Efficacy and tolerability of topical terbinafine in the treatment of tinea cruris Larry E. Millikan, MD New Orleans, Louisiana Thirty menwith clinical and mycologic evidence oftinea cruris were enrolled ina controlled, randomized, double-blind trialcomparing terbinafine 1% cream and itscream vehicle asplacebo. Patients applied thetestmedications totheaffected area twice daily for 2weeks. Therapeutic response was evaluable in18 patients after each week oftreatment and at afollow-up visit 2 weeks after therapy ended. At each visit, terbinafine was found to bemore effective than the cream vehicle in the reduction of thesigns and symptoms ofinfection and in the conversion ofculture andmicroscopy findings tonegative ornormal. Attheend oftreatment, therapy was effective in67% ofthenine terbinafine-treated patients compared with only 11 % of thenine placebo-treated patients. At thefollow-up examination, efficacy rates were 78% intheterbinafine treatment group and33% intheplacebo group-a difference ofborderline statistical significance (p = 0.077). Possible reasons for this result may include thehigher incidence ofchronic disease intheterbinafine group andthelarge number ofpatients who were classified asdelayed exclusions because ofnegative initial culture for dermatophytes. Noside effects or significant alterations in laboratory or hematologic tests were observed in either treatment group. (J AM ACAD DERMATOL 1990;23:795-9.) Terbinafine (Lamisil) is a new allylamine antifungal effective against a wide range of pathogenic fungi. I, 2 Dermatophytes have been shown to be particularly susceptible, and comparative in vitro investigations havedemonstratedthat terbinafine is significantlymoreactivethanotherantifungaldrugs, including econazole, ketoconazole, and griseofulvin.' In preclinical investigations in experimental animal models of dermatophytosis, topical applicationsofterbinafine resulted in the rapidresolution of the signs ofinfection, as well as the eradication ofthe causative fungi," 5 This article gives the results of a double-blind, placebo-controlled trial of terbinafine 1% cream in the treatment of tinea cruris. PATIENTS AND METHODS
Patients eligible for participation in this randomized trial weremen between 18 and 65 yearsof age with clinical and microscopic evidence of tinea cruris,subsequently confirmed by culture. Patientswith concomitant yeast or bacterial infections of the skin From the Department of Dermatology, Tulane University School of Medicine. Supportedin part by an educational grant fromSandozPharmaceuticals Corp., East Hanover, N.J. Reprint requests: Larry E. Millikan, MD, Chairman, Department of Dermatology, Tulane University Schoolof Medicine, 1430Tulane Avenue, New Orleans, LA 70112.
16/0/23516
were excluded, as werethose treated withsystemic antifungal drugs within the 4 weeks preceding study enrollment or with topical antifungal therapy within the preceding 2 weeks. Concomitant therapy for chronic diseases, such as diabetes or hypertension, was permitted. After providing informed consent, patients who met the studyentrycriteriawere randomly assigned to treatment with either terbinafine I % cream or placebo, which consisted ofthecreamvehicle. These patients were instructed to rub the cream into the affected area twice daily-morning and eveningfor 2 weeks. Instructions for application stipulated that the entire visibly affected surface was to be treated, as well as a l-inch wide margin ofhealthy skin surrounding the lesion. Patientswereseen before treatment was started, after 1and2 weeks oftherapy,and 2 weeks afterthe conclusion of therapy, At eachvisit, skin scrapings wereobtained fordirectmicroscopic examination of KOH preparations and forculture. If a patientwith abnormal microscopy findings before treatment failed to have cultureconfirmation after the 2-week culture incubation period, he was categorized as a delayed exclusion and was notincluded in the evaluation of drug efficacy. Clinical response to treatmentwasevaluated at eachvisit onthe basis of signs and symptoms ofinfection (i.e., erythema, pustules, desquamation, incrustation, vesiculation, exudation,
795
Journal of the American Academy of Dermatology
796 Millikan Table I. Patient population characteristics
I
T erbinafine
I
Placebo
I
Total
No. of patients 9 18 9 Mean age (yr) 29 28 29 (range) (19-39) (18-42) (18-42) Median illness duration 24 6 (wk) Infecting organism (No. of patients) Trichophyton rubrum 7 7 14 Epidermophyton 1 1 2 floccosum Microsporum canis 1 0 1 T. tonsurans 1* 0 1 Type of lesion Single 2 1 3 Multiple 8 7 15 Previous antifungal Rx I 6 7 *Thispatientalso had concomitant infection with E. fioccosum.
and pruritus), scored individually on a scale of 0 to 3 (0 = absent, 1 = mild, 2 = moderate, 3 = severe). At the end of treatment and at the 2-week followup examination, therapeutic responsein each patient was categorized as follows: complete cure-microscopy normal and culture negative, no residual clinical signs and symptoms; mycologic cure-microscopy normal and culture negative with mild residual erythema and/or desquamation and/or pruritus (total score :$2), but no other signs and symptoms; improvement-culture negative with greater than or less than 50% reduction in signs and symptoms, or culture positivewith significant reduction in signs and symptoms;failure-culture positiveand persistent signs and symptoms. Therapy was defined as "effective" if either a complete cure or mycologic cure was achieved and as "ineffective" if any other response occurred. In addition to this objectiveevaluation of response, the study investigator also provided a subjective assessment of the clinical response to treatment. Bloodsamples were obtained for hematologic and biochemical tests at the initial examination and again at the end of the 2-week treatment period. These tests were repeated at the discretion of the investigator at the follow-upexamination if values detected before or during treatment were significantly outside the accepted normal range. At each visit, local irritation or redness, burning or stinging on application of the medication, and dryness were rated on a scale of 1 to 3 (1 =mild, 2 = moderate,
3 = severe). Other adverse events that may have occurred during treatment were also recorded and rated according to this same scale. Statistical methods Sign tests were used descriptively to assesschanges from baseline separately for microscopy, culture, and each sign or symptom. The total score of signs and symptoms was calculated, and comparison between study groups was made at each visit on the total score and its change from baseline by means of Wilcoxon-Mann-Whitney U tests. The one-tailed Fisher exact test was used for confirmative testing of the null hypothesis that terbinafine was equivalent in efficacy to placebo. Changes from baseline for patients in the final study population were assessed by sign tests for laboratory variables. RESULTS
The original study population consisted of 30 male patients, 15 in each treatment group. Data from eight patients, including five treated with terbinafine and three treated with placebo, were excluded from efficacy analyses because of negative pretreatment cultures. In addition, one terbinafinetreated patient and three placebo-treated patients were dropped from the study because of failure to comply with the study visit schedule. Thus analyses of clinical and myocologic response to treatment were based on data from 18 patients-nine treated with terbinafine and nine treated with placebo. The characteristics of the patient population are noted in Table 1. Most of the patients in the study group were either white (50%) or black (44%). The terbinafine-treated and placebo-treated groups were similar with respect to age and race distribution and all clinical features, with the following exceptions: tinea cruris infection was classified as chronic in eight patients and acute in lO, and the prevalence of chronic disease was substantially higher in the terbinafine-treated group (67%) than in the placebotreated group (22%). Terbinafine-treated patients also had a longer median duration of disease before therapy than those assigned to the placebo-treated group. Trichophyton rubrum was the most common causative organism, occurring in 78% of each treatment group. Clinical efficacy Before the start of treatment, erythema, desquamation, and pruritus (the three major signs and
Volume 23 Number 4, Part 2 October 1990
Topical terbinafine in tinea cruris 797 7 --.-
e
6
en E
5
~
.s Q.
E >(/)
Il!I
TERBINAFINE
--0- Placebo
4
Ul
c: en
.21
:ffl
3
.s c:
I'll
Ql
::E
2
o-l-----~_---..,.__---------..,....-----J 4 2 o (follow-up)
Treatment week
Fig. 1. Reduction in meantotalsigns and symptoms score intreatment oftinea cruris with terbinafine or placebo. Score includes erythema, desquamation, pruritus, incrustation, pustules, and vesiculation; total possible score, 18.
symptoms) were present in all 18 study subjects. Mean scores for each of these signs and symptoms declined rapidly in patientstreated withterbinafine. In contrast, resolution of these clinical manifestations of infection was slower and much less pronounced in the placebo-treated patients. For allsigns and symptoms combined, terbinafine treatment led to a marked reduction in comparison to placebo (Fig. 1). After 1 week of treatment,the meantotal scorein the terbinafine-treated grouphad declined from 6.56 at baseline to 2.67. A reduction to 1.56 wasnotedat the endofthe 2-week treatment period, and an even lower score of 0.78 wasrecorded at the 2-week follow-up examination. The clinical response of the placebo-treated patients was much less marked, thereby resulting in a statistically significant difference between thetwotreatmentgroups in favor of terbinafine at all treatment assessment intervals. The mean changein the total score from baseline was alsosignificantly greater in the terbinafine-treated group than in the placebo-treated group at each examination (p = 0.046, 0.034, and 0.024 at weeks 1,2, and 4, respectively). Mycologic efficacy
After 1 weekof treatment, both microscopy and culture findings had reverted to normal or negative
in sixof eight terbinafine-treated patients examined at that timebutinonly threeofeightplacebo-treated patients (Fig. 2). (Onepatient in eachgroup missed the first visit, but both were evaluable at end of treatment and follow-up). Bythe end of the study, mycologic findings werenegative in allpatients who received terbinafine andinonly threeofninepatients in the placebo-treated group. At the 2-week followup, microscopy andculturefindings were normalor negative in seven terbinafine-treated patients compared with only three placebo-treated patients. Overall efficacy TableII shows theoverall number ofpatients who received effective treatment. At the end of 2 weeks of treatment, 67% of the terbinafine-treated group was categorized as having received effective treatment (complete or mycologic cure with only residual signs andsymptoms). Although mycologic cure withimprovement in symptoms wasnoted inthe remaining terbinafine-treated patients, theirsymptom response didnot meetthe criteria for effective therapy. Only 11 % ofthe placebo-treated patients were categorized as having received effective treatment. The difference between the twogroups in overall efficacy at the endoftreatmentwas ofborderline statistical significance (p = 0.077). The one terbin-
Journal of the American Academy of Dermatology
798 Millikan
--.~
>.
~ 100
! Q)
~
TERBINAFINE Placebo
80
ljll c
~
60
~
40
"-; c,
Cl'l!
20
Oo-----...,.------.,r------------,.-------' o
4
2
(follow-up)
Treatment week
Fig. 2. Percentage ofpatients with normal microscopy findings andnegative culture during andafter treatment with terbinafine or placebo for tinea cruris.
Table II. Overallevaluation of clinical and mycologic response to treatment of tinea cruris with terbinafine versus placebo End of therapy
Response"
Complete cure Mycologic cure Effective therapy Improvement Failure Ineffective therapy
Terbinaline
I
4
.f
6 (67%) 3
Q
3 (33%)
Follow-up Placebo
0
1
1 (11%) 2
.Q
8 (89%)
Terbinaline
4
J
7 (78%) 1
1
2 (22%)
I
Placebo
1
.f
3 (33%) 1
s
6 (67%)
*Complete cure, negative culturewith no signsand symptoms; mycologic cure, negativeculture with minimalsignsand symptoms (score
Patients eligible for participation in this randomized trial weremen between 18 and 65 yearsof age with clinical and microscopic evidence of tinea cruris,subsequently confirmed by culture. Patientswith concomitant yeast or bacterial infections of the skin From the Department of Dermatology, Tulane University School of Medicine. Supportedin part by an educational grant fromSandozPharmaceuticals Corp., East Hanover, N.J. Reprint requests: Larry E. Millikan, MD, Chairman, Department of Dermatology, Tulane University Schoolof Medicine, 1430Tulane Avenue, New Orleans, LA 70112.
16/0/23516
were excluded, as werethose treated withsystemic antifungal drugs within the 4 weeks preceding study enrollment or with topical antifungal therapy within the preceding 2 weeks. Concomitant therapy for chronic diseases, such as diabetes or hypertension, was permitted. After providing informed consent, patients who met the studyentrycriteriawere randomly assigned to treatment with either terbinafine I % cream or placebo, which consisted ofthecreamvehicle. These patients were instructed to rub the cream into the affected area twice daily-morning and eveningfor 2 weeks. Instructions for application stipulated that the entire visibly affected surface was to be treated, as well as a l-inch wide margin ofhealthy skin surrounding the lesion. Patientswereseen before treatment was started, after 1and2 weeks oftherapy,and 2 weeks afterthe conclusion of therapy, At eachvisit, skin scrapings wereobtained fordirectmicroscopic examination of KOH preparations and forculture. If a patientwith abnormal microscopy findings before treatment failed to have cultureconfirmation after the 2-week culture incubation period, he was categorized as a delayed exclusion and was notincluded in the evaluation of drug efficacy. Clinical response to treatmentwasevaluated at eachvisit onthe basis of signs and symptoms ofinfection (i.e., erythema, pustules, desquamation, incrustation, vesiculation, exudation,
795
Journal of the American Academy of Dermatology
796 Millikan Table I. Patient population characteristics
I
T erbinafine
I
Placebo
I
Total
No. of patients 9 18 9 Mean age (yr) 29 28 29 (range) (19-39) (18-42) (18-42) Median illness duration 24 6 (wk) Infecting organism (No. of patients) Trichophyton rubrum 7 7 14 Epidermophyton 1 1 2 floccosum Microsporum canis 1 0 1 T. tonsurans 1* 0 1 Type of lesion Single 2 1 3 Multiple 8 7 15 Previous antifungal Rx I 6 7 *Thispatientalso had concomitant infection with E. fioccosum.
and pruritus), scored individually on a scale of 0 to 3 (0 = absent, 1 = mild, 2 = moderate, 3 = severe). At the end of treatment and at the 2-week followup examination, therapeutic responsein each patient was categorized as follows: complete cure-microscopy normal and culture negative, no residual clinical signs and symptoms; mycologic cure-microscopy normal and culture negative with mild residual erythema and/or desquamation and/or pruritus (total score :$2), but no other signs and symptoms; improvement-culture negative with greater than or less than 50% reduction in signs and symptoms, or culture positivewith significant reduction in signs and symptoms;failure-culture positiveand persistent signs and symptoms. Therapy was defined as "effective" if either a complete cure or mycologic cure was achieved and as "ineffective" if any other response occurred. In addition to this objectiveevaluation of response, the study investigator also provided a subjective assessment of the clinical response to treatment. Bloodsamples were obtained for hematologic and biochemical tests at the initial examination and again at the end of the 2-week treatment period. These tests were repeated at the discretion of the investigator at the follow-upexamination if values detected before or during treatment were significantly outside the accepted normal range. At each visit, local irritation or redness, burning or stinging on application of the medication, and dryness were rated on a scale of 1 to 3 (1 =mild, 2 = moderate,
3 = severe). Other adverse events that may have occurred during treatment were also recorded and rated according to this same scale. Statistical methods Sign tests were used descriptively to assesschanges from baseline separately for microscopy, culture, and each sign or symptom. The total score of signs and symptoms was calculated, and comparison between study groups was made at each visit on the total score and its change from baseline by means of Wilcoxon-Mann-Whitney U tests. The one-tailed Fisher exact test was used for confirmative testing of the null hypothesis that terbinafine was equivalent in efficacy to placebo. Changes from baseline for patients in the final study population were assessed by sign tests for laboratory variables. RESULTS
The original study population consisted of 30 male patients, 15 in each treatment group. Data from eight patients, including five treated with terbinafine and three treated with placebo, were excluded from efficacy analyses because of negative pretreatment cultures. In addition, one terbinafinetreated patient and three placebo-treated patients were dropped from the study because of failure to comply with the study visit schedule. Thus analyses of clinical and myocologic response to treatment were based on data from 18 patients-nine treated with terbinafine and nine treated with placebo. The characteristics of the patient population are noted in Table 1. Most of the patients in the study group were either white (50%) or black (44%). The terbinafine-treated and placebo-treated groups were similar with respect to age and race distribution and all clinical features, with the following exceptions: tinea cruris infection was classified as chronic in eight patients and acute in lO, and the prevalence of chronic disease was substantially higher in the terbinafine-treated group (67%) than in the placebotreated group (22%). Terbinafine-treated patients also had a longer median duration of disease before therapy than those assigned to the placebo-treated group. Trichophyton rubrum was the most common causative organism, occurring in 78% of each treatment group. Clinical efficacy Before the start of treatment, erythema, desquamation, and pruritus (the three major signs and
Volume 23 Number 4, Part 2 October 1990
Topical terbinafine in tinea cruris 797 7 --.-
e
6
en E
5
~
.s Q.
E >(/)
Il!I
TERBINAFINE
--0- Placebo
4
Ul
c: en
.21
:ffl
3
.s c:
I'll
Ql
::E
2
o-l-----~_---..,.__---------..,....-----J 4 2 o (follow-up)
Treatment week
Fig. 1. Reduction in meantotalsigns and symptoms score intreatment oftinea cruris with terbinafine or placebo. Score includes erythema, desquamation, pruritus, incrustation, pustules, and vesiculation; total possible score, 18.
symptoms) were present in all 18 study subjects. Mean scores for each of these signs and symptoms declined rapidly in patientstreated withterbinafine. In contrast, resolution of these clinical manifestations of infection was slower and much less pronounced in the placebo-treated patients. For allsigns and symptoms combined, terbinafine treatment led to a marked reduction in comparison to placebo (Fig. 1). After 1 week of treatment,the meantotal scorein the terbinafine-treated grouphad declined from 6.56 at baseline to 2.67. A reduction to 1.56 wasnotedat the endofthe 2-week treatment period, and an even lower score of 0.78 wasrecorded at the 2-week follow-up examination. The clinical response of the placebo-treated patients was much less marked, thereby resulting in a statistically significant difference between thetwotreatmentgroups in favor of terbinafine at all treatment assessment intervals. The mean changein the total score from baseline was alsosignificantly greater in the terbinafine-treated group than in the placebo-treated group at each examination (p = 0.046, 0.034, and 0.024 at weeks 1,2, and 4, respectively). Mycologic efficacy
After 1 weekof treatment, both microscopy and culture findings had reverted to normal or negative
in sixof eight terbinafine-treated patients examined at that timebutinonly threeofeightplacebo-treated patients (Fig. 2). (Onepatient in eachgroup missed the first visit, but both were evaluable at end of treatment and follow-up). Bythe end of the study, mycologic findings werenegative in allpatients who received terbinafine andinonly threeofninepatients in the placebo-treated group. At the 2-week followup, microscopy andculturefindings were normalor negative in seven terbinafine-treated patients compared with only three placebo-treated patients. Overall efficacy TableII shows theoverall number ofpatients who received effective treatment. At the end of 2 weeks of treatment, 67% of the terbinafine-treated group was categorized as having received effective treatment (complete or mycologic cure with only residual signs andsymptoms). Although mycologic cure withimprovement in symptoms wasnoted inthe remaining terbinafine-treated patients, theirsymptom response didnot meetthe criteria for effective therapy. Only 11 % ofthe placebo-treated patients were categorized as having received effective treatment. The difference between the twogroups in overall efficacy at the endoftreatmentwas ofborderline statistical significance (p = 0.077). The one terbin-
Journal of the American Academy of Dermatology
798 Millikan
--.~
>.
~ 100
! Q)
~
TERBINAFINE Placebo
80
ljll c
~
60
~
40
"-; c,
Cl'l!
20
Oo-----...,.------.,r------------,.-------' o
4
2
(follow-up)
Treatment week
Fig. 2. Percentage ofpatients with normal microscopy findings andnegative culture during andafter treatment with terbinafine or placebo for tinea cruris.
Table II. Overallevaluation of clinical and mycologic response to treatment of tinea cruris with terbinafine versus placebo End of therapy
Response"
Complete cure Mycologic cure Effective therapy Improvement Failure Ineffective therapy
Terbinaline
I
4
.f
6 (67%) 3
Q
3 (33%)
Follow-up Placebo
0
1
1 (11%) 2
.Q
8 (89%)
Terbinaline
4
J
7 (78%) 1
1
2 (22%)
I
Placebo
1
.f
3 (33%) 1
s
6 (67%)
*Complete cure, negative culturewith no signsand symptoms; mycologic cure, negativeculture with minimalsignsand symptoms (score
