Phase 2 Study of XAF5 (XOPH5) Ointment for Reduction of Excess Eyelid Fat (Steatoblepharon): Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Phase 2 Study of XAF5 (XOPH5) Ointment for Reduction of Excess Eyelid Fat (Steatoblepharon) (NCT02230761), a randomized phase 2 study. The primary outcome is Lower Eyelid Steatoblepharon Severity (LESS) Score--Clinician-Reported.

2. Clinical Question

The primary outcome is titled “Lower Eyelid Steatoblepharon Severity (LESS) Score--Clinician-Reported.” Its description identifies a clinician-reported photonumeric scale ranging from 0 to 4, with 0 meaning absence of steatoblepharon and 4 meaning very severe steatoblepharon. However, the posted primary results are participant counts rather than group-level scale summaries. The registry record does not state the binary event threshold used to produce those counts. As a result, the counts can be compared statistically, but their specific clinical criterion should not be inferred from the scale description alone.

The question is therefore about a between-group comparison in the reported participant outcome, not a complete account of changes across every possible score on the scale. The results include 27 participants in the XOPH5 group and 6 in the placebo group among the outcome counts, with group sizes of 60 and 30, respectively. The posted analysis reports a chi-squared p-value of 0.020. These figures describe the registry's outcome data; they do not, by themselves, establish how the unreported threshold was defined or what a particular score change meant for an individual participant.

3. Trial Design

This was a phase 2, randomized, parallel-group study of XOPH5 ointment and placebo for lower eyelid steatoblepharon. The registry record lists 90 participants enrolled. The primary outcome analysis includes 60 participants in the XOPH5 ointment group and 30 in the placebo ointment group. Those group sizes sum to the recorded enrollment, although the record does not separately describe participant flow or explain the allocation ratio.

The brief summary describes once-daily application to the lower eyelids for 10 weeks. The primary outcome timeframe is 11 weeks. The record identifies the study as completed, with a start date of 2014-09 and primary completion of 2014-12. The sponsor is Topokine Therapeutics, Inc. These details establish the broad setting and schedule, but do not supply a detailed protocol or a full account of follow-up procedures.

There is an inconsistency in how masking is described: the structured study information lists quadruple masking, while the official title calls the study double-masked. The registry record does not explain the difference or identify which roles were masked. It is therefore possible to report both descriptions, but not to resolve the discrepancy from this record.

The placebo is described as an ointment matching XOPH5 but lacking its active ingredient. The record lists three outcome measures, but only the primary outcome is characterized in the results details available for this analysis. No secondary outcomes are posted. Detailed eligibility criteria, the original sample-size justification, allocation procedures, and the trial's own statistical analysis plan are not reported in the registry record. The design can be described as randomized and placebo-controlled, but additional methodological details should not be assumed.

4. Participant Flow and Accounting

The registry reports how participants moved through each stage of the study. All counts below are exactly as posted; missing counts are not inferred from other stages.

Overall Study

Analysis population for the primary outcome, as defined in the registry: intention-to-treat

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 Lower Eyelid Steatoblepharon Severity (LESS) Score--Clinician-Reported, measured over 11 weeks.

The primary outcome is named as a clinician-reported Lower Eyelid Steatoblepharon Severity (LESS) Score. It uses a photonumeric scale from 0 to 4: 0 represents absence of steatoblepharon and 4 represents very severe steatoblepharon. A clinician-reported scale can provide a structured way to describe severity, using common anchors rather than relying only on an unstructured impression. This makes it possible to compare severity assessments between groups, provided the scoring and analysis are clearly defined.

The registry lists the outcome unit as participants and the result type as a number. The posted results therefore present participant counts, not means or distributions of the 0-to-4 scores. They report 27 participants in the XOPH5 group and 6 in the placebo group for this outcome, with group sizes of 60 and 30. The record does not define the binary event threshold that converts the severity assessment into these participant counts. It also does not state, in the available outcome description, whether the count represents a particular improvement, score category, or another criterion.

The primary timeframe is 11 weeks, while the brief summary describes application once daily for 10 weeks. The outcome population is identified as intention-to-treat. The endpoint can thus be described as a clinician-reported severity measure represented in the posted results by participant counts at the stated timeframe. Its clinical interpretation is limited by the missing event definition and by the absence of posted score distributions or secondary outcomes.

7. Results Posted in the Registry

• XOPH5 Ointment: 45.0% (27/60) versus 20.0% (6/30) on control; risk difference 25.0 percentage points (95% CI 5.9 to 44.1), risk ratio 2.25 (1.04–4.85); unadjusted two-proportion z-test p = 0.020.

8. Statistical Interpretation

9. Statistical Methods Explained

The reported outcome is binary in the posted results: each group has a count of participants with an event and a group size. The XOPH5 group has 27 events among 60 participants, and the placebo group has 6 among 30. A binary comparison reduces each participant's outcome to one of two categories for the analysis. That makes group proportions and measures such as a risk difference, risk ratio, and odds ratio possible. In this trial, however, the registry record does not define the event threshold, so the statistical form of the outcome is clearer than its exact clinical meaning.

What does the risk difference express?

The risk difference is the difference between the two groups' observed event proportions. Its recalculated estimate is 0.25, with a 95% confidence interval from 0.059 to 0.441. In general, this measure stays on the absolute probability scale and is often directly interpretable as a contrast in event frequency. Here it describes the gap between the proportions represented by the posted counts. It should not be translated into a more specific clinical change because the event definition is not reported.

How do the relative measures differ?

The risk ratio compares the event proportions as a ratio; the recalculated estimate is 2.25, with a 95% confidence interval from 1.043 to 4.852. The odds ratio compares the odds of an event rather than the probabilities themselves; its recalculated estimate is 3.273, with a 95% confidence interval from 1.169 to 9.159. These are different scales for describing the same two-group counts. In general, an odds ratio is not interchangeable with a risk ratio, and relative measures can appear numerically more pronounced than absolute measures, particularly when events are not rare. The confidence intervals convey substantial uncertainty about the relative contrast.

What does the chi-squared test assess?

The registry reports a chi-squared analysis with p = 0.020. In general, a chi-squared test evaluates whether the observed distribution of categorical outcomes across groups is compatible with a specified no-association or no-difference model. The test summarizes evidence against that model under its assumptions; it does not estimate the size or clinical importance of the difference. The estimate and confidence interval are needed to describe magnitude and precision. The registry record does not give additional details about the specific chi-squared implementation, such as a continuity correction or other variant.

The posted recalculations are unadjusted calculations from the summary counts and group sizes. They are not adjusted for baseline characteristics or other covariates. The registry record does not report a covariate-adjusted analysis for this outcome. The sponsor's reported analysis is also a chi-squared test, with p = 0.020. The recalculated p-value is 0.02, which is consistent with the reported value at the displayed precision. The registry entries indicate no discrepancy between the reported analysis and the recalculation.

How should a confidence interval be read?

In general, a confidence interval is a range generated by a statistical procedure that reflects sampling uncertainty, conditional on the procedure's assumptions. It does not mean that there is a 95% probability that the fixed underlying effect lies in this particular interval. For the risk difference, zero is the value representing no difference between groups. For the risk ratio and odds ratio, one represents no relative difference. The reported intervals do not include those respective null values, but the breadth of the intervals remains important: a result can be statistically distinguishable from a null value while still leaving considerable uncertainty about effect magnitude.

The registry record does not report the original sample-size justification, a prespecified analysis plan, interim analyses, or details of multiplicity adjustment. It also does not describe how missing outcome data were handled. Those omissions limit assessment of whether the reported test and outcome definition were fully prespecified and how sensitive the result might be to analytic choices. No claims about such procedures can be made from the posted information.

The planning illustrations associated with the observed effect are not an analysis of the trial's achieved power. In general, power is a design concept concerning the probability of detecting a specified effect under stated assumptions. A calculation based on an observed effect uses the result after the study and can be misleading if treated as evidence that the study was adequately powered. These illustrations can instead be read as hypothetical design quantities under their stated assumptions; the trial's own original design assumptions are not reported in the registry record.

10. Confidence Intervals and Precision

The risk-difference estimate is 0.25, and its 95% confidence interval runs from 0.059 to 0.441. The interval is compatible with a range of positive absolute contrasts, rather than one precisely determined value. It does not include zero, the null value for a risk difference under the calculation used. That is consistent with the reported chi-squared p-value of 0.020, although the p-value and interval answer related but distinct questions.

The relative-effect estimates also have wide intervals: the risk ratio is 2.25 with a 95% confidence interval from 1.043 to 4.852, and the odds ratio is 3.273 with a 95% confidence interval from 1.169 to 9.159. Their lower bounds are close to the null value of one, while their upper bounds allow substantially larger relative contrasts. This spread signals that the magnitude is uncertain even though the intervals exclude their respective null values. The different measures should not be treated as numerically interchangeable.

Precision is affected by the amount of information in the comparison. The primary results include 60 participants in one group and 30 in the other, with 27 and 6 events, respectively. The group sizes are unequal, and the smaller group contributes less information to the contrast. The confidence intervals capture sampling uncertainty under the calculation method, but they do not account for unreported features such as uncertainty in the event definition or missing-data procedures.

In general, a confidence interval is more useful than a point estimate alone because it communicates a range of estimates compatible with the data under the method's assumptions. It does not guarantee that the true effect lies within the observed interval, and it does not establish that every value in the interval has equal plausibility. Here, precision should be described as limited: the estimates indicate the direction of the observed contrast, but the intervals leave uncertainty about its size. The clinical meaning of any value remains further constrained by the absence of a stated binary event criterion.

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 are hypothetical design illustrations based on the observed effect and are not observed power. The stated assumptions are a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation; the effect to detect is set to the stated fraction of the observed effect. The trial's own original sample-size assumptions and justification are not reported in the registry record.

The 80% power column gives the number of participants per arm that the planning calculation estimates would be needed to have an 80% chance of detecting the specified effect under those assumptions. The 90% power column gives the corresponding per-arm planning number for a 90% chance. These are design targets for hypothetical studies, not a retrospective measure of how likely the completed trial was to produce a statistically significant result.

Planning for 100% of the observed effect gives 54 participants per arm for 80% power and 72 per arm for 90% power. Planning for 75% of the observed effect gives 92 per arm for 80% power and 122 per arm for 90% power. Planning for 50% of the observed effect gives 194 per arm for 80% power and 259 per arm for 90% power. The pattern illustrates a general principle: smaller effects are harder to detect and require more participants, all else being equal. The illustrations rely on the observed estimate, which is uncertain, and should not be treated as a guarantee that a future study with those numbers would achieve the stated power in practice.

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 = 0.200; treatment proportion p₁ = 0.450; average p̄ = 0.325.
2. First term: z_1−α/2 × √[2p̄(1−p̄)] = 1.96 × 0.6624 = 1.2982.
3. Second term: z_1−β × √[p₀(1−p₀) + p₁(1−p₁)] = 0.842 × 0.6384 = 0.5373.
4. n = (1.2982 + 0.5373)² / (0.2500)² = 53.9, rounded up to 54 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 <- 0.2                          # control proportion
p1 <- 0.45                          # 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(2230761)
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 = 54 (80% power), 72 (90% power)
 75% of observed effect: n per arm = 92 (80% power), 122 (90% power)
 50% of observed effect: n per arm = 194 (80% power), 259 (90% power)
power.prop.test: 53.9 
Simulated power at n = 54 per arm: 0.806 (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. Analyses Reported by the Sponsor

The registry's own reported analysis is a chi-squared test with p = 0.020. The simple unadjusted recalculation from the posted participant counts gives p = 0.02. These values agree at the precision displayed, and the record indicates no discrepancy. The sponsor's reported analysis is therefore the primary reported inferential result; the recalculation serves as a check based on the summary counts rather than a replacement for a fuller trial analysis.

The recalculation also provides an unadjusted risk difference of 0.25, with a 95% confidence interval from 0.059 to 0.441, as well as relative measures. These estimates help describe the size and uncertainty of the group contrast, while the registry's reported test gives the stated significance result. Neither can clarify the clinical definition of the counted event, which is not reported in the registry record.

The registry does not provide a detailed sponsor analysis report, adjustment details, or a complete statistical analysis plan. It is not possible to determine from this record whether other analyses were conducted or how the posted analysis relates to any unpublished analyses. The agreement of the reported p-value and the unadjusted recalculation is a narrow consistency check on the posted counts and test result, not independent confirmation of all aspects of the trial's analysis.

14. Multiplicity, Missing Data and Analysis Populations

The registry record lists three outcome measures, but no secondary outcomes are posted in the available results information. Only the primary outcome is described with participant counts and a reported analysis. The record does not report whether multiple outcomes, time points, or analyses were considered in the study's statistical plan, nor whether any multiplicity adjustment was planned or used.

Multiplicity is a general concern when several statistical tests are conducted: the chance of obtaining at least one nominally notable result can increase as the number of tests grows. Whether that issue applies to this result, and how it was addressed, cannot be established because the trial's complete analysis plan and results are not reported in the registry record. The p-value should therefore be read as the result of the posted primary comparison, without assuming that multiplicity was or was not controlled.

The primary outcome population is identified as intention-to-treat. In general, an intention-to-treat analysis aims to retain participants in the groups to which they were assigned, regardless of adherence or treatment received. The record does not provide a participant-flow account, analysis exclusions, or a detailed statement of how the intention-to-treat population was implemented for this outcome. The reported group sizes are 60 and 30, but the handling of any missing outcome observations is not reported in the registry record.

Missing data can matter when outcomes are unavailable for some participants, particularly if the likelihood of missingness differs by group or relates to outcome status. In general, complete-case analysis, imputation, and other approaches can yield different results under different assumptions. No missing-data method is described, so none should be attributed to the trial. It is also not reported whether the study performed sensitivity analyses for missing outcomes.

The registry does not report interim analyses, stopping rules, a prespecified statistical analysis plan, or detailed procedures for defining the binary event. These are distinct issues: the analysis population label gives some information about the intended framework, but does not resolve the missing outcome definition or missing-data handling. Such omissions do not alter the posted counts, but they limit the ability to assess how fully the reported result reflects the planned analysis.

15. 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: guillan-barre syndrome (3.3%).

The adverse-event information lists serious adverse events for 0 of 60 participants in the XOPH5 ointment group and 1 of 30 in the placebo ointment group. The registry also lists other adverse events for 11 of 60 participants in the XOPH5 group and 0 of 30 in the placebo group. These are separate categories in the record; the other-event counts should not be added to the serious-event counts or interpreted as a measure of severity.

The registry lists “Guillan-Barre syndrome” as a top serious adverse event term, with 3.3%. It does not provide enough detail in the registry record to attribute that term to a particular arm or to describe its clinical course. Death counts are not reported in the registry record. The record also does not supply event-level detail, timing, duration, or an assessment of whether an event was related to treatment.

These figures are descriptive counts in groups of different sizes. They do not establish comparative safety, and a lack of reported serious events in one group does not prove that no risk exists. The small number of serious events also means the record offers limited information about uncommon outcomes. Safety interpretation should remain confined to the listed counts and term, without inferring causality or making treatment recommendations.

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

The posted primary results show a higher observed count proportion for the registry's binary outcome in the XOPH5 group than in the placebo group: 27 of 60 compared with 6 of 30. The unadjusted risk difference is 0.25, and the registry reports a chi-squared p-value of 0.020. The confidence intervals indicate that the estimated contrast is uncertain in magnitude, even though the reported intervals exclude the corresponding null values.

This is evidence about the recorded outcome in this completed phase 2 trial, not a complete account of severity-score changes. The outcome title refers to a clinician-reported 0-to-4 LESS scale, but the results are participant counts. Because the binary event threshold is not reported in the registry record, it is not possible to say precisely what participants had to experience or achieve to be counted. The counts should not be described as a particular score improvement or a specified degree of eyelid-fat reduction.

The study enrolled 90 participants and the outcome groups contain 60 and 30. The result pertains to the study's reported population and timeframe, not automatically to other populations, settings, or longer periods. No secondary outcomes are posted, and detailed missing-data methods, the original sample-size rationale, and the full statistical plan are not reported in the registry record. These gaps constrain assessment of robustness and completeness.

Statistical significance is not the same as clinical importance. A p-value does not quantify the size or value of an outcome, while the confidence interval does not resolve the missing event definition. The observed counts and estimates support a description of the trial's between-group statistical result, but do not establish what the result means for any individual or settle broader questions that were not measured or reported.

17. Why This Trial Matters Statistically

This trial illustrates why a headline p-value is not enough to interpret a clinical comparison. The registry reports a chi-squared p-value of 0.020, but understanding the result also requires the group counts, the event proportions, effect measures, and confidence intervals. The recalculated risk difference and relative measures show both the direction of the observed contrast and the uncertainty around its magnitude.

It also demonstrates the importance of aligning outcome labels with reported data. The primary outcome is described as a clinician-reported severity score on a 0-to-4 scale, yet the results are binary participant counts. Without the event threshold, a reader cannot map those counts back to a specific score change or clinical criterion. This distinction affects interpretation even when the arithmetic comparison is straightforward.

The record's masking descriptions do not agree: structured information says quadruple-masked, while the official title says double-masked. That inconsistency does not negate the reported comparison, but it limits what can be said about masking procedures. The missing details on analysis planning, missing outcomes, and secondary results further show why registry results need to be read with attention to reporting completeness.

Finally, the sample-size illustrations are based on the observed effect and stated planning assumptions. They help show how design targets change when the effect considered is smaller, but they do not reconstruct the original trial's design rationale. Together, these features make the trial useful for teaching the distinction between a statistical result, its precision, and the information needed to understand its clinical interpretation.

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 most important outcome-specific limitation is that the registry describes the primary endpoint as a clinician-reported severity score but reports participant counts. The binary event definition is not reported in the registry record. Without that criterion, the counts cannot be linked confidently to a particular score, change, or threshold, and the clinical meaning of the risk difference remains unclear.

The analysis groups are unequal in size: 60 participants for XOPH5 ointment and 30 for placebo. The registry record lists 90 participants enrolled, but does not give a detailed flow of participants through assignment, follow-up, and outcome assessment. Although the primary outcome population is labeled intention-to-treat, implementation details and missing-outcome handling are not reported in the registry record.

There is also a masking-description inconsistency between quadruple masking in the structured information and double masking in the official title. The record does not explain which description reflects the procedures used. The original sample-size justification, statistical analysis plan, interim analyses, and multiplicity procedures are not reported in the registry record. No secondary outcomes are posted, limiting the ability to consider other measured outcomes alongside the primary result.

The relative-effect confidence intervals are broad, and the group sizes and event counts leave uncertainty about the magnitude of the contrast. Safety information is also limited: death counts are not reported, and the listed serious adverse event term lacks arm attribution and event-level detail in the information available. These limits call for a measured reading of the posted results, not an assumption that missing details favor either group.

19. Related Tutorials

20. Related Statistical Calculators

21. Sources

• ClinicalTrials.gov: Phase 2 Study of XAF5 (XOPH5) Ointment for Reduction of Excess Eyelid Fat (Steatoblepharon) — NCT02230761.
• Registry record last updated 2016-02-08; status last verified 2015-12.
• Results first posted 2016-02-08.
• 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

NCT02230761 is a completed phase 2, randomized, parallel-group study of XOPH5 ointment and placebo for lower eyelid steatoblepharon. The brief summary describes once-daily application for 10 weeks. The primary clinician-reported LESS outcome has an 11-week timeframe and is identified as intention-to-treat.

The posted primary counts are 27 of 60 for XOPH5 ointment and 6 of 30 for placebo ointment. The registry reports a chi-squared p-value of 0.020; the unadjusted recalculation gives a risk difference of 0.25, with a 95% confidence interval from 0.059 to 0.441. The record does not state the binary event threshold behind the counts.

The registry lists three outcome measures, but no secondary outcomes are posted. It does not report the original sample-size justification, detailed missing-data handling, or the full statistical analysis plan. The structured masking description and the official-title description differ, and the record does not resolve that discrepancy.