Randomized Placebo-controlled Study of ISA247 in Plaque Psoriasis: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Randomized Placebo-controlled Study of ISA247 in Plaque Psoriasis (NCT00244842), a randomized phase 3 study. The primary outcome is Proportion of Subjects Achieving a PASI-75 at 12 Weeks at Each of the 3 Dose Levels of Voclosporin..

2. Clinical Question

The registry describes a randomized, placebo-controlled study intended to determine which voclosporin dose is effective in treating plaque psoriasis compared with placebo. The primary endpoint focuses on whether a participant met the PASI-75 response criterion at twelve weeks. The posted results give participant counts and group denominators, alongside comparative estimates against placebo.

The question is dose-specific: each of the three voclosporin groups has its own comparison with placebo. The results therefore describe three treatment-versus-control contrasts, not one pooled comparison of all voclosporin participants with placebo. A difference between dose groups is not itself reported as a formal comparison.

3. Trial Design

The registry describes a phase III, randomized, multicentre, double-blind, placebo-controlled study with a parallel-group model. Masking is recorded as quadruple. The record does not specify which roles were masked, so the masking label should not be expanded into a claim about particular participants or study personnel. The study status is completed, and enrollment is listed as 451.

Four groups appear in the posted primary-outcome results: placebo and voclosporin at 0.2, 0.3, and 0.4. The intervention descriptions give the voclosporin doses as 0.2 mg/kg po BID, 0.3 mg/kg po BID, and 0.4 mg/kg po BID. The primary endpoint timeframe is twelve weeks. The endpoint denominators are not identical across groups, and the registry record does not explain why they differ from one another or from total enrollment.

Random assignment and a placebo comparator provide the design for comparing each dose group with control. The posted record does not give details on the randomization procedure, allocation concealment, sites, recruitment criteria, treatment duration beyond the primary endpoint timeframe, or participant flow. Such details are not reported in the registry record.

Secondary objectives concern safety and tolerability, pharmacokinetics and pharmacodynamics after chronic dosing in a subset, and quality of life. The registry lists three posted secondary outcomes. It does not provide posted analysis records, despite reporting outcome results, and does not describe the statistical methods used for the trial's original design or sponsor analysis.

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 Proportion of Subjects Achieving a PASI-75 at 12 Weeks at Each of the 3 Dose Levels of Voclosporin., measured over Twelve Weeks.

The primary endpoint is the proportion of participants achieving a PASI-75 response at twelve weeks, reported in the registry as participant counts. It is a binary outcome: each participant either meets the response criterion or does not. The posted group results give the number meeting the endpoint and the number in the corresponding endpoint denominator.

A responder endpoint can make a clinical outcome easier to interpret as a count or proportion of participants meeting a specified threshold. Here, the measure is tied to the PASI-75 criterion, rather than reporting only an average change in a score. The registry identifies the endpoint and its timeframe, but does not provide further details about how the criterion was assessed, who assessed it, or how missing endpoint observations were handled.

The comparative results express the observed difference between each voclosporin group and placebo on the risk-difference scale, with confidence intervals. These estimates describe the separation between the observed group proportions while retaining the original binary endpoint. The registry record does not state whether any other endpoint definition or analysis population was used by the trial's sponsor.

7. Results Posted in the Registry

• Voclosporin 0.2: 13.3% (14/105) versus 3.5% (4/113) on control; risk difference 9.8 percentage points (95% CI 2.5 to 17.1), risk ratio 3.77 (1.28–11.08); unadjusted two-proportion z-test p = 0.009.
• Voclosporin 0.3: 23.4% (26/111) versus 3.5% (4/113) on control; risk difference 19.9 percentage points (95% CI 11.3 to 28.5), risk ratio 6.62 (2.39–18.34); unadjusted two-proportion z-test p = <0.001.
• Voclosporin 0.4: 38.9% (44/113) versus 3.5% (4/113) on control; risk difference 35.4 percentage points (95% CI 25.8 to 45.0), risk ratio 11.00 (4.09–29.60); unadjusted two-proportion z-test p = <0.001.

8. Statistical Interpretation

9. Statistical Methods Explained

The primary endpoint is binary because it records whether each participant achieved the specified PASI-75 response by twelve weeks. For a binary outcome, the basic group summary is a count of participants with the event and a denominator of participants assessed or included in that result. The registry posts these counts for placebo and each dose group. It does not explain the analysis population behind each denominator or the treatment of participants without an observed endpoint.

What does the risk difference express?

The risk difference subtracts the observed event proportion in the control group from the observed event proportion in the comparison group. It is expressed on the proportion scale, so a value of zero would represent equal observed proportions. The reported estimates are 0.098 for voclosporin 0.2, 0.199 for voclosporin 0.3, and 0.354 for voclosporin 0.4, each compared with placebo. These are unadjusted comparisons based on the posted group summaries; the registry record does not describe an adjusted model.

A risk difference is often directly interpretable as an absolute difference in proportions, while a relative measure describes a ratio. The posted results also include risk ratios and odds ratios. For voclosporin 0.2, the reported risk ratio is 3.767 with an interval from 1.28 to 11.08, and the odds ratio is 4.192 with an interval from 1.333 to 13.18. For voclosporin 0.3, the risk ratio is 6.617 with an interval from 2.387 to 18.34, and the odds ratio is 8.335 with an interval from 2.802 to 24.8. For voclosporin 0.4, the risk ratio is 11.0 with an interval from 4.088 to 29.6, and the odds ratio is 17.38 with an interval from 5.978 to 50.51. Relative measures can appear large when the control event proportion is small; they should be read alongside the group counts and absolute risk differences.

How should a confidence interval be read?

In general, a confidence interval is a range of values compatible with the observed data under the method used to construct it. It gives information about statistical precision: a narrower range indicates less uncertainty in the estimate than a wider range, for that method and data. It is not a guarantee that the true value lies in the interval, nor does it account automatically for unreported sources of bias or analysis choices. The registry gives intervals for the comparative estimates but does not state the interval-construction method.

What does an unadjusted p-value tell the reader?

In general, a p-value describes how unusual data at least as discrepant as those observed would be under a specified null model. It does not give the probability that the null hypothesis is true, the probability that a finding is due to chance, or the size of an effect. The posted p-values are unadjusted: 0.009 for the 0.2 comparison and <0.001 for each of the 0.3 and 0.4 comparisons. The registry record does not report a multiplicity adjustment or a full testing hierarchy. With multiple dose comparisons, whether and how multiplicity was addressed is relevant to interpreting the p-values.

The registry lists no formal analysis records. That absence does not establish that the trial sponsor did not perform analyses; it means analysis details are not reported in the registry record. The record also does not specify whether the reported estimates come from a prespecified model, how covariates were selected, or whether any sensitivity analyses were conducted. No such methods should be inferred from the summary estimates alone.

Why do event counts and denominators matter?

Counts make the scale of the data visible. The number of endpoint events is limited in each group, particularly in placebo, and the estimates consequently have uncertainty. The denominators shown for the endpoint differ by group. A difference between an enrollment count and an endpoint denominator can arise for multiple reasons, but the registry record does not identify the reason in this study. It also does not report imputation methods, rules for handling withdrawals, or whether all randomized participants were included in the primary analysis.

General statistical interpretation should separate the effect estimate, its uncertainty, and the testing result. The risk difference describes observed absolute separation; the confidence interval describes precision under its method; and the p-value addresses evidence against a null model. None of these alone resolves the unreported details of the original statistical plan or analysis population.

10. Confidence Intervals and Precision

The risk-difference confidence intervals are 0.025 to 0.171 for voclosporin 0.2 versus placebo, 0.113 to 0.285 for voclosporin 0.3 versus placebo, and 0.258 to 0.450 for voclosporin 0.4 versus placebo. Each interval gives a range of plausible values for the comparative estimate under the interval method, which is not specified in the registry record. The posted intervals are all above zero; this is consistent with the positive point estimates and unadjusted p-values.

Precision is not the same as importance. An interval communicates uncertainty in an estimate, not whether a difference matters to participants or clinicians. The intervals also do not incorporate potential biases from missing outcomes, departures from the intended analysis, or other design and conduct issues. The registry record does not describe the handling of missing data or identify the analysis population.

The relative-effect intervals are broad, especially for comparisons involving the smaller observed event counts. For example, the reported risk-ratio interval for voclosporin 0.2 runs from 1.28 to 11.08. Relative estimates should therefore be read with care and alongside the absolute risk differences and event counts. Interval width reflects sampling uncertainty under the method used; it does not establish the reliability of unreported assumptions or eliminate uncertainty about multiplicity.

The estimates apply to the twelve-week endpoint and the denominators posted for that outcome. The registry record does not provide longer-term precision estimates or interval methods for the primary results. Conclusions about precision should stay specific to the outcome and comparisons reported.

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 sample-size illustrations give participants per arm for 80% power and participants per arm for 90% power. They are calculated separately for each dose-versus-placebo comparison and for planning effects set at 100%, 75%, or 50% of the observed effect. They are not the trial's original design calculations; the trial's own sample-size assumptions and justification are not reported in the registry record.

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. For the binary outcome, the entries are participants per arm, not total events. The convention for time-to-event outcomes would instead be total events, but this primary endpoint is not time-to-event.

In general, 80% power means an 80% chance of detecting the specified effect under the stated planning assumptions if that effect is the true effect; 90% power describes a higher chance under the same conditions. The 90% power column therefore gives larger participant requirements than the 80% column for a given assumed effect. Planning for a smaller fraction of the observed effect requires more participants because smaller differences are harder to distinguish from random variation. These figures are planning illustrations, not observed power. The plotted curve expresses the same general relationship between the assumed effect and the participant requirement; it should be read using the stated assumptions rather than as a prediction of the trial's actual results.

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 = 0.035; treatment proportion p₁ = 0.133; average p̄ = 0.084.
2. First term: z_1−α/2 × √[2p̄(1−p̄)] = 1.96 × 0.3931 = 0.7704.
3. Second term: z_1−β × √[p₀(1−p₀) + p₁(1−p₁)] = 0.842 × 0.3869 = 0.3256.
4. n = (0.7704 + 0.3256)² / (0.0979)² = 125.2, rounded up to 126 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 <- 0.0353982300884956                          # control proportion
p1 <- 0.133333333333333                          # 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(244842)
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 = 126 (80% power), 168 (90% power)
 75% of observed effect: n per arm = 194 (80% power), 259 (90% power)
 50% of observed effect: n per arm = 368 (80% power), 492 (90% power)
power.prop.test: 125.2 
Simulated power at n = 126 per arm: 0.821 (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

There are three posted primary comparisons, one for each voclosporin dose versus placebo. The registry reports unadjusted p-values for these comparisons. It does not report a multiplicity correction, a prespecified hierarchy, or a procedure for controlling the family-wise error rate. This leaves uncertainty about how the sponsor intended to interpret evidence across the set of dose comparisons. The unadjusted results should not be described as multiplicity-adjusted findings.

The registry record does not describe how missing primary endpoint data were handled. It does not state whether participants without an observed twelve-week assessment were counted as nonresponders, excluded, imputed, or handled using another approach. The endpoint denominators differ across groups, but the record does not give participant-flow details that explain those denominators.

The record also does not identify the primary analysis population, such as whether the results used all randomized participants or a restricted population. It does not report a per-protocol analysis, sensitivity analyses, or rules for protocol deviations. These omissions limit assessment of the relationship between randomization and the analysis set used for the posted results.

The registry contains no formal analysis records, and the original statistical plan is not reported in the registry record. This means the posted material does not establish whether endpoint definitions, comparisons, missing-data rules, or multiplicity procedures were specified before results were known. The absence of those details is a reporting limitation, not proof that no such procedures existed.

14. Safety Results

The registry reports serious adverse events as affected participants divided by participants at risk.

Deaths

Other (non-serious) adverse events

Participants with at least one non-serious event at or above the registry's 5% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: convulsion (0.9%), basal cell carcinoma (0.9%), myocardial infarction (0.9%), dyspnea (0.9%), parapharyngeal abscess (0.9%).

The serious adverse event figures are counts of affected participants and the corresponding number at risk in each group. The registry posts 4 of 115 for placebo, 2 of 107 for voclosporin 0.2, 4 of 113 for voclosporin 0.3, and 1 of 116 for voclosporin 0.4. Death counts are listed separately as 1, 0, 1, and 0, respectively. These figures should be read as group counts, not as a complete description of event timing, severity, or attribution.

The registry lists serious-event terms including Convulsion, Basal Cell Carcinoma, Myocardial Infarction, Dyspnea, Parapharyngeal Abscess, and Accidental Death, each at 0.9%. The record does not connect these terms to particular dose groups in the registry record, so no group-specific attribution should be inferred. It also does not provide detailed event narratives, exposure-adjusted rates, or the sponsor's assessment of causality.

Serious adverse event counts and primary efficacy counts use different denominators. They answer different questions and should not be directly compared as if they were the same outcome. The registry record also includes other adverse event counts, but these serious-event figures alone do not summarize the full safety results.

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

The posted results show that more participants met the PASI-75 criterion in each voclosporin group than in the placebo group, both in the event counts and in the reported proportions. The corresponding risk-difference estimates are positive for all three dose-versus-placebo comparisons. This is a description of the outcome data recorded at twelve weeks; it is not a recommendation about treatment or a conclusion about an individual's likely outcome.

The findings do not establish a formal difference among the three voclosporin doses. The increasing observed response proportions across dose groups are descriptive, and the registry does not post a direct dose-to-dose analysis. The record also does not specify whether multiplicity was addressed in the sponsor's analysis, how missing observations were handled, or which analysis population was used.

The results do not by themselves provide a complete benefit-risk assessment. The primary endpoint is one measure at one timeframe. The registry lists safety and tolerability, pharmacokinetic and pharmacodynamic, and quality-of-life objectives, but detailed results for these objectives are not part of the registry entries. The adverse event counts also lack some context needed to interpret event patterns, such as attribution and timing.

Confidence intervals and p-values characterize the comparative estimates under their statistical methods; they do not account for every possible source of uncertainty. A positive estimated risk difference is not the same as a guarantee of benefit for every participant, and a statistical result does not alone establish clinical importance. The registry record supports a focused interpretation of the posted twelve-week response data, while leaving important design and analysis details unreported.

16. Why This Trial Matters Statistically

This trial illustrates the statistical structure of a multi-arm randomized comparison. The three voclosporin dose groups each have a placebo comparison, producing a set of estimates rather than a single treatment contrast. That structure makes the distinction between dose-specific evidence and direct dose-to-dose evidence important: the registry posts the former but not the latter.

The binary response endpoint supports clear counts and group proportions, while the risk difference expresses the absolute separation between groups. Reporting counts, proportions, estimates, and confidence intervals together allows readers to see both the observed data scale and uncertainty. The relative measures provide another scale, but can be less intuitive when event counts in the control group are small.

The record also illustrates why statistical interpretation depends on reporting beyond point estimates. Multiplicity handling, missing-data rules, and analysis-population definitions affect how the results should be understood, yet these details are not reported in the registry record. A registry result can communicate useful comparative information while still leaving these methodological questions unresolved.

Finally, planning illustrations based on observed effects are not interchangeable with a trial's original design rationale. Their assumptions can help readers understand how sample requirements vary with the effect targeted, but they do not reveal the assumptions used to plan this trial. Keeping those distinct prevents a post hoc planning exercise from being mistaken for a prospective design justification.

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 does not report the original sample-size justification, planned statistical methods, or interim analysis procedures. It also does not describe the randomization method, allocation concealment, eligibility criteria in detail, or participant flow. These omissions limit evaluation of the design and conduct beyond the broad labels of randomized, multicentre, double-blind, placebo-controlled, parallel-group, and quadruple masking.

For the primary endpoint, the record does not specify the analysis population, missing-data handling, or whether the posted estimates were adjusted for any covariates. It lists unadjusted p-values but does not report a multiplicity procedure for the three dose comparisons. Formal direct comparisons among dose groups are not posted. The endpoint denominators vary, and the reasons are not reported in the registry record.

The primary result concerns a single twelve-week response measure. The registry lists other study objectives, but their detailed findings are not included in the registry record for these explanations. Safety figures are counts with at-risk denominators, without event timing, detailed attribution, or full participant-level context. These limitations constrain interpretation of both the efficacy comparisons and the safety summary.

The record reports a completed study and enrollment of 451, but the posted primary endpoint denominators do not equal that enrollment. No explanation for this is given in the registry record. The listed results should therefore be understood as the outcome-specific data posted, not as a complete account of all randomized participants or all analyses performed.

18. Related Tutorials

19. Related Statistical Calculators

20. Sources

• ClinicalTrials.gov: Randomized Placebo-controlled Study of ISA247 in Plaque Psoriasis — NCT00244842.
• Registry record last updated 2023-03-27; status last verified 2023-03.
• Results first posted 2023-03-27.
• 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

NCT00244842 is a completed phase III, randomized, multicentre, double-blind, placebo-controlled, parallel-group study of voclosporin in plaque psoriasis, with enrollment of 451. The registry lists placebo and three voclosporin dose groups. The primary endpoint is the proportion of participants achieving a PASI-75 response at twelve weeks.

Posted results give participant counts and denominators for each group and risk-difference comparisons of each dose with placebo. The observed response proportions and risk-difference estimates are higher for each listed dose group than for placebo. The registry reports unadjusted p-values and confidence intervals, but does not report the original statistical plan, multiplicity handling, missing-data methods, or analysis populations.

The record also lists secondary objectives concerning safety and tolerability, pharmacokinetics and pharmacodynamics, and quality of life. Serious adverse event counts and selected event terms are posted, but further context is limited. Overall, the registry supports interpretation of the specified twelve-week endpoint and its dose-versus-placebo comparisons, with important methodological details not reported in the registry record.