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.
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.
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).
[FIGURE 1 OMITTED]
The patients were questioned about missed doses of terbinafine and/or missed applications of ciclopirox nail lacquer at each visit. Medication bottles were inspected to confirm product use.
Clinical success was defined as 90% or more reduction in the disease area, and mycological cure was defined as negative KOH and culture. Effective cure was a combination of mycological cure and clinical success.
All response rates were analyzed using 95% confidence intervals. A significance level of 0.05 was used for all statistical tests. The primary time point of interest was 48 weeks. All subjects with dermatophyte toenail onychomycosis who received at least one dose of the treatment medication were included in the analysis.
The distribution of patients in each treatment arm was 21 (P[L.sub.8]), 27 (P[L.sub.12]), and 25 ([L.sub.12]). Of these patients 19 (90.5%), 23 (85.2%), and 21 (84.0%) respectively, completed the study. There were no significant differences in demographic and baseline characteristics for this population (Table 1). Patient compliance was high. Greater than 90% of patients took at least 80% of their assigned treatment regimen.
At week 48 (end of treatment), mycological cure was observed in 66.7% (14/21) of patients in the P[L.sub.8] group, 70.4% (19/27) in P[L.sub.12], and 56.0% (14/25) in [L.sub.12] (P: not significant) (Figure 2).
At week 48, clinical success was observed in 45.0% (9/20), 37.5% (9/24), and 43.5% (10/23) of patients respectively (P: not significant) (Figure 2).
By week 48, 40.0% (8/20) of the P[L.sub.8] group, 33.3% (8/24) of P[L.sub.12], and 34.8% (8/23) of [L.sub.12] had achieved simultaneous mycological cure and clinical success (P: not significant) (Figure 2).
Adverse events possibly related to study medication were minimal and evenly distributed among treatment groups: 20.5% (P[L.sub.8]), 21.4% (P[L.sub.12]), and 22.0% ([L.sub.12]). The adverse events reported by more than one patient, and possibly related to study medication, included gastrointestinal disorders, skin and subcutaneous tissue disorders, and abnormal investigations (eg, elevated laboratory values).
In vitro studies (6,11,12) suggest that certain combinations of antifungals may actually interact synergistically, yielding greater efficacy than would be expected from the sum of the efficacy of the 2 drugs alone.
We observed a numerically higher mycological cure rate in patients receiving 8 weeks of non-continuous terbinafine plus ciclopirox nail lacquer compared with patients receiving 12 weeks of terbinafine monotherapy (P: not significant). The sample size may not have been large enough to detect statistical significance; however, these findings provide a basis for larger clinical studies evaluating the efficacy of the P[L.sub.8] combination regimen for the management of onychomycosis.
Clinical success rates were also statistically similar among the 3 treatment arms. This evaluation occurred at the end of treatment, however, toenails require approximately 18 months (13,14) to fully grow out, and in future studies, a longer follow-up period may provide more meaningful results.
The adverse events reported for each treatment arm were similar and no patient discontinued therapy because of adverse events. In the P[L.sub.8] group, the reduced duration for which the patient is on an oral antifungal agent may be preferred by some patients, especially if they are on multiple drugs, or if they experience an adverse event while on oral therapy. From a pharmacoeconomic perspective, the P[L.sub.8] regimen may have a lower drug acquisition cost compared to terbinafine monotherapy.
The results of this study provide a basis for performing larger studies evaluating the efficacy of the P[L.sub.8] regimen (terbinafine 4 weeks on, 4 weeks off, 4 weeks on, administered in conjunction with 48 weeks of ciclopirox nail lacquer) for the management of dermatophyte onychomycosis, including moderate to severe disease presentations.
Acknowledgements: Onychomycosis Combination Therapy Study Group: Dr. Raza Aly, San Francisco, CA; Dr. Michael W. Bell, Nashville, TN; Dr. Michael T. Jarratt, Austin, TX; Dr. Peter Lee, Minneapolis, MN; Dr. Amit G. Pandya, Dallas, TX; Dr. Michael Saruk, Paoli, PA; Dr. Leonard J. Swinyer, Salt Lake City, UT; Dr. Jeffrey Weinberg, New York, NY.
Disclosures: This study was supported by Dermik Laboratories.
1. Gupta AK, Cooper E. Management of onychomycosis: combination therapy is not a new concept. J Am Acad Dermatol. 2004;50:104 [Abstract P401].
2. Evans EG. The rationale for combination therapy. Br J Dermatol. 2001;145 Suppl 60:9-13.
3. Evans EG. Drug synergies and the potential for combination therapy in onychomycosis. Br J Dermatol. 2003;149 Suppl 65:11-13.
4. Hay RJ. The future of onychomycosis therapy may involve a combination of approaches. Br J Dermatol. 2001;145 Suppl 60:3-8.
5. Olafsson JH, et al. Combination therapy for onychomycosis. Br J Dermatol. 2003;149 Suppl 65:15-18.
6. Gupta AK, Kohli Y. In vitro susceptibility testing of ciclopirox, terbinafine, ketoconazole and itraconazole against dermatophytes and nondermatophytes, and in vitro evaluation of combination antifungal activity. Br J Dermatol. 2003;149:296-305.
7. Gupta AK, Lynch LE. Management of onychomycosis: examining the role of monotherapy, dual, triple, or quadruple therapies. Cutis. 2004;74 (suppl 1):5-9.
8. Seebacher C. Action mechanisms of modern antifungal agents and resulting problems in the management of onychomycosis. Mycoses. 2003;46:506-510.
9. Bohn M, Kraemer KT. Dermatopharmacology of ciclopirox nail lacquer topical solution 8% in the treatment of onychomycosis. J Am Acad Dermatol. 2000;43:S57-S69.
10. Gupta AK, Baran R. Ciclopirox nail lacquer solution 8% in the 21st century. J Am Acad Dermatol. 2000;43:S96-S102.
11. Barchiesi F, et al. In vitro activities of terbinafine in combination with fluconazole and itraconazole against isolates of Candida albicans with reduced susceptibility to azoles. Antimicrob Agents Chemother. 1997;41:1812-1814.
12. Barchiesi F, et al. In vitro interaction of terbinafine with amphotericin B, fluconazole and itraconazole against clinical isolates of Candida albicans. J Antimicrob Chemother. 1998;41:59-65.
13. Baran R, et al. Onychomycosis: the current approach to diagnosis and therapy. Martin Dunitz Ltd., London; 1999:11.
14. De Cuyper C, Hindryckx PH. Long-term outcomes in the treatment of toenail onychomycosis. Br J Dermatol. 1999;141 Suppl 56:15-20.
Aditya K. Gupta MD PhD FRCP(C), (a,b) the Onychomycosis Combination Therapy Study Group
a. Division of Dermatology, Department of Medicine, Sunnybrook and Women's College Health Sciences Center (Sunnybrook site) and the University of Toronto, Toronto, Canada
b. Mediprobe Research Inc., London, Ontario, Canada
Address for Correspondence
Aditya K. Gupta MD PhD FRCP(C)
645 Windermere Road
Canada N5X 2P1
Phone: 519 657 4222
Fax: 519 657 4233
COPYRIGHT 2005 Journal of Drugs in Dermatology, Inc.
COPYRIGHT 2005 Gale Group