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Long-Term Effectiveness of Treatment with Terbinafine Vs Itraconazole in Onychomycosis a 5-Year Blinded Prospective Follow-Up Study

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Long-Term Effectiveness of Treatment with Terbinafine Vs Itraconazole in Onychomycosis a 5-Year Blinded Prospective Follow-Up Study STUDY Long-term Effectiveness of Treatment With Terbinafine vs Itraconazole in Onychomycosis A 5-Year Blinded Prospective Follow-up Study Ba´rður Sigurgeirsson, MD, PhD; Jo´n H. O´ lafsson, MD, PhD; Jo´n þ. Steinsson, MD Carle Paul, MD; Stephan Billstein, MD; E. Glyn V. Evans, PhD Objective: To examine long-term cure and relapse rates microscopy and culture at the end of follow-up and no re- after treatment with continuous terbinafine and inter- quirement of second intervention treatment. Secondary ef- mittent itraconazole in onychomycosis. ficacy criteria included clinical cure without second inter- vention treatment and mycological and clinical relapse rates. Design: Long-term prospective follow-up study. Results: Median duration of follow-up was 54 months. Setting: Three centers in Iceland. At the end of the study, mycological cure without second intervention treatment was found in 34 (46%) of the 74 Subjects: The study population comprised 151 pa- terbinafine-treated subjects and 10 (13%) of the 77 itra- tients aged 18 to 75 years with a clinical and mycologi- conazole-treated subjects (PϽ.001). Mycological and clini- cal diagnosis of dermatophyte toenail onychomycosis. cal relapse rates were significantly higher in itraconazole- vs terbinafine-treated patients (53% vs 23% and 48% vs Interventions: In a double-blind, double-dummy study, 21%, respectively). Of the 72 patients who received sub- patients were randomized to receive either terbinafine (250 sequent terbinafine treatment, 63 (88%) achieved myco- mg/d) for 12 or 16 weeks or itraconazole (400 mg/d) for logical cure and 55 (76%) achieved clinical cure. 1 week in every 4 for 12 or 16 weeks (first intervention). Patients who did not achieve clinical cure at month 18 or Conclusion: In the treatment of onychomycosis, continu- experienced relapse or reinfection were offered an addi- ous terbinafine provided superior long-term mycological tional course of terbinafine (second intervention). and clinical efficacy and lower rates of mycological and clini- cal relapse compared with intermittent itraconazole. Main Outcome Measures: The primary efficacy crite- rion was mycological cure, defined as negative results on Arch Dermatol. 2002;138:353-357 NYCHOMYCOSIS is a com- multicenter, double-blind, double-dum- mon disease, and recent my study (the Lamisil vs Itraconazole in population studies have Onychomycosis [LION] study) that pa- shown a prevalence of be- tients treated with continuous terbin- tween 2% and 8%.1-3 This afine achieved significantly superior my- disease is more common in older age groups cological and clinical cure rates compared From the Department O and in selected populations, such as swim- with patients treated with intermittent itra- of Dermatology, University mers and individuals with diabetes melli- conazole.9,10 of Iceland and Landspitali 4-6 University Hospital, Reykjavik, tus or psoriasis. Onychomycosis can be While both itraconazole and terbin- Iceland (Drs Sigurgeirsson and an infection reservoir for dermatomycoses afinehaveproventobeeffectiveagainstony- O´ lafsson); Húðlæknasto¨ðin, of the adjacent skin, such as interdigital or chomycosis, very little is known about the Dermatology Center plantar (“moccasin type”) tinea pedis. Stud- long-term maintenance of cure and relapse (Dr Steinsson); the Department ies have shown that onychomycosis can rates observed with both drugs.11 The ob- of Dermatology, Mulhouse have severe impact on quality of life,7 and jective of the present study was to exam- Hospital, Mulhouse, France; this disease should not be trivialized.8 ine long-term mycological and clinical cure Clinical Research, Novartis For several years treatment of ony- rates after treatment with terbinafine and Pharma AG, Basel, Switzerland chomycosis was limited to griseofulvin, itraconazole for onychomycosis. Similarly, (Dr Paul); Clinical Research, which provided low cure rates and long mycological and clinical relapse rates were Novartis Pharmaceutical Corporation, East Hanover, NJ treatment times. Modern antifungal agents, examined. A secondary objective was to (Dr Billstein); and Mycology such as terbinafine and itraconazole, are evaluate the effect of subsequent treatment Reference Centre, University of significantly more effective with shorter withterbinafineinpatientswhoexperienced Leeds and General Infirmary, treatment times. It has previously been relapses or failed the original treatment with Leeds, England (Dr Evans). demonstrated in a randomized controlled, terbinafine or itraconazole. (REPRINTED) ARCH DERMATOL / VOL 138, MAR 2002 WWW.ARCHDERMATOL.COM 353 ©2002 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/28/2021 PATIENTS AND METHODS Mycology and Ethics PROTOCOL All mycological examinations were undertaken at a single laboratory (Mycology Reference Centre, Leeds, England). Study Outline The study protocol conformed to good clinical practice: all patients gave written informed consent to participate, and Patients were recruited from a multinational, prospective, the study protocol was subjected to approval by the insti- randomized, double-blind, double-dummy study compar- tutional review board. ing the safety and efficacy of continuous terbinafine with intermittent itraconazole treatment in onychomycosis. The Primary and Secondary Efficacy Criteria clinical courses of 496 patients were followed up to month 18.9,10 Of these 496 patients, 144 from the 3 Icelandic cen- The primary efficacy criterion was the proportion of pa- ters were followed up prospectively (Figure 1). Iceland tients who remained mycologically cured at the end of fol- was the most suitable country to do this follow-up be- low-up without requiring second intervention treatment cause there was a large number of patients enrolled in the with terbinafine. Mycological cure was defined as nega- trial, and patients were easy to follow-up for long periods tive results on both microscopy and culture of samples taken because of the unique geographic location. from the target toenail. Secondary efficacy criteria in- cluded (1) clinical cure (defined as 100% normal- Inclusion and Exclusion Criteria appearing nail) at the end of follow-up without the require- ment of second intervention treatment, (2) complete cure The study population comprised men and women aged be- defined as mycological plus clinical cure, (3) clinical and tween 18 and 75 years with a clinical diagnosis of onychomy- mycological relapse over time, (4) mycological and clini- cosis of the toenail confirmed by positive mycological culture cal cure over time, and (5) the effect of subsequent terbi- and microscopic (potassium hydroxide examination) find- nafine treatment on clinical and mycological outcome. A ings for a dermatophyte.9,10 All patients belonging to the mycological relapse was defined as a patient who achieved intention-to-treat population were followed up prospectively. mycological cure at month 12 but had mycologically posi- tive test results at any time thereafter. A clinical relapse was Planned Interventions defined as a patient who achieved clinical cure at month 18 and showed clinical signs of infection at any time there- First Intervention. Terbinafine was given at a dosage of 250 after. The difference in times for the assessment of myco- mg/d for 12 or 16 weeks; itraconazole, at a dosage of 400 logical and clinical cure can be explained by the slow growth mg/d for 1 week every 4 for 12 (3 cycles) or 16 (4 cycles) rate of nails. A duration of 18 months is needed to assess weeks. The 4 treatment groups were compared at baseline, clinical cure, whereas 12 months is adequate to assess my- and at weeks 4, 8, 12, 16, 32, 48, and 72 (LION study). The cological cure.9 cure rates at month 18 (week 72) were very similar for both terbinafine groups and both itraconazole groups. There- Rationale and Methods for Statistical Analysis fore, in view of the smaller number of patients in the fol- low-up study, only 2 treatment groups were considered for All efficacy assessments were based on the intention-to- prospective analysis, namely, patients treated with terbin- treat population defined as all randomized patients who sat- afine (for 12 or 16 weeks) and patients treated with itra- isfied all inclusion criteria and had at least 1 primary effi- conazole (for 3 or 4 cycles). Patients included in the fol- cacy measurement at month 6. Treatment comparisons for low-up study were checked for clinical and mycological status mycological cure rate and mycological relapse rate were made at approximately 6-month intervals for up to 5 years (LION by the Fisher exact test, using the SAS statistical package (SAS Icelandic Extension Study). Institute Inc, Cary, NC). The “last observation carried for- ward” method was used to impute missing observations.12 Second Intervention. From month 18 onward, an addi- tional 12-week course of oral terbinafine, 250 mg/d, was ASSIGNMENT AND BLINDING offered on clinical signs of reinfection. If necessary, fur- ther additional courses of terbinafine were offered on signs Details on assignment and blinding have been described of reinfection or if previously negative mycological find- previously.9 After 18 months the study continued to be ings became positive with signs of clinical disease. Pa- blinded to patients and investigators until an interim analy- tients with positive mycological findings but with normal sis was performed in September 1999, after 4 years of fol- nails were not treated. low-up on average. RESULTS treatment, 151
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