups received glucocorticoid treatment, while the combination group also received methotrexate. Comparing total glucocorticoid dose therefore describes whether the cumulative amount administered differed between the treatment strategies during the reported period. A higher total dose represents more glucocorticoid exposure within the endpoint’s definition; the endpoint alone does not describe disease activity, function, adverse effects, or the reasons clinicians changed doses.

The registry reports a mean of 124.0 mg/kg in the Prednison group and 135.0 mg/kg in the Prednison Methotrexate group. The registry does not give a fuller endpoint definition, including how dose changes, incomplete treatment, or missing measurements were handled. It also does not report a separate protocol-level rationale for selecting this endpoint. The question answered by the posted result is consequently limited to the reported group means and their estimated difference in total glucocorticoid dose.

7. Results Posted in the Registry

• Prednison Methotrexate 2: mean 135.00 versus 124.00 on control; difference 11.00 (95% CI -28.49 to 50.49), standardized effect d = 0.19; z-test p = 0.585.

8. Statistical Interpretation

9. Statistical Methods Explained

The primary endpoint is continuous: each participant’s total glucocorticoid dose is expressed as a quantity in mg/kg, and the arm-level summaries are means and standard deviations. The posted comparison reports the difference between those means. A mean difference retains the endpoint’s original units, so its interpretation stays tied to mg/kg rather than converting the outcome into a different scale.

What does the mean describe?

In general, the arithmetic mean is the sum of observed values divided by the number of observations. It gives a measure of the group’s average, but it does not describe every participant’s value or the shape of the distribution. Two groups can have similar means while differing in their spread or in the pattern of individual observations. The registry reports the means and standard deviations, but it does not provide participant-level values or a distribution plot of the primary endpoint.

The reported arm means are 124.0 mg/kg and 135.0 mg/kg, and the reported standard deviations are 65.7 and 45.2, respectively. A standard deviation describes dispersion around a mean: larger values indicate greater variation among observed values, in the same measurement units as the endpoint. The standard deviations are descriptive summaries and are not themselves confidence intervals for the means.

What does the mean difference describe?

The reported mean difference is 11.0 mg/kg, comparing the combination group with the prednisone-alone group. It represents the estimated contrast between group averages, not an individual participant’s change and not a change from baseline. The estimate is accompanied by an interval from -28.49 to 50.49 mg/kg. The registry presents this comparison as a mean difference but does not report the precise inferential method used to produce the interval or p-value.

In general, a confidence interval expresses uncertainty about an estimate under the method used to calculate it. Intervals that include zero for a difference are compatible with no group difference at the corresponding confidence level. The confidence level for this interval is not reported in the registry record, so its exact coverage interpretation should not be assumed. The reported p-value is unadjusted and is 0.585; it is another summary of statistical compatibility with a null comparison, not a probability that the null is true.

Why does variation matter?

In general, variability affects the precision of an estimated group difference. When participant outcomes vary widely, a group mean can be less precise unless the study includes enough observations to characterize that variation. The arm standard deviations indicate that the observed endpoint values varied, while the group sizes of 16 and 15 limit how much information is available in the posted summaries. A standard error, confidence interval, or test also depends on the method and assumptions used; those details are not fully reported for the primary analysis.

Over-dispersion is a general concern when a statistical model assumes less variability than the data contain. If variability is greater than the model allows, standard errors can be too small and uncertainty can be understated. The primary endpoint is continuous, and the registry does not report a model or a dispersion assessment. Over-dispersion should therefore be treated as a general statistical concept, not as a reported finding in this trial.

What is standardized effect size?

The posted comparison includes a standardized effect size of 0.194 and a pooled standard deviation of 56.74. In general, standardizing a mean difference expresses its size relative to a measure of variation, which can help describe magnitude without retaining the original measurement units. Such a summary depends on the chosen standardization method. The registry does not give enough detail to assess all analytical choices behind this value. It should not replace the original-unit result, which is easier to relate to the mg/kg endpoint.

What can be inferred from randomization?

In general, random allocation is intended to make treatment groups comparable at the point of assignment, including with respect to measured and unmeasured factors on average. It does not guarantee that the groups will be identical, particularly in a study with small group sizes. The registry describes randomization based on computer-generated random numbers. It does not report the sequence generation details, concealment procedures, stratification, or the analysis population. The stated assessor-blind design may reduce some opportunities for outcome assessment to be influenced by knowledge of treatment, but the study is also described as open-label. The masking details for participants and clinical teams are not reported beyond that description.

The registry record does not report the primary analysis model, handling of missing observations, covariate adjustment, distributional diagnostics, or whether analyses followed an intention-to-treat principle. Consequently, the reported arm summaries and comparison can be interpreted as posted results, while methodological details beyond the registry description remain unknown. No additional analysis choices should be inferred from the reported effect estimate, interval, or p-value.

10. Confidence Intervals and Precision

The estimated mean difference in total glucocorticoid dose is 11.0 mg/kg, with a reported interval from -28.49 to 50.49 mg/kg. This interval is wide and includes zero. It therefore conveys considerable uncertainty about both the direction and size of the group contrast. The result is compatible with a lower mean dose in the combination group as well as a higher mean dose, under the interval’s unspecified method and confidence level.

An interval is more informative about precision than the point estimate alone because it shows a range of values that remain compatible with the data and analysis. It does not indicate that every value in the interval is equally likely, and it does not guarantee that the true effect lies within its limits. The confidence level and interval-calculation method are not reported in the registry record, so the conventional coverage interpretation cannot be checked from the posted information.

The arm summaries are based on 16 participants in the Prednison group and 15 in the Prednison Methotrexate group. The observed standard deviations are 65.7 and 45.2. Group size and outcome variability both matter to the precision of an estimated difference. The small posted groups and visible spread are relevant context, but they do not explain the interval’s width by themselves; the analysis method and any missing-data handling are also not reported.

The unadjusted p-value is 0.585. It does not make the interval narrow, establish equivalence, or show that the group means are identical. The information supports a cautious description of the estimated contrast and its uncertainty rather than a precise claim about the size of a difference.

11. Planning a Similar Trial: Sample Size

This is a planning illustration, not a re-evaluation of the original trial. It asks: if a new study wanted to detect a difference like the one observed, or a smaller one, how large would it need to be? It is deliberately not “observed power” of the finished trial, which is not a meaningful quantity.

The planning figures are illustrations based on the observed effect, not the trial’s original design justification. The registry record does not report the original sample-size assumptions or calculation. The displayed planning values are participants per arm, not total participants and not total events. Total-event wording applies to time-to-event calculations, whereas the primary endpoint is continuous and the figures are per arm.

The illustration uses a two-sided significance level of 0.05, equal allocation between the two arms, and a normal approximation. It considers effects set at 100%, 75%, and 50% of the observed effect. For each assumed effect, the 80% power column gives the estimated number of participants per arm for a design with an 80% chance of detecting that assumed effect under the planning assumptions, if that effect and those assumptions were correct. The 90% power column gives the corresponding per-arm planning number for a design with a 90% chance under those assumptions.

Smaller effects are harder to distinguish from random variation, so planning for a smaller fraction of the observed effect requires more participants per arm. The figures are prospective illustrations and are not a measure of the probability that this completed trial detected an effect. This is not observed power. The trial’s actual enrollment was 31, while its brief description proposed 50 participants; the reason for that difference is not reported in the registry record.

12. How the Sample Size Is Derived

Power is the probability that a study of a given size rejects the null hypothesis when a specific true effect exists. It depends on four things: the effect to detect, the variability of the outcome, the significance level (here a two-sided α of 0.05, so z_1−α/2 = 1.960) and the desired power (z_1−β = 0.842 for 80% and 1.282 for 90%).

Formula

n is the number of participants in each arm, Δ is the difference in means to detect and σ is the common standard deviation.

Worked calculation for this trial

1. Observed difference Δ = 11.000; pooled standard deviation σ = 56.736.
2. n = 2 × (1.96 + 0.842)² × 56.736² / 11.000² = 417.6, rounded up to 418 participants per arm for 80% power.

The smaller-effect rows in the table above repeat the same calculation with the effect multiplied by 0.75 and 0.5 (for ratios, applied to the logarithm of the ratio).

R code

alpha <- 0.05
z_a   <- qnorm(1 - alpha / 2)          # two-sided
delta <- 11                      # observed difference in means
sigma <- 56.7359005726806                     # pooled standard deviation
n_per_arm <- function(power, frac = 1) {
  ceiling(round(2 * (z_a + qnorm(power))^2 * sigma^2 / (delta * frac)^2, 6))
}
for (f in c(1, 0.75, 0.5))
  cat(sprintf("%3.0f%% of observed effect: n per arm = %s (80%% power), %s (90%% power)\n", 100 * f,
              format(n_per_arm(0.80, f), big.mark = ","), format(n_per_arm(0.90, f), big.mark = ",")))

# Check against R's built-in function (t-based, so very slightly larger)
cat("power.t.test:", round(power.t.test(delta = delta, sd = sigma, power = 0.80)$n, 1), "\n")

# Simulation: exact two-sample t-test using simulated means and variances
set.seed(651040)
n    <- n_per_arm(0.80)
reps <- 20000
m_diff <- rnorm(reps, delta, sigma * sqrt(2 / n))             # difference in sample means
s2     <- sigma^2 * rchisq(reps, 2 * (n - 1)) / (2 * (n - 1))   # pooled sample variance
tstat  <- m_diff / sqrt(s2 * 2 / n)
cat(sprintf("Simulated power at n = %s per arm: %.3f (%d replicates)\n", format(n, big.mark = ","), mean(abs(tstat) > qt(0.975, 2 * (n - 1))), reps))

Output from running the code

100% of observed effect: n per arm = 418 (80% power), 560 (90% power)
 75% of observed effect: n per arm = 743 (80% power), 994 (90% power)
 50% of observed effect: n per arm = 1,671 (80% power), 2,237 (90% power)
power.t.test: 418.6 
Simulated power at n = 418 per arm: 0.805 (20000 replicates)

The simulation draws many sets of group means and variances at the planned sample size and counts how often the two-sample t-test rejects the null. It should land close to the target power; at very small required sample sizes it can fall below it, because the normal approximation is rough there.

13. Multiplicity, Missing Data and Analysis Populations

The registry lists secondary outcome areas that include disease activity and damage, muscle strength and endurance, enzyme levels, glucocorticoid side effects and dose, HAQ, SF-36, and treatment failures. The registry record does not report a multiplicity strategy explaining whether or how statistical testing across outcomes or time points was controlled. It also does not specify a hierarchy of outcomes beyond identifying the primary endpoint. Without those details, the primary endpoint should be distinguished from the broader list of secondary questions, and the unadjusted p-value should not be treated as if it accounts for multiple comparisons.

One secondary outcome is listed as posted, but a full set of secondary numerical results and analysis details is not reported in the registry record. The posted record identifies two outcome measures overall and contains no posted analysis entries. The registry does not explain which secondary result was reported, how it was analyzed, or whether the other listed outcomes were measured but not entered as results. Missing detail should not be interpreted as evidence that an outcome was not assessed.

The registry record does not describe how missing outcome values were handled, whether any participants withdrew, or whether all randomized participants contributed to the primary analysis. It does not state whether the analysis followed an intention-to-treat, per-protocol, or other population definition. The reported primary arm counts are 16 and 15, but those counts alone do not establish the flow of participants from randomization through analysis.

There is also no reported explanation for the difference between the planned total of 50 in the study description and the actual enrollment of 31. Reasons might include recruitment or eligibility issues, but such explanations are not reported and should not be presumed. These gaps limit assessment of selective reporting, missing-data bias, and the relationship between the planned analysis and the posted results.

14. 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: tumor (20.0%), worsening of muscles (12.5%), worsening of skin (6.7%), synkopa (6.7%).

The serious adverse event summaries report 4 affected participants among 16 in the Prednison group and 5 among 15 in the Prednison Methotrexate group. The other adverse event summaries report 14 among 16 in the Prednison group and 11 among 15 in the Prednison Methotrexate group. These are participant counts with the respective group denominators; they are not measures of event severity beyond the registry’s serious-versus-other categorization.

The registry also lists serious-event terms with percentages: tumor, 20.0%; worsening of muscles, 12.5%; worsening of skin, 6.7%; and synkopa, 6.7%. The record does not provide enough detail alongside these terms to establish their group-specific distribution, whether a participant could contribute more than one event, or the exact denominator used for each percentage. They should therefore be read as reported terms and percentages rather than as a complete event-by-arm comparison.

Deaths are not reported in the registry record. The safety summaries are descriptive and do not, on their own, establish a comparative risk or explain causality. The registry record does not provide additional detail about event timing, severity gradation, relatedness, or follow-up for these events.

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

The primary result describes average total glucocorticoid dose over 1 year in the two randomized groups. The reported mean was 124.0 mg/kg with prednisone alone and 135.0 mg/kg with prednisone plus methotrexate. The estimated mean difference was 11.0 mg/kg, with an interval from -28.49 to 50.49 and an unadjusted p-value of 0.585. Together, these figures show an imprecise estimated contrast rather than a narrowly determined difference.

The interval includes zero and extends in both directions. Accordingly, the posted primary outcome does not precisely establish the direction or magnitude of the average dose difference. A p-value of 0.585 does not prove that the groups are equivalent or that any difference is absent. Equivalence or noninferiority would require an appropriate prespecified margin and analysis, neither of which is reported in the registry record.

The endpoint is cumulative glucocorticoid dose, not a direct measurement of disease control, muscle strength, functional ability, quality of life, or treatment failure. A difference in dose, if present, would not by itself determine whether disease outcomes differed or whether any difference was important to patients. Likewise, the primary endpoint result does not resolve the safety comparison. Those questions require their own outcome definitions and results.

The study enrolled 31 participants, with primary outcome summaries for 16 and 15 participants in the two groups. The brief description proposed 50 participants. The reason for the lower actual enrollment is not reported. The modest group sizes are relevant when considering the interval’s breadth, but the registry does not report enough analysis and missing-data detail to identify all sources of uncertainty.

These results should be understood as the registry’s posted evidence for this trial’s primary dose endpoint, not as a definitive conclusion about the overall treatment strategies. The record does not report a complete set of secondary outcome results, full analysis methods, or the original sample-size justification. Conclusions beyond the reported cumulative-dose summaries would go beyond the posted information.

16. Why This Trial Matters Statistically

This trial illustrates an important distinction between a point estimate and the certainty around it. The reported mean difference of 11.0 mg/kg is easy to state, but its interval, from -28.49 to 50.49 mg/kg, shows that the estimate is not precise. Looking only at the point estimate would leave out substantial uncertainty about both direction and magnitude.

It also illustrates why non-significance should not be translated into proof of no difference. The unadjusted p-value is 0.585, and the interval includes zero, but neither statement establishes equivalence. A study with limited enrollment can leave a broad range of contrasts unresolved. The actual enrollment of 31 is lower than the 50 described as planned, yet the registry record does not explain the difference or report the original sample-size justification.

The endpoint itself provides a focused statistical question: how the cumulative glucocorticoid dose differed between groups over the treatment period. Keeping that endpoint separate from disease activity, function, safety, and quality-of-life outcomes prevents overreading a single primary result. The registry lists several secondary domains, but the detailed numerical evidence for them is limited.

Finally, the record highlights how much interpretation depends on transparent reporting. The randomization and assessor-blind design are described, but key details about the analysis population, missing values, multiplicity, and interval method are not reported. The result can still be read accurately as a posted group comparison, while recognizing that the absent methodological detail restricts independent evaluation of its precision and scope.

17. 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.

Several trial-specific limitations constrain interpretation of the posted result. The registry reports actual enrollment of 31, although the study summary describes a planned total of 50 participants. The reason for the difference is not reported in the registry record. The primary endpoint summaries are based on 16 participants in one group and 15 in the other, and the record does not provide a participant flow account or explain whether these are all randomized participants.

The primary comparison is reported with arm means, standard deviations, an interval, and an unadjusted p-value, but the analysis method and interval confidence level are not reported. Covariate adjustment, distributional assessment, missing-data handling, and the analysis population are also not described. This limits the ability to evaluate how the estimate was produced or whether analysis choices could affect it.

The registry identifies secondary outcome domains but reports limited numerical secondary results. It does not report a multiplicity plan, a complete hierarchy beyond the primary endpoint, or an explanation for which secondary findings are posted. This restricts assessment of the wider outcome pattern and the possibility of selective reporting.

The study is described as open-label and assessor-blind, but the registry does not give further detail about masking procedures or the success of blinding. The record also does not provide center-level information, participant characteristics, adherence, treatment discontinuation, or endpoint data by follow-up status. These omissions prevent a fuller assessment of generalizability and how the intended treatment regimens were implemented in practice.

Safety reporting is likewise limited: deaths are not reported in the registry record, and the listed serious-event terms lack detail about group assignment, event timing, and denominator definitions. The posted summaries therefore support a restricted description of the results, not a comprehensive evaluation of every clinical outcome or potential source of bias.

18. Related Tutorials

19. Related Statistical Calculators

20. Sources

• ClinicalTrials.gov: Combined Treatment of Methotrexate + Glucocorticoids Versus Glucocorticoids Alone in Patients With PM and DM — NCT00651040.
• Registry record last updated 2016-05-12; status last verified 2016-04.
• Results first posted 2016-05-12.
• 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.

21. Record Summary

The registry record describes a completed Phase 3 randomized, parallel-group study comparing prednisone alone with prednisone plus methotrexate in patients with polymyositis or dermatomyositis. It reports actual enrollment of 31 and primary completion in 2014-11. The primary endpoint was total glucocorticoid dose over 1 year, expressed in mg/kg.

The primary outcome means were 124.0 mg/kg for prednisone alone and 135.0 mg/kg for the combination group. The reported mean difference was 11.0 mg/kg, with an interval from -28.49 to 50.49 and an unadjusted p-value of 0.585. The interval indicates substantial uncertainty around the estimated difference.

The registry record does not report the original sample-size justification, detailed analysis methods, missing-data approach, or a complete set of secondary results. It reports serious adverse events in 4 of 16 participants in the prednisone group and 5 of 15 in the combination group; deaths are not reported in the registry record.