Monotherapy for Toenail Onychomycosis

A Systematic Review and Network Meta-analysis

A.K. Gupta; K.A. Foley; R.R. Mays; N.H. Shear; V. Piguet


The British Journal of Dermatology. 2020;182(2):287-299. 

In This Article


Results of the Search

There were 10 845 records identified by our literature search (PubMed, Scopus, OVID, and (Figure 1). A total of 75 records met the inclusion criteria and were included in the quantitative analysis. Only 26[24–49] (31 clinical trials) of the 75 records included in the quantitative analysis met the criteria necessary for an NMA (e.g. cure rates or adverse events reported). Additionally, at least two clinical trials for a particular treatment were required for inclusion in the NMA, with each trial contributing at least two treatment arms to the network. The included trials had 8136 randomized participants. The average age of participants was 51·6 ± 6·8 years.

Figure 1.

Summary of literature search for randomized controlled trials. NMA, network meta-analysis.

Treatments that were eligible for the evidence network were ciclopirox 8% topical solution (daily for 48 weeks);[36] efinaconazole 10% topical solution (daily for 36–48 weeks);[33,47] fluconazole (150 mg, 300 mg or 450 mg once weekly for 9–12 months);[42,43] itraconazole 200 mg continuous (daily for 12 weeks);[26–28,30,40] itraconazole 400-mg pulse (200 mg twice daily for 1 week then 3 weeks off for 12–16 weeks);[35,37–40,44,46] terbinafine 250 mg continuous (daily for 12–16 weeks);[24–29,31,32,35,37–39,41,44–46,48,49] terbinafine 500-mg pulse (250 mg twice daily for 1 week then 3 weeks off for 12–16 weeks);[46,48] or tavaborole 5% topical solution (daily for 48 weeks).[34] Amorolfine, ciclopirox 8% hydrolacquer, griseofulvin, device-based therapies and combination therapies could not be included in the network.

Detailed information for all the studies included in the NMA is presented in Table 1. A network graph summarizing the comparisons is provided in Figure 2. We were able to perform NMA for mycological cure and adverse events. A lack of studies reporting complete cure (i.e. particularly in the case of oral antifungals), treatment success and QoL prevented NMAs from being conducted. QoL was reported in only one RCT.[42] A possible explanation is that the time period in which many of the studies were conducted preceded the use of consistent outcome measures seen in recent years with topical antifungals. Table S3 (see Supporting Information) shows information for the studies not included in the NMA.

Figure 2.

Network graph of (a) mycological cure and (b) adverse events. The network graph shows the evidence network for all selected interventions. The size of an intervention's circle reflects the total number of participants for that intervention. Lines signify that interventions are connected through at least one study, with thicker lines indicating more connecting studies.
CPX, ciclopirox 8% topical solution; EFZ, efinaconazole 10% topical solution; FLZ, fluconazole; ITZ, itraconazole; TRB, terbinafine; TVB, tavaborole

Risk of Bias

The 31 included trials were judged as 'low risk', 'unclear risk' or 'high risk' of bias (Figure S2; see Supporting Information). Five studies were rated as low risk of bias across all domains,[24,34,35,48] while three studies were rated as low risk of bias on all but one domain.[33,47] Twenty-six trials (84%) were judged as having low risk of bias for both attrition and reporting bias, while 48% and 36% of trials described blinding of participants/personnel and outcome assessors, respectively. Description of randomization procedures (36%) and allocation concealment (29%) was quite low.

Quality of Evidence

For mycological cure, evidence for direct comparisons of treatments (vs. placebo or comparator) was of moderate or high quality (Table S4; see Supporting Information). The exceptions to this were low quality of evidence for pulse itraconazole 400 mg compared with both continuous itraconazole 200 mg and continuous terbinafine 250 mg. In the case of continuous itraconazole, evidence was based on one RCT with a low sample size. In the case of continuous terbinafine, results across studies were variable, leading to downgrading of evidence based on inconsistency and imprecision (Table S4; see Supporting Information).

Evidence was more variable for direct comparisons of adverse events (treatment vs. placebo or comparator). Evidence was moderate or high for the three topical antifungals (ciclopirox 8% lacquer, efinaconazole 10% solution, tavaborole 5% solution) and for continuous terbinafine 250 mg compared with both continuous and pulse itraconazole (Table S4; see Supporting Information). Evidence was low or very low for the remaining comparisons due to concerns with risk of bias, low number of trials, low number of events and/or variable results across trials (Table S4; see Supporting Information).

Efficacy and Safety of Direct Comparisons of Monotherapy vs. Placebo

Direct comparisons with placebo yielded significantly greater ORs of achieving mycological cure for all treatments; the most efficacious treatments were continuous itraconazole 200 mg [OR 18·61, 95% confidence interval (CI) 7·40–46·81] and continuous terbinafine 250 mg (OR 16·41, 95% CI 6·49–41·47). The ORs of adverse events occurring with any of the treatments were not significantly different from placebo, with the exception of efinaconazole 10%, where transient application-site reactions were the majority of adverse events reported[33] (OR 1·28, 95% CI 1·02–1·61) (Table 2; Figure S3; see Supporting Information).

Mixed Treatment Comparisons

Continuous terbinafine 250 mg was almost two times more likely to achieve mycological cure compared with pulse itraconazole 400 mg (OR 1·95, 95% CI 1·04–3·65) and pulse terbinafine 500 mg (1·80, 95% CI 1·13–2·87; Table 2, Figure S4; see Supporting Information). The effects of continuous terbinafine 250 mg and continuous itraconazole 200 mg were significantly greater compared with all topical treatments. Fluconazole, and pulse regimens of terbinafine 500 mg and itraconazole 400 mg were not significantly different from topical treatments: efinaconazole, tavaborole and ciclopirox. Additionally, the ORs of achieving mycological cure with any of the topical treatments were equivalent (Table 3 and Table 4). Adverse events with continuous terbinafine 250 mg were two times more likely than with pulse itraconazole 400 mg (OR 2·02, 95% CI 1·30–3·14). The ORs of experiencing adverse events with any other oral or topical treatments were equivalent (Table 2 and Table 3; Figure S5; see Supporting Information).

Inconsistency Analysis

There were no significant inconsistencies between the direct and indirect evidence; however, this does not exclude the possibility of inconsistency as the number of studies making a direct comparison is low for many of the treatment comparisons (Table 5).

Ranking of Treatments by Efficacy

Continuous terbinafine 250 mg and continuous itraconazole 200 mg were ranked the most likely to produce mycological cure according to 'surface under the cumulative ranking curves' (SUCRA), followed by itraconazole 400-mg pulse and terbinafine 500-mg pulse. The probability that continuous terbinafine 250 mg would rank first for a random sample is 48·9%, compared with continuous itraconazole 200 mg (29·0%) and terbinafine 500-mg pulse (16·2%) (Table 6; Figure S6; see Supporting Information).

Ranking Treatments by Safety

Tavaborole 5% and placebo were ranked the least likely to lead to adverse events according to SUCRA, followed by continuous itraconazole 200 mg and efinaconazole 10%. The probability that tavaborole 5% would rank first (adverse events least likely) for a random sample is 55·5% followed by placebo (26·9%) (Table 6; Figure S6; see Supporting Information).