A Clinical Study to Evaluate the Pharmacokinetics of Testosterone Gel Using an Applicator: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for A Clinical Study to Evaluate the Pharmacokinetics of Testosterone Gel Using an Applicator (NCT01464879), a non-randomized phase 2 study. The primary outcome is Responder Rate: Percentage of Subjects Whose Average Steady State Concentration (Cavg) of Serum Total Testosterone Levels Are Between 300 and 1050 ng/dL Following Treatment With Each of Three Volumes of FE 999303 Applied With an Applicator..

2. Clinical Question

The focus is pharmacokinetics: how testosterone concentrations are represented over time after gel application. The responder measure reduces the concentration information to whether Cavg falls within a specified range. That makes the endpoint understandable as a proportion, but it does not show the full distribution of concentrations or how close individual values are to either boundary.

The title describes a Phase 2, open-label, sequential dose escalation study. The registry lists no masking and nonrandomized allocation. Accordingly, the central statistical question is descriptive: what response proportions and pharmacokinetic profiles were recorded under the listed application conditions? A randomized treatment-effect question cannot be answered from this design description alone.

Although the study includes hand application as a reference condition, the registry record does not describe a randomized comparison. Differences between conditions, if reported, would therefore need cautious interpretation. Numerical primary-outcome results are not reported in the registry record, so the responder proportions and their precision cannot be assessed from the posted results.

3. Trial Design

This is a Phase 2 study sponsored by Ferring Pharmaceuticals. The record lists the study as completed, with an enrollment of 20, a start date of 2011-12, and primary completion in 2012-05. Its official title describes an open-label, sequential dose escalation design in adult hypogonadal males. The registry also classifies allocation as nonrandomized, masking as none, and the model as single group.

The intervention was testosterone gel (FE 999303). The arm descriptions identify four application conditions: 2.50 mL by hand; 1.25 mL by applicator; 2.50 mL by applicator; and 3.75 mL by applicator. Each description specifies self-application to the shoulder or upper arm every day for seven days. For the 2.50 mL hand condition, one stroke was applied to each shoulder or upper arm. The applicator instructions describe one, two, or three strokes according to the volume.

These descriptions do not establish that participants were assigned randomly to independent groups. The record's sequential-dose-escalation title and single-group classification should be read alongside its four condition descriptions rather than treated as evidence of a parallel randomized trial. The exact order in which participants received conditions, and any washout or other transition procedures, are not reported in the registry record.

The primary endpoint was a responder rate based on Cavg of serum total testosterone, with the stated target range of 300 to 1050 ng/dL for each applicator volume. Its timeframe lists Days 15-21, Days 22-28, and Days 29-35. Secondary outcomes include a hand-application responder rate and pharmacokinetic measures for total testosterone and dihydrotestosterone (DHT), including AUCτ, Tmax, Cmax, Cavg, Cmin, and Tmin.

The primary outcome description says results were presented using descriptive statistics. The registry record does not report a sample-size justification, a detailed statistical analysis plan, or interim analyses. It also does not report numerical primary-outcome results.

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: Apart from having history of hypogonadism, the study subjects were required to present with one or more symptoms of testosterone deficiency (i.e. fatigue, decreased muscle mass, reduced libido, reduced sexual functioning of a non-mechanical nature). The study subjects needed to be in good health despite exhibiting hypogonadism.

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: Full Analysis Set (FAS) population was used for this analysis, which comprised of all subjects who had any available Pharmacokinetic (PK) data.

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: The data are presented for Intent-to-treat (ITT) population, which comprised of all subjects who received at least one dose of the Investigational Medicinal Product (IMP).

6. Primary Endpoint

The registry lists the primary outcome as Responder Rate: Percentage of Subjects Whose Average Steady State Concentration (Cavg) of Serum Total Testosterone Levels Are Between 300 and 1050 ng/dL Following Treatment With Each of Three Volumes of FE 999303 Applied With an Applicator., measured over Days 15-21, Days 22-28 & Days 29-35.

The primary endpoint is the percentage of subjects whose average steady-state concentration (Cavg) of serum total testosterone was between 300 and 1050 ng/dL following each of the three applicator volumes. The record gives the outcome timeframe as Days 15-21, Days 22-28, and Days 29-35. The analysis population is the Full Analysis Set, defined in the record as subjects with any available pharmacokinetic data.

A responder-rate endpoint converts measured concentrations into a count of participants who meet a stated criterion and a percentage of the analysis population. This can make it easier to describe how often concentrations fall within a clinically specified range than to interpret many concentration measurements separately. It also discards information: participants just inside and well inside the range are both counted as responders, while the measure does not describe how far nonresponders fall from the boundaries.

As a general statistical point, a percentage is an estimate of a population proportion, and its precision depends in part on how many participants contribute data and how their outcomes are distributed. A confidence interval, if reported, would help show uncertainty around that estimate. No numerical responder rates or confidence intervals are reported in the registry record, so neither the observed proportions nor their precision can be described.

The registry lists descriptive statistics for this outcome. It does not report a formal hypothesis test or a prespecified decision threshold for interpreting the responder rate. The endpoint therefore supports a descriptive pharmacokinetic summary, not a conclusion about comparative efficacy.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The primary outcome is a binary responder measure: each subject is classified according to whether Cavg of serum total testosterone is within the range from 300 to 1050 ng/dL. The group-level result is expressed as a percentage of subjects meeting that criterion. This approach is simple to interpret, but it compresses a continuous concentration measure into two categories. The underlying concentration values and their spread would be needed to understand how participants were distributed within and outside the target range.

What does a descriptive analysis tell us?

The record states that descriptive statistics were used for the primary outcome. In general, descriptive statistics summarize what was observed in the analyzed participants; they do not automatically test a prespecified hypothesis or estimate a causal effect. For a responder endpoint, a descriptive report might include the number meeting the criterion and the percentage, with a denominator showing how many participants contributed data. The registry record does not report those numerical primary-outcome results or their denominators by timeframe.

The distinction between a point estimate and its uncertainty is important. A percentage summarizes an observed proportion. A confidence interval, as a general statistical concept, describes a range of values compatible with the data under a stated method and assumptions. It helps readers judge precision, especially when the analyzed sample is small. No confidence interval for the primary responder rate is reported in the registry record. No interval method is reported either.

Why do the other pharmacokinetic measures matter?

The secondary outcomes include AUCτ, Tmax, Cmax, Cavg, Cmin, and Tmin for total testosterone and DHT. As general definitions, Cmax is the maximum observed concentration and Cmin is the minimum observed concentration; Tmax and Tmin identify the times at which those extrema are observed. Cavg represents an average concentration, while AUCτ summarizes concentration over the stated dosing interval. These measures capture different aspects of a concentration-time profile. AUC and average concentration summarize exposure, while peak, trough, and timing measures describe profile shape and timing. The registry lists these outcomes but does not report their numerical results.

The endpoint description gives multiple time windows: Days 15-21, Days 22-28, and Days 29-35. Repeated windows can help describe measurements over the study period, but interpretation depends on knowing how data were collected, which observations were included, and whether the windows were analyzed separately or combined. Those details are not reported in the registry record.

How should comparisons be approached?

The trial is listed as nonrandomized, unmasked, and single group. In general, randomization reduces the risk that pre-existing differences between groups explain an observed contrast. Without random allocation, differences in outcomes across application conditions could reflect condition, order, participant characteristics, or other influences. The title describes sequential dose escalation, but the sequence and any procedures intended to address carryover are not reported in the registry record. The registry's design description does not support treating the hand condition as a randomized control arm.

The record does not report hypothesis tests, confidence intervals, or a detailed model for comparing conditions. It also does not describe adjustments for repeated measures or other features of the data. A statistical method should not be inferred from the fact that several pharmacokinetic outcomes are listed.

What does the sample-size information represent?

The planning illustration is described as using the observed effect, a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation. It is a planning exercise, not an observed trial result or evidence of observed power. Sample-size estimates based on a fraction of an observed effect describe hypothetical design requirements under the stated assumptions; they do not establish that the study had a particular probability of detecting an effect. The registry record does not report the trial's own sample-size justification. Numerical planning outputs are not reported in the registry record.

In general, over-dispersion means that observed variability is greater than a model assumes. If a method assumes less variability than is present, uncertainty can be understated and inference can become too optimistic. The registry record does not report a dispersion model or evidence that over-dispersion was assessed; this general consideration should not be mistaken for a feature documented in this study.

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("Testosterone 1.25 mL (Applicator)", "Testosterone 2.50 mL (Applicator)", "Testosterone 3.75 mL (Applicator)")
n      <- c(18, 18, 18)
events <- c(3, 9, 14)
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  Testosterone 1.25 mL (Applicator)  18  3  16.7  3.6  41.4  5.8  39.2  6.1  39.6
ARM  Testosterone 2.50 mL (Applicator)  18  9  50.0  26.0  74.0  29.0  71.0  28.9  71.1
ARM  Testosterone 3.75 mL (Applicator)  18  14  77.8  52.4  93.6  54.8  91.0  54.4  90.9

11. Multiplicity, Missing Data and Analysis Populations

The study lists a primary responder-rate outcome for three applicator volumes and multiple secondary pharmacokinetic outcomes for total testosterone and DHT. Considering several outcomes or time windows creates a multiplicity issue: the more distinct questions examined, the greater the chance that some apparent patterns may arise by chance when inferential testing is used. A prespecified hierarchy or adjustment can help control that risk. The registry record does not report a multiplicity strategy, and it does not report numerical tests or comparisons for the primary outcome.

The record says descriptive statistics were used for the primary outcome. Descriptive summaries do not require the same interpretation as a collection of hypothesis tests, but readers still need to know which outcomes and time windows were selected for emphasis and whether analyses were prespecified. A detailed statistical analysis plan is not reported in the registry record.

The Full Analysis Set comprised subjects with any available pharmacokinetic data. This definition indicates that data availability was relevant to inclusion, but it does not explain how missing measurements were handled. The record does not report the number missing for each outcome or timeframe, reasons for missingness, imputation methods, or sensitivity analyses. Those details are important because missing data can affect both the estimated responder proportion and its uncertainty.

The enrollment is 20, but the record does not give endpoint-specific analysis denominators. It therefore cannot be assumed that all enrolled participants contributed to every outcome or timeframe. Interim analyses are not reported in the registry record. The record lists zero analysis records; this does not supply the missing outcome estimates or establish that no analyses were performed outside the registry record.

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

The posted safety figures list 20 participants at risk in each of the four application-condition groups. Serious adverse events are recorded as 0 in each group, and no serious adverse-event terms are listed. The record also gives an other adverse-event figure of 0 for hand application, 0 for 1.25 mL by applicator, 0 for 2.50 mL by applicator, and 1 for 3.75 mL by applicator. These are the recorded counts; the registry does not provide event descriptions for the other adverse event in the listed safety information.

The figures should be read as counts within the registry's safety categories, not as a complete description of all possible harms. Each group has a denominator of 20 in the safety data, but the record's single-group and nonrandomized design means these entries should not be treated as evidence from independent randomized groups. The death figures are not reported in the registry record. The absence of a listed serious event does not establish that the study rules out uncommon events or that the application conditions have equivalent safety. The registry record does not provide further safety detail or comparative statistical analyses.

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

This record describes a Phase 2 pharmacokinetic study of testosterone gel applied by hand or with an applicator. The applicator conditions used 1.25 mL, 2.50 mL, or 3.75 mL, and the primary outcome was the percentage of subjects whose Cavg was within 300 to 1050 ng/dL. The study was open-label and nonrandomized, and the registry classifies it as a single-group model.

The posted information establishes the question the study set out to examine, the application conditions, the primary outcome definition, and the stated analysis population. It does not report the numerical primary responder rates. Consequently, it does not show how often participants met the endpoint, whether response proportions differed among the applicator volumes, or how precise any such estimates were. The numerical results for the listed secondary pharmacokinetic outcomes are also not reported in the registry record.

Even if numerical condition-specific results were available, the design would limit causal interpretation. Without random allocation, contrasts could reflect factors other than application method or volume. The registry describes sequential dose escalation but does not report the order, transition procedures, or details of how possible period or carryover effects were addressed. The hand-application condition should not be described as a randomized control comparison.

The safety entries record no serious adverse events in the listed groups and one other adverse event in the 3.75 mL applicator group. These counts are limited to the registry's reported categories and do not establish comparative safety. Death figures are not reported in the registry record.

Overall, the record defines a pharmacokinetic question but does not provide the primary numerical outcomes needed to assess what was observed. It cannot support a conclusion about treatment benefit, comparative effectiveness, or equivalence between application conditions.

14. Why This Trial Matters Statistically

This trial is statistically informative as an example of the distinction between an outcome definition and an outcome result. The registry clearly defines a responder endpoint, identifies its target concentration range, and lists the analysis population and timeframe. Yet the numerical responder results are not reported in the registry record. A well-described endpoint is not enough to evaluate the observed response or its uncertainty.

The study also illustrates how design labels shape interpretation. The record identifies nonrandomized allocation, no masking, and a single-group model, while the title describes sequential dose escalation. These features differ from a randomized parallel-group comparison. Statistical contrasts among the application conditions cannot be read as randomized treatment effects without additional design information.

Another statistical issue is the use of a threshold to summarize a continuous pharmacokinetic measure. A responder rate can be convenient, but it does not convey how concentrations vary within the target range or how far values outside it lie from the boundaries. Continuous measures such as Cavg, AUCτ, Cmax, and Cmin offer complementary information, but their numerical results are not reported in the registry record.

The record names several secondary outcomes and multiple time windows, raising the general importance of prespecification and multiplicity control when inferential tests are used. The registry does not report a multiplicity approach or a detailed statistical analysis plan. It also defines the Full Analysis Set by availability of pharmacokinetic data without reporting endpoint-specific missingness or handling methods.

These features make the record useful for understanding what was measured and how cautiously such results should be interpreted. They also show why transparent reporting of estimates, denominators, uncertainty, and analysis decisions is necessary for readers to evaluate a clinical trial statistically.

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 most important limitation for interpreting the posted results is that numerical primary-endpoint results are not reported in the registry record. There are no responder proportions, endpoint-specific denominators, or confidence intervals with which to assess the observed data or precision. Numerical results for the listed secondary pharmacokinetic measures are also not reported.

The design is nonrandomized, unmasked, and classified as single group. The title describes sequential dose escalation, but the registry record does not report the sequence of conditions, transition procedures, or methods for addressing possible order or carryover effects. It is therefore not possible to treat the listed application conditions as independent randomized comparisons or to determine how condition contrasts were analyzed.

The enrollment is 20, and the registry defines the Full Analysis Set as subjects with any available pharmacokinetic data. It does not report how many participants contributed data to each outcome or timeframe, the extent or reasons for missing data, or any missing-data procedure. The trial's sample-size justification is not reported in the registry record; the planning illustration is not a substitute for a trial-specific rationale.

The registry does not report a detailed statistical analysis plan, a multiplicity strategy, interim analyses, confidence-interval methods, or inferential tests for the primary endpoint. The safety record contains limited adverse-event counts, and death figures are not reported. These omissions constrain assessment of both efficacy-related pharmacokinetic summaries and safety. They should not be filled in by assumptions about common practices in pharmacokinetic studies.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: A Clinical Study to Evaluate the Pharmacokinetics of Testosterone Gel Using an Applicator — NCT01464879.
• Registry record last updated 2017-09-13; status last verified 2017-08.
• Results first posted 2017-07-28.
• 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

This completed Phase 2 study of testosterone gel (FE 999303) enrolled 20 adult hypogonadal males. The registry describes an open-label, nonrandomized, single-group study and lists hand application at 2.50 mL alongside applicator application at 1.25 mL, 2.50 mL, and 3.75 mL.

The primary outcome was the percentage of subjects whose Cavg serum total testosterone was between 300 and 1050 ng/dL, assessed over Days 15-21, Days 22-28, and Days 29-35. The Full Analysis Set included subjects with any available pharmacokinetic data, and descriptive statistics were stated for the primary outcome.

Numerical primary and secondary outcome results are not reported in the registry record. The safety figures list no serious adverse events in the listed groups and one other adverse event in the 3.75 mL applicator group. The design and reporting limitations prevent interpretation as a randomized comparison.