- Email: [email protected]
Oral terbinafine in the treatment of toenail onychomycosis: North American multicenter trial
Oral terbinafine in the treatment of toenail onychomycosis: North American multicenter trial Lynn A. Drake, MD, a Neil H. Shear, MD, b Jon R Arlette, MD, c Richard Cloutier, MD, d Frederick W. Danby, e Boni E. Elewski, MD, f Sylvia Garnis-Jones, MD,g Jean-Mario Giroux, MD, h David Gratton, MD, i Wayne Gulliver, MD,J Peter Hull, MD, k H. Earl Jones, MD, 1 Michel Journet, MD, h Alfons L. Krol, MD, m James J. Leyden, MD, n Smart C. Maddin, MD, ° J. Barrie Ross, MD,P Ronald C. Savin, MD,q Richard K. Scher, MD, r Gary R. Sibbald, MD, s Naji H. Tawfik, MD, t Nardo Zaias, MD, u Mark Tolpin, MD, v Sandra Evans, PhD, v Christian Marsolais, PhD, v Thomas Chin, v Tsuang-Hua Lin, PhD, v Thomas Maher, MS, v and Jay E. Birnbaum, PhD v
Boston, Massachusetts; Toronto, Kingston, Ottawa, and Mississauga, Ontario; Calgary and Edmonton, Alberta; Laval and Montrdal, Quebec; Cleveland, Ohio; St. Johns, Newfoundland; Saskatoon, Saskatchewan; Fairhope, Alaska; Philadelphia, Pennsylvania; Vancouver, British Columbia; Halifax, Nova Scotia; New Haven, Connecticut; New York, New York," Winnipeg, Manitoba; Miami Beach, Florida; and East Hanover, New Jersey Background." Onychomycosis is an increasing problem with limited therapeutic options. Objective: We evaluated the safety and efficacy of oral terbinafine, a new fungicidal antimycotic, in patients with toenail onychomycosis.
Methods: A North American multicenter, double-blind, placebo-controlled study evaluated the mycologic and clinical efficacy of oral terbinafine 250 rag/day for 12 or 24 weeks in 358 patients with toenail onychomycosis. Results: A total of 74% of patients treated with 12 or 24 weeks of terbinafine achieved a successful clinical outcome. Approximately 11% of terbinafine responders showed evidence of relapse 18 to 21 months after cessation of treatment. Terbinafine was well tolerated; most adverse events were transient and mild to moderate in severity. Conclusion: The results of this study confirm that oral terbinafine is a safe and effective therapy for the treatment of onychomycosis. (J Am Acad Dermatol 1997;37:740-5.)
From Massachusetts General Hospital, Bostona; University of Toronto, Ontariob; University of Calgary, AlbertaC; University of Laval, Quebecd; Queen's University, Kingston, Ontarioe; University Hospitals of Cleveland, Ohiof; University of Ottawa, Ontariog; Universit6 de Montrral h and Centre Hospitalier Cotedes-Neiges, i Montrral, Quebec; Memorial University of Newfoundland, St. Johnsi; University of Saskatchewan, Saskatoonk; Thomas Hospital, Fairhope, Alaska1; University of Alberta, Edmontonm; Hospital of the University of Pennsylvania, Philadelphian; University of British Columbia, Vancouver°; Dalhousie University, Halifax, Nova ScotiaP; Yale-New Haven Hospital, Connecticutq; Columbia Presbyterian Hospital, New Yorkr; University of Toronto, Mississauga, OntarioS; University of Manitoba, Winnipegt; Mt. Sinai Medical Center, Miami Beach'S; and Novartis Pharmaceuticals Corporation, East Hanover.v Supported by Novartis Pharmaceuticals Corporation, East Hanover, N.J. Accepted for publication July 23, 1997. Reprint requests: Lynn A. Drake, MD, Massachusetts General Hospital, Dermatology-BAR 604, 40 Blossom St., Boston, MA 02114-2698. Copyright © 1997 by the American Academy of Dermatology, Inc. 0190-9622/97/$5.00 + 0 16/1/84863
740
Onychomycosis represents a significant and increasingly common problem that affects 2.7% to 13% of the adult population. 1,2 Therapeutic options have been limited and the results disappointing, especially for onychomycosis of the toenails. Terbinafine (Lamisil), a new, orally active fungicidal allylamine, has shown effectiveness in fingernail and toenail onychomycosis 3-6 and is currently widely approved for these indications. This report presents the results of the first U.S./Canadian multicenter study of terbinafine in patients with toenail onychomycosis. The objectives of this study were to compare safety and efficacy of 12 and 24 weeks' treatment with oral terbinafine tablets (250 mg/day) versus placebo in patients with onychomycosis and to determine the relapse rate in effectively treated patients at 72 and 96 weeks' follow-up.
Journal of the American Academy of Dermatology Volume 37, Number 5, Part 1
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100
741
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0 0 4 8 12 16 20 24 28 32 36 40 44 48 Weeks Fig. 1. Time course of mycologic response: Percent of patients with (A) negative microscopy or (B) negative culture. Terbinafine 12- or 24-week versus placebo: p < 0.05 at week 12 (microscopy or culture); p < 0.001 during weeks 18 to 48 (microscopy or culture).
METHODS
A total of 358 patients 18 to 70 years of age with distal subungual onychomycosis of the toenails were enrolled at seven U.S. and 15 Canadian centers. The study protocol was approved by the review boards of all participating centers before its initiation. Written informed consent was obtained from all participating patients. Eligible patients had onychomycosis of at least one great toenail with the diagnosis confirmed by potassium hydroxide (KOH) wet mount and culture for a dermatophyte, and at least 2 mm of unaffected proximal nail (evidence of ability of the nail to grow). Patients were excluded if they had received systemic antifungal therapy 3 months or less before entry or topical antifungal therapy 1 month or less before entry, or had psoriasis (irrespective of nail involvement), proximal subungual onychomycosis, or superficial white onychomycosis. The 96-week study included a double-blind treatment phase of 24 weeks in which patients were randomly assigned to one of three parallel groups in a 2:2:1 ratio: oral terbinafine (n -= 142, 250 mg once daily) for 12 weeks then placebo for 12 weeks, oral terbinafine (n = 145,250 nag once daily) for 24 weeks,
or placebo (n = 71) for 24 weeks. This phase was followed by 24 weeks of blinded follow-up without treatment (weeks 24 to 48). A cohort of patients (designated as the "follow-up population"), with negative mycologic findings (culture and KOH) and at least 5 mm of unaffected new nail growth by week 48, was observed for up to an additional 48 weeks (96 weeks total) to assess long-term clinical effectiveness and relapse. Mycologic (KOH microscopy and culture) and clinical assessments were performed on the "target" nail (the most severely affected great toenail) at intervals of 4 or 6 weeks during the 48-week blinded phase of the study. Length of unaffected nail (distance between the proximal nailfold and the most proximal point of fungal involvement) and percent nail involvement (estimated to the nearest 10%) were determined to assess disease progression and nail growth. In addition, patients were asked to provide an overall assessment of their response to therapy as excellent, very good, slight improvement, fair, poor/no effect. Patients with a 90% to 100% clear nail were designated as having achieved clinical success. Mycologic and clinical assessments also were performed for the terbinafine-treated followup population during the open follow-up phase (weeks 72 and 96). Safety and tolerability of oral terbinafine
742
Journal of the AmericanAcademyof Dermatology November 1997
Drake et al.
Table I. Baseline characteristics among study groups* Study groups Variable
Terbinafine 12-wk
Mean age (yr) Male sex (%) Median disease duration (mo) (range) Mean nail involvement (%) Mean No. affected nails Pathogens isolated at enrollment (%)
Terbinafine 24-wk
Placebo
45 -+ 1 71 72 (4 to 360) 57 +- 2 6.2 _+0.2
45_+ 1 81 84 (2 to 600) 58-+ 2 6.1 _+0.3
45 +- 2 80 60 (8 to 540) 57 +_3 6.7 -+ 0.3
95 1 0 4
90 2 1 8
94 4 0 1
Trichophyton rubrum Trichophyton mentagrophytes Epidermophyton floccosum Other *Values represent means _ SEM unless otherwise stated.
Table II. Long-term clinical outcomes: Percentage (fraction) patients in follow-up population* Outcome
Clinical success t Week 48 Week 72 Week 96 Last observation Anytime Relapse* (time after cure) _< 12 mo > 12 mo Total Failures §
Terbinafine 12 wk
82% 94% 81% 79% 94%
(58/71) (60/64) (47/58) (56/71) (67/71)
4% 11% 15% 6%
Terbinafine 24 wk
90% 92% 89% 85% 94%
(86/96) (75/82) (65/73) (82/96) (90/96)
2% 6% 8% 6%
*Terbinafine-treated patients with negative KOH/culture and at least 5 mm of new unaffected nail growth by week 48 were designated by protocol to be followed up for an additional 48 weeks. t_> 90% clear nail. *>_90% clear nail at any time and < 90% at last visit. §>_90% clear nail at no time.
were assessed by physical examination, vital signs, laboratory evaluation, and reports of adverse experiences. Statistical differences in clinical or mycologic efficacy between the terbinafine or placebo groups were assessed by means of the Cochran-Mantel-Haenszel test (binary variables) and two-way ANOVA (continuous variables) using center as the stratification variable] Fisher's exact test was used to compare the incidence of adverse events in the terbinafine and placebo groups.
RESULTS The terbinafine and placebo groups were well
balanced with respect to age, sex, disease duration, percent nail involvement, and number of affected nails (Table I). Trichophyton rubrum accounted for 90% to 95% of infections.
Mycologic response During the 48-week blinded phase, the percentage of terbinafme-treated patients with negative microscopy or negative culture progressively increased even after cessation of 12 or 24 weeks of therapy (Fig. 1). At week 48, 70% of patients treated with terbinafine for 12 weeks and 87% of patients treated for 24 weeks exhibited both negative microscopy and negative culture versus 9% for placebo-treated patients. For the terbinafine treatment groups, median response times were 12 to 18 weeks for negative culture and 18 to 24 weeks for negative microscopy.
Clinical efficacy Terbinafine treatment produced a significant and progressive decrease in the percent involvement of target nails and a corresponding increase in unaffected nail growth during therapy and after cessation of therapy (Fig. 2). By contrast, placebo= treated patients showed further worsening, as evidenced by an increase in nail involvement at week 48 and a progressive decrease in uninvolved nail relative to baseline. By week 48 at least 5 mm of unaffected nail growth was achieved in 61% of the terbinafine 12-week group and 73% of the terbinafine 24-week group. Zero percent nail involvement was observed in 40% of the terbinafine 12-week group and 50% of the
Journal of the American Academy of Dermatology Volume 37, Number 5, Part 1
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~
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, 0
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B
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0 0
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Fig. 2. Time course of clinical response. A, Percent nail involvement and (B) millimeters of unaffected nail growth. Terbinafine 12- or 24-week versus placebo: p < 0.001 during weeks 12 to 48 (nail involvement or nail growth).
terbinafine 24-week group. Clinical success rates corresponded with patient satisfaction ratings (Fig. 3). At week 48, the last blinded observation point, a high level of response as measured by both evaluations was achieved in approximately 60% of the terbinafine 12-week group and 75% of the terbinafine 24-week group. Although not all patients were observed beyond week 48, 71% or 101 of 142 of the terbinafine 12-week group and 77% or 112 of 145 of the terbinafine 24-week group achieved clinical success at some point during the 96-week study. Long-term outcomes/relapse in follow-up pop-
were no significant differences in mycologic or clinical responses between the 12- and 24-week treatment groups. The median duration of observation of this group was 16.5 months after achievement of clinical success. Of those patients with negative KOH and negative culture at the beginning of the extended observation, 95% and 88%, respectively, were still negative at their last evaluation (up to week 96). In terms of clinical response, 6% of the follow-up population failed to achieve clinical success during the 96 weeks, and 11% exhibited evidence of relapse during the follow-up period.
ulation
Safety
A total of 167 (of 358) terbinafine-treated (but no placebo) patients had negative mycologic findings and at least 5 mm of unaffected new nail growth by week 48 (Table II). These patients, observed from weeks 48 to 96 showed durability in both their mycologic and clinical responses to treatment. Within the follow-up population, there
The adverse events most frequently reported in the terbinafine and placebo groups are shown in Table III. No significant differences were noted between terbinafine groups (12 or 24 weeks alone or combined) and placebo. Most adverse events considered possibly or probably drug-related were mild to moderate in severity and were transient.
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November 1997
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Fig 3. Effectiveness. A, Clinical success: Percent of patients with at least 90% clear nail at week 48. Terbinafine 12- or 24-week versus placebo: p < 0.001, terbinafine 12-week versus 24-week: p < 0.01. B, Patient satisfaction: Percent of patients rating response as excellent/very good based on global assessment of all nails at last blinded evaluation. Terbinafine 12- or 24-week versus placebo: p < 0.001; terbinafine 12-week versus 24-week: p < 0.05.
Table III. Most frequently reported adverse events (% of patients) A d v e r s e event
URTI Headache Rhinitis Diarrhea Flatulence Back pain
Terbinafine 12-wk
Terbinafine 24-wk
Placebo
15.4 12.6 4.9 7.7 1.4 5.6
20.5 9.6 6.8 5.5 5.5 2.1
15.7 8.6 7.1 4.3 4.3 1.4
URT1, Upper respiratory tract infection.
All nine severe adverse events considered possibly or probably drug-related involved the gastrointestinal system or skin; five required discontinuation of terbinafine treatment. Two of 142 patients in the 12-week terbinafine group discontinued therapy because of rash (one) or diarrhea (one). Three of 145 patients in the 24-week group discontinued therapy because of rash (two patients) or abdominal pain (one). No clinically meaningful changes in hematology values from baseline were noted with terbinafine therapy. No clinically meaningful differences were observed between terbinafine and placebo treatment groups for SGOT, SGPT, alkaline phosphatase, and bilirubin. There was no evidence of increased severity of adverse events with increased treatment duration. DISCUSSION
This study confirms the results of European
studies showing oral terbinaflne to be an effective and safe therapy for toenail onychomycosis) ,5,6 Administration of terbinafine (250 mg/day) resulted in a rapid mycologic and clinical response that continued to improve after cessation of therapy. Although drug dosing was stopped after 12 or 24 weeks, normal unaffected nails continued to grow. A total of 74% of patients treated with terbinafine achieved a successful clinical outcome. A normal nail plate was observed in approximately 45% of terbinafine-treated patients at the end of the blinded portion of the study, and this percentage increased during follow-up. The overall response rates of the two treatment groups was comparable (71% vs 77% for 12 and 24 weeks, respectively); however, the data suggest that some patients with extensive involvement of the great toenails may benefit from treatment longer than 12 weeks. Terbinafine was well tolerated. Most adverse events were transient and mild to moderate in severity. Relapse rates assessed in a predesignated responder population up to 18 to 21 months after cessation of treatment were estimated to be approximately 11%. The high, sustained response with a 3-month course of terbinaflne treatment stands in contrast to the low cure rate (20% to 60% or less) and high relapse rate (40% to 70% or more) observed with even prolonged (9 to 12 months or longer) treatment of toenail onychomycosis with griseofulvin. 8-1° In contrast to griseofulvin and the azoles, which are fungistatic, terbinafine is fungicidal. 11 Furthermore, terbina-
Journal of the American Academy of Dermatology Volume 37, Number 5, Part 1
fine is h i g h l y keratophilic, r e a c h i n g the nail plate within the first w e e k o f therapy and persisting there at c o n c e n t r a t i o n s e x c e e d i n g its cidal c o n c e n tration against d e r m a t o p h y t e s b y 100 times or m o r e for several m o n t h s after d i s c o n t i n u a t i o n o f therapy. 12-14 T h e ability o f terbinafine to achieve h i g h cure rates with short treatment duration, a low incid e n c e o f relapse and side effects, and a lack o f significant drug interactions associated with its use 15 represent significant advantages. REFERENCES
1. Roberts DT. Prevalence of dermatophyte onychomycosis in the United Kingdom: results of an omnibus survey. Br J Dermatol 1992;126(Suppl 39):23-7. 2. Andr6 J, Achten G. Onychomycosis. Int J Dermatol 1987 ;26:481-90. 3. Villars VV, Jones TC. Special features of the clinical use of oral terbinafine in the treatment of fungal diseases. Br J Dermatol 1992;126(Suppl 39):61-9. 4. Zaias N, Serrano L. The successful treatment of finger Trichophyton rubrum onychomycosis with oral terbinafine. Clin Exp Dermatol 1989; 14:120-3. 5. Goodfield MJD, Andrew L, Evans EGV. Short term treatment of dermatophyte onychomycosis with terbinafine. BMJ 1992;304:1151-4.
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6. Van Der Schroeff JG, Cirkel PKS, Crijns MB, et al. A randomized treatment duration-finding study of terbinafine in onychomycosis. Br J Dermatol 1992; 126(Suppl 39):36-9. 7. Mantel N, Haenszel W. Statistical aspect of the analysis of data from retrospective studies of disease. J Natl Cancer Inst 1959;22:719-48. 8. Onychomycosis and terbinafine. Lancet 1990;335:636. 9. Korting HC, Sch~ifer-Korting M. Is tinea unguium still widely incurable? Arch Dermatol 1992;128:243-8. 10. Hay RJ, Clayton YM, Griffiths WAD, Dowd PM. A comparative double blind study of ketoconazole and griseofulvin in dermatophytosis. Br J Dermatol 1985; 112:691-6. 11. Ryder NS. The mechanism of action of terbinafine. Clin Exp Dermatol 1989;14:98-100. 12. Finlay AY. Pharmacokinetics of terbinafine in the nail. Br J Dermatol 1992;126(Suppl 39):28-32. 13. Faergemann J, Zehender H, Millerioux L. Levels of terbinaflne in plasma, stratum comeum, dermis-epidermis (without stratum corneum), sebum, hair and nails during and after 250 mg terbinafine orally once daily for 7 and 14 days. Clin Exp Dermatol 1994;19:121-6. 14. Clayton YM. Relevance of broad-spectrum and fungicidal activity of antifungals in the treatment of dermatomycoses. Br J Dermatol 1994;130(Suppl 43):7-8. 15. Back DJ, Tjia JF, Abel SM. Azoles, allylamines and drug metabolism. Br J Dermatol 1992;126(Suppl 39): 14-8.
Boston, Massachusetts; Toronto, Kingston, Ottawa, and Mississauga, Ontario; Calgary and Edmonton, Alberta; Laval and Montrdal, Quebec; Cleveland, Ohio; St. Johns, Newfoundland; Saskatoon, Saskatchewan; Fairhope, Alaska; Philadelphia, Pennsylvania; Vancouver, British Columbia; Halifax, Nova Scotia; New Haven, Connecticut; New York, New York," Winnipeg, Manitoba; Miami Beach, Florida; and East Hanover, New Jersey Background." Onychomycosis is an increasing problem with limited therapeutic options. Objective: We evaluated the safety and efficacy of oral terbinafine, a new fungicidal antimycotic, in patients with toenail onychomycosis.
Methods: A North American multicenter, double-blind, placebo-controlled study evaluated the mycologic and clinical efficacy of oral terbinafine 250 rag/day for 12 or 24 weeks in 358 patients with toenail onychomycosis. Results: A total of 74% of patients treated with 12 or 24 weeks of terbinafine achieved a successful clinical outcome. Approximately 11% of terbinafine responders showed evidence of relapse 18 to 21 months after cessation of treatment. Terbinafine was well tolerated; most adverse events were transient and mild to moderate in severity. Conclusion: The results of this study confirm that oral terbinafine is a safe and effective therapy for the treatment of onychomycosis. (J Am Acad Dermatol 1997;37:740-5.)
From Massachusetts General Hospital, Bostona; University of Toronto, Ontariob; University of Calgary, AlbertaC; University of Laval, Quebecd; Queen's University, Kingston, Ontarioe; University Hospitals of Cleveland, Ohiof; University of Ottawa, Ontariog; Universit6 de Montrral h and Centre Hospitalier Cotedes-Neiges, i Montrral, Quebec; Memorial University of Newfoundland, St. Johnsi; University of Saskatchewan, Saskatoonk; Thomas Hospital, Fairhope, Alaska1; University of Alberta, Edmontonm; Hospital of the University of Pennsylvania, Philadelphian; University of British Columbia, Vancouver°; Dalhousie University, Halifax, Nova ScotiaP; Yale-New Haven Hospital, Connecticutq; Columbia Presbyterian Hospital, New Yorkr; University of Toronto, Mississauga, OntarioS; University of Manitoba, Winnipegt; Mt. Sinai Medical Center, Miami Beach'S; and Novartis Pharmaceuticals Corporation, East Hanover.v Supported by Novartis Pharmaceuticals Corporation, East Hanover, N.J. Accepted for publication July 23, 1997. Reprint requests: Lynn A. Drake, MD, Massachusetts General Hospital, Dermatology-BAR 604, 40 Blossom St., Boston, MA 02114-2698. Copyright © 1997 by the American Academy of Dermatology, Inc. 0190-9622/97/$5.00 + 0 16/1/84863
740
Onychomycosis represents a significant and increasingly common problem that affects 2.7% to 13% of the adult population. 1,2 Therapeutic options have been limited and the results disappointing, especially for onychomycosis of the toenails. Terbinafine (Lamisil), a new, orally active fungicidal allylamine, has shown effectiveness in fingernail and toenail onychomycosis 3-6 and is currently widely approved for these indications. This report presents the results of the first U.S./Canadian multicenter study of terbinafine in patients with toenail onychomycosis. The objectives of this study were to compare safety and efficacy of 12 and 24 weeks' treatment with oral terbinafine tablets (250 mg/day) versus placebo in patients with onychomycosis and to determine the relapse rate in effectively treated patients at 72 and 96 weeks' follow-up.
Journal of the American Academy of Dermatology Volume 37, Number 5, Part 1
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741
T e r b i n a f i ~
8O
6o
Terbinafine 12 wk
40
A
20 0 0 4 8 12 16 20 24 28 32 36 40 44 48 Weeks
100
T e r b i n a f i n e ~
80
B
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,
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i
.
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.
.
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I
I
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0 0 4 8 12 16 20 24 28 32 36 40 44 48 Weeks Fig. 1. Time course of mycologic response: Percent of patients with (A) negative microscopy or (B) negative culture. Terbinafine 12- or 24-week versus placebo: p < 0.05 at week 12 (microscopy or culture); p < 0.001 during weeks 18 to 48 (microscopy or culture).
METHODS
A total of 358 patients 18 to 70 years of age with distal subungual onychomycosis of the toenails were enrolled at seven U.S. and 15 Canadian centers. The study protocol was approved by the review boards of all participating centers before its initiation. Written informed consent was obtained from all participating patients. Eligible patients had onychomycosis of at least one great toenail with the diagnosis confirmed by potassium hydroxide (KOH) wet mount and culture for a dermatophyte, and at least 2 mm of unaffected proximal nail (evidence of ability of the nail to grow). Patients were excluded if they had received systemic antifungal therapy 3 months or less before entry or topical antifungal therapy 1 month or less before entry, or had psoriasis (irrespective of nail involvement), proximal subungual onychomycosis, or superficial white onychomycosis. The 96-week study included a double-blind treatment phase of 24 weeks in which patients were randomly assigned to one of three parallel groups in a 2:2:1 ratio: oral terbinafine (n -= 142, 250 mg once daily) for 12 weeks then placebo for 12 weeks, oral terbinafine (n = 145,250 nag once daily) for 24 weeks,
or placebo (n = 71) for 24 weeks. This phase was followed by 24 weeks of blinded follow-up without treatment (weeks 24 to 48). A cohort of patients (designated as the "follow-up population"), with negative mycologic findings (culture and KOH) and at least 5 mm of unaffected new nail growth by week 48, was observed for up to an additional 48 weeks (96 weeks total) to assess long-term clinical effectiveness and relapse. Mycologic (KOH microscopy and culture) and clinical assessments were performed on the "target" nail (the most severely affected great toenail) at intervals of 4 or 6 weeks during the 48-week blinded phase of the study. Length of unaffected nail (distance between the proximal nailfold and the most proximal point of fungal involvement) and percent nail involvement (estimated to the nearest 10%) were determined to assess disease progression and nail growth. In addition, patients were asked to provide an overall assessment of their response to therapy as excellent, very good, slight improvement, fair, poor/no effect. Patients with a 90% to 100% clear nail were designated as having achieved clinical success. Mycologic and clinical assessments also were performed for the terbinafine-treated followup population during the open follow-up phase (weeks 72 and 96). Safety and tolerability of oral terbinafine
742
Journal of the AmericanAcademyof Dermatology November 1997
Drake et al.
Table I. Baseline characteristics among study groups* Study groups Variable
Terbinafine 12-wk
Mean age (yr) Male sex (%) Median disease duration (mo) (range) Mean nail involvement (%) Mean No. affected nails Pathogens isolated at enrollment (%)
Terbinafine 24-wk
Placebo
45 -+ 1 71 72 (4 to 360) 57 +- 2 6.2 _+0.2
45_+ 1 81 84 (2 to 600) 58-+ 2 6.1 _+0.3
45 +- 2 80 60 (8 to 540) 57 +_3 6.7 -+ 0.3
95 1 0 4
90 2 1 8
94 4 0 1
Trichophyton rubrum Trichophyton mentagrophytes Epidermophyton floccosum Other *Values represent means _ SEM unless otherwise stated.
Table II. Long-term clinical outcomes: Percentage (fraction) patients in follow-up population* Outcome
Clinical success t Week 48 Week 72 Week 96 Last observation Anytime Relapse* (time after cure) _< 12 mo > 12 mo Total Failures §
Terbinafine 12 wk
82% 94% 81% 79% 94%
(58/71) (60/64) (47/58) (56/71) (67/71)
4% 11% 15% 6%
Terbinafine 24 wk
90% 92% 89% 85% 94%
(86/96) (75/82) (65/73) (82/96) (90/96)
2% 6% 8% 6%
*Terbinafine-treated patients with negative KOH/culture and at least 5 mm of new unaffected nail growth by week 48 were designated by protocol to be followed up for an additional 48 weeks. t_> 90% clear nail. *>_90% clear nail at any time and < 90% at last visit. §>_90% clear nail at no time.
were assessed by physical examination, vital signs, laboratory evaluation, and reports of adverse experiences. Statistical differences in clinical or mycologic efficacy between the terbinafine or placebo groups were assessed by means of the Cochran-Mantel-Haenszel test (binary variables) and two-way ANOVA (continuous variables) using center as the stratification variable] Fisher's exact test was used to compare the incidence of adverse events in the terbinafine and placebo groups.
RESULTS The terbinafine and placebo groups were well
balanced with respect to age, sex, disease duration, percent nail involvement, and number of affected nails (Table I). Trichophyton rubrum accounted for 90% to 95% of infections.
Mycologic response During the 48-week blinded phase, the percentage of terbinafme-treated patients with negative microscopy or negative culture progressively increased even after cessation of 12 or 24 weeks of therapy (Fig. 1). At week 48, 70% of patients treated with terbinafine for 12 weeks and 87% of patients treated for 24 weeks exhibited both negative microscopy and negative culture versus 9% for placebo-treated patients. For the terbinafine treatment groups, median response times were 12 to 18 weeks for negative culture and 18 to 24 weeks for negative microscopy.
Clinical efficacy Terbinafine treatment produced a significant and progressive decrease in the percent involvement of target nails and a corresponding increase in unaffected nail growth during therapy and after cessation of therapy (Fig. 2). By contrast, placebo= treated patients showed further worsening, as evidenced by an increase in nail involvement at week 48 and a progressive decrease in uninvolved nail relative to baseline. By week 48 at least 5 mm of unaffected nail growth was achieved in 61% of the terbinafine 12-week group and 73% of the terbinafine 24-week group. Zero percent nail involvement was observed in 40% of the terbinafine 12-week group and 50% of the
Journal of the American Academy of Dermatology Volume 37, Number 5, Part 1
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70
=Eso > 50
4o
A
~30 20 c
10
=E
0
t~
~
k -
Terbinafine 24 wk
, 0
4
, , ~ , i , , , , , , 8 12 16 20 24 28 32 36 40 44 48 Weeks
10
Terbinafine 24 wk
B
--,04 Placebo
0 0
4
8
12 16 20 24 28 32 36 40 44 48 Weeks
Fig. 2. Time course of clinical response. A, Percent nail involvement and (B) millimeters of unaffected nail growth. Terbinafine 12- or 24-week versus placebo: p < 0.001 during weeks 12 to 48 (nail involvement or nail growth).
terbinafine 24-week group. Clinical success rates corresponded with patient satisfaction ratings (Fig. 3). At week 48, the last blinded observation point, a high level of response as measured by both evaluations was achieved in approximately 60% of the terbinafine 12-week group and 75% of the terbinafine 24-week group. Although not all patients were observed beyond week 48, 71% or 101 of 142 of the terbinafine 12-week group and 77% or 112 of 145 of the terbinafine 24-week group achieved clinical success at some point during the 96-week study. Long-term outcomes/relapse in follow-up pop-
were no significant differences in mycologic or clinical responses between the 12- and 24-week treatment groups. The median duration of observation of this group was 16.5 months after achievement of clinical success. Of those patients with negative KOH and negative culture at the beginning of the extended observation, 95% and 88%, respectively, were still negative at their last evaluation (up to week 96). In terms of clinical response, 6% of the follow-up population failed to achieve clinical success during the 96 weeks, and 11% exhibited evidence of relapse during the follow-up period.
ulation
Safety
A total of 167 (of 358) terbinafine-treated (but no placebo) patients had negative mycologic findings and at least 5 mm of unaffected new nail growth by week 48 (Table II). These patients, observed from weeks 48 to 96 showed durability in both their mycologic and clinical responses to treatment. Within the follow-up population, there
The adverse events most frequently reported in the terbinafine and placebo groups are shown in Table III. No significant differences were noted between terbinafine groups (12 or 24 weeks alone or combined) and placebo. Most adverse events considered possibly or probably drug-related were mild to moderate in severity and were transient.
Journal of the American Academy of Dermatology
744
November 1997
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Fig 3. Effectiveness. A, Clinical success: Percent of patients with at least 90% clear nail at week 48. Terbinafine 12- or 24-week versus placebo: p < 0.001, terbinafine 12-week versus 24-week: p < 0.01. B, Patient satisfaction: Percent of patients rating response as excellent/very good based on global assessment of all nails at last blinded evaluation. Terbinafine 12- or 24-week versus placebo: p < 0.001; terbinafine 12-week versus 24-week: p < 0.05.
Table III. Most frequently reported adverse events (% of patients) A d v e r s e event
URTI Headache Rhinitis Diarrhea Flatulence Back pain
Terbinafine 12-wk
Terbinafine 24-wk
Placebo
15.4 12.6 4.9 7.7 1.4 5.6
20.5 9.6 6.8 5.5 5.5 2.1
15.7 8.6 7.1 4.3 4.3 1.4
URT1, Upper respiratory tract infection.
All nine severe adverse events considered possibly or probably drug-related involved the gastrointestinal system or skin; five required discontinuation of terbinafine treatment. Two of 142 patients in the 12-week terbinafine group discontinued therapy because of rash (one) or diarrhea (one). Three of 145 patients in the 24-week group discontinued therapy because of rash (two patients) or abdominal pain (one). No clinically meaningful changes in hematology values from baseline were noted with terbinafine therapy. No clinically meaningful differences were observed between terbinafine and placebo treatment groups for SGOT, SGPT, alkaline phosphatase, and bilirubin. There was no evidence of increased severity of adverse events with increased treatment duration. DISCUSSION
This study confirms the results of European
studies showing oral terbinaflne to be an effective and safe therapy for toenail onychomycosis) ,5,6 Administration of terbinafine (250 mg/day) resulted in a rapid mycologic and clinical response that continued to improve after cessation of therapy. Although drug dosing was stopped after 12 or 24 weeks, normal unaffected nails continued to grow. A total of 74% of patients treated with terbinafine achieved a successful clinical outcome. A normal nail plate was observed in approximately 45% of terbinafine-treated patients at the end of the blinded portion of the study, and this percentage increased during follow-up. The overall response rates of the two treatment groups was comparable (71% vs 77% for 12 and 24 weeks, respectively); however, the data suggest that some patients with extensive involvement of the great toenails may benefit from treatment longer than 12 weeks. Terbinafine was well tolerated. Most adverse events were transient and mild to moderate in severity. Relapse rates assessed in a predesignated responder population up to 18 to 21 months after cessation of treatment were estimated to be approximately 11%. The high, sustained response with a 3-month course of terbinaflne treatment stands in contrast to the low cure rate (20% to 60% or less) and high relapse rate (40% to 70% or more) observed with even prolonged (9 to 12 months or longer) treatment of toenail onychomycosis with griseofulvin. 8-1° In contrast to griseofulvin and the azoles, which are fungistatic, terbinafine is fungicidal. 11 Furthermore, terbina-
Journal of the American Academy of Dermatology Volume 37, Number 5, Part 1
fine is h i g h l y keratophilic, r e a c h i n g the nail plate within the first w e e k o f therapy and persisting there at c o n c e n t r a t i o n s e x c e e d i n g its cidal c o n c e n tration against d e r m a t o p h y t e s b y 100 times or m o r e for several m o n t h s after d i s c o n t i n u a t i o n o f therapy. 12-14 T h e ability o f terbinafine to achieve h i g h cure rates with short treatment duration, a low incid e n c e o f relapse and side effects, and a lack o f significant drug interactions associated with its use 15 represent significant advantages. REFERENCES
1. Roberts DT. Prevalence of dermatophyte onychomycosis in the United Kingdom: results of an omnibus survey. Br J Dermatol 1992;126(Suppl 39):23-7. 2. Andr6 J, Achten G. Onychomycosis. Int J Dermatol 1987 ;26:481-90. 3. Villars VV, Jones TC. Special features of the clinical use of oral terbinafine in the treatment of fungal diseases. Br J Dermatol 1992;126(Suppl 39):61-9. 4. Zaias N, Serrano L. The successful treatment of finger Trichophyton rubrum onychomycosis with oral terbinafine. Clin Exp Dermatol 1989; 14:120-3. 5. Goodfield MJD, Andrew L, Evans EGV. Short term treatment of dermatophyte onychomycosis with terbinafine. BMJ 1992;304:1151-4.
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