Study Comparing SUBA™-Itraconazole With SPORANOX® (Itraconazole) in the Treatment of Onychomycosis: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Study Comparing SUBA™-Itraconazole With SPORANOX® (Itraconazole) in the Treatment of Onychomycosis (NCT00791219), a randomized phase 2 study. The primary outcome is Non-inferiority Will be Determined by Evaluating the Difference Between the Proportion of Patients in the Test and Reference Treatment Groups Who Are Considered a "Therapeutic Cure" at the End of Study Visit (Week 24).

2. Clinical Question

The clinical question therefore has two related but separate parts: whether the test formulation performs sufficiently close to the active reference under a specified non-inferiority margin, and whether either formulation differs from placebo. Those questions require different comparisons and should not be answered by treating the placebo contrast as if it were the direct active-treatment contrast.

3. Trial Design

This was a completed, randomized, double-blind, parallel-group phase 2 study sponsored by Halcygen Pharmaceuticals Limited. It enrolled 175 participants with onychomycosis. The registry lists the study start as 2008-11 and primary completion as 2010-07. Three groups received SUBA-itraconazole, SPORANOX (itraconazole), or placebo. The registry describes a multiple-site, placebo-controlled study, but the number or location of sites is not reported in the registry record.

The test regimen is described as 50 mg SUBA-itraconazole capsules taken at 100 mg approximately 30 minutes before breakfast for 12 weeks. The reference regimen is described as SPORANOX 100 mg capsules taken at 200 mg with breakfast. The placebo group took two placebo capsules approximately 30 minutes before breakfast. The registry identifies double masking but does not report which study roles were masked or how masking was maintained.

The primary outcome was therapeutic cure at Week 24, and the stated primary comparison was non-inferiority of the test group to the reference group. The registry also lists placebo superiority analyses and secondary cure outcomes at Week 12. The primary efficacy population required a positive baseline mycological culture, at least one dose, and at least one post-baseline evaluation. How this population relates to every randomized participant, and how participants were allocated to each group, are not reported in the registry record. The protocol’s full statistical analysis plan, the non-inferiority margin justification, and details of monitoring during the study are also 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 Efficacy evaluation was performed on the intent to treat population, which included all patients that met all the following criteria; positive baseline mycological culture, dosed with the study drug at least once and had at least one post-baseline evaluation

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 Non-inferiority Will be Determined by Evaluating the Difference Between the Proportion of Patients in the Test and Reference Treatment Groups Who Are Considered a "Therapeutic Cure" at the End of Study Visit (Week 24), measured over Week 24.

The primary endpoint counts participants considered a therapeutic cure at the Week 24 visit. The registry says the assessment was evaluated in an intent-to-treat population, which it defines as patients with a positive baseline mycological culture, at least one dose of study drug, and at least one post-baseline evaluation. The operational definition of therapeutic cure, including the clinical or laboratory criteria used to classify a participant, is not reported in the registry record.

The endpoint is binary at the participant level: each eligible participant is classified as meeting or not meeting the cure criterion. A count of participants meeting the criterion can be interpreted alongside the number assessed in each group, while a comparison of proportions describes the difference in observed event frequency. For a non-inferiority question, the key issue is not simply whether the observed results look similar. The estimate and its confidence interval must be considered relative to a prespecified margin, with the direction and scale of that margin clearly defined.

The record’s endpoint description refers to the difference between the test and reference proportions and states a lower-bound criterion involving 20. The scale and direction are not fully explained in the posted description. The registry reports a direct non-inferiority analysis, but the cure definition and detailed interpretation of the margin are not reported in the registry record.

7. Results Posted in the Registry

• Test: 10.5% (8/76) versus 0.0% (0/24) on control; risk difference 10.5 percentage points (95% CI 3.6 to 17.4); unadjusted two-proportion z-test p = 0.097.
• Reference: 4.1% (3/74) versus 0.0% (0/24) on control; risk difference 4.1 percentage points (95% CI -0.4 to 8.5); unadjusted two-proportion z-test p = 0.316.

8. Secondary Efficacy Endpoints

The registry also posts results for secondary outcomes. For each outcome below, the endpoint type, the test applied to the posted summary statistics, the result and its interpretation are given in turn. Secondary endpoints are usually not adjusted for multiple testing, so they support rather than confirm the primary finding.

Non-inferiority Will be Determined by Evaluating the Difference Between the Proportion of Patients in the Test and Reference Treatment Groups Who Are Considered a "Clinical Cure" at the End of Study Visit (Week 12)

• Endpoint type: Binary: the number of participants with the event, compared as proportions.
• Test: Unadjusted two-proportion z-test, with a Wald 95% confidence interval for the risk difference.
• Result:
  • Test: 1.3% (1/76) versus 0.0% (0/24) on control; risk difference 1.3 percentage points (95% CI -1.2 to 3.9); unadjusted two-proportion z-test p = 0.572.
  • Reference: 0.0% (0/74) versus 0.0% (0/24) on control; risk difference 0.0 percentage points (95% CI 0.0 to 0.0); unadjusted two-proportion z-test p = n/a.
• Interpretation:
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between Test and the control. The interval gives the range of effects that remain compatible with the data.
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between Reference and the control. The interval gives the range of effects that remain compatible with the data.

Non-inferiority Will be Determined by Evaluating the Difference Between the Proportion of Patients in the Test and Reference Treatment Groups Who Are Considered a "Mycological Cure" at the End of Study Visit (Week 12)

• Endpoint type: Binary: the number of participants with the event, compared as proportions.
• Test: Unadjusted two-proportion z-test, with a Wald 95% confidence interval for the risk difference.
• Result:
  • Test: 21.1% (16/76) versus 12.5% (3/24) on control; risk difference 8.6 percentage points (95% CI -7.5 to 24.6), risk ratio 1.68 (0.54–5.29); unadjusted two-proportion z-test p = 0.352.
  • Reference: 21.6% (16/74) versus 12.5% (3/24) on control; risk difference 9.1 percentage points (95% CI -7.1 to 25.3), risk ratio 1.73 (0.55–5.43); unadjusted two-proportion z-test p = 0.326.
• Interpretation:
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between Test and the control. The interval gives the range of effects that remain compatible with the data.
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between Reference and the control. The interval gives the range of effects that remain compatible with the data.

The secondary outcomes extend the assessment beyond the primary Week 24 therapeutic-cure comparison. They include clinical cure and mycological cure at Week 12, and the registry identifies additional cure outcomes among its posted measures. In the available secondary results, the patterns differ by outcome: clinical-cure events are rare, while mycological-cure counts are more frequent and similar in the two active groups. The placebo group also has recorded mycological-cure events. These observations do not replace the primary endpoint or establish the primary non-inferiority criterion.

The Week 12 outcomes use a different assessment time from the primary Week 24 outcome. Differences in endpoint definition and timing mean that apparent agreement or disagreement across outcomes should not be treated as a direct replication of the primary result. The detailed operational definitions for clinical cure, mycological cure, and therapeutic cure are not reported in the registry record, limiting assessment of how the classifications relate to one another.

The registry posts a non-inferiority analysis for the test-versus-reference mycological-cure comparison, with a reported value of -0.57 and a 95% confidence interval lower bound of -12.91. Its upper confidence limit is not reported. The record does not post an explicit conclusion for that analysis. For the clinical-cure outcome, no sponsor-reported comparison analysis is listed. The recalculated placebo comparisons are unadjusted and should not be confused with those sponsor analyses.

Unadjusted secondary results carry less weight than a prespecified primary analysis because multiple outcomes and contrasts increase the opportunity to observe apparently notable results by chance. Whether and how the study controlled multiplicity is not reported in the registry record. Secondary endpoints can be informative about the breadth and consistency of observed patterns, but they are not independent confirmations merely because several outcomes are listed. Interpretation should account for the different definitions, visit times, sparse counts, and missing detail about the analysis plan.

Secondary outcomes registered for this trial, for reference (only those above were recalculated):

• The Proportion of Patients in Each Treatment Group Who Are Considered a "Therapeutic Cure" at the End of Treatment Visit (Week 12) 12).
• Non-inferiority Will be Determined by Evaluating the Difference Between the Proportion of Patients in the Test and Reference Treatment Groups Who Are Considered a "Clinical Cure" at the End of Study Visit (Week 12)
• Non-inferiority Will be Determined by Evaluating the Difference Between the Proportion of Patients in the Test and Reference Treatment Groups Who Are Considered a "Mycological Cure" at the End of Study Visit (Week 12)

9. Statistical Interpretation

10. Statistical Methods Explained

What does a risk difference describe?

For a binary outcome, a risk difference is the difference between the proportions of participants with the event in two groups. A positive estimate means the event proportion is higher in the first group as defined for that comparison; a negative estimate means it is lower. The registry’s recalculated risk differences compare each active group with placebo. They are simple, unadjusted comparisons based on posted counts and group sizes. They are not the primary test-versus-reference non-inferiority estimate.

The meaning of a risk difference depends on the outcome being counted and on the order of groups in the contrast. Here the event is being classified as therapeutic cure. The recalculated placebo contrasts can describe how the observed cure proportions differ, but they do not incorporate an adjustment for other variables or resolve whether the active treatments are sufficiently similar under a non-inferiority margin. No adjusted model is reported in the registry record.

How should a p-value be read?

A p-value describes how compatible the observed data are with a specified statistical null model, under the assumptions of the test. It is not the probability that the null hypothesis is true, and it is not a measure of the size or clinical importance of an effect. The unadjusted p-values of 0.097 and 0.316 belong to the recalculated active-versus-placebo contrasts. They should not be attributed to the sponsor’s direct non-inferiority comparison, for which the registry does not post a p-value.

The registry separately records a one-sided continuity-corrected Z-test for superiority comparing placebo with the test group, with p < 0.05. This is a sponsor-reported superiority analysis, not the direct active-treatment non-inferiority comparison. A continuity correction is a method adjustment used in some tests of proportions to account for the discrete nature of binary counts when using a normal approximation. The record does not give enough detail to reconstruct that analysis independently.

What makes non-inferiority different?

Non-inferiority asks whether the test treatment is not worse than the active reference by more than a prespecified margin. This is not the same as testing whether a difference is exactly zero, and it is not established merely because a conventional test fails to find a statistically significant difference. The margin is central: it defines how much difference the study would accept while still describing the test treatment as non-inferior. Its clinical and statistical justification is not reported in the registry record.

Confidence-interval interpretation in a non-inferiority analysis depends on the direction of the contrast, the signed margin, and the rule set in advance. The registry’s primary description says the lower bound must be greater than 20, while the reported analysis lists a parameter of -20 and a lower confidence bound of -1.77. Without a clear explanation of scale and sign convention, those entries cannot be reconciled confidently from the registry record alone. The direct comparison is still the relevant sponsor analysis, but its interpretation should not be expanded beyond what is explicitly documented.

What does the confidence interval add?

A confidence interval gives a range of values compatible with the data under the statistical procedure used. It conveys uncertainty around an estimate, not a guarantee that the true value lies in that particular interval. Narrower intervals generally indicate greater precision, while wider intervals indicate more uncertainty. For binary outcomes with few events, intervals can be broad even when the point estimate is notable. The confidence intervals in the recalculated placebo comparisons should be read as uncertainty ranges for those contrasts, not for the primary test-versus-reference comparison.

What can planning illustrations tell us?

The registry includes planning illustrations for the mycological-cure comparison. They use fractions of the observed effect and state assumptions of a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation. The listed values are participants per arm for 80% power and participants per arm for 90% power. For planning at 100% of the observed effect, the test-versus-placebo illustration lists 299 participants per arm for 80% power and 400 for 90% power; the reference-versus-placebo illustration lists 266 and 356. The illustrations also list planning for 75% and 50% of the observed effect.

These are hypothetical design illustrations based on observed results, not the study’s original sample-size justification and not observed power. They do not show that the trial was planned using these assumptions. The actual sample-size calculation, target effect, allowance for attrition, and power objective are not reported in the registry record. Because the illustrations use observed effects, they should be treated as exploratory planning aids rather than definitive design recommendations.

11. Confidence Intervals and Precision

Precision is conveyed by the width of a confidence interval as well as by the point estimate. In general, a wider interval leaves more uncertainty about the magnitude and possibly the direction of an effect. For binary outcomes with sparse events, estimates can vary substantially with only a few participants changing classification. This matters for the Week 24 endpoint, where the observed cure counts are small relative to the group sizes.

The recalculated risk-difference interval for test versus placebo excludes zero, while the reference-versus-placebo interval includes zero. The corresponding unadjusted p-values are 0.097 and 0.316. These intervals concern separate placebo contrasts; they do not express the precision of the primary test-versus-reference non-inferiority estimate. Their interpretation should remain tied to the specific contrast and recalculation from which they arose.

For the sponsor-reported primary non-inferiority analysis, the registry gives a value of 6.47 and a 95% confidence interval with a lower bound of -1.77, but no upper confidence limit is posted. Without the full interval and a clear account of the margin’s sign and scale, the interval cannot be fully assessed against the stated decision rule. The non-inferiority margin’s rationale and the detailed method used to form the interval are not reported in the registry record.

Confidence intervals are not measures of clinical importance, and a wide interval does not prove that there is no difference. It indicates that the data are compatible with a range of possible effects. Conversely, a point estimate alone can appear more decisive than the uncertainty warrants. The sparse event counts and incomplete reporting of the primary interval make precision an important constraint on interpretation.

12. Analyses Reported by the Sponsor

The registry reports the sponsor’s direct comparison of the test and reference groups for Week 24 therapeutic cure as a non-inferiority analysis. It lists a value of 6.47, a 95% confidence interval lower bound of -1.77, and a margin-related parameter of -20. The registry’s endpoint description separately says non-inferiority would be demonstrated if the lower bound were greater than 20. The record does not explain the apparent difference in sign or scale between that wording and the reported parameter, nor does it post the upper confidence limit.

The sponsor’s analysis addresses the primary active-treatment comparison. The recalculated risk differences instead compare each active group with placebo, so those calculations neither reproduce nor challenge the sponsor’s non-inferiority analysis. The registry also lists a sponsor-reported one-sided continuity-corrected Z-test for superiority of the test group compared with placebo, with p < 0.05. That result answers a different comparison question.

The posted result fields do not include an explicit statement that the non-inferiority criterion was met or not met. The reported analysis should therefore be described as the sponsor’s direct result, with its estimate and available interval information, while avoiding a definitive conclusion that the registry record itself does not state. The detailed analysis method, margin justification, and interpretation convention are not reported in the registry record.

13. Multiplicity, Missing Data and Analysis Populations

The registry lists seven outcome measures and nine analyses. It describes a primary Week 24 therapeutic-cure non-inferiority question, placebo superiority testing, and secondary Week 12 cure outcomes. When several endpoints and comparisons are examined, the chance of at least one apparently notable result can increase. Statistical approaches to multiplicity can control or describe that issue, but the multiplicity strategy is not reported in the registry record. It is therefore not possible to determine from the posted record whether the secondary analyses were adjusted, hierarchically ordered, or treated as exploratory.

The registry defines the primary efficacy population using three conditions: a positive baseline mycological culture, at least one dose of study drug, and at least one post-baseline evaluation. This is the population described for the efficacy evaluation. The record does not state how participants who were randomized but did not meet these criteria were handled in the primary analysis, or whether additional analysis populations were used. The name intent-to-treat should not be taken as evidence that every randomized participant was included, given the specific eligibility conditions stated in the record.

Missing outcome data can affect binary cure analyses, particularly if the probability of missingness differs between groups or relates to the outcome. The registry does not report the number of participants with missing Week 24 results, the approach used to handle missing outcomes, or sensitivity analyses for alternative assumptions. Details about withdrawals and reasons for missing assessments are not reported in the registry record. Without that information, the impact of missing data on the estimates cannot be evaluated.

The record also does not report the full prespecified analysis plan, the timing of any interim analyses, the sample-size justification, or the method used to select the non-inferiority margin. These are distinct from the posted outcome summaries. Their absence does not establish that the trial lacked such procedures; it means their details are not reported in the registry record. The available evidence supports description of the posted analyses, but not assumptions about unreported design or analysis decisions.

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 2% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: lumbar spinal stenosis (1.3%), pulmonary embolism (1.3%), intervertebral disc protusion (1.3%).

The safety results list serious adverse events for the groups with denominators of 24 for placebo, 76 for the test group, and 75 for the reference group. The recorded serious adverse events were 0, 2, and 1, respectively. No deaths are listed in any of these groups. The safety denominator for the reference group differs from the efficacy group size, so the two sets of results should not be treated as using identical analysis populations.

The registry lists lumbar spinal stenosis, pulmonary embolism, and intervertebral disc protusion among the top serious-event terms, each reported as 1.3%. The record does not identify group attribution for those terms in the posted summary. It also lists other, non-serious adverse events affecting 13 participants in placebo, 42 in the test group, and 35 in the reference group. These counts describe recorded events and do not by themselves establish that an event was caused by treatment.

Serious adverse events are uncommon in the posted counts, so comparisons are imprecise and should be interpreted descriptively. The registry record does not provide event-level timing, duration, severity details beyond the serious classification, or a causal assessment in this summary. The safety figures should not be combined with efficacy findings to make a treatment recommendation.

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

The results establish what the registry records for this trial: observed cure counts in three randomized groups, a sponsor-reported direct non-inferiority analysis, recalculated active-versus-placebo contrasts, secondary outcomes, and adverse-event counts. They do not by themselves settle whether the test formulation met the non-inferiority criterion. The primary result requires interpreting the direct test-versus-reference estimate and its confidence interval against the prespecified margin, but the registry’s wording and signed values are not fully aligned in the posted description.

The calculated placebo comparisons answer a separate question. Their point estimates and unadjusted p-values describe the observed active-versus-placebo contrasts, not the difference between the two itraconazole formulations. A comparison that is statistically notable against placebo cannot establish non-inferiority to an active reference, and an imprecise placebo comparison cannot be used to conclude that the groups are equivalent.

Nor do the posted counts establish a general statement about all patients with toenail onychomycosis. The primary efficacy population had specific baseline and post-baseline requirements, and the registry record does not report all details needed to assess representativeness or missing data. The results also concern the study’s particular regimens and assessment times; the record does not justify extending them to other doses, schedules, populations, or outcomes.

Confidence intervals communicate statistical uncertainty, while the non-inferiority margin expresses the largest difference considered acceptable under the study’s rule. Neither a point estimate nor a p-value alone conveys the full balance of those considerations. The record omits the margin rationale, the complete primary interval, and an explicit sponsor conclusion. The appropriate meaning is therefore bounded: the posted results describe observations and analyses, while important details needed for a full assessment of the primary decision are not reported in the registry record.

16. Why This Trial Matters Statistically

This trial illustrates why non-inferiority questions must be read differently from ordinary tests for a difference. Similar-looking arm counts are not enough to demonstrate non-inferiority; the analysis must use a prespecified margin, a clearly oriented contrast, and an uncertainty interval that can be evaluated against that margin. The registry’s direct active-treatment analysis is consequently more relevant to the primary question than the recalculated placebo contrasts, even though the latter are easier to reconstruct from posted counts.

It also demonstrates how sparse binary outcomes affect interpretation. The primary cure counts are small, so each event contributes appreciably to the observed proportion. Point estimates can appear separated while remaining uncertain, and a confidence interval is essential for judging precision. The secondary outcomes add context but also introduce multiple endpoints and different assessment times, making an unadjusted result less decisive than a prespecified primary analysis.

Finally, the record shows the value of transparent reporting. A non-inferiority margin, its sign convention, complete confidence interval, population definition, missing-data handling, and multiplicity strategy all shape how results should be understood. Several of those details are not reported in the registry record. That absence calls for restrained interpretation, not an assumption that the underlying study procedures were absent. For clinical researchers and biostatisticians, the case is a reminder to distinguish the sponsor’s direct analysis from recalculations and to make the contrast, margin, and target population 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.

Several trial-specific reporting gaps limit independent assessment. The registry gives the primary therapeutic-cure endpoint and a brief decision rule, but it does not report the operational cure criteria. Without those definitions, it is difficult to assess exactly what clinical and laboratory findings qualified a participant as cured or how the Week 24 classification relates to the Week 12 clinical and mycological outcomes.

The primary non-inferiority result is incomplete for interpretation: the reported value is 6.47, the 95% confidence interval lower bound is -1.77, and the upper bound is not reported. The record lists a margin-related parameter of -20, while the endpoint description uses a lower-bound rule greater than 20. The record does not explain the scale or sign convention that connects these entries. The rationale for the margin and the detailed method used for the primary analysis are not reported in the registry record.

The efficacy population definition is stated, but the handling of participants outside that definition, missing Week 24 outcomes, withdrawals, and alternative analysis populations is not reported. Nor are the multiplicity strategy, full protocol analysis plan, interim-analysis details, or original sample-size justification reported. These omissions restrict evaluation of the robustness and prespecification of the reported analyses.

The randomized, double-blind description and the listed regimens give useful design context, but masking procedures, allocation details, and site information are not reported. Safety summaries have a different reference-group denominator from the efficacy results, and the posted serious-event terms lack group attribution. These limitations do not erase the observed results, but they constrain how far the results can be independently checked or generalized.

18. Related Tutorials

19. Related Statistical Calculators

20. Sources

• ClinicalTrials.gov: Study Comparing SUBA™-Itraconazole With SPORANOX® (Itraconazole) in the Treatment of Onychomycosis — NCT00791219.
• Registry record last updated 2020-08-25; status last verified 2020-08.
• Results first posted 2020-08-25.
• 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

NCT00791219 is a completed randomized, double-blind, parallel-group phase 2 study of SUBA-itraconazole, SPORANOX (itraconazole), and placebo in toenail onychomycosis. The registry lists enrollment of 175 and a primary Week 24 therapeutic-cure non-inferiority comparison between the test and reference groups. The primary efficacy population required a positive baseline mycological culture, at least one dose, and at least one post-baseline evaluation.

The posted primary counts are 8 of 76 in the test group, 3 of 74 in the reference group, and 0 of 24 in placebo. The sponsor-reported non-inferiority result lists a value of 6.47 and a 95% confidence interval lower bound of -1.77, but does not include an upper bound or an explicit conclusion. Recalculated placebo contrasts are separate from that direct comparison. Details about the margin convention, missing data, multiplicity, and several analysis methods are not reported in the registry record.