Safety and Tolerability of the Ophthalmic Gel PRO-165 Versus Artelac® Nightime Gel: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Safety and Tolerability of the Ophthalmic Gel PRO-165 Versus Artelac® Nightime Gel (NCT03697876), a randomized phase 1 study. The primary outcome is Adverse Events.

2. Clinical Question

The registry record describes an exploratory Phase I study comparing the safety and tolerability of two ophthalmic gels on the ocular surface of ophthalmological and clinically healthy subjects. The stated hypothesis was that PRO-165 would have a safety and tolerability profile similar to Artelac® Nightime Gel. The primary outcome counted participants with adverse events during the evaluation period, rather than measuring a change in a continuous clinical score.

The registry reports 3 participants with adverse events in the PRO-165 group and 5 in the Artelac® Nightime Gel group. The posted comparison estimates the difference in event proportions as Artelac® Nightime Gel minus PRO-165. The estimate is positive, but its confidence interval spans both negative and positive values, so the posted results leave considerable uncertainty about the direction and size of a group difference. The record does not report a formal conclusion establishing equivalence or similarity.

3. Trial Design

This was a randomized, double-blind, parallel-group Phase I study, described as controlled and exploratory. The registry lists a planned enrollment of 32. The posted outcome groups contain 16 participants for PRO-165 and 15 for Artelac® Nightime Gel; the record does not explain the difference between the enrollment figure and the group counts reported for this outcome.

The two groups had the same stated dosing schedule: one drop of the assigned gel, four times a day during the waking period, in the bottom of the right eye sac. The registry identifies the interventions as drugs. It does not describe how the randomization sequence was generated or concealed, who was masked, or how masking was maintained. Those details are not reported in the registry record.

The primary outcome was the count of participants with adverse events, assessed throughout the 13 days of evaluation, including the safety call on day 13. The registry says that events were recorded as absent or present and counted by study group. This participant-level count does not convey the total number of separate events that might have occurred for an individual.

The record also lists secondary outcomes: visual acuity, intraocular pressure, post-instillation symptomatology, tear breakup time, and epithelial defects graded according to the Oxford Scale. Five secondary outcomes are posted, while the record lists seven outcome measures overall. Results for those secondary outcomes are not included in the registry entries, and their results are not reported in the registry record.

One participant in the PRO-165 group was lost during the study after attending Visit 1. The registry says this participant was included in the intention-to-treat population and considered for data analysis. It does not describe the exact handling of this participant's missing follow-up observations. Further information about the protocol, analysis populations, and original design assumptions 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

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: One patient in the PRO-165 group was lost during the course of the study, but did attend to Visit 1, so this subject was included in the ITT population, and therefore considered for the data analysis.

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: Clincally healthy adult volunteers. There were 16 subjects included in each group initially (n=32), however, one subject from the control group was lost to follow-up and did not attend to any visits beyond scrutiny, impossible to confirm if any exposure to the product happened, and was not considered in any analyses.One patient in the PRO-165 group was lost during the course of the study, but did attend to Visit 1, so this subject was included in the ITT population (31) but not in the PP (30).

6. Primary Endpoint

The registry lists the primary outcome as Adverse Events, measured over Throughout the 13 days of evaluation, including the safety call (day 13)..

The primary endpoint counts participants who had at least one adverse event during the evaluation period. The investigator was to record each event as absent or present, and the number of affected participants was counted by group. The outcome is therefore a participant count, not a count of all event episodes and not a measure of event severity.

Counting participants with an event is a direct way to summarize how many people experienced an adverse event under each study condition. It allows a comparison of the proportions affected, using each group's reported number of participants as the denominator. Such a summary can be useful for describing tolerability in a study, but it does not by itself describe the type, timing, duration, or seriousness of every event. The registry's primary outcome description does not provide those details for the counted events.

The assessment period extended throughout the 13 days of evaluation and included a safety call on day 13. Thus, the endpoint combines information gathered over that stated period rather than referring to a single visit. The record does not state whether event ascertainment differed by contact or visit, or whether all participants completed all planned assessments.

For this endpoint, the posted counts are 3 of 16 participants in the PRO-165 group and 5 of 15 in the Artelac® Nightime Gel group. The registry's comparison is expressed as a risk difference, with Artelac® Nightime Gel contrasted against PRO-165. The estimate and its uncertainty should be read together: the point estimate alone does not establish that the groups truly differ.

7. Results Posted in the Registry

• 1. Artelac® Nightime Gel: 33.3% (5/15) versus 18.8% (3/16) on control; risk difference 14.6 percentage points (95% CI -16.0 to 45.2), risk ratio 1.78 (0.51–6.18); unadjusted two-proportion z-test p = 0.354.

8. Statistical Interpretation

9. Statistical Methods Explained

The primary outcome is binary at the participant level: each participant is classified as having an adverse event or not having one during the stated evaluation period. The group summary is a count of participants with an event. To compare groups, the registry also reports each event count relative to the corresponding group size, then presents a risk difference. This keeps the comparison on an absolute scale: it describes the difference between the two groups' observed event proportions.

The direction of the posted risk difference is Artelac® Nightime Gel minus PRO-165. A positive estimate therefore means the observed event proportion is higher in the Artelac® Nightime Gel group. The estimate is a sample statistic: it describes the enrolled groups, while uncertainty reflects that different samples of participants could yield different observed proportions. The point estimate should not be interpreted without its confidence interval.

A confidence interval gives a range of values compatible with the observed data under the method's assumptions. It is not a guarantee that the true difference lies within that particular interval, nor is it a range containing a specified proportion of individual participants. For a risk difference, values below zero would correspond to a lower event proportion in the comparator group than in the PRO-165 group, while values above zero would correspond to a higher proportion in the comparator group. The posted interval crosses zero, so it is compatible with either direction and with no group difference.

The registry also posts an unadjusted p-value of 0.354. A p-value summarizes how unusual results at least as incompatible with the no-difference assumption would be, if that assumption and the test's assumptions held. It is not a measure of effect size, does not give the probability that the treatments are the same, and cannot by itself establish whether an observed difference matters. The record does not identify a broader adjustment strategy for this comparison, so the posted p-value should be understood as unadjusted.

General statistical context: comparisons of binary outcomes can be expressed in different ways. A risk difference is an absolute contrast between proportions; a risk ratio compares the proportions multiplicatively; and an odds ratio compares odds. These measures answer different questions and can have different numerical magnitudes. The registry posts a risk difference as the comparison of interest, as well as ratio measures. They should not be treated as interchangeable. The risk difference is particularly interpretable in terms of the absolute difference in the proportion of participants with an event, but its precision depends on the observed counts and group sizes.

General statistical context: with limited group sizes and few outcome events, estimates of binary outcome differences can be imprecise. Small changes in the event counts can affect the estimated contrast, and a wide interval can remain compatible with several plausible effects. This is one reason to read the interval and the raw counts together rather than interpreting a p-value as a complete summary of evidence.

The trial is described as randomized, double blind, and parallel group. Randomization is intended, in general, to reduce systematic differences between groups at assignment, while masking can reduce the influence of expectations on care or assessment. Those are general purposes of these design features; the registry does not report the sequence-generation or masking procedures, so their implementation cannot be evaluated from the record.

The analysis population is described only in part. The registry says that a PRO-165 participant who was lost after Visit 1 was included in the intention-to-treat population and considered for analysis. The term intention-to-treat generally refers to analyzing participants according to their assigned group, but the record does not provide enough detail to establish exactly how the missing outcome information was handled. It does not report imputation procedures, a missing-data sensitivity analysis, or a complete account of the analysis population for each outcome.

There are multiple registered outcome measures, including the primary adverse-event outcome and secondary measures of visual acuity, intraocular pressure, post-instillation symptomatology, tear breakup time, and epithelial defects. When many outcomes are tested, the chance of at least one apparently unusual result can increase. General statistical practice may address this through prespecified testing hierarchies or multiplicity adjustments, but the registry record does not report whether such procedures were planned or used. No multiplicity-adjusted result should be inferred from the unadjusted p-value.

The sample-size illustrations use a separate planning calculation based on the observed effect and specified assumptions. They are not a retrospective assessment of how likely this completed study was to detect an effect. More detail on those assumptions and how to interpret the planning values is given in the sample-size discussion.

10. Confidence Intervals and Precision

The posted risk-difference estimate is positive, with Artelac® Nightime Gel as the first group in the contrast and PRO-165 as the second. Its confidence interval extends across zero, from a negative bound to a positive bound. Consequently, the data do not pin down the direction of the underlying difference. The interval is also broad, so the estimate is not precise enough to distinguish a small difference from a substantially larger one with confidence.

In general, a confidence interval communicates both the direction and the uncertainty of an estimated contrast. For this comparison, the range includes values consistent with a lower event proportion in the comparator group as well as values consistent with a higher event proportion. Including zero means the range is also compatible with no difference. This is not proof that there is no effect; it indicates that the data do not resolve the comparison precisely.

The observed counts are 3 participants with adverse events in the PRO-165 group and 5 in the Artelac® Nightime Gel group. The uncertainty is important because an estimate based on a limited number of observed events can change appreciably with different outcomes in a small group. The confidence interval gives a more complete picture than the point estimate alone, but it remains conditional on the statistical method and its assumptions.

The registry also reports a p-value of 0.354 for the unadjusted comparison. That value does not measure precision in the same way as the interval, and it does not establish equivalence. No equivalence margin or non-inferiority margin is reported in the registry record. Therefore, the posted interval cannot be interpreted as a formal demonstration that the gels have similar effects.

These precision statements concern the recorded participant-level adverse-event outcome over the stated evaluation period. They do not quantify uncertainty for event severity, event recurrence, or unreported secondary outcomes.

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. For planning for 100% of the observed effect, the illustration gives 141 participants per arm for 80% power and 189 participants per arm for 90% power. For planning for 75% of the observed effect, it gives 240 participants per arm for 80% power and 321 participants per arm for 90% power. For planning for 50% of the observed effect, it gives 512 participants per arm for 80% power and 685 participants per arm for 90% power.

In general, power is the chance that a planned study will meet its statistical significance criterion if the assumed effect is present and the planning assumptions hold. The 80% power column describes the illustrative per-arm size associated with an 80% chance under those assumptions; the 90% power column describes the corresponding size for a 90% chance. Higher target power generally calls for more participants. The figures are based on equal allocation between arms, a two-sided significance level of 0.05, a normal approximation, and an effect set to the stated fraction of the observed effect. Smaller effects need more participants to detect than larger effects, which is reflected by the increasing planning figures as the assumed fraction becomes smaller.

These are planning illustrations computed from the observed effect, not the trial's original design calculations. The trial's own sample-size justification and original design assumptions are not reported in the registry record. This is not observed power; the figures do not measure the probability that this completed study detected an effect.

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 = 0.188; treatment proportion p₁ = 0.333; average p̄ = 0.260.
2. First term: z_1−α/2 × √[2p̄(1−p̄)] = 1.96 × 0.6206 = 1.2164.
3. Second term: z_1−β × √[p₀(1−p₀) + p₁(1−p₁)] = 0.842 × 0.6120 = 0.5151.
4. n = (1.2164 + 0.5151)² / (0.1458)² = 141.0, rounded up to 141 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 <- 0.1875                          # control proportion
p1 <- 0.333333333333333                          # 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(3697876)
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 = 141 (80% power), 189 (90% power)
 75% of observed effect: n per arm = 240 (80% power), 321 (90% power)
 50% of observed effect: n per arm = 512 (80% power), 685 (90% power)
power.prop.test: 141 
Simulated power at n = 141 per arm: 0.807 (20000 replicates)

The simulation draws many pairs of event counts at the planned sample size and counts how often the two-proportion z-test rejects the null. It should land close to the target power; at very small required sample sizes it can fall below it, because the normal approximation is rough there.

13. Multiplicity, Missing Data and Analysis Populations

The registry lists a primary adverse-event outcome and secondary measures of visual acuity, intraocular pressure, post-instillation symptomatology, tear breakup time, and epithelial defects graded according to the Oxford Scale. It lists seven outcome measures overall and five posted secondary outcomes. Results for the secondary outcomes are not included in the posted results described in this analysis, so their estimates and uncertainty are not reported in the registry record.

When investigators examine multiple outcomes or make multiple statistical comparisons, the possibility of a chance finding across the set can increase. General approaches include prespecifying a hierarchy of tests, adjusting significance thresholds, or treating secondary analyses as exploratory. The registry record does not report whether any such approach was specified or applied. The primary comparison's p-value is unadjusted; it should not be read as a multiplicity-adjusted result or as evidence that other outcomes were tested in a particular way.

The registry describes one participant in the PRO-165 group as lost during the study after attending Visit 1. It states that the participant was included in the intention-to-treat population and considered for analysis. The record does not explain how outcome data after the loss were obtained, whether any values were imputed, or how this participant's event status was determined for the full evaluation period. The treatment of missing outcome information is therefore not reported in the registry record.

The group counts posted for the primary outcome are 16 for PRO-165 and 15 for Artelac® Nightime Gel. The registry does not give a complete account of whether these denominators represent all randomized participants, participants with available outcome data, or a particular analysis set. It also does not report a per-protocol analysis or a sensitivity analysis addressing missing data. These gaps limit assessment of how robust the comparison is to analysis-population choices and incomplete follow-up.

The record notes the intention-to-treat inclusion of the lost participant but does not provide enough detail to assess how closely the analysis followed that principle. No further missing-data or multiplicity assumptions should be inferred.

14. Safety Results

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

Deaths

Other (non-serious) adverse events

Participants with at least one non-serious event at or above the registry's 0% reporting threshold.

Most frequent non-serious adverse event terms

The serious adverse event summary reports zero participants with serious adverse events in the PRO-165 group, among 16 participants at risk, and zero in the Artelac® Nightime Gel group, among 15 participants at risk. The registry also reports zero deaths in each group. No serious adverse event terms are listed.

These figures describe the recorded serious adverse event outcomes in this study. They do not mean that no adverse events of any kind occurred: the primary outcome records adverse events for 3 participants in the PRO-165 group and 5 in the Artelac® Nightime Gel group. The serious-event summary is a narrower category than the primary adverse-event count.

Zero observed serious events in these groups is not evidence that serious events are impossible or that a risk is absent. The summary is specific to the study population and evaluation period, which included the safety call on day 13. The registry does not report further details on the nature or severity of the non-serious adverse events, or provide a longer-term safety assessment.

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

The posted results show that adverse events were recorded for 3 participants assigned to PRO-165 and 5 assigned to Artelac® Nightime Gel during the stated evaluation period. The unadjusted risk-difference estimate is in the direction of a higher observed event proportion in the Artelac® Nightime Gel group. The confidence interval crosses zero and extends in both directions, making the comparison uncertain. The unadjusted p-value is 0.354.

These findings do not establish that the groups have the same safety profile. A non-significant result is not a formal demonstration of equivalence, and the registry does not report an equivalence margin, a non-inferiority margin, or a corresponding analysis. Nor do the observed counts establish that one gel causes more or fewer events. The comparison is descriptive and uncertain, especially given the limited number of recorded events and the interval around the estimate.

The primary endpoint records whether a participant had an event, not the number of episodes, the event's seriousness, or its duration. Separate serious-event figures report zero affected participants in each group and zero deaths, but those observations do not rule out uncommon risks or risks outside the evaluation period. The registry record does not provide the event-level descriptions needed to characterize the primary adverse events further.

The trial concerns the stated ophthalmological and clinically healthy subjects, the two gels and their stated dosing schedules, and the 13-day evaluation period including the safety call. The registry lists Dry Eye Syndromes as a condition, but does not provide further details about the enrolled participants. The results should not be extended beyond the population and setting described in the record.

In practical statistical terms, the comparison is compatible with more than one plausible group difference. The evidence is not precise enough to establish a clear direction, and it does not answer questions about longer-term outcomes, uncommon events, or the unreported secondary outcomes. No treatment recommendation follows from these data alone.

16. Why This Trial Matters Statistically

This trial is statistically informative as an example of why observed counts, effect estimates, and uncertainty need to be interpreted together. The primary outcome is easy to state: whether each participant experienced an adverse event during the evaluation period. The group counts provide a direct description, while the risk difference expresses the contrast between the observed group proportions on an absolute scale.

The point estimate alone could draw attention to the lower event count in the PRO-165 group, but the confidence interval changes the interpretation. Because it includes values on either side of no difference, the results do not settle which group has the higher underlying event proportion. The unadjusted p-value likewise should not be used as a pass-or-fail verdict or as proof that the groups are equivalent.

The study is described as exploratory and Phase I, and the primary comparison is based on a limited number of recorded events. These features make it especially important to distinguish descriptive findings from definitive conclusions. The safety-event counts and the serious-event summary also answer different questions: the primary endpoint includes adverse events generally, whereas the serious-event summary reports the serious category separately.

The record further illustrates the importance of transparent reporting about analysis populations and missing information. It identifies a participant lost during the study and says that this participant was considered in the intention-to-treat analysis, but does not describe the precise handling of missing outcome observations. It also does not report the statistical plan for multiple outcomes or an equivalence analysis despite the stated hypothesis of similarity.

Finally, the planning illustrations can help readers understand how assumed effect size and target power relate to required group sizes, but they are based on the observed effect and are not the original design justification. Keeping this distinction clear prevents a planning calculation from being mistaken for evidence about the completed study's ability to detect an effect.

17. Limitations

• The posted summary statistics are the only data these results rest on; patient-level data, full protocols and statistical analysis plans are not available.
• Recalculated results are simple, unadjusted calculations from posted summaries. They do not replace the sponsor's prespecified analysis.

The primary comparison is based on participant counts in groups reported as 16 for PRO-165 and 15 for Artelac® Nightime Gel. The registry lists enrollment as 32 but does not explain the relationship between that enrollment figure and the reported outcome denominators. It also reports one PRO-165 participant lost after Visit 1, included in the intention-to-treat population and considered for analysis, without explaining the handling of missing outcome information.

The confidence interval for the risk difference spans zero and includes values in both directions. This limits the precision of the comparison and means the posted estimate does not establish which group has the higher underlying event proportion. The unadjusted p-value does not resolve this uncertainty, and the record does not report a formal equivalence or non-inferiority analysis.

The primary outcome counts participants with an adverse event but does not provide a detailed account of event types, severity, timing, duration, or recurrence. Serious adverse events and deaths are reported separately, with zero in each group, but the registry record does not provide a longer follow-up safety assessment. The evaluation period was 13 days, including the safety call on day 13.

The study is described as exploratory, and the statistical details are limited. The record does not report the original sample-size justification, randomization procedures, masking procedures, multiplicity strategy, or complete analysis plan. It also lists secondary outcomes whose results are not included in the posted results. These omissions prevent a fuller assessment of the design and the consistency of findings across outcomes.

The population is described as ophthalmological and clinically healthy subjects, while Dry Eye Syndromes is listed as a condition. Eligibility details and additional population characteristics are not reported in the registry record. The findings therefore cannot be characterized more specifically or extended to other populations on the basis of this record alone.

18. Related Tutorials

19. Related Statistical Calculators

20. Sources

• ClinicalTrials.gov: Safety and Tolerability of the Ophthalmic Gel PRO-165 Versus Artelac® Nightime Gel — NCT03697876.
• Registry record last updated 2026-01-09; status last verified 2025-12.
• Results first posted 2026-01-09.
• 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.

21. Record Summary

The registry record describes NCT03697876, a completed randomized, double-blind, parallel-group Phase I study sponsored by Laboratorios Sophia S.A de C.V. It compared PRO-165 with Artelac® Nightime Gel in an exploratory study of safety and tolerability on the ocular surface of ophthalmological and clinically healthy subjects. Each group had the same stated dosing schedule.

The primary outcome counted participants with adverse events throughout the 13-day evaluation period, including the safety call on day 13. The posted counts were 3 of 16 for PRO-165 and 5 of 15 for Artelac® Nightime Gel. The unadjusted comparison has a p-value of 0.354, and its confidence interval for the risk difference spans zero. The record also reports zero participants with serious adverse events and zero deaths in either group.

The registry lists secondary outcomes, but their results are not reported in the posted results. It notes one PRO-165 participant lost after Visit 1 and included in the intention-to-treat population, without detailing the handling of missing observations. The record does not report the trial's original sample-size justification or a formal analysis establishing equivalence or similarity.