A Safety and Efficacy Study of Ustekinumab in Patients With Plaque Psoriasis Who Have Had an Inadequate Response to Methotrexate: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for A Safety and Efficacy Study of Ustekinumab in Patients With Plaque Psoriasis Who Have Had an Inadequate Response to Methotrexate (NCT01059773), a randomized phase 4 study. The primary outcome is Number of Patients Experiencing One or More Adverse Events Occurring From Week 0 Through Week 12.

2. Clinical Question

The registry describes the study as an exploratory assessment of naturalistic safety and efficacy outcomes after transition from previous methotrexate therapy. Its stated purpose included comparing immediate methotrexate discontinuation with a transition involving overlap and gradual dose reduction. The primary posted endpoint is a safety count, not a measure of psoriasis response. The registry lists additional psoriasis outcomes, including change in mean PASI score and the proportions achieving PASI 50, PASI 75 and PASI 90 responses, alongside other safety outcomes.

The result should be read as a comparison between transition strategies in the enrolled trial population. It does not establish what would happen in people with different disease characteristics, treatment histories or care settings. The registry record does not report detailed eligibility criteria or a fuller description of the clinical setting.

3. Trial Design

This was a phase 4, randomized, open-label, parallel-group study. Participants were assigned to one of two approaches to transitioning from methotrexate to ustekinumab. In the immediate cessation group, methotrexate was stopped before baseline. In the gradual withdrawal group, methotrexate was reduced over the 4 week period after week 0. Both groups were scheduled to receive ustekinumab by subcutaneous injection at Weeks 0, 4, 16, 28 and 40.

The registry lists enrollment as 490. The primary endpoint results use 244 participants in the immediate cessation group and 245 in the gradual withdrawal group. The endpoint population is described as randomized participants who took at least one dose of study medication and had post-baseline safety information. The registry record does not give further detail about how that population relates to all enrolled participants.

The study was not masked. This matters for interpretation because participants and study staff could know which methotrexate transition approach was assigned. The outcome is a count of participants experiencing adverse events, but the registry does not describe how events were collected or whether outcome assessment used any masking procedures.

The study status is completed. Its listed start is 2009-10 and its primary completion is 2010-11. The sponsor is Janssen-Cilag International NV. The registry record does not report the original sample-size justification, the planned statistical analysis in detail, interim analyses, or a protocol-level account of allocation procedures beyond stating that allocation was randomized.

The primary endpoint covers events from week 0 through week 12. Although the scheduled ustekinumab injections continued beyond that interval, this primary safety result is limited to the stated period. Other listed outcomes concern safety during the study period and psoriasis measures, but their definitions, analysis timing and numerical results 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.

Before assignment: One patient received on-study methotrexate only but no ustekinumab and was therefore excluded from the analysis.

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: All randomized patients who took at least one dose of study medication and set who had any post-baseline safety information.

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 Number of Patients Experiencing One or More Adverse Events Occurring From Week 0 Through Week 12, measured over from week 0 to week 12.

The primary endpoint is the number of participants experiencing one or more adverse events from week 0 through week 12. It is a participant count: each person who experienced at least one event contributes to the endpoint, rather than each separate event being counted as a separate participant. A person with multiple events is therefore still represented as a participant with an event in this endpoint.

In the immediate methotrexate cessation group, 149 of 244 participants were recorded as experiencing one or more adverse events. In the gradual withdrawal group, the corresponding count was 158 of 245. The registry also gives the arm-level proportions as 0.611 and 0.645, respectively.

A safety endpoint of this kind is used to describe how often participants experience at least one adverse event during a specified period after treatment initiation. It gives a broad summary of event occurrence but does not, by itself, describe event severity, seriousness, cause, duration or clinical importance. The registry lists other safety outcomes that address some of those dimensions, including serious adverse events and severe adverse events, but their numerical results are not reported in the registry record. The primary endpoint also does not measure psoriasis improvement; that is addressed by the separately listed PASI outcomes.

The endpoint population is described as randomized participants who took at least one dose of study medication and had post-baseline safety information. This definition is relevant because it is narrower than an unspecified group of everyone enrolled. The registry record does not report additional detail about missing safety information or how such cases were handled.

7. Results Posted in the Registry

• UST / MTX Gradually Withdrawn: 64.5% (158/245) versus 61.1% (149/244) on control; risk difference 3.4 percentage points (95% CI -5.1 to 12.0), risk ratio 1.06 (0.92–1.21); unadjusted two-proportion z-test p = 0.433.

8. Statistical Interpretation

9. Statistical Methods Explained

The reported endpoint is a binary participant outcome: a participant either experienced one or more adverse events within the stated period or did not. The arm-level counts are 149 of 244 and 158 of 245. The registry presents those counts alongside arm-level proportions and a comparison between the two randomized groups. The endpoint is not an event rate per unit of follow-up time; it is the number of participants with at least one event over the specified interval.

What does a risk difference express?

The risk difference expresses the absolute difference between the proportions with an event in the two groups. The registry reports the gradual withdrawal group relative to the immediate cessation group, with an estimate of 0.034 and a 95% confidence interval from -0.051 to 0.120. Because the interval includes zero, the data are compatible with no absolute difference under the interval method, as well as with differences in either direction. The point estimate alone should not be treated as a precise measure of the contrast.

In general, an absolute difference is often useful when considering how far apart the observed event proportions are on their original probability scale. It remains specific to the population, endpoint definition and observation period used. It should not be translated into a clinical consequence without information about event types, severity and context.

Why are relative measures also reported?

The registry also reports a risk ratio and an odds ratio. The risk ratio is 1.056, with a confidence interval from 0.921 to 1.211. The odds ratio is 1.158, with a confidence interval from 0.802 to 1.671. A risk ratio compares the two group risks as a ratio; an odds ratio compares their odds. These measures use different scales, so they are not interchangeable. Their confidence intervals include the value representing no relative difference. Neither measure is described as adjusted for other participant characteristics in the registry record.

In general, relative measures can give a compact description of a contrast, but their interpretation depends on the baseline risk and on the measure used. The odds ratio is not itself a risk difference. When the outcome is common, the odds ratio can be farther from the null value than the risk ratio, so the two should be reported and read by their own definitions.

What does the p-value contribute?

The unadjusted p-value is 0.433. In general, a p-value measures how compatible the observed data are with a specified null hypothesis and statistical model. It is not the probability that there is no difference, and it does not measure the size or importance of an effect. A result with a p-value of 0.433 does not prove that the transition approaches have identical event risks. It also does not establish that any observed difference is caused by the transition approach.

The word unadjusted indicates that the posted p-value is not presented as adjusted for multiple comparisons. The registry record does not report whether a multiplicity procedure was planned or used. The p-value should therefore be read as the posted comparison statistic, not as a comprehensive account of all possible analyses.

How does randomization inform the comparison?

Randomized allocation is intended to make the assigned groups comparable on average with respect to measured and unmeasured characteristics. It supports a comparison of the assigned transition strategies, but it does not eliminate uncertainty, guarantee identical groups in a finite trial, or resolve limitations in outcome collection and analysis. The study was open-label, so participants and study personnel were not masked to the assigned approach. The registry record does not describe any masked outcome assessment.

The endpoint population includes randomized participants who took at least one dose and had post-baseline safety information. This is the population specified for the primary result, rather than a documented analysis of every randomized participant regardless of treatment exposure or follow-up information. The record does not explain how many randomized participants lacked qualifying safety information or how missing information was handled.

What is not specified?

The registry record does not report the trial’s detailed statistical analysis plan, the method used to construct the confidence intervals, a sample-size justification, or interim analyses. It also does not report whether the primary analysis adjusted for baseline factors, how protocol deviations were handled, or whether any sensitivity analyses were conducted. The published comparison statistics can be described as posted, but these absent details limit independent assessment of the full analysis process.

The registry lists eight secondary outcomes, including adverse-event categories and PASI measures. Their numerical results are not reported in the registry record. Without those results and a stated multiplicity strategy, it is not possible to assess the pattern of secondary findings or the extent to which multiple testing was addressed.

10. Confidence Intervals and Precision

The risk difference estimate is 0.034, and its 95% confidence interval extends from -0.051 to 0.120. The interval includes zero, so the data do not precisely distinguish a positive difference from no difference or a negative difference on the absolute risk scale. The interval is broad enough to encompass a range of plausible contrasts in either direction. The point estimate should therefore be read together with the interval rather than as a definitive value.

The relative measures convey similar uncertainty. The risk ratio is 1.056, with a confidence interval from 0.921 to 1.211; the odds ratio is 1.158, with a confidence interval from 0.802 to 1.671. Each interval includes its scale’s no-difference value. These intervals do not establish equality between groups; instead, they show that the estimates remain uncertain across values compatible with the observed data and the method used.

In general, a confidence interval is a measure of statistical precision, not a range containing every plausible clinical interpretation. Its width reflects, among other things, the amount of information available and the variability of the data. A more precise estimate would have a narrower interval under the same method. The registry record does not identify the interval construction method, so the interval is best understood as the confidence interval reported with the posted comparison.

Precision is also limited in scope by the endpoint itself. The interval concerns the proportion of participants with one or more adverse events from week 0 through week 12. It does not quantify uncertainty about all adverse-event types, later follow-up, or psoriasis response. The record does not report confidence intervals for the separately listed serious adverse-event counts or secondary outcomes.

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 participants per arm, not total events. They illustrate the sample size that would be needed under stated assumptions to detect a specified fraction of the observed effect. For 100% of the observed effect, the illustration gives 3,128 participants per arm for 80% power and 4,186 participants per arm for 90% power. For 75% of the observed effect, it gives 5,587 participants per arm for 80% power and 7,478 participants per arm for 90% power. For 50% of the observed effect, it gives 12,626 participants per arm for 80% power and 16,902 participants per arm for 90% power.

The planning assumptions are a two-sided significance level of 0.05, equal allocation between the two arms and a normal approximation. The effect to detect is the stated fraction of the observed effect. The trial’s original design assumptions and sample-size justification are not reported in the registry record.

In general, power is the probability that a study will detect an effect of a specified size under the assumed model and design. The 80% and 90% columns describe different planning targets: the latter aims for a greater chance of detecting the specified effect, and therefore requires more participants under these assumptions. Smaller effects require more participants to detect with the same target power. These figures are planning illustrations based on the observed effect, not observed power and not evidence that the trial was designed around these assumptions.

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, p₀ and p₁ are the control and treatment proportions, and p̄ is their average.

Worked calculation for this trial

1. Control proportion p₀ = 0.611; treatment proportion p₁ = 0.645; average p̄ = 0.628.
2. First term: z_1−α/2 × √[2p̄(1−p̄)] = 1.96 × 0.6836 = 1.3399.
3. Second term: z_1−β × √[p₀(1−p₀) + p₁(1−p₁)] = 0.842 × 0.6832 = 0.5750.
4. n = (1.3399 + 0.5750)² / (0.0342)² = 3,127.2, rounded up to 3,128 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
p0 <- 0.610655737704918                          # control proportion
p1 <- 0.644897959183673                          # treatment proportion
n_per_arm <- function(power, frac = 1) {
  q1 <- p0 + (p1 - p0) * frac               # smaller effect = fraction of the observed difference
  pbar <- (p0 + q1) / 2
  z_b <- qnorm(power)
  ceiling(round((z_a * sqrt(2 * pbar * (1 - pbar)) + z_b * sqrt(p0 * (1 - p0) + q1 * (1 - q1)))^2 / (q1 - p0)^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 (unrounded n per arm)
cat("power.prop.test:", round(power.prop.test(p1 = p0, p2 = p1, power = 0.80)$n, 1), "\n")

# Simulation: how often does the z-test reject at the 80%-power sample size?
set.seed(1059773)
n    <- n_per_arm(0.80)
reps <- 20000
x0 <- rbinom(reps, n, p0); x1 <- rbinom(reps, n, p1)
ph <- (x0 + x1) / (2 * n)
z  <- ((x1 - x0) / n) / sqrt(ph * (1 - ph) * 2 / n)
cat(sprintf("Simulated power at n = %s per arm: %.3f (%d replicates)\n", format(n, big.mark = ","), mean(abs(z) > z_a, na.rm = TRUE), reps))

Output from running the code

100% of observed effect: n per arm = 3,128 (80% power), 4,186 (90% power)
 75% of observed effect: n per arm = 5,587 (80% power), 7,478 (90% power)
 50% of observed effect: n per arm = 12,626 (80% power), 16,902 (90% power)
power.prop.test: 3127.2 
Simulated power at n = 3,128 per arm: 0.797 (20000 replicates)

The simulation draws many pairs of event counts at the planned sample size and counts how often the two-proportion z-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 the primary adverse-event endpoint and eight secondary outcomes. The secondary outcomes include overall and serious adverse events, severe or reasonably related events, adverse events leading to discontinuation, infections, malignancies and other events of clinical interest, change in mean PASI score, and PASI 50, PASI 75 and PASI 90 responses. Numerical results for those secondary outcomes are not reported in the registry record.

When several outcomes or comparisons are examined, the chance of at least one apparently notable result can increase. In general, multiplicity methods are used to control or describe that issue, for example by adjusting significance thresholds or by specifying a hierarchy of tests. The registry record does not report whether a multiplicity adjustment, testing hierarchy or other strategy was planned or used. The primary comparison is accompanied by an unadjusted p-value of 0.433; the record does not state how that value relates to any broader testing plan.

The endpoint population is described as randomized patients who took at least one dose of study medication and had post-baseline safety information. That description sets out who contributed to the primary safety result, but it does not provide a full account of all randomized participants, exclusions, follow-up completeness or protocol deviations. The registry record does not report the number of participants with missing safety information, the reasons for missingness, or the method used to handle missing data.

In general, missing-data handling matters because the interpretation of an analysis can depend on why information is absent and whether participants with missing outcomes differ from those observed. No assumptions about missingness or imputation should be inferred in the absence of a report. The registry record also does not report whether additional analysis populations, such as an intention-to-treat population, were defined for the primary result.

The absence of these details does not establish that multiplicity or missing data were ignored. It means that the registry information does not permit a reader to assess the methods used. The posted result can be described as an unadjusted comparison in the stated safety population, while the broader analysis strategy remains not reported in the registry record.

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 5% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: psoriasis (1.2%), ankle fracture (0.8%), meniscus lesion (0.8%), abdominal pain (0.8%), hepatitis b (0.4%).

The serious adverse-event counts are 20 among 244 participants in the immediate methotrexate cessation group and 20 among 245 participants in the gradual withdrawal group. These are participant counts in the registry’s serious adverse-event summary, distinct from the primary endpoint, which counts participants with one or more adverse events of any kind from week 0 through week 12. The registry does not provide a comparative confidence interval or p-value for the serious adverse-event counts.

The record lists several serious adverse-event terms with their reported proportions: Psoriasis, 1.2%; Ankle fracture, 0.8%; Meniscus lesion, 0.8%; Abdominal pain, 0.8%; Hepatitis B, 0.4%; and Foot fracture, 0.4%. These terms describe events recorded in the registry and should not be treated as an exhaustive account of all safety findings. The registry record does not provide enough detail to determine the clinical circumstances, attribution or overlap among terms.

The number of deaths is not reported in the registry record. Counts of serious adverse events describe how many participants were recorded in that category; they do not by themselves establish a causal relationship to treatment or compare the severity of all events across the groups.

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

The posted results describe adverse-event occurrence in two randomized groups that followed different methotrexate transition strategies while receiving ustekinumab. During the primary period from week 0 through week 12, the registry records one or more adverse events in 149 of 244 participants after immediate methotrexate cessation and in 158 of 245 participants after gradual withdrawal. The estimated risk difference is 0.034, with a 95% confidence interval from -0.051 to 0.120. This interval includes zero and values on either side, so the comparison is uncertain about the direction and size of the difference.

The result is specifically about participants with at least one adverse event, not the number of events experienced, their severity, or whether they were related to either drug or the transition process. Serious adverse-event counts are reported separately as 20 in each group. The registry record does not report the number of deaths. It also does not give numerical results for the listed secondary psoriasis outcomes, so the primary safety comparison should not be treated as evidence about psoriasis response.

The result does not prove that the transition strategies have identical safety profiles, and it does not show that one strategy is superior. A confidence interval that includes no difference reflects uncertainty; it is not proof of equivalence. The study’s open-label design, the specified safety population and the limited detail about missing data and analysis methods also matter when interpreting the comparison.

In general, randomized comparisons can support assessment of differences between assigned approaches, but their conclusions remain bounded by the population, endpoints, follow-up and methods reported. This result pertains to the trial population and the stated primary endpoint period. It should not be generalized automatically to other populations or longer periods, and it does not establish cause for individual adverse events.

16. Why This Trial Matters Statistically

This trial raises a statistical question that is narrower than simply comparing two drugs: it compares two transition strategies while ustekinumab is used in both groups. The contrast concerns whether methotrexate is stopped before baseline or reduced gradually after ustekinumab begins. That design makes the primary comparison relevant to the transition approach, rather than a comparison of ustekinumab with no ustekinumab.

The primary endpoint is a participant-level safety outcome over a defined period. Its simplicity makes the group counts and risk difference relatively direct to interpret, but the broad category combines events that may differ substantially in seriousness and type. The registry’s separate serious adverse-event counts and listed event terms add context, although the record does not provide a full numerical account of all secondary safety findings.

The estimate and confidence interval also demonstrate why a point estimate alone is not enough. The observed risk difference is 0.034, but the 95% confidence interval from -0.051 to 0.120 covers both directions. A reader can see the estimated contrast while also recognizing that the data leave substantial uncertainty about its size and direction. The unadjusted p-value of 0.433 does not resolve that uncertainty or establish equivalence.

Finally, the registry record illustrates the importance of transparent reporting. It identifies randomization, open-label masking status, the endpoint population and several outcomes, but does not report the detailed analysis plan, multiplicity strategy, missing-data handling or original sample-size justification. Those details are important for understanding how the estimates were generated and what conclusions the trial was designed to support.

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.

The registry record has limited detail for assessing the full analysis. It does not report the original sample-size justification, the trial’s detailed statistical analysis plan, interim analyses, confidence-interval construction method, or whether the primary comparison was adjusted for baseline characteristics. The planning illustration is based on the observed effect and is not evidence of the assumptions used to design the trial.

The study was open-label, so participants and study staff were not masked to transition assignment. The record does not describe whether adverse-event collection or assessment included safeguards against knowledge of assignment. Because the primary endpoint is a broad any-event measure, it also does not convey the nature or severity of all events. The listed serious-event counts provide additional information but do not include a reported comparative interval or test.

The endpoint population required at least one dose of study medication and post-baseline safety information. The registry record does not report the number of randomized participants who did not meet that description, reasons for missing information, or the approach to missing data. It also does not explain how protocol deviations were addressed or whether sensitivity analyses were performed.

Eight secondary outcomes are listed, but their numerical results are not reported in the registry record. The record does not state whether multiplicity was addressed. The number of deaths is not reported in the registry record. These omissions limit assessment of the full safety and efficacy pattern, but they do not establish that analyses or procedures were not performed.

The registry describes the study population as people with moderate to severe plaque psoriasis transitioning after an inadequate response to methotrexate, but detailed eligibility criteria and setting information are not reported. Therefore, the applicability of these results to populations beyond the enrolled participants cannot be fully assessed from the registry record.

18. Related Tutorials

19. Related Statistical Calculators

20. Sources

• ClinicalTrials.gov: A Safety and Efficacy Study of Ustekinumab in Patients With Plaque Psoriasis Who Have Had an Inadequate Response to Methotrexate — NCT01059773.
• Registry record last updated 2014-11-24; status last verified 2014-11.
• Results first posted 2012-01-30.
• 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

This completed phase 4 randomized, open-label, parallel-group study compared immediate methotrexate cessation with gradual methotrexate withdrawal during transition to ustekinumab in people with plaque psoriasis. The registry lists enrollment as 490 and reports primary endpoint groups of 244 and 245 participants.

The primary outcome was the number of participants experiencing one or more adverse events from week 0 through week 12. The counts were 149 in the immediate cessation group and 158 in the gradual withdrawal group. The risk difference was 0.034, with a 95% confidence interval from -0.051 to 0.120; the unadjusted p-value was 0.433.

Serious adverse events were recorded for 20 participants in each group. The record lists eight secondary outcomes, but their numerical results and the detailed statistical analysis plan are not reported in the registry record.