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Meta-analyses Comparing Topical Treatments for Tinea Pedis
note, a proportion of the studies included in the meta-analysis were versus each comparator with its 95% CI. It should be emphasised
of relatively poor quality. Many sample sizes, although greater than that the variance of the indirect effect is the sum of the variances
30, were nonetheless relatively small. related to the two overall treatment effects versus vehicle, which
adequately accounts for the inherent loss of precision involved in
In most trials, mycological cure was clearly defined as a negative deriving an indirect effect.
fungal culture and negative microscopy. This outcome was chosen as
the efficacy end-point for the meta-analyses. Fungal culture and Clinical Relevance of Findings
microscopy were assessed independently in a few studies. In this When considering a reference mycological cure rate of 60%, a 15%
case, the mycological cure rate was defined with reference to the absolute decrease (i.e. corresponding to a 45% mycological cure rate)
lower of the negative microscopy rates and the negative culture rate. represents a relative 25% decrease in rate, which is usually
By definition, this approach overestimates the mycological cure rate, considered to be clinically relevant. Even an absolute 10% decrease
but the resultant bias is unlikely to be large. It is noteworthy that represents approximately a relative 15% decrease, and could be
clinical cure was inconsistently defined across the trials and, considered as a minimal clinically relevant difference. In contrast, a
therefore, since it measured different constructs, clinical cure rate difference in mycological cure rates of less than 10% might be
could not be used as an efficacy end-point. Where terbinafine FFS 1% considered clinically unimportant and indicative of a reasonable non-
was the active treatment, it was administered in a single application inferiority margin when discussing meta-analysis results. Indeed, this
and the main results were assessed six weeks after this single 10% margin, although defined post hoc in the context of a
application. For other topical treatments (including other terbinafine retrospective meta-analysis, is often considered appropriate for other
formulations), the duration of treatment was two to four weeks in pathologies for which success rates are of similar levels.
most trials. Whenever it was feasible, efficacy was assessed six
weeks after the first application to be comparable with the As a convention, with regard to direct comparisons of active treatments
terbinafine 1% FFS efficacy assessment (made six weeks after versus vehicle, the treatment effect is the difference in rates between
the single application). active treatment and vehicle. For indirect comparisons between
terbinafine 1% FFS and comparators, the indirect effect is the
Statistical Methods difference in rates between terbinafine 1% FFS and comparator. From a
The analyses were based on the intention-to-treat (ITT) principle, i.e. purely descriptive viewpoint, a positive difference in cure rates means
based on randomised patients receiving at least one dose of the that the effect is to the advantage of terbinafine 1% FFS. If the observed
randomised treatment. As a general rule, ITT patients with missing difference versus comparator is greater than -10%, terbinafine 1% FFS
mycological cure outcome were considered as not cured. is descriptively non-inferior to the comparator. In addition, if the lower
bound of the 95% CI is greater than -10%, statistical non-inferiority of
Initially, two separate meta-analyses were carried out: the first pooled terbinafine 1% FFS can be claimed over the comparator. If the observed
trials of terbinafine 1% FFS versus vehicle and the second pooled trials difference versus comparator is greater than >10%, terbinafine 1% FFS
of each of the other active treatments (other formulations of is descriptively superior to the comparator. In addition, if the lower
terbinafine 1% or other topical treatments) versus vehicle. These two bound of the 95% CI is larger than 0%, statistical superiority of
meta-analyses provide an overall estimate of each treatment effect. terbinafine 1% FFS can be claimed over the comparator.
Treatment effects were estimated on the rate difference scale and,
therefore, the overall treatment effect is the overall difference in Results
mycological cure rates between treatment and vehicle. The choice of Meta-analyses of Antifungals versus Vehicle
the difference scale rather than the rate ratio scale is justified by the The mycological cure rates observed in the vehicle groups are
fact that it enables easier clinical interpretation of the results, relatively consistent over time and across studies (data not shown).
especially when assessing non-inferiority between treatments. For Although the studies included in the different meta-analyses were
each meta-analysis (using methods previously published),
4–9
the performed at different times, this constancy strengthens the validity
homogeneity of the treatment effect across trials was assessed and of indirect comparisons between a single terbinafine 1% FFS and
tested (Cochran Q test). The overall treatment effect was estimated corresponding comparators. The meta-analyses based on the
either in a fixed-effects model (when low and non-significant difference in mycological cure rates between each agent or group of
heterogeneity was observed) or in a random effects model, so as to agents and vehicle are discussed below.
account for heterogeneity if applicable. In the latter case, the length of
the confidence intervals (CIs) reflects the additional variability due to Terbinafine
heterogeneity of treatment effects across trials. Except in the meta- The studies with terbinafine FFS gave consistent results and the
analysis of terbinafine 1% FFS versus vehicle, where the treatment meta-analysis provided a difference from vehicle in mycological cure
effect was particularly consistent across trials, heterogeneity turned rate of 53.5±4.4% (95% CI 44.9–62.1%) (see Figure 1). For terbinafine
out to be relatively substantial and the overall treatment effect was cream a similar difference from vehicle of 54.3±8.1% (95% CI
systematically estimated based on the random effects model. Ninety- 38.4–70.3%) was observed (see Figure 1). When the meta-analysis
five per cent CIs of the true treatment effect were also derived and the includes the cream, solution and gel formulations of terbinafine, a
null hypothesis (that there is no effect) was tested using asymptotic similar difference in mycological cure rates from vehicle of 57.9±5.5%
normal considerations. p-values presented are two-sided. (95% CI 47.2–68.7%) was observed for this group (see Figure 1).
Subsequently, the difference in the two overall treatment effects (i.e. Other Topically Active Allylamines (Butenafine, Naftifine)
terbinafine 1% FFS versus vehicle and comparator versus vehicle) In the studies with butenafin, the overall difference from vehicle in
was estimated so as to derive an indirect effect of terbinafine 1% FFS mycological cure rates was 44.8±8.5% (95% CI 28.2–61.4%).
EUROPEAN DERMATOLOGY 21
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