A Clinical Study to Test How Effective and Safe GLPG1690 is for Participants With Systemic Sclerosis: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for A Clinical Study to Test How Effective and Safe GLPG1690 is for Participants With Systemic Sclerosis (NCT03798366), a randomized phase 2 study. The primary outcome is Change From Baseline in mRSS at Week 4.

2. Clinical Question

The posted primary result is a change in mRSS, with negative values representing a reduction from baseline. The reported group means are negative in both arms. The sponsor’s mixed-model analysis estimates a small negative difference between groups, but its confidence interval includes zero and extends to values on either side of zero. The registry record therefore shows uncertainty about the direction and size of the between-group difference at this early assessment.

The study also aimed to assess safety and tolerability, disease progression, and quality of life. The posted primary endpoint addresses only the Week 4 mRSS change. It should not be taken as a complete account of those other aims. The registry record does not report the detailed protocol context needed to interpret how Week 4 was selected as the primary assessment or how the analysis relates to later outcomes.

3. Trial Design

This is a randomized, double-blind, placebo-controlled, multicenter phase 2a study of orally administered GLPG1690 in participants with systemic sclerosis. The registry lists quadruple masking and a parallel-group model. The study is marked completed. Its recorded start date is 2019-01-14, and its primary completion date is 2020-05-21. The registry lists enrollment as 33.

The active group received GLPG1690 600 mg orally once daily for 24 weeks. The control group received matching placebo on the same schedule. The study summary says GLPG1690 was assessed together with standard-of-care treatment. Which standard-of-care treatments participants received, and whether they were required to follow a particular regimen, are not reported in the registry record.

The registry lists 21 participants in the GLPG1690 arm and 12 in the placebo arm for the posted primary outcome. These are the group counts attached to that result; the record does not explain the allocation ratio or provide a detailed account of participant flow in the registry entries. Randomization is stated, but the method used to generate the allocation sequence and the procedures for concealing it are not reported in the registry record.

The primary outcome was change from baseline in mRSS at Week 4. The registry describes the primary analysis population as participants in the FAS. The meaning and membership of that population are not reported in the registry record. The outcome timeframe is listed as baseline and Week 4, while the assigned treatment period was 24 weeks. The record identifies a secondary outcome for treatment-emergent adverse events and serious treatment-emergent adverse events. It also lists five outcome measures and four analyses, but does not give a complete statistical analysis plan or explain how all planned outcomes and analyses relate to one another.

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: A total of 40 participants were screened, of whom 33 participants were randomized and treated.

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: Participants in the FAS were analyzed.

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: Full analysis set (FAS) consisted of all randomized participants who received at least 1 dose of investigational product.

6. Primary Endpoint

The registry lists the primary outcome as Change From Baseline in mRSS at Week 4, measured over Baseline, Week 4.

The primary endpoint is change from baseline in the modified Rodnan Skin Score (mRSS) at Week 4. The mRSS is a physical examination method for estimating skin thickness. It assesses 17 body sites, each rated from 0 (uninvolved) to 3 (severe thickening), for a total score ranging from 0 (best) to 51 (worst). Higher scores indicate greater severity of skin thickening.

Change from baseline expresses how the score differs at follow-up from its starting value. A negative change indicates a lower score at Week 4 than at baseline; a positive change indicates a higher score. The outcome is continuous, so the posted group summaries use means rather than counts of participants meeting a threshold. The primary result reports least-squares means and their standard errors for each arm.

The mRSS is used because it provides a structured, standardized examination-based measure of skin thickness. It captures one clinically relevant feature of systemic sclerosis, but it does not directly measure every organ system, symptom, or quality-of-life dimension. The study summary identifies broader aims, including effects on skin and other affected areas, disease progression, and quality of life. The primary endpoint reported for this comparison is specifically the Week 4 mRSS change, so it cannot by itself answer those broader questions.

The registry record does not report why Week 4 was chosen as the primary time point, whether the endpoint was selected before enrollment, or how missing Week 4 measurements were handled. Those details would help clarify the intended interpretation of this early assessment.

7. Results Posted in the Registry

• GLPG1690 600 mg: mean -2.20 versus -1.60 on control; difference -0.60 (95% CI -3.23 to 2.03), standardized effect d = -0.16; z-test p = 0.655.

8. Statistical Interpretation

9. Statistical Methods Explained

The posted primary outcome is a continuous measure, summarized using least-squares means and standard errors. A continuous outcome can take values across a scale rather than being limited to categories. The group summaries describe average change in mRSS, while the between-group estimate addresses how those average changes compare.

What is a least-squares mean?

In general, a least-squares mean is a model-based estimate of a group average. It can differ from the raw arithmetic mean when the analysis model includes other terms, such as baseline values or design factors. The registry identifies the sponsor’s method as Mixed Models Analysis and its reported parameter as a least-square mean difference. The model’s exact terms, assumptions, and handling of repeated or incomplete measurements are not reported in the registry record. Accordingly, the posted least-squares estimate should be distinguished from a simple comparison calculated directly from the arm summaries.

What does the standard error describe?

In general, a standard error describes the statistical uncertainty in an estimated mean. It is not the spread of individual participant measurements. The posted standard errors are 0.85 for GLPG1690 and 1.04 for placebo. Standard errors contribute to uncertainty around the group means, but they do not by themselves show the distribution of participants’ mRSS changes. The registry does not provide the underlying participant-level values in the registry record for this analysis.

How should the confidence interval be read?

In general, a confidence interval gives a range of estimates compatible with the data under the analysis assumptions and procedure. The sponsor reports a 95% confidence interval for the mean difference, from -3.1 to 2.0. It crosses zero, the value corresponding to no difference in the estimated group changes. The interval therefore does not isolate a difference in one direction. Its breadth also conveys that the data do not estimate the comparison with high precision. A confidence interval is not a guarantee that the true effect lies within its limits, and it does not describe the range of individual responses.

What does the p-value contribute?

In general, a p-value measures how unusual the observed data, or data more extreme, would be under a specified null hypothesis and statistical model. It is not the probability that the null hypothesis is true, nor is it a measure of clinical importance. The sponsor’s reported p-value is above the 0.05 significance level stated for the planning illustration. That comparison does not replace examination of the estimated difference and confidence interval. The registry record does not specify the sponsor analysis’s significance threshold or whether the p-value was adjusted for multiple testing.

Why is the recalculation different?

The unadjusted recalculation uses the posted arm means and standard errors to estimate a difference, interval, and p-value. It gives a mean difference of -0.6, a confidence interval from -3.233 to 2.033, and an unadjusted p-value of 0.655. The calculation is a summary-statistic approximation, not a reconstruction of the sponsor’s mixed model. Its pooled standard deviation is marked as approximate in the analysis details. Differences in adjustment, model specification, or analysis data can affect estimates and uncertainty; the details needed to identify the reasons are not reported in the registry record. The sponsor’s analysis remains the relevant reported analysis, while the recalculation is a separate, unadjusted reference.

What does randomization contribute?

In general, random assignment is intended to make treatment groups comparable at the start of a trial, on average, and to reduce systematic allocation differences. It does not guarantee that all measured or unmeasured characteristics are balanced, especially in a study with relatively small groups. The registry identifies the design as randomized, but does not describe the sequence-generation or allocation-concealment procedures. The record also does not list baseline mRSS distributions or other baseline characteristics in the registry record for this analysis.

What is not established by these methods?

The registry record does not report a full analysis plan, the model covariates, assumptions, missing-data procedures, sensitivity analyses, or any interim-analysis plan. It also does not state whether the primary comparison was adjusted for other outcomes or analyses. These omissions limit independent assessment of analytic choices. General statistical explanations describe how these methods are ordinarily interpreted; they do not fill in protocol details that are absent from the registry record.

10. Confidence Intervals and Precision

The sponsor’s 95% confidence interval for the primary mean difference runs from -3.1 to 2.0 around a point estimate of -0.5. It includes zero, the value indicating no difference between the estimated group changes. It also includes negative and positive values, so the data do not narrowly determine the direction of the comparison. Given that a lower mRSS indicates less severe skin thickening, the estimate is centered in the direction of a greater decrease with GLPG1690, but the interval allows for effects in the opposite direction as well.

The interval’s width matters because it indicates that several materially different values remain compatible with the analysis. The point estimate is not a precise prediction of the true difference, and the interval should not be read as a range containing individual participants’ changes. It describes uncertainty about the group-level estimate under the analysis method and its assumptions.

The unadjusted recalculation has a mean difference of -0.6 and a confidence interval from -3.233 to 2.033. This also spans zero and both directions. Its interval is based on an approximation from the posted summaries, whereas the sponsor’s interval comes from the mixed-model analysis. The two should not be treated as interchangeable estimates from the same method.

The group counts attached to the primary outcome are 21 for GLPG1690 and 12 for placebo. The registry record does not report a precision target or the original sample-size justification. The intervals therefore provide the most direct posted indication of uncertainty for this comparison; they do not reveal whether the study was designed to estimate a particular clinically important difference with a specified degree of precision.

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 for 80% power and participants per arm for 90% power. They are based on a two-sided significance level of 0.05, equal allocation between the arms, and a normal approximation. The effect used for planning is a stated fraction of the observed effect. The displayed scenarios are planning for 100%, 75%, and 50% of the observed effect.

In general, power is the probability that a planned study will detect an effect of a specified size under the assumptions used for its calculation. The 80% power column gives the estimated participants per arm under which the calculation would have an 80% chance of detecting the assumed effect. The 90% power column gives the corresponding requirement for a 90% chance. These are design-planning quantities, not probabilities that the observed result is correct.

The figures are 628 participants per arm for 80% power and 841 participants per arm for 90% power when planning for 100% of the observed effect. For 75% of the observed effect, they are 1,116 participants per arm for 80% power and 1,494 participants per arm for 90% power. For 50% of the observed effect, they are 2,511 participants per arm for 80% power and 3,362 participants per arm for 90% power. Smaller effects require more participants under the same assumptions, because smaller differences are harder to distinguish from random variation.

These are illustrative calculations based on the observed effect, not observed power and not the trial’s original design requirements. The original design assumptions and sample-size justification are not reported in the registry record. The calculations do not account for design choices or analysis details that are not included in the stated assumptions, and should not be read as a reconstruction of the study protocol.

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 = -0.600; pooled standard deviation σ = 3.794.
2. n = 2 × (1.96 + 0.842)² × 3.794² / -0.600² = 627.7, rounded up to 628 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 <- -0.6                      # observed difference in means
sigma <- 3.79397314935998                     # 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(3798366)
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 = 628 (80% power), 841 (90% power)
 75% of observed effect: n per arm = 1,116 (80% power), 1,494 (90% power)
 50% of observed effect: n per arm = 2,511 (80% power), 3,362 (90% power)
power.t.test: 628.6 
Simulated power at n = 628 per arm: 0.802 (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. Analyses Reported by the Sponsor

The sponsor reports a Mixed Models Analysis with a least-squares mean difference of -0.5, a 95% confidence interval from -3.1 to 2.0, and a p-value above the planning illustration’s 0.05 level. This is the registry’s own analysis of the primary comparison.

The separate recalculation uses posted summary statistics and is explicitly unadjusted. It estimates a mean difference of -0.6, a confidence interval from -3.233 to 2.033, and an unadjusted p-value of 0.655. It is useful as a check on the approximate scale and direction of the comparison, but it is not a substitute for the sponsor’s model-based result. The recalculation does not reproduce the mixed model, and the registry record does not give enough detail to reconstruct that model independently.

The posted analysis details do not mark a discrepancy between the sponsor result and recalculation. Their estimates are close in direction and magnitude, and both intervals include zero. The interpretation should still give precedence to the sponsor’s analysis as the reported primary analysis, while making clear that the recalculation is a distinct unadjusted exercise. Neither estimate alone establishes a treatment effect.

14. Multiplicity, Missing Data and Analysis Populations

Multiplicity arises when a study evaluates several outcomes, time points, comparisons, or analyses. In general, making many statistical tests can increase the chance of obtaining a nominally notable result by chance if no adjustment or prespecified testing strategy is used. Appropriate interpretation depends on which outcomes were prespecified as primary, how secondary analyses were organized, and whether any multiplicity control was planned.

The registry lists five outcome measures and four analyses, and one secondary outcome is posted: the number of participants with treatment-emergent adverse events and serious treatment-emergent adverse events. The registry entries identify change from baseline in mRSS at Week 4 as the primary outcome. They do not describe the complete hierarchy of outcomes or explain whether the sponsor adjusted for multiple testing. A multiplicity procedure, if any, is not reported in the registry record.

The registry also does not report the full statistical analysis plan, model covariates, treatment of missing outcome values, sensitivity analyses, or an interim-analysis plan. It states that participants in the FAS were analyzed, but does not define that population or explain how participants with unavailable Week 4 values were handled. It is therefore not possible to assess from the registry record whether the analysis used all randomized participants, a modified population, or a particular missing-data method.

In general, missing data can affect an estimate if the availability of measurements is related to participants’ outcomes or treatment group. Different assumptions and methods can produce different results. That general concern does not show that missing data biased this study; the information needed to assess its presence and handling is not reported in the registry record.

The reported p-value should consequently be interpreted as belonging to the sponsor’s stated mixed-model comparison, not as evidence that all outcomes and analyses were considered together. The record’s limited detail makes it difficult to evaluate prespecification, multiplicity control, and the robustness of the primary result to alternative analysis choices.

15. 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 0% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: sepsis (9.5%), foreign body in gastrointestinal tract (8.3%), device related infection (4.8%), pharyngitis (4.8%).

The registry reports serious adverse events for participants at risk in each group: 2 of 21 in the GLPG1690 arm and 1 of 12 in the placebo arm. It reports other treatment-emergent adverse events for 20 of 21 in the GLPG1690 arm and 11 of 12 in the placebo arm. Deaths are reported as 0 in both groups.

These are observed counts in the study groups, not estimates of comparative risk adjusted for follow-up or participant characteristics. The registry’s listed serious-event terms and percentages are Sepsis, 9.5%; Foreign body in gastrointestinal tract, 8.3%; Device related infection, 4.8%; and Pharyngitis, 4.8%. The record does not provide further context in the registry record for this analysis about event timing, recurrence, seriousness criteria, relatedness assessments, or whether a participant could contribute more than one event term.

Adverse-event counts describe events recorded during the study; they do not establish that the study drug caused an event. The group counts are limited, and the registry record does not report a detailed comparative safety analysis. These figures should therefore be read descriptively, not as a definitive estimate of relative safety.

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

The result is a comparison of Week 4 mRSS change in a randomized, placebo-controlled study of GLPG1690 in systemic sclerosis. The posted arm means show decreases in both groups. The sponsor’s estimated between-group difference is -0.5, with a 95% confidence interval from -3.1 to 2.0. The interval includes zero and spans values in both directions, so the result is uncertain about the direction and size of the between-group difference.

This does not establish that GLPG1690 produces a greater reduction in mRSS than placebo. It also does not establish that the groups have identical outcomes or rule out differences that the study did not estimate precisely. A result that does not distinguish the groups statistically is not the same as proof of no effect. The point estimate, interval, study design, and analysis details need to be considered together.

The endpoint reflects skin thickness measured by mRSS, not every feature of systemic sclerosis. It is assessed at Week 4, although treatment was assigned for 24 weeks. The result therefore does not answer what happened at later time points, nor does it settle the study’s broader aims involving other affected areas, disease progression, quality of life, or safety. Those questions require their own outcome results and interpretation.

The registry reports some adverse-event counts, including serious events and deaths. Those observations are descriptive and do not establish causality or provide a definitive comparison of safety. Likewise, the planning illustrations are not observed trial outcomes and do not indicate how likely the posted finding is to be true.

The most defensible reading is that the registry’s primary estimate is centered on a modest difference in the direction of a greater mRSS decrease with GLPG1690, but the interval is broad and includes no difference and values in the opposite direction. The posted evidence is not sufficiently precise to make a firm claim about the between-group effect. Details about the analysis plan, missing data, and the full outcome set are not reported in the registry record.

17. Why This Trial Matters Statistically

This trial is statistically informative because it illustrates the difference between an estimated effect and the certainty around that estimate. The sponsor’s point estimate is negative, but the confidence interval crosses zero and extends in both directions. Looking only at the point estimate would hide the uncertainty; looking only at a thresholded p-value would also omit the range of effects compatible with the analysis.

The randomized, double-blind, placebo-controlled design provides a framework for comparing the groups while limiting some sources of bias. At the same time, the group counts attached to the primary result are 21 and 12, and the resulting estimate is imprecise. Randomization does not make a small study automatically conclusive, and masking does not remove uncertainty due to limited information.

The comparison also shows why the analysis method matters. The sponsor reports a mixed-model least-squares mean difference, while the recalculation is a simple unadjusted estimate from summary statistics. The two approaches address the same broad contrast but are not identical procedures. Distinguishing them prevents a quick recalculation from being mistaken for the trial’s primary analysis.

Finally, the endpoint is a specific measure at a specific time. Week 4 mRSS change is not interchangeable with later outcomes, safety, disease progression, or quality of life. Reading the result with attention to its measurement, timing, uncertainty, and analysis population helps prevent a narrow statistical comparison from being stretched into a broader conclusion than the registry record supports.

18. 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, the assumptions used to plan enrollment, or the precision the investigators intended to achieve. The planning illustrations based on the observed effect cannot fill that gap and should not be interpreted as the trial’s original design rationale.

Important analysis details are absent from the registry record, including the full mixed-model specification, covariates, missing-data approach, sensitivity analyses, and any interim-analysis plan. The FAS is named as the primary analysis population but is not defined. Without these details, the sponsor’s estimate cannot be independently reproduced from the registry entries.

The primary endpoint is assessed at Week 4 even though assigned treatment continued for 24 weeks. The registry entries do not give later primary-outcome results or explain the choice of assessment time. The mRSS measures skin thickness and does not represent all disease manifestations or the other study aims described in the summary.

The registry lists five outcome measures and four analyses, but the registry entries do not describe the complete outcome hierarchy or any multiplicity strategy. This limits assessment of how the primary result sits among the study’s other analyses. The posted safety counts are also descriptive; details on event timing, recurrence, relatedness, and follow-up are not reported in the registry record.

The study is described as multicenter, randomized, and quadruple-masked, but the registry entries do not provide the randomization procedures, the allocation concealment method, or details of masking implementation. These limitations do not negate the posted results; they identify where the registry record leaves uncertainty about design and analysis choices.

19. Related Tutorials

20. Related Statistical Calculators

21. Sources

• ClinicalTrials.gov: A Clinical Study to Test How Effective and Safe GLPG1690 is for Participants With Systemic Sclerosis — NCT03798366.
• Registry record last updated 2021-05-04; status last verified 2021-04.
• Results first posted 2021-05-04.
• 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.

22. Record Summary

The registry identifies NCT03798366 as a completed phase 2a randomized, double-blind, placebo-controlled, multicenter study of GLPG1690 in systemic sclerosis. The recorded start date is 2019-01-14, the primary completion date is 2020-05-21, and enrollment is listed as 33. Treatment was GLPG1690 600 mg orally once daily or matching placebo for 24 weeks.

The primary outcome was change from baseline in mRSS at Week 4. The sponsor reported a mixed-model least-squares mean difference of -0.5, with a 95% confidence interval from -3.1 to 2.0. The interval includes zero and indicates uncertainty about the direction and size of the comparison. The registry also reports adverse-event counts and a secondary outcome concerning treatment-emergent and serious treatment-emergent adverse events.

The registry record does not report a complete analysis plan, missing-data procedures, multiplicity handling, or the original sample-size justification. These omissions limit how fully the posted result can be independently assessed.