Efficacy and Safety of Ciprofloxacin Plus Fluocinolone Acetonide Otic Solution in the Treatment of Acute Otitis Externa: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Efficacy and Safety of Ciprofloxacin Plus Fluocinolone Acetonide Otic Solution in the Treatment of Acute Otitis Externa (NCT04636957), a randomized phase 3 study. The primary outcome is Clinical Cure.

2. Clinical Question

This is an active-controlled comparison: both groups received ciprofloxacin, while the intervention also included fluocinolone acetonide. The posted primary outcome therefore addresses the relative clinical-cure results for these two study regimens, rather than comparing treatment with no active treatment. The registry record also describes a pharmacokinetic objective in 12 selected adult subjects, alongside the efficacy and safety objectives. The primary outcome figures discussed in the posted results are for clinical cure, not the pharmacokinetic objective.

3. Trial Design

The registry identifies NCT04636957 as a completed Phase III study of treatment for acute otitis externa, sponsored by Lee's Pharmaceutical Limited. It describes a randomized, single-masked, parallel-group, active-controlled trial. The official title specifies evaluator-blinding; the record does not describe the masking procedures in further detail. Enrollment was 600. The recorded study start was 2021-01-04 and primary completion was 2021-10-17.

Participants were assigned to ciprofloxacin 0.3% plus fluocinolone acetonide 0.025% otic solution or ciprofloxacin 0.3% otic solution alone. The brief summary describes a 1:1 allocation and 7 consecutive days of treatment in either group. The primary outcome assessment was at End of Study (Visit 4, Day 15+2). The description also states that participants who achieved clinical cure at Visit 3 and completed the study early had their Visit 3 cure assessment carried forward to the end-of-study assessment.

The posted primary endpoint results use a Clinical Intent-to-Treat Population, defined in the record as all randomized participants who received at least one dose. The arm counts for this endpoint are 295 for the combination group and 297 for ciprofloxacin alone. These are the endpoint population counts, not a substitute for the total enrollment figure. The record lists secondary outcomes including microbiological cure, overall therapeutic cure, clinical improvement, changes in individual signs and symptoms, granulation tissue, ear pain, and time to the end of ear pain. Numerical findings for these secondary outcomes are not reported in the registry record.

The registry record does not report the planned allocation procedures in detail, the basis for the enrollment target, or the trial's original sample-size assumptions. It also does not give a fuller account of the analysis plan, including any model specification or planned interim analyses. Those details should not be inferred from the posted endpoint figures.

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: Among the 101 screening failures, 21 subjects did not meet inclusion criteria, 77 met exclusion criteria, 2 withdrew voluntarily, and 3 were excluded for other reasons.

Overall Study

Analysis population for the primary outcome, as defined in the registry: Clinical Intent-to-Treat Population (CITT), defined as all randomized participants who received at least one dose of study treatment.

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: Baseline characteristics were summarized for the Clinical Intent-to-Treat (CITT) Population, defined as all randomized participants who received at least 1 dose of study treatment. Of 600 randomized participants, 8 did not receive study treatment (5 in the combination arm and 3 in the ciprofloxacin arm) and were excluded. Therefore, 295 participants in the combination arm and 297 participants in the ciprofloxacin arm (592 total) were included in the baseline analysis.

6. Primary Endpoint

The registry lists the primary outcome as Clinical Cure, measured over End of Study (Visit 4, Day 15+2).

The primary endpoint is clinical cure at End of Study (Visit 4, Day 15+2). It counts participants who had a score of 0, or absent, for each of three signs or symptoms: edema, otorrhea, and ear tenderness. Investigators rated each item on a 4-point scale from 0 to 3, where 1 was mild, 2 was moderate, and 3 was severe. A score greater than 0 on any item was classified as clinical failure. Higher scores represented more severe symptoms and a worse outcome.

This definition turns the assessment into a binary outcome for each participant: either all three items meet the cure criterion or at least one item does not. The registry reports the number of participants with clinical cure in each group. For participants who achieved cure at Visit 3 and completed the study early, the Visit 3 assessment was carried forward to the end-of-study outcome.

In general, a defined clinical endpoint makes the outcome rule explicit and allows the groups to be compared using the same criteria. A clinical-cure endpoint captures the combined status of the three specified signs and symptoms at the assessment time; it does not, by itself, describe the course of each symptom or establish what happened after the study assessment. The endpoint population was the Clinical Intent-to-Treat Population, consisting of randomized participants who received at least one dose.

7. Results Posted in the Registry

• Ciprofloxacin 0.3%: 71.7% (213/297) versus 84.4% (249/295) on control; risk difference -12.7 percentage points (95% CI -19.3 to -6.1), risk ratio 0.85 (0.78–0.93); unadjusted two-proportion z-test p = <0.001.

8. Statistical Interpretation

9. Statistical Methods Explained

The primary outcome is binary: a participant either met the all-three-items cure criterion or was classified as a clinical failure. The registry reports counts of participants with cure and the corresponding endpoint population sizes for the two groups. This is a natural way to present a binary outcome because readers can see how many participants contributed to each group result, as well as the proportion represented by those counts.

What does the risk difference express?

In general, the risk difference compares the event proportions by subtracting one group proportion from the other. Its scale is the probability scale, so it describes an absolute contrast rather than a relative one. The registry reports a risk difference of -0.127 for ciprofloxacin alone relative to the combination group. The sign depends on the ordering of the groups in the comparison; in this record, the negative direction corresponds to the lower observed cure proportion for ciprofloxacin alone. The confidence interval for this contrast is -0.193 to -0.061.

A risk difference is often useful for interpreting an outcome because it describes the absolute separation between groups. It is specific to the outcome frequency in the populations being compared. A different baseline event frequency can lead to a different absolute contrast even when relative measures are similar. This is a general feature of effect measures, not a separate finding from this trial.

How do relative measures differ?

The registry also reports a risk ratio of 0.850 and an odds ratio of 0.468, each comparing ciprofloxacin alone with the combination group as coded. The risk ratio is a ratio of event probabilities. The odds ratio compares event odds, where odds relate the chance of an event to the chance of no event. These measures answer related but distinct questions and use different scales. In general, odds ratios can differ in magnitude from risk ratios when outcomes are not rare. The registry does not give a rare-outcome assumption for interpreting the odds ratio, so its value should not be read as if it were a risk ratio.

The reported confidence interval for the risk ratio is 0.779 to 0.927; for the odds ratio it is 0.313 to 0.701. In general, confidence intervals describe uncertainty around an estimate under the statistical method used. The null value is 1 for ratios, whereas it is 0 for a difference. Both reported ratio intervals lie below 1, and the reported risk-difference interval lies below 0. These observations describe the posted intervals; they do not replace consideration of the chosen analysis and its assumptions.

What does the p-value add?

The registry reports an unadjusted p-value of <0.001 for the comparison. In general, a p-value measures how unusual data at least as incompatible with a specified null hypothesis would be if that null hypothesis and the test assumptions held. It is not a measure of the probability that the null is true, nor a direct measure of effect size. The registry record does not report the details needed to identify the test specification beyond the posted comparison and its unadjusted label. No additional model or adjustment should be presumed.

How should the analysis population be understood?

The primary outcome population is defined as randomized participants who received at least one dose. This definition makes receipt of treatment part of inclusion in the endpoint population, so it is not identical by definition to every person randomized. The arm-specific endpoint counts are 295 and 297. The record does not report a detailed participant flow or describe the handling of every possible missing assessment. It does describe one specific rule: for participants who achieved clinical cure at Visit 3 and completed the study early, the Visit 3 cure assessment was carried forward to End of Study.

In general, carrying a prior assessment forward substitutes that earlier measurement for the later endpoint for the cases covered by the rule. Such a rule affects how the endpoint is defined for those participants and should be considered when interpreting the results. The registry does not report how many participants were affected by this rule or whether other missing-data approaches were used.

What analysis details are unavailable?

The posted comparison includes the estimate, confidence intervals, and unadjusted p-value, but the registry record does not report the full statistical analysis plan, the named statistical test or model, covariate adjustment details, or interim-analysis procedures. It also does not report the original sample-size justification. The separate sample-size planning figures are illustrations based on the observed effect, not evidence about the trial's original design or its achieved probability of detecting an effect.

In general, the meaning of an estimate depends both on the outcome definition and on the population and analysis rules used to obtain it. Here, the endpoint definition, the stated Clinical Intent-to-Treat Population, and the posted group counts provide important context. The reported measures should be interpreted with those features and the unreported analysis details in mind.

10. Confidence Intervals and Precision

The primary risk-difference estimate is -0.127, with a confidence interval from -0.193 to -0.061. This interval communicates uncertainty around the estimated contrast: values throughout the interval are more compatible with the data under the method used than values far outside it, but the interval does not assign a probability to each possible true effect. In general, a confidence interval is a range produced by a statistical procedure that would have a stated coverage property over repeated use when its assumptions hold.

For this outcome, the reported interval is entirely below zero, the null value for a risk difference. The posted risk-ratio interval, 0.779 to 0.927, is also entirely below its null value of 1. The odds-ratio interval is 0.313 to 0.701. These intervals express precision on different scales; they are not interchangeable. The risk-difference interval is especially useful for seeing uncertainty in the absolute contrast, while the ratio intervals describe relative contrasts.

The intervals do not capture every source of uncertainty. In general, they reflect sampling variability under the calculation method, not uncertainty caused by endpoint choices, missing assessments, measurement practices, or differences between the trial population and another population. The registry record does not provide enough detail to assess all such sources. The primary outcome includes the stated carry-forward rule for early completers who achieved cure at Visit 3, and the record does not report how many participants were affected.

The posted estimates are based on 295 participants in the combination group and 297 in the ciprofloxacin-alone group. A confidence interval should be read together with the endpoint definition, analysis population, and the limitations of the reported analysis details, rather than as a standalone measure of certainty.

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 sample-size figures are planning illustrations based on the observed effect, not the trial's original design assumptions. The registry record does not report the original sample-size justification. These figures use a two-sided significance level of 0.05, equal allocation between the two arms, and a normal approximation; the effect to detect is the stated fraction of the observed effect. The entries are participants per arm, not total participants or total events.

The 80% power column gives the number of participants per arm in the illustration for a design with an 80% chance of detecting the specified effect under the stated assumptions, if that effect were the true one. The 90% power column gives the corresponding number for a 90% chance. These are planning concepts: they describe the operating characteristics of a hypothetical study design under assumptions, rather than the probability that the observed finding is correct. This is not observed power.

The rows consider planning for 100% of the observed effect, 75% of the observed effect, and 50% of the observed effect. The figures increase as the assumed effect becomes smaller: a smaller difference is harder to distinguish from random variation, so a larger sample is generally needed to reach the same planned power under otherwise comparable assumptions. The figures do not establish that the original trial was designed using these assumptions, and they should not be treated as the trial's actual enrollment target calculation.

The registry enrollment was 600, while the primary endpoint counts were 295 and 297. Those observed counts and the planning illustrations answer different questions: the first describe the recorded trial population, while the latter illustrate sample sizes for hypothetical future planning based on the observed contrast.

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 = 0.844; treatment proportion p₁ = 0.717; average p̄ = 0.781.
2. First term: z_1−α/2 × √[2p̄(1−p̄)] = 1.96 × 0.5852 = 1.1470.
3. Second term: z_1−β × √[p₀(1−p₀) + p₁(1−p₁)] = 0.842 × 0.5783 = 0.4867.
4. n = (1.1470 + 0.4867)² / (-0.1269)² = 165.8, rounded up to 166 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 <- 0.84406779661017                          # control proportion
p1 <- 0.717171717171717                          # 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(4636957)
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 = 166 (80% power), 222 (90% power)
 75% of observed effect: n per arm = 280 (80% power), 375 (90% power)
 50% of observed effect: n per arm = 594 (80% power), 794 (90% power)
power.prop.test: 165.8 
Simulated power at n = 166 per arm: 0.806 (20000 replicates)

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

13. Multiplicity, Missing Data and Analysis Populations

The registry lists seven secondary outcomes: microbiological cure, overall therapeutic cure, clinical improvement, improvement in each sign and symptom, improvement in granulation tissue, improvement of ear pain, and time to the end of ear pain. It also records eight outcome measures. Numerical findings for the listed secondary outcomes are not reported in the registry record, so their results cannot be interpreted alongside the primary endpoint from the posted information.

Multiplicity arises when several outcomes, time points, subgroups, or comparisons are tested. In general, conducting many statistical tests can increase the chance of at least one apparently unusual result even if none of the underlying effects is real. Researchers may address this through a prespecified hierarchy, adjustment procedure, or other strategy. The registry record does not report whether any multiplicity strategy was planned or used. The primary comparison is labeled unadjusted; no family-wise adjustment or hierarchy should be inferred.

The primary population is the Clinical Intent-to-Treat Population, defined as randomized participants who received at least one dose. The registry record does not provide a full account of missing endpoint data or all analysis populations. It reports that participants who achieved clinical cure at Visit 3 and completed the study early had the Visit 3 assessment carried forward to End of Study. The number of participants covered by this rule, the handling of other missing assessments, and any sensitivity analyses are not reported in the registry record.

These omissions matter because endpoint definitions and missing-data rules can influence a binary outcome analysis. In general, sensitivity analyses test whether conclusions are robust to reasonable alternative assumptions about incomplete data. The registry record does not report such analyses. It also does not report a full statistical analysis plan, detailed interim-analysis procedures, or the original sample-size justification. Consequently, the posted primary result can be described as reported, but the available record does not permit a complete evaluation of prespecification, multiplicity control, or robustness to missing-data assumptions.

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 5% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: tuberculosis (0.3%), knee deformity (0.3%).

The registry reports serious adverse events for groups of 296 participants at risk in each arm. There were 2 serious adverse events in the ciprofloxacin-plus-fluocinolone group and 0 in the ciprofloxacin-alone group. The serious-event terms listed are Tuberculosis and Knee deformity, each recorded as 0.3%. The record reports 0 deaths in each group.

These are serious adverse event counts, not counts of all adverse events. The registry separately reports other adverse events affecting 34 participants in the combination group and 41 in the ciprofloxacin-alone group, each among 296 at risk. The serious-event counts should not be combined with those other-event counts: they are distinct registry categories, and the record does not provide further details about overlap or event-level timing.

In general, safety counts describe what was recorded in the study and are interpreted in relation to the number of participants observed and the definitions used. Small counts provide limited precision about uncommon events. The posted figures alone do not establish whether an event was caused by treatment, and they do not characterize risks beyond the trial population or observation period. The registry record does not report further detail about seriousness criteria, event adjudication, or causal assessments.

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

The result describes clinical cure as defined by the trial: scores of 0 for edema, otorrhea, and ear tenderness at End of Study (Visit 4, Day 15+2), with any score greater than 0 counted as failure. In the Clinical Intent-to-Treat Population, the posted cure counts were 249 of 295 for ciprofloxacin plus fluocinolone acetonide and 213 of 297 for ciprofloxacin alone. The reported risk difference for ciprofloxacin alone relative to the combination group was -0.127, with a confidence interval from -0.193 to -0.061 and an unadjusted p-value of <0.001.

These data describe the observed primary outcome contrast in this randomized, active-controlled trial. They do not by themselves establish that the same contrast would occur in other settings or populations. They also do not answer every question about symptom-specific change, microbiological outcomes, longer-term outcomes, or the balance of benefits and harms. Numerical results for the secondary outcomes are not reported in the registry record.

Statistical significance and clinical importance are different considerations. In general, a p-value addresses compatibility with a null hypothesis under a test's assumptions, while the effect estimate describes the magnitude and direction of the observed contrast. Whether a difference is important in a clinical context requires considerations beyond the p-value. The registry record does not state a threshold for clinical importance, so none should be inferred from the statistical result alone.

The confidence interval conveys uncertainty in the estimated contrast, but does not account for every possible limitation. The record's specific early-completion rule carried the Visit 3 cure assessment forward for participants who had achieved cure and completed the study early. The number of participants affected and the handling of other missing data are not reported. The record also does not report a full analysis plan or original sample-size justification. These features limit what can be concluded from the registry entry alone.

The safety counts are also descriptive. Serious adverse events were recorded in both the combination and ciprofloxacin-alone groups, with no deaths reported in either group. These counts do not establish causation, and uncommon events may be estimated imprecisely. The primary efficacy comparison and the safety counts therefore answer different questions and should be interpreted separately.

16. Why This Trial Matters Statistically

This trial presents a useful setting for understanding how a binary clinical endpoint can be summarized and compared. Clinical cure required all three assessed signs or symptoms to be absent, so a participant with any nonzero score was classified as a failure. This all-items rule is straightforward to state, but it also means the endpoint combines information across edema, otorrhea, and ear tenderness rather than reporting each item as the primary outcome.

The registry reports the primary result using event counts, group proportions, a risk difference, relative measures, confidence intervals, and a p-value. Reading these together illustrates why no single statistic tells the whole story. The risk difference gives an absolute contrast, while the risk ratio and odds ratio express relative contrasts on different scales. The confidence intervals indicate precision under the reported methods, and the p-value addresses a null comparison rather than the size or importance of the effect.

The comparison is active-controlled: both groups received ciprofloxacin, with fluocinolone acetonide included in one regimen. This makes the estimated contrast specific to those study regimens, outcome definitions, and assessment time. The trial also demonstrates why endpoint population definitions and missing-data rules matter. The stated population required randomization and at least one dose, and an early-completion carry-forward rule was used for a specified group of participants.

Finally, the record illustrates the difference between reported trial results and hypothetical planning calculations. The planning figures based on the observed effect are not the original design assumptions and are not observed power. The original sample-size justification and important elements of the statistical plan are not reported in the registry record. A careful interpretation can describe the posted result while keeping those limits explicit.

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 outcome is a combined clinical-cure classification based on three investigator-rated items. A participant was considered a failure if any one item had a score greater than 0. The endpoint therefore does not show, by itself, which individual sign or symptom contributed to a participant's classification. Although the registry lists secondary outcomes for symptom and sign improvement, numerical results for those outcomes are not reported in the registry record.

The primary results use the Clinical Intent-to-Treat Population, defined as randomized participants who received at least one dose. This definition excludes randomized participants who did not receive any dose, and the registry record does not give a detailed participant-flow account. Endpoint counts were 295 in the combination group and 297 in the ciprofloxacin-alone group, while the safety groups each had 296 participants at risk. The record does not explain the difference in these analysis denominators.

The registry specifies a carry-forward rule for participants who achieved clinical cure at Visit 3 and completed the study early. It does not report how many participants were handled this way, how other missing assessments were addressed, or whether sensitivity analyses were conducted. The full statistical analysis plan, test or model details, multiplicity procedures, interim analyses, and original sample-size justification are also not reported in the registry record.

The posted safety information gives event counts and selected serious-event terms, but does not provide further details about event timing, adjudication, or causal assessment. In addition, the primary endpoint is limited to the recorded end-of-study assessment. The registry record does not report follow-up findings beyond that assessment. These limitations constrain interpretation of the posted efficacy and safety figures and do not support extrapolation beyond the trial's stated outcome and population.

18. Related Tutorials

19. Related Statistical Calculators

20. Sources

• ClinicalTrials.gov: Efficacy and Safety of Ciprofloxacin Plus Fluocinolone Acetonide Otic Solution in the Treatment of Acute Otitis Externa — NCT04636957.
• Registry record last updated 2026-10-13; status last verified 2026-10.
• Results first posted 2026-10-13.
• 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

NCT04636957 is a completed Phase III randomized, single-masked, parallel-group, active-controlled trial of treatment for acute otitis externa. The official title describes evaluator blinding. Enrollment was 600; the recorded start was 2021-01-04 and primary completion was 2021-10-17. The regimens were ciprofloxacin 0.3% plus fluocinolone acetonide 0.025% otic solution and ciprofloxacin 0.3% otic solution alone, each for 7 consecutive days.

The primary outcome was clinical cure at End of Study (Visit 4, Day 15+2), based on absent edema, otorrhea, and ear tenderness. Cure was recorded for 249 of 295 participants in the combination group and 213 of 297 in the ciprofloxacin-alone group. The reported risk difference for ciprofloxacin alone relative to the combination group was -0.127, with a confidence interval from -0.193 to -0.061 and an unadjusted p-value of <0.001. The registry also reports serious adverse events and other adverse events by group; the record does not report numerical findings for the listed secondary outcomes.