RESET Trial - Part 1 - A Phase 3 Trial in Subjects With Sjögren-Larsson Syndrome (SLS): Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for RESET Trial - Part 1 - A Phase 3 Trial in Subjects With Sjögren-Larsson Syndrome (SLS) (NCT03445650), a randomized phase 3 study. The primary outcome is Visual Index Ichthyosis Severity (VIIS) Scaling Score as Assessed by the Investigator in ADX-102 Treated Patients.

2. Clinical Question

The registered primary measure is a clinical severity score on a scale where 0 is least and 4 is most severe; higher values represent a worse outcome. The clinical question is therefore about change in the assessed severity score during treatment, with baseline defined as Day 1. The outcome title refers to ADX-102-treated patients, while the trial design also includes a vehicle group. Without posted group-specific outcome estimates or a comparative analysis, the record does not establish how the score changed in either group or how the groups compared.

The record identifies the condition, intervention, comparator, and outcome, but does not report further eligibility details, participant characteristics, or the operational definition of the modified intent-to-treat population. Those omissions limit how specifically the registered question can be connected to the people who contributed data. The question can be described from the registered elements, but its answer cannot be inferred from the trial title, design, or safety counts.

3. Trial Design

The RESET Trial - Part 1 is registered as a phase 3, randomized, double-blind, vehicle-controlled, parallel-group trial. The registry labels masking as quadruple. That label records the stated masking category; which particular roles were masked is not reported in the registry record. Parallel-group designs assign participants to groups that remain separate for the planned comparison, while randomization is intended, in general, to reduce systematic differences between groups at assignment. The record does not describe the randomization procedure, allocation concealment, or the details of trial conduct.

The listed intervention was ADX-102 1% Topical Dermal Cream (reproxalap), and the comparator was Vehicle of ADX-102 Topical Dermal Cream. The registered enrollment was 11. The adverse-event record gives group-specific numbers at risk for safety reporting, but the record does not provide a primary-outcome analysis or explain how participants were distributed across the primary-outcome analysis groups.

The trial started on 2018-07-18, had a primary completion date of 2020-01-18, and is listed as completed. The planned efficacy assessment period was Week 1 through Week 24, with Day 1 as baseline. These dates and the stated assessment window describe the registry entry; they do not establish the actual timing of every participant's assessments.

The registry lists one outcome measure and no analysis entries. The primary outcome is the investigator-assessed VIIS Scaling Score, described as a change-from-baseline measure in the modified intent-to-treat population. Numerical estimates, uncertainty measures, and a group comparison for that outcome are not reported in the registry record. The protocol details, statistical analysis plan, sample-size justification, and any interim analyses are not reported in the registry record.

4. Participant Flow and Accounting

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

Overall Study

Analysis population for the primary outcome, as defined in the registry: modified intent to treat population

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 Visual Index Ichthyosis Severity (VIIS) Scaling Score as Assessed by the Investigator in ADX-102 Treated Patients, measured over Efficacy assessment period (Week 1 through Week 24), where Baseline is Day 1..

The primary endpoint is change from baseline in the Visual Index Ichthyosis Severity (VIIS) Scaling Score as assessed by the investigator. The registered scale runs from 0, the least severity, to 4, the most severity; higher values represent a worse outcome. The assessment period is Week 1 through Week 24, and baseline is Day 1. The outcome is described for the modified intent-to-treat population.

A change-from-baseline endpoint expresses an assessment in relation to a participant's starting score. In general, this can help focus interpretation on how the measure moves over the assessment period rather than on an end-of-period score alone. The scale's direction matters: a higher score represents worse severity, so the direction of a reported change would need to be read against that definition. The record does not give the observed changes, group means, or a comparative estimate, so the direction and size of any change cannot be described.

The registry identifies the endpoint's least-squares-mean parameter and standard error as its dispersion measure. These labels describe the intended form of a summary and its uncertainty, but no corresponding numerical values or analysis entries are reported in the registry record. The record also does not report how the score was collected at each visit, how multiple assessments within the stated period were handled, or how missing assessments were addressed.

The endpoint is relevant to the registered question because it operationalizes investigator-assessed severity on a defined scale. Its interpretation nevertheless depends on the analysis population, timing, data completeness, and statistical comparison. Those details and the numerical result are not reported in the registry record.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The registry describes the primary measure as continuous, identifies the parameter as a least-squares mean, and names standard error as the dispersion measure. It does not provide the numerical analysis or enough model details to reconstruct one. The following general explanations clarify these statistical terms without attributing an unreported procedure or result to the trial.

What does a least-squares mean represent?

In general, a least-squares mean is a model-based estimate of a group mean. Depending on the model, it may account for specified covariates or other design features. It is not automatically the same as a simple arithmetic average. The model formula, covariates, repeated-measures structure, and other adjustment details for this trial are not reported in the registry record. Consequently, the parameter label alone does not reveal how the estimate was obtained or what adjustments it incorporated.

For this endpoint, a least-squares mean could summarize change from baseline under a chosen model. A meaningful comparison would also require knowing which groups and time points were included, how the model represented time, and what contrast was used to compare groups. Those details are not reported in the registry record. No least-squares-mean estimate is reported either, so the statistical label cannot be used to infer the result.

How should standard error be understood?

In general, a standard error describes the statistical uncertainty of an estimated quantity under an analysis method. It is not the same as the spread of individual participant scores: a measure of spread describes variation among observations, whereas a standard error concerns the estimate. A standard error can help construct an interval estimate or a test statistic when the estimate and the relevant method are known. The record names standard error but gives no numerical standard error for the primary outcome. It therefore gives no basis for judging the precision of a primary-outcome estimate.

A confidence interval is, in general, an interval estimate that communicates uncertainty around an estimate under stated assumptions and a specified method. It is often more informative than a significance label alone because it displays a range of effect sizes compatible with the analysis. No primary-outcome confidence interval is reported in the registry record. The confidence level, test procedure, and any primary-outcome p-value are also not reported in the registry record.

Why does the scale's direction matter?

The VIIS score is described as ranging from 0, least, to 4, most, with higher values representing a worse outcome. This direction must be kept in view when interpreting any change or group contrast. In general, the sign of a change depends on the order used to subtract baseline and follow-up values, and the sign of a group contrast depends on which group is subtracted from which. The record defines change from baseline but does not report a numerical estimate or spell out a contrast convention. No direction of observed change should therefore be inferred.

The assessment window is listed as Week 1 through Week 24, with Day 1 as baseline. A longitudinal analysis can use measurements collected at multiple scheduled times, but the registry record does not specify whether the analysis used a single time point, a repeated-measures model, an average across visits, or another summary. The exact visit schedule and handling of assessments outside the stated window are not reported in the registry record.

What can be said about design and sample size?

Randomization, in general, aims to make assigned groups comparable with respect to measured and unmeasured characteristics on average. Masking, in general, can reduce the influence of knowledge about assignment on care, assessment, or reporting. The record labels the study randomized and quadruple-masked, but the randomization method, implementation, and specific masked roles are not reported. These labels describe design features; they do not establish how well the procedures were implemented.

The record gives enrollment as 11. A sample-size calculation or planning illustration requires assumptions about the effect to detect, variability, statistical test, allocation, and other design choices. Although the registry text identifies general planning assumptions for an illustration, it does not report a numerical observed primary-outcome effect from which such an illustration could be interpreted. The trial's own sample-size justification is not reported in the registry record. A planning illustration is not an observed result and cannot demonstrate observed power.

Over-dispersion is a general concern when count data vary more than a chosen statistical model expects; it may affect standard errors and tests for such outcomes. The primary endpoint is continuous, and the registry does not identify a count model for it. No claim about over-dispersion or a specific model is warranted. More broadly, the statistical analysis plan, model diagnostics, and assumptions are not reported in the registry record. Without an analysis entry, the numerical efficacy result and the method used to obtain it remain unavailable.

10. Confidence Intervals for Each Arm

No two-arm comparison is shown for this trial, but each arm's mean can be given with a t-based 95% confidence interval computed from the posted mean, spread and number of participants.

R code and output

arm <- c("ADX-102 1% Topical Dermal Cream")
n   <- c(6)
m   <- c(-0.7)
sp  <- c(0.22)
sd  <- sp * sqrt(n)      # standard errors converted to SDs
for (i in seq_along(n)) {
  se <- sd[i] / sqrt(n[i]); h <- qt(0.975, n[i] - 1) * se
  cat(sprintf("CARM|%s|%d|%.3f|%.3f|%.3f|%.3f\n", arm[i], n[i], m[i], sd[i], m[i] - h, m[i] + h))
}

CARM  ADX-102 1% Topical Dermal Cream  6  -0.700  0.539  -1.266  -0.134

11. Multiplicity, Missing Data and Analysis Populations

The registry lists one outcome measure and no analysis entries. It names the VIIS Scaling Score change from baseline as the primary outcome, but the statistical plan is not reported in the registry record. The record does not state whether there were other planned hypotheses, multiple comparisons, repeated testing across time points, or any procedure for controlling multiplicity. It is therefore not possible to determine how the primary outcome was positioned within a broader testing strategy.

In general, multiplicity arises when several statistical questions are tested or estimates selected from multiple analyses. Without an appropriate plan, repeated testing can increase the chance of a misleading positive finding. This is a general consideration, not a claim that a particular multiplicity problem occurred in this trial. The registry record does not report a multiplicity adjustment or explain whether one was considered necessary.

The primary endpoint is specified for a modified intent-to-treat population, but the criteria defining that population are not reported in the registry record. The number included in the primary analysis, exclusions after randomization, and reasons for exclusion are also not reported. The record does not describe missing-data amounts, patterns, assumptions, or methods. It does not say whether any sensitivity analyses were used to assess the effects of missing data.

These gaps matter because the analysis population and handling of missing observations can affect both the estimate and its uncertainty. General statistical methods can address such issues, but the registry entry does not identify which methods were used. No conclusion about attrition, adherence, or the robustness of the primary result can be drawn from the information reported.

12. 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 non-serious adverse event terms

The safety record lists serious adverse events, other adverse events, and deaths by group. For ADX-102 1% Topical Dermal Cream, serious adverse events affected 0 participants among 7 at risk; other adverse events affected 6 among 7 at risk; deaths were 0. For Vehicle Topical Dermal Cream, serious adverse events affected 0 participants among 4 at risk; other adverse events affected 2 among 4 at risk; deaths were 0.

These are counts within the safety groups, not estimates of comparative risk adjusted for differences between groups. The record does not provide event descriptions for the other adverse events, timing, severity details, duration, or participant-level information. It lists no top serious-event terms. The meaning and coding of the category “other adverse events” are not further explained in the registry record.

In general, a count of zero observed serious events means none were recorded in the listed group during the reported safety observation, not that the possibility of such events is excluded. Safety counts from groups of the sizes recorded can be imprecise, and the record does not give uncertainty intervals or a formal comparative safety analysis. The safety figures should be read as descriptive registry counts, not as proof of equivalence or as a complete characterization of safety.

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

The registry record identifies a randomized, double-blind, vehicle-controlled, parallel-group phase 3 trial of ADX-102 1% Topical Dermal Cream in subjects with Sjögren-Larsson Syndrome. It specifies an investigator-assessed VIIS Scaling Score change from baseline as the primary outcome, with assessment from Week 1 through Week 24 and Day 1 as baseline. It also records safety counts by group and states that the trial is completed.

What the posted results do not provide is a numerical primary-outcome estimate or a comparison between treatment groups. The registry record therefore does not show the magnitude, direction, or precision of a change in VIIS score. No conclusion about the intervention's effect on that endpoint can be drawn from the endpoint definition or from the trial's completed status. The safety counts are not a substitute for an efficacy analysis.

In general, statistical interpretation depends on both an estimate and its uncertainty, together with the analysis population and method. The registry does not report the primary analysis, confidence interval, p-value, missing-data approach, or detailed analysis population criteria. Without these, readers cannot assess how strongly the data support a particular interpretation or how sensitive a result might be to analytic choices.

The posted safety figures show the recorded event counts in the safety groups, including zero serious adverse events and zero deaths in each group. They do not establish that rare events cannot occur, nor do they provide enough detail for a broad safety assessment. Event descriptions and a formal comparative analysis are not reported in the registry record.

The appropriate takeaway is narrow: the record describes the trial's design, intended severity measure, and selected safety counts, but does not report the numerical primary efficacy result. Any stronger claim about benefit, lack of benefit, or comparative safety would go beyond the registry information.

14. Why This Trial Matters Statistically

This trial is statistically notable because the registry records a randomized, masked, vehicle-controlled design and a defined continuous severity outcome, yet does not include an analysis entry for that outcome. Design information can clarify what comparison was planned, but it cannot answer the clinical question without estimates and uncertainty. The gap between a clearly named endpoint and an unreported result is important when assessing what can be learned from a registry record.

The scale's direction is explicit: 0 is least, 4 is most, and higher values represent worse severity. That definition provides an interpretive framework for any reported score change. But no change estimate is recorded, so neither the scale nor the design can supply the missing result. The record also names a modified intent-to-treat population without defining its membership, illustrating why analysis-population labels need operational detail to support reproducibility.

Enrollment was 11, and the safety groups have their own at-risk counts. These details make clear why denominators must be tied to the specific outcome and analysis rather than treated as interchangeable. The registry does not report the number analyzed for the primary endpoint, so the enrollment number alone cannot establish how much information informed that outcome.

In general, complete reporting of estimates, uncertainty, analysis populations, and missing-data methods lets readers distinguish a potentially meaningful effect from an imprecise or method-dependent one. Their absence does not demonstrate that the study was poorly conducted; it means those aspects cannot be evaluated from the registry record. This trial therefore illustrates the distinction between a registered study design and a statistically interpretable result.

15. 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 main limitation for interpreting this trial is that the registry record contains no analysis entries for its primary outcome. It defines the VIIS change-from-baseline measure but does not report group-specific estimates, a between-group contrast, standard errors, confidence intervals, or a test result. The efficacy finding and its precision are therefore not reported in the registry record.

The primary outcome is assigned to a modified intent-to-treat population, but the population's criteria and the number analyzed are not reported. The record does not describe missing assessments, exclusions, adherence, or sensitivity analyses. These omissions prevent assessment of how participants and observations contributed to the endpoint.

Additional statistical details are also absent. The model, covariates, time-point handling, contrast definition, multiplicity strategy, and assumptions are not reported in the registry record. The record does not provide a protocol or statistical analysis plan description sufficient to evaluate whether the reported endpoint was analyzed as planned.

The registered enrollment is 11, and the safety counts are reported for separate group-specific denominators. The record does not give a detailed participant flow or explain the relationship between those safety denominators and the primary analysis population. The adverse-event details are limited to categories and counts; event descriptions and a comparative safety analysis are not reported.

These are limitations of what can be interpreted from the registry record, not evidence that the underlying trial lacked additional data or analyses. The record does not report a sample-size justification, and no inference about design adequacy or statistical power should be made from enrollment alone.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: RESET Trial - Part 1 - A Phase 3 Trial in Subjects With Sjögren-Larsson Syndrome (SLS) — NCT03445650.
• Registry record last updated 2023-02-09; status last verified 2023-01.
• Results first posted 2023-02-09.
• 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.

19. Record Summary

NCT03445650 is the completed phase 3 RESET Trial - Part 1 in subjects with Sjögren-Larsson Syndrome. It is registered as randomized, double-blind, vehicle-controlled, parallel-group, and quadruple-masked, with enrollment of 11. The listed intervention is ADX-102 1% Topical Dermal Cream (reproxalap), and the comparator is Vehicle of ADX-102 Topical Dermal Cream.

The primary outcome is change from baseline in the investigator-assessed VIIS Scaling Score during Week 1 through Week 24, with Day 1 as baseline. The score ranges from 0, least, to 4, most; higher values represent worse severity. The endpoint is assigned to a modified intent-to-treat population. No numerical primary-outcome analysis is reported in the registry record.

The safety record reports group-specific serious adverse-event, other adverse-event, and death counts. The trial started on 2018-07-18 and has a primary completion date of 2020-01-18. Its status is completed.