First-in-Human Study of LHA510 in Elderly Subjects and Patients With Age-Related Macular Degeneration: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for First-in-Human Study of LHA510 in Elderly Subjects and Patients With Age-Related Macular Degeneration (NCT02076919), a randomized phase 1 study. The primary outcome is Number of Subjects With a Serious Adverse Event That, in the Opinion of the Investigator, is Related to the Study Drug, Part 1.

2. Clinical Question

3. Trial Design

This was a Phase 1, randomized, double-masked, vehicle-controlled, parallel-group, first-in-human study. The registry record lists an enrollment of 110 and the status as completed. The study was designed to assess safety, tolerability, and pharmacokinetics of topically delivered LHA510 across single and multiple ascending doses. The registry record does not report the allocation ratio or the sequence-generation and concealment procedures.

The study had two parts with different dosing schedules. In Part 1, four LHA510 groups received one of four concentrations as a single drop in the study eye on one occasion. A vehicle group received a single drop. In Part 2, LHA510 groups received the assigned concentration once, twice, or three times daily for 7 days; the vehicle group followed corresponding schedules. The registry record does not report the detailed concentration values or the full assignment process among dose groups.

The primary endpoint was assessed in Part 1 and included all enrolled Part 1 subjects. The posted primary results give group sizes of 6.0 for each of the four LHA510 Part 1 groups and 8.0 for the Part 1 vehicle group. Those arm-specific figures describe the primary endpoint results; they should not be confused with the overall enrollment listed for the study.

Pharmacokinetic outcomes listed for Part 2 included maximum concentration, time to maximum concentration, area under the concentration-time curve through the last quantifiable concentration, and terminal elimination half-life. Blood-pressure changes were also listed among secondary outcomes. Although the study is completed, the registry record does not report the full protocol, detailed visit schedule, or a statistical analysis plan.

4. Participant Flow and Accounting

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

Before assignment: Of the 110 enrolled, 30 subjects were exited as screen failures prior to randomization. This reporting group includes all randomized subjects (80).

Overall Study

Analysis population for the primary outcome, as defined in the registry: This analysis population includes all enrolled subjects in Part 1.

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: This analysis population includes all enrolled subjects.

Only the first 6 of 13 groups are shown.

6. Primary Endpoint

The registry lists the primary outcome as Number of Subjects With a Serious Adverse Event That, in the Opinion of the Investigator, is Related to the Study Drug, Part 1, measured over From time of consent until 30 days after stopping the trial/study drug.

The primary endpoint counts participants with a serious adverse event that the investigator judged to be related to study drug during Part 1. The registry definition of serious adverse event includes events that are fatal or life-threatening, require or prolong hospitalization, cause significant or permanent disability or incapacity, constitute a congenital anomaly or birth defect, or are medically significant and may jeopardize the participant or require intervention to prevent one of those outcomes.

This endpoint is used to capture serious safety events while distinguishing them from events that are not considered serious. The investigator-related condition makes attribution part of the outcome definition: the count is not simply a count of every serious event, regardless of the investigator’s judgment. The registry record does not report the criteria or process used by investigators to make that attribution beyond identifying it as the investigator’s opinion.

The timeframe began at consent and extended until 30 days after stopping the trial or study drug. The primary population comprised all enrolled Part 1 subjects. Results are reported as participant counts by group, rather than as a comparative effect estimate. A count of zero in a group means no participant in that group was recorded with an event meeting this endpoint; it does not establish that the underlying risk is zero.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The primary outcome is binary at the participant level: each participant either had at least one event meeting the endpoint definition during the specified period or did not. The registry reports the number of participants with the event and the number in each group. These are counts, not rates per unit of follow-up time. The record does not report individual follow-up durations, so a time-adjusted event rate cannot be described from the posted information.

What does a zero event count mean?

A zero count means that no qualifying event was recorded for that group in the analyzed population. It is a statement about observed participants and the registry’s event classification. It is not a claim that the population risk is exactly zero. General statistical principle: estimates based on small groups are uncertain, and observing no events does not rule out a nonzero underlying risk. Confidence intervals are one way to express uncertainty around an estimate; no confidence intervals are reported for these primary results.

Why does investigator attribution matter?

The endpoint requires both seriousness and the investigator’s judgment that the event is related to study drug. An event can be serious without meeting the attribution condition, and an event can be an adverse event without being serious. General statistical principle: changing an outcome definition changes which observations count as events, so interpretation should stay tied to the precise definition. The registry record does not describe additional attribution rules, independent adjudication, or a blinded review process for event relatedness.

What can group comparisons establish?

The study was randomized and vehicle-controlled, features intended to support comparison of assigned groups. However, the posted primary outcome gives only arm-level counts, with no comparative estimate, confidence interval, or test result. The registry record also lists no analysis entries. It is therefore not possible to report a formal statistical comparison from the registry results. General statistical principle: a difference between groups is interpreted alongside uncertainty, study design, and the analysis plan; counts alone do not supply all of that information.

How should repeated-dose and pharmacokinetic outcomes be separated?

The primary safety endpoint applies to Part 1. Part 2 used repeated dosing for 7 days and included pharmacokinetic outcomes such as maximum concentration, time to maximum concentration, area under the concentration-time curve through the last quantifiable concentration, and terminal elimination half-life. These outcomes describe exposure and disposition, not the Part 1 serious-event endpoint. The registry record lists 10 posted secondary outcomes, but the listed outcome names and posted primary results do not provide enough information to infer numerical pharmacokinetic findings.

What does the planning framework represent?

The study’s sample-size planning illustration is described as a calculation based on the observed effect, using a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation. It is a planning illustration, not observed power and not a report of the study’s original design justification. The registry record does not report the protocol’s sample-size justification. General statistical principle: planning calculations describe the sample size associated with stated assumptions; they do not show the probability that a completed study has demonstrated an effect. The posted information does not give a numerical planning result for this endpoint in the registry record described by the registry.

For binary outcomes, sample-size calculations depend on assumptions about event probabilities and the effect to be detected. With no primary events observed in any group, an observed event contrast is not available for a meaningful event-based comparison. General statistical principle: calculations built around an observed effect should be interpreted cautiously, particularly when event counts are sparse or zero. The registry record does not report a separate prespecified power target, target event rate, or statistical test for the primary endpoint.

10. Exact Estimates for Each Arm

No two-arm comparison is shown for this trial, but each arm's result can still be summarized with exact interval estimates computed from the posted counts. The Clopper-Pearson interval is exact and conservative; the Wilson interval is a common closer-to-nominal alternative; the Bayesian credible interval uses a uniform Beta(1, 1) prior. For small groups the three can differ noticeably.

R code and output

arm    <- c("LHA510 Lowest, Part 1", "LHA510 Next Lowest, Part 1", "LHA510 Next Highest, Part 1", "LHA510 Highest, Part 1", "Vehicle, Part 1")
n      <- c(6, 6, 6, 6, 8)
events <- c(0, 0, 0, 0, 0)
for (i in seq_along(n)) {
  ci <- binom.test(events[i], n[i])$conf.int          # Clopper-Pearson exact interval
  cr <- qbeta(c(0.025, 0.975), 1 + events[i], 1 + n[i] - events[i])   # Bayesian, uniform Beta(1,1) prior
  wi <- (function(x, n) { p <- x / n; z <- qnorm(0.975); d <- 1 + z^2 / n
    c((p + z^2 / (2 * n) - z * sqrt(p * (1 - p) / n + z^2 / (4 * n^2))) / d, (p + z^2 / (2 * n) + z * sqrt(p * (1 - p) / n + z^2 / (4 * n^2))) / d) })(events[i], n[i])
  cat(sprintf("ARM|%s|%d|%d|%.1f|%.1f|%.1f|%.1f|%.1f|%.1f|%.1f\n", arm[i], n[i], events[i], 100 * events[i] / n[i],
              100 * ci[1], 100 * ci[2], 100 * wi[1], 100 * wi[2], 100 * cr[1], 100 * cr[2]))
}

ARM  LHA510 Lowest, Part 1  6  0  0.0  0.0  45.9  0.0  39.0  0.4  41.0
ARM  LHA510 Next Lowest, Part 1  6  0  0.0  0.0  45.9  0.0  39.0  0.4  41.0
ARM  LHA510 Next Highest, Part 1  6  0  0.0  0.0  45.9  0.0  39.0  0.4  41.0
ARM  LHA510 Highest, Part 1  6  0  0.0  0.0  45.9  0.0  39.0  0.4  41.0
ARM  Vehicle, Part 1  8  0  0.0  0.0  36.9  0.0  32.4  0.3  33.6

11. Multiplicity, Missing Data and Analysis Populations

The study lists multiple outcomes, including the primary serious adverse event count, pharmacokinetic measures, and blood-pressure changes. The registry record does not report a multiplicity adjustment or a hierarchy for interpreting tests across outcomes. It also does not report whether any interim analyses were planned or conducted. Without that information, the extent to which any statistical testing was adjusted for multiple comparisons is not reported in the registry record.

The primary analysis population is described as all enrolled subjects in Part 1. The registry record does not specify how missing observations, incomplete follow-up, withdrawals, or participants without complete safety data were handled. It does not report imputation procedures or sensitivity analyses. No inference should be made about those procedures from the reported group counts alone.

The registry record lists 14 outcome measures and 10 posted secondary outcomes, while the analysis count is 0. The record does not provide a statistical analysis plan explaining the distinction between outcome reporting and analysis entries. Numerical secondary outcome results and detailed analysis methods are not reported in the registry record for the information. The primary endpoint results are descriptive arm-level counts without posted inferential comparisons.

General statistical principle: missing-data methods and multiplicity choices can affect the interpretation of estimates and tests. Their absence from the registry record limits assessment of how these issues were handled; it does not establish that any particular method was or was not used outside the information recorded there.

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 non-serious adverse event terms

For the primary Part 1 endpoint, the registry reports 0.0 participants with an investigator-related serious adverse event in each LHA510 concentration group and in the vehicle group. The associated reported group sizes are 6.0 for each LHA510 group and 8.0 for vehicle. The observation window was from consent until 30 days after stopping the trial or study drug. These are observed counts, not estimates of zero risk.

The broader adverse-event listing distinguishes serious events from other adverse events. It reports zero serious events in the at-risk count for each listed group, while counts of other adverse events vary across groups. These broader counts should not be conflated with the primary endpoint, which also requires investigator attribution and applies specifically to Part 1. The registry record does not report death counts in the adverse-event listing.

Counts do not describe event duration, severity among non-serious events, or clinical course. The registry record does not provide detailed event narratives or uncertainty intervals for the counts. General statistical principle: sparse safety data are best read as a description of events observed during the recorded follow-up, not as a guarantee about events that could occur with different exposure or in a larger population.

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

The primary result answers a narrow question: how many enrolled Part 1 subjects had a serious adverse event judged by the investigator to be related to study drug during the recorded observation period? The registry reports zero such participants in every Part 1 group, including vehicle. The findings therefore describe an absence of recorded primary-endpoint events among the participants represented in those group counts.

The result does not establish that LHA510 has no serious risks. A zero count in a group does not prove zero underlying risk, especially when group sizes are limited. The registry record supplies no confidence intervals to indicate the range of uncertainty around the observed counts. It also does not report detailed event adjudication procedures, missing-data methods, or comparative statistical tests.

The findings do not show whether LHA510 is effective for age-related macular degeneration. The study is described as a first-in-human safety, tolerability, and pharmacokinetic study; the primary endpoint is a safety count, not a clinical efficacy outcome. Nor do the primary Part 1 findings establish the safety profile of repeated dosing in Part 2: the dosing schedule and study part differ, and the primary endpoint is specified for Part 1.

Interpretation should also distinguish serious adverse events from other adverse events. Counts of other events do not alter the definition of the primary outcome, and the registry does not provide enough detail to characterize their clinical importance. The posted results are informative about the events recorded under the stated definitions and timeframe, but they do not resolve questions about rare events, longer-term exposure, or outcomes beyond those recorded in the registry.

14. Why This Trial Matters Statistically

This trial illustrates a common statistical feature of early-phase safety studies: the primary endpoint may be an event count in relatively small dose groups, and the resulting data can be sparse. Here, the Part 1 primary counts are zero across the listed LHA510 concentration groups and vehicle. That pattern is easy to describe but does not yield a precise estimate of the underlying event risk or a useful observed contrast among groups.

The endpoint definition also matters. It combines seriousness with investigator attribution, so it represents a narrower outcome than all adverse events or even all serious adverse events. Keeping that definition in view prevents a broad safety conclusion from being drawn from a specific count. The separate counts of other adverse events provide context but do not substitute for the primary outcome.

Randomization, masking, and a vehicle comparator are relevant design features for interpreting group-level observations. Yet design features cannot replace information about uncertainty, analysis methods, follow-up completeness, and the treatment of multiple outcomes. Those details are not reported in the registry record. The record therefore supports a careful descriptive reading rather than a formal comparative conclusion.

Finally, sample-size planning and observed results answer different questions. A planning illustration based on assumptions is not observed power and does not turn a zero-event result into proof of safety. This distinction is important when interpreting early-phase findings intended to characterize tolerability and pharmacokinetics before broader conclusions are considered.

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 primary endpoint has zero observed events in every Part 1 group, leaving no observed event contrast for a comparative estimate. The group sizes reported for this outcome are small, and the registry record provides no confidence intervals or test results to quantify uncertainty. The findings therefore describe recorded observations rather than precise underlying risks.

The primary outcome is limited to investigator-related serious adverse events in Part 1. It does not represent all adverse events, all serious events regardless of attribution, or the full safety profile of repeated dosing. Part 2 used different dosing schedules, and the primary endpoint is not identified for that part. The registry record does not report detailed event narratives, the process for determining relatedness, or death counts in the adverse-event listing.

Further limitations include the absence of a reported statistical analysis plan, multiplicity procedures, interim-analysis information, missing-data handling, and detailed follow-up completeness. The record lists secondary outcomes, but does not provide numerical results for them in the information. It also does not report detailed participant characteristics, concentration values, or the protocol’s sample-size justification. These omissions limit assessment of precision, generalizability, and the full analysis approach; they should not be replaced by assumptions about what the protocol may have specified.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: First-in-Human Study of LHA510 in Elderly Subjects and Patients With Age-Related Macular Degeneration — NCT02076919.
• Registry record last updated 2016-04-01; status last verified 2016-03.
• Results first posted 2015-09-04.
• Data retrieved from ClinicalTrials.gov on 2026-11-09.
• Group sizes, means, event counts and sponsor-reported p-values are reproduced as posted. Effect estimates, confidence intervals and p-values not attributed to the sponsor are independently calculated from the posted summary statistics.

19. Record Summary

The registry record describes NCT02076919 as a completed Phase 1 randomized, double-masked, vehicle-controlled, parallel-group first-in-human study of topical LHA510. The study’s stated purpose was to assess safety, tolerability, and pharmacokinetics in elderly subjects and patients with age-related macular degeneration. Overall enrollment is listed as 110.

Part 1 compared four single-dose LHA510 concentration groups with vehicle. Part 2 evaluated repeated dosing for 7 days. The primary Part 1 endpoint counted participants with a serious adverse event considered related to study drug, from consent through 30 days after stopping study drug. The registry reports 0.0 participants meeting this endpoint in each Part 1 group.

The record does not report a formal comparative analysis, confidence intervals, a statistical analysis plan, or methods for missing data and multiplicity. The posted primary finding is therefore best read as a descriptive count within the stated population and follow-up period.