Safety and Efficacy Study of R932348 Ophthalmic Solution in Chronic Ocular Graft Versus Host Disease Patients(DROPS-2): Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Safety and Efficacy Study of R932348 Ophthalmic Solution in Chronic Ocular Graft Versus Host Disease Patients(DROPS-2) (NCT02040623), a randomized phase 2 study. The primary outcome is Change From Baseline (Visit 1) of Total Corneal Fluorescein Staining Score at 12 Weeks..

2. Clinical Question

3. Trial Design

This completed phase 2 study was randomized, multicenter, parallel-group, placebo-controlled, and quadruple-masked. Its official title describes an assessment of the safety and efficacy of 0.2% and 0.5% R932348 ophthalmic solutions for keratoconjunctivitis sicca in patients with chronic ocular graft-versus-host disease. The registry lists the interventions as R348 ophthalmic solution at the two concentrations and placebo ophthalmic solution. The roles covered by quadruple masking are not reported in the registry record.

Each active-treatment description specifies 2 drops per eye twice a day; the placebo description specifies the same administration. The treatment period in the stated objectives was 12 weeks. Enrollment was 35. The study start is recorded as 2014-03, and primary completion as 2016-07. The listed sponsor is Rigel Pharmaceuticals.

The primary outcome is reported for the per-protocol population, defined in the record as excluding subjects with significant protocol deviations or early study termination. The posted outcome summaries include 7 participants in the 0.2% group, 6 in the 0.5% group, and 9 in the placebo group. These arm-specific counts describe the primary outcome summaries; they should not be treated as the randomized enrollment counts. The registry record does not explain the reasons for the difference between enrollment and the per-protocol outcome counts, or report the number assigned to each group at randomization.

The record lists one outcome measure and no secondary outcomes posted. It does not report further details of the randomization procedure, allocation concealment, masking implementation, or study sites. The status is completed, but a completion date beyond the recorded primary completion date is 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: The per-protocol (PP) population excludes subjects with significant protocol deviations or with early study termination

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 Change From Baseline (Visit 1) of Total Corneal Fluorescein Staining Score at 12 Weeks., measured over Baseline to 12 weeks.

The primary endpoint is change from baseline (Visit 1) in total corneal fluorescein staining score at 12 weeks. Corneal fluorescein staining is an objective measure of staining across regions of the cornea. The score range is 0-20: 0 represents no fluorescein staining of any region, while 20 represents severe staining across the entire cornea.

The endpoint is expressed as a change from baseline, so it describes how the score at follow-up differs from the participant’s starting score. A negative change indicates a lower score at 12 weeks than at baseline. Since lower scores correspond to less staining on the described scale, the direction of change provides a way to describe whether staining scores moved up or down during the study. The registry reports the group mean change and standard deviation for each arm.

General: an objective endpoint can complement participants’ subjective reports by measuring a clinical feature using a defined scoring system. Repeated measurement also allows the outcome to be expressed relative to baseline rather than as a follow-up score alone. Interpretation still depends on how the measure was collected, the population analyzed, and the uncertainty around the group estimates. Details of measurement procedures beyond the score description are not reported in the registry record.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

What do the mean changes describe?

The endpoint is continuous: it records a numerical score, and the registry reports the mean change for each group. A mean is the arithmetic average of the observed changes in that group. It gives a concise description of the group’s central tendency, but it does not show every participant’s response or the shape of the response distribution. Here, the reported means are -4.2 for R348 0.2%, -6.2 for R348 0.5%, and -2.1 for placebo.

Because the outcome is a change from baseline, a negative mean means that the group’s average follow-up score was lower than its average baseline score. The scale description gives direction to that change: lower staining scores indicate less staining. This interpretation applies to the score, not necessarily to every participant in a group. A group mean can combine a range of individual changes, including changes that differ in direction and size.

What does the standard deviation show?

The standard deviation describes variability among the observed participant changes around the group mean. The posted standard deviations are 2.9, 3.7, and 2.6 for the 0.2%, 0.5%, and placebo groups, respectively. General: a larger standard deviation indicates greater spread in the observations, while a smaller one indicates that observations are more closely clustered around the mean. It is a measure of dispersion, not a measure of precision for the mean and not an estimate of the treatment-versus-placebo effect.

Precision for a mean or a contrast is usually conveyed with a confidence interval. A confidence interval reflects sampling uncertainty under the analysis assumptions and shows a range of values compatible with the observed data. The registry does not report confidence limits for the group means or for a treatment-versus-placebo contrast. It also does not report p-values or a formal test for this endpoint. Consequently, the arm summaries do not show how uncertain a comparative estimate would be.

Why is a direct group comparison important?

When a trial has treatment and placebo groups, the central statistical question is usually about how the groups differ, not simply whether each group changed from its own baseline. Improvement or decline from baseline can occur for reasons unrelated to the assigned intervention, including natural variation over time and features of measurement. Randomization supports a comparison between assigned groups, but an analysis is needed to estimate and quantify that comparison.

General: a treatment-effect estimate is a contrast between groups, accompanied by an uncertainty measure such as a confidence interval. A p-value, when reported, addresses compatibility of the data with a specified null hypothesis under a statistical model; it does not measure the size or clinical importance of an effect. Neither a contrast nor its uncertainty is available in the registry results for this endpoint. The record explicitly notes that values are missing or not estimable for a two-arm comparison. No between-group effect should therefore be inferred by calculating one from the displayed arm summaries.

What does over-dispersion mean in general?

Over-dispersion arises when observed variation is greater than a statistical model expects. It is a concern for some outcomes and models, especially counts, because underestimated variation can make confidence intervals too narrow and tests too optimistic. General: models may account for over-dispersion when the outcome and analysis warrant it. This trial’s posted primary outcome is continuous and is summarized with means and standard deviations. The registry does not describe a model, an over-dispersion assessment, or an adjustment for it; there is no basis to claim that over-dispersion was present or addressed.

How should planning illustrations be understood?

General: sample-size calculations are planning tools that estimate how many participants per arm might be needed to detect a specified effect under stated assumptions. The assumptions recorded for the planning illustration use a two-sided significance level of 0.05, equal allocation, a normal approximation, and an effect defined as a stated fraction of the observed effect. Such illustrations are not the trial’s observed results and are not observed power. The registry record does not report numerical sample-size illustration results or the trial’s own sample-size justification. They cannot be used to infer the trial’s design rationale.

The distinction between planning and observed analysis is important. A planning calculation uses assumptions about a future study, whereas an analysis estimates an effect from data collected in a completed study. A calculation based on an observed effect can be especially sensitive to the estimate used and does not establish that the study was adequately powered. No power conclusion follows from the posted arm means or the planning assumptions alone.

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("R348 Ophthalmic Solution, 0.2%", "R348 Ophthalmic Solution, 0.5%", "Placebo")
n   <- c(7, 6, 9)
m   <- c(-4.2, -6.2, -2.1)
sp  <- c(2.9, 3.7, 2.6)
sd  <- sp      # posted standard deviations
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  R348 Ophthalmic Solution, 0.2%  7  -4.200  2.900  -6.882  -1.518
CARM  R348 Ophthalmic Solution, 0.5%  6  -6.200  3.700  -10.083  -2.317
CARM  Placebo  9  -2.100  2.600  -4.099  -0.101

11. Multiplicity, Missing Data and Analysis Populations

The registry lists one outcome measure and no secondary outcomes posted. That does not establish that no other outcomes were collected or analyzed; those details are not reported in the registry record. The record does not describe a multiplicity procedure, such as an adjustment for testing several outcomes or comparisons. It is therefore not possible to determine from this record whether multiplicity was considered in the study’s own analysis.

The primary result is specified for the per-protocol population, which excludes subjects with significant protocol deviations or early study termination. The record does not provide the criteria used to identify significant deviations, the number excluded for each reason, or an analysis of all randomized participants. Arm-specific outcome counts are 7 for R348 0.2%, 6 for R348 0.5%, and 9 for placebo. The randomized group counts and the reasons for the differences are not reported in the registry record.

Missing outcome data can affect both the precision and interpretation of a trial result, particularly if the chance of missingness differs between groups or relates to participants’ outcomes. General: statistical approaches to missing data rely on assumptions about why values are missing. The record does not describe missing-data handling, imputation, sensitivity analyses, or the amount and pattern of missing endpoint data. It also does not report a registered comparative analysis for the primary outcome. These gaps limit assessment of the robustness and generalizability of the posted per-protocol summaries.

12. 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 0% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: pneumonitis (9.1%), pulmonary fibrosis (9.1%), microembolism (9.1%), hyperbilirubinaemia (8.3%), clostridium difficile infection (8.3%).

The registry reports serious adverse events among participants at risk in each group: 1 among 11 in the R348 0.2% group, 2 among 12 in the R348 0.5% group, and 1 among 12 in the placebo group. These counts describe the reported number affected and the group recorded as at risk. They do not establish whether events were caused by the assigned solution. The record does not report deaths.

The listed serious adverse event terms are pneumonitis (9.1%), pulmonary fibrosis (9.1%), microembolism (9.1%), hyperbilirubinaemia (8.3%), Clostridium Difficile infection (8.3%), and pneumonia (8.3%). The registry record does not identify the treatment group for each listed term, so these percentages should not be assigned to a particular arm. It also does not provide enough context to determine whether a term represents one event or multiple events across groups.

General: safety counts are descriptive. Comparisons can be difficult to interpret when event counts are small, follow-up differs, or the underlying risks vary between participants. Serious events may occur during a trial without being caused by its intervention. These figures alone do not establish comparative safety or causation. Other adverse events affected 11 participants in the 0.2% group, 10 in the 0.5% group, and 9 in the placebo group, using the recorded groups at risk of 11, 12, and 12, respectively. The registry does not provide further event-level context in these summaries.

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

The registered outcome summaries describe average change in corneal staining score over the 12-week treatment period among per-protocol participants. Each group had a negative mean change, and the mean decreases were numerically larger in both R348 groups than in the placebo group. On the described score, a lower value represents less staining. These are descriptive findings, not a reported statistical comparison or proof of a treatment effect.

The record does not report a confidence interval, p-value, or estimated between-group contrast for the primary outcome. Without a comparative estimate and its uncertainty, readers cannot assess how compatible the observed difference in group means is with chance variation under a specified analysis. The reported standard deviations describe within-group spread, not the uncertainty of the treatment comparison.

The endpoint is also limited to a particular measurement and time frame. A change in total corneal fluorescein staining score does not, by itself, describe every aspect of ocular disease, symptoms, functioning, or longer-term outcomes. The record’s stated primary population is per-protocol rather than all randomized participants, and it does not report a corresponding intention-to-treat analysis or the handling of missing measurements.

Safety summaries list serious adverse events and other adverse events by group, but do not establish causation. The serious-event terms are not linked to treatment groups in the record. As a result, these counts and terms cannot support a definitive comparison of harms between the interventions.

Overall, the posted data allow a description of arm-level mean changes and adverse-event counts. They do not support a definitive conclusion about the comparative efficacy or safety of either concentration. A complete interpretation would require the planned analysis, treatment-effect estimates with uncertainty, and further information about participant flow, missing data, and the safety events.

14. Why This Trial Matters Statistically

This trial illustrates why a randomized comparison is interpreted through the contrast between groups rather than by looking only at change from baseline. The registry posts mean changes for each arm, and their directions are easy to describe. But a difference in the size of those means is not itself a reported estimate of treatment effect. An analysis that accounts for the study design and reports uncertainty is needed to judge the comparative evidence.

It also shows why descriptive dispersion and precision should not be confused. Standard deviations describe how participant changes vary within each arm. They do not show the uncertainty around a between-group estimate. Confidence intervals and a specified analysis would help readers understand the range of comparative effects compatible with the data; those results are not reported in the registry record.

The per-protocol population is another important statistical feature. Excluding participants with significant protocol deviations or early termination may affect interpretation, particularly when the reasons for exclusion and the outcomes of excluded participants are not described. Randomization is most directly preserved in an analysis based on all randomized participants, but the record does not post such an analysis for this endpoint.

Finally, the safety summaries demonstrate the need to separate event counts, event terms, and attribution. Counts can describe what was recorded during a study, but they do not establish that an intervention caused an event. The group assignment for the listed serious-event terms is not reported. Clear reporting of comparative estimates, missing-data methods, participant flow, and safety context would help readers assess the strength and limits of the evidence.

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 posted primary outcome is a per-protocol summary rather than a reported analysis of all randomized participants. The registry defines the per-protocol population by excluding subjects with significant protocol deviations or early study termination, but does not give the number or reasons for exclusions. The arm-specific outcome counts are 7, 6, and 9, while enrollment is 35; the record does not explain the relationship between enrollment, randomized group sizes, and these analysis counts.

The registry reports group means and standard deviations but no comparative estimate, confidence interval, or p-value. It notes that values are missing or not estimable for a two-arm comparison. This prevents assessment of the precision and statistical compatibility of a treatment-versus-placebo contrast from the registered results. The record does not describe a statistical analysis plan, missing-data methods, sensitivity analyses, or multiplicity handling.

The primary endpoint is a scored measure of corneal staining at 12 weeks. The record does not provide further measurement procedures, baseline group summaries, or results at other time points. No secondary outcomes are posted, and the record does not clarify whether other outcomes were collected.

Safety reporting includes serious and other adverse-event counts, but the listed serious-event terms are not assigned to treatment groups. Deaths are not reported in the registry record. The posted safety summaries do not provide event narratives or attribution, and they cannot establish causation. These reporting limits restrict assessment of both comparative effects and safety from the registry results alone.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Safety and Efficacy Study of R932348 Ophthalmic Solution in Chronic Ocular Graft Versus Host Disease Patients(DROPS-2) — NCT02040623.
• Registry record last updated 2016-10-10; status last verified 2016-08.
• Results first posted 2016-10-10.
• 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

NCT02040623 is a completed, randomized, quadruple-masked, parallel-group, phase 2 study sponsored by Rigel Pharmaceuticals. It evaluated R348 ophthalmic solution at 0.2% and 0.5% against placebo in patients with chronic ocular graft-versus-host disease and keratoconjunctivitis sicca. Each solution was administered as 2 drops per eye twice a day, with outcomes assessed over 12 weeks. Enrollment was 35.

The primary outcome was change from baseline in total corneal fluorescein staining score at 12 weeks, reported as mean change and standard deviation in the per-protocol population. The registry posts arm-level summaries and safety counts but no comparative statistical analysis for the primary endpoint. It does not report confidence intervals, p-values, missing-data methods, or an intention-to-treat result. The listed serious-event terms are not linked to treatment groups. The record supports description of the posted outcomes, but not a definitive conclusion about comparative efficacy or safety.