Ciclopirox topical solution, 8% combined with oral terbinafine to treat onychomycosis: a randomized, evaluator-blinded study

Journal of Drugs in Dermatology, July-August, 2005 by Aditya K. Gupta

Abstract

This randomized, evaluator-blind, 3-arm parallel, comparator controlled, multicenter pilot study evaluated the safety and efficacy of ciclopirox nail lacquer topical solution, 8% in combination with oral terbinafine for the treatment of moderate to severe toenail onychomycosis ([greater than or equal to]60% disease involvement of target nail and/or lunula/matrix involvement) (N = 73). Patients were randomized to 1 of 3 treatment arms: ciclopirox nail lacquer once daily for 48 weeks plus 4 weeks of terbinafine 250 mg/day, followed by 4 weeks of rest (no terbinafine), then another 4 weeks of terbinafine 250 mg/day (P[L.sub.8]); ciclopirox nail lacquer once daily for 48 weeks plus terbinafine 250 mg/day for 12 weeks (P[L.sub.12]); or terbinafine 250 mg/day for 12 weeks ([L.sub.12]). At week 48, mycological cure (negative microscopy and culture) occurred in 66.7% (14/21) (P[L.sub.8]), 70.4% (19/27) (P[L.sub.12]), and 56.0% (14/25) ([L.sub.12]) of patients confirmed dermatophyte positive, respectively (P: not significant). At this time point, effective cure (simultaneous mycological cure and [greater than or equal to]90% reduction in the disease area) was observed in 40.0% (8/20), 33.3% (8/24), and 34.8% (8/23) of patients, respectively (P: not significant). The P[L.sub.8] regimen was well-tolerated and had high compliance. The data suggest that combination therapy (P[L.sub.8]) may be an alternative regimen to continuous terbinafine ([L.sub.12]) in the treatment of moderate to severe dermatophyte toenail onychomycosis.

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Introduction

Combination regimens are well-established for the treatment of several dermatological conditions, (1) including psoriasis, acne vulgaris, rosacea, atopic dermatitis, and actinic keratosis. Combining 2 or more therapeutic approaches has the potential to increase cure rates, decrease intake of systemic antifungals, shorten treatment duration, and reduce drug acquisition costs, (2-6) making the combination approach a logical consideration in the management of hard to treat or moderate to severe onychomycosis. Ideally, a combination strategy should involve antifungal agents with complementary delivery systems, broad-spectrum activity, and complementary mechanisms of action. (2-5,7)

Ciclopirox is fungicidal in vitro against proliferating and dormant fungal cells. (8) Ciclopirox chelates polyvalent cations ([Fe.sup. 3] and [Al.sup. 3]) involved in enzymatic activity, ultimately interrupting intracellular energy production and toxic peroxide degradation. (9) This mechanism differs from that of allylamine antifungals, such as terbinafine, that inhibit squalene epoxidase production and subsequent ergosterol biosynthesis. These complementary modes of action make ciclopirox and terbinafine candidates for combination therapy. (10)

Synergy between ciclopirox and terbinafine was also demonstrated in vitro (6) against 5 of 6 nondermatophyte species tested (Scopulariopsis brevicaulis, Aspergillus sydowii, Onychocola canadensis, Scytalidium dimidiatum, and Fusarium solani). No antagonism was observed for this antifungal combination. The current study is the first to test this concept in vivo using a combination of ciclopirox nail lacquer and oral terbinafine for the treatment of severe toenail onychomycosis.

Patients and Methods

This was a randomized, evaluator-blind, 3-arm parallel, comparator controlled, multicenter pilot study designed to assess the efficacy and safety of combined ciclopirox nail lacquer and oral terbinafine in the treatment of moderate to severe onychomycosis involving at least one great toenail. Patients were recruited from 8 North American dermatology clinical trial centers.

Inclusion and Exclusion Criteria

To be eligible for enrollment, a patient needed to have a clinical and mycological (positive potassium hydroxide [KOH] or culture) diagnosis of fungal infection of at least one great toenail with 60% or more involvement and/or lunula/matrix involvement. Patients were excluded if they possessed any disease or condition that could interfere with treatment efficacy and evaluation (eg, severe tinea pedis, liver function abnormalities, psoriasis, nail abnormalities, etc). Patients who failed previous therapy with a standard course of terbinafine or itraconazole, or used systemic or topical antifungal therapy within 12 months or 4 weeks respectively, prior to screening were excluded. All patients provided written informed consent. This study protocol was approved by an Institutional Review Board.

Study Design

Patients meeting inclusion/exclusion criteria with mycologically confirmed onychomycosis were assigned to 1 of 3 treatment arms (Figure 1) according to a predetermined randomization schedule: ciclopirox nail lacquer once daily for 48 weeks plus 4 weeks of terbinafine 250 mg/day, followed by 4 weeks of rest (no terbinafine), then another 4 weeks of terbinafine 250 mg/day (P[L.sub.8]); ciclopirox nail lacquer once daily for 48 weeks plus terbinafine 250 mg/day for 12 weeks (P[L.sub.12]); or terbinafine 250 mg/day for 12 weeks ([L.sub.12]). Designated evaluators remained blinded during the entire study period. Patients were instructed to apply ciclopirox nail lacquer evenly to all toenails regardless of involvement, covering the entire surface of the nail plate, as well as approximately 5 mm of surrounding skin. Patients returned for assessment at weeks 4, 8, 12, 24, 36, and 48 (end of treatment).