Treatment of tinea cruris with topical terbinafine Donald L. Greer, PhD, and Henry W. Jolly, Jr, MD New Orleans, Louisiana Twenty-three patients were enrolled in a randomized, double-blind trial of terbinafine 1% cream versus itsvehicle (placebo) inthetreatment of tineacruris. Onepatient had a negative initial culture and was excluded, and two patients were dropouts, onebecause of poor study compliance (terbinafine) andonebecause ofan adverse event (placebo). Twenty patients were examined for efficacy of treatment (9 terbinafine-treated, 11 placebo-treated). Bothgroups were similar in age, sex, duration ofdisease, priortherapy, sizeand location oflesion, infecting organism, and predisposing factors. Terbinafine 1% creamwas moreeffective than vehicle cream inthe reduction ofthe signs andsymptoms oftineacruris. In addition, therewas a higher conversion rate to negative culture and normal microscopy findings in the terbinafine-treated group. Clinical results combined withevaluation ofmycologic tests at end oftherapy showed terbinafine to bea rapidandsignificantly moreeffective treatmentfortinea cruris thanplacebo (78% vs18% curerate,respectively). Follow-up cureratesconfirmed these findings (89% and 18%, respectively). No significant adverse events occurred during terbinafine treatment. (J AM ACAD DERMATOL 1990;23:800-4.) Treatment of cutaneous fungal infectionshas entered into the age of "designerdrugs." 1 Griseofulvin has been the principal antifungal agent against dermatophytes for the past 35 years; however, the need for broad-spectrum agents resulted in the development of two groups of antifungals-polyenes and azoles. Most recently a new chemical family has shownpromise in the treatment of fungal infections. These new antifungals,the allylamines, are naftifine and terbinafine (Lamisil). Terbinafine is active both orally and topically against a wide range of pathogenic fungi- 3 and more active than most other antifungal drugs." Investigations in animal models of dermatophytosis indicated that topical terbinafine rapidly resolvedsignsof infection and eradicated the causative fungi.5, 6 Phase II human trials of oral terbinafine in the treatment of tinea corporis revealed that it was significantly more effective than griseofulvin." Numerous clinical studies to evaluate the efficacy and safety of terbinafine revealeda unique prolongedeffect in some chronictinea infectionsas well as its efFromtheSchool ofMedicine, Department of Dermatology, Louisiana State University Medical Center. Supported in part by an educational grantfromSandozPharmaceuticalsCorp., East Hanover, N.J. Reprint requests: Donald L. Greer, PhD,Professor of Clinical Mycology,Department ofDermatology, Louisiana State University Medical Center, 1542TulaneAvenue, New Orleans, LA 70112.
16/0/23515
800
fectiveness against nail infections.S 9 Reported herein are the results of a double-blind, placebocontrolled trial of terbinafine 1%cream in the treatment of tinea cruris. PATIENTS AND METHODS
In this randomized trial, 23 men with tinea crurisbetween 18 and 65 years of age documented clinically and by positive KOH microscopy were recruited. Patients withconcomitant yeast or bacterial infections of the skin wereexcluded, as were those treated withsystemic antifungal drugs within the preceding 4 weeks or with topical antifungal therapy within the preceding 2 weeks. Concomitant therapyforchronic diseases, suchas diabetes or hypertension, was allowed. After providing informed consent, patients who met the study entry criteriawere randomly assigned to treatmentwitheitherterbinafine 1% creamor its creamvehicle (placebo). Thesepatients wereinstructed to rub the cream twice daily for 2 weeks into the entire visibly affected area to a l-inchwide marginofhealthyskinsurrounding the lesion. Study visits were scheduled before treatmentwasstarted,after 1and2 weeks oftherapy, and again 2 weeks after the completion of therapy. At each visit, skin scrapings were takenfor microscopic examinationbyKOH preparation andforculture. If a patientwith abnormal microscopy findings before treatment failed to havecultureconfirmation after the 2-week cultureincubationperiod, he was categorized as a delayed exclusion and was not included in the evaluation of drug efficacy. In addition to mycology, sixsigns and symptoms were assessed at eachstudyvisit (erythema, pustules, desqua-
Volume 23 Number4, Part 2 October 1990
Response of tinea cruris to topical terbinafine 801
100 >.
Cl
~
90
E
80
~
Q)
.~
'iii g' c
:: 'j .!!l cQ)
TERBINAFINE
- 0 - Placebo
60 50
....10
40
*-
30
a.
--.-
70
20
10 4 (follow-up)
Treatment week
Fig. 1. Percentage of patients withnormal microscopy findings andnegative culture before, during, and after topical terbinafine or placebo treatmentfor tineacruris. mation, incrustation, vesiculation, and pruritus) and were scored on a scale of 0 to 3 (0 =absent, I =mild, 2 = moderate, 3 = severe). Blood samples were obtained for hematologic and biochemical tests at the initial examination and againat theendofthe 2-weektreatment period. These tests could be repeated the follow-up examination at the discretion of the investigator if values detected earlier were significantly outside the accepted normal range. At each visit, local irritation or redness, burningor stinging on application of themedication, and dryness were rated on a scale of 1 to 3 (1 =mild, 2 = moderate, 3 = severe). Other adverse events that may haveoccurred during treatment were also recorded and rated according to this same scale. At the end of treatment and at the 2-week follow-up examination, therapeutic response in each patient was categorized as follows: complete cure-normal microscopyfindings and negative culture, no residual signs and symptoms; mycologic cure-normal microscopy findings and negative culture, mildresidual erythema andjor desquamation andj orpruritus(totalscore::::;2), butno other signs and symptoms; improvement-significant reduction in signs and symptoms, but residual signs and symptoms (total score>2) andjor presence of pathogen; failure-no significant response totherapyorexacerbation of signs and symptoms. If a patient achieved a complete cure or a mycologic cure with mildresidual signs or symptoms, the response
Table I. Patient population characteristics
I
Terbinafine
No. of 9 patients Mean age (yr) 38 (range) (22-64) Duration of illness 16 (wk) Infecting organism Trichophyton rubrum 8 Epidermophyton 1 floccosum T. mentagrophytes 0 Previous antifungal Rx 5
I
Placebo
11
I
Total
20
41 (25-63) (22-64) 20 10 0
18 1
I
1 8
3
to treatment was considered to be "effective." Therapy was defined as "ineffective" if any other response 0ccurred. In addition to this objective evaluation of response, the study investigator also provided a subjective assessment of the clinical response to treatment. Statistical analyses. Sign tests were used to assess changes from baseline for microscopy, culture, and each sign or symptom. Comparison oftotalscores ofsigns and symptoms at eachstudy visit, aswell as their change from baseline, was accomplished by means of WilcoxonMann-Whitney U tests. The one-tailed Fisher exacttest wasusedfor confirming the null hypothesis that terbin-
Journal of the American Academy of Dermatology
802 Greer and Jolly 10 CIl
9
~
8
l!!
•
CIl
E sac. E
7
CIl
S
>0-
-0-
TERBINAFINE Placebo
~ CIl
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'0
E
5
4
p
~
CIl
r::: al
s
0.025
3
Q)
::!:
2
o
L---.------=====:::=:::::::=$.-----.J o
4
2
(follow-up)
Treatment week
Fig. 2. Mean sum of scores for signsand symptoms by weekof treatment with topical terbinafineor placebo for tinea cruris infections; includes erythema,pustules, desquamation, incrustation, vesiculation, and pruritus. Total possible score, 18.
Table II. Overall evaluation of clinical and mycologic response to topical terbinafine versus placebo in treatment of tinea cruris Follow-up
End of therapy Terbinafine
Complete cure Mycotic cure with minimal signs EffectiveRx Mycologic cure with symptom improvement Mycologic failure with symptom improvement Failure Ineffective Rx
afine was equivalent in efficacy to placebo. Changes in laboratory variables from baseline were assessed individually by means of sign tests.
RESULTS One patient who began treatment with terbinafine became categorized as a delayed exclusion because of negative initial culture for dermatophytes, and two patients were considered dropouts because they failed to attend study visits (one terbinafine, one placebo). The final study group thus included 20 patients, nine treated with terbinafine and 11 treated
I
Placebo
0
5 2
2
Terbinafine
7 1
I
Placebo
1 1
"7 (78%)
:2 (18%)
8" (89%)
:2 (18%)
1
0 5 4
0 0
0 1
T (11%)
9 (82%)
0
1
:2 (22%)
9 (82%)
1
8
with placebo. Three patients (one terbinafine, two placebo) terminated the study prematurely because of lack of efficacy after I week. They are classified as failures in the overall efficacy of evaluation. The two treatment groups were demographically similar (Table I). Most of the patients were either white (35%) or black (60%). Tinea cruris infection was classified as chronic in six patients and acute in 14 and was evenly divided between the two treatment groups. Drug efficacy was evaluated by the determination of mycologic response (time to normal microscopy
Volume 23 Number 4, Part 2 October 1990
findings and negative culture), signs and symptoms, and a combination of the two. Mycologic efficacy At all study time points, terbinafine showed a higher percentage of patients with conversion to normal microscopy findings and negative culture than did placebo treatment (Fig. 1). By the end of the 2-weektreatment period and at follow-up, 100% of the terbinafine-treated patients had achieved conversion to normal microscopy findings and negative culture versus 22% (two of nine) and 29%(two of seven), respectively, in the placebo-treated group. Clinical efficacy The most frequently reported signsand symptoms before therapy were erythema (100%), desquamation (100%), and pruritus (100%). Each of these resolved at a rapid rate in the terbinafine-treated group and at only a limited rate in the placebo-treated group. Fig. 2 shows the mean sum of scores for all signs and symptoms combined before, during, and after treatment. Although a marked reduction in the mean scores was observed in both groups, a significant difference in response between the two groups was observed at the 2-week posttreatment follow-up favoring terbinafine (p < 0.025). Overall efficacy Table II shows the response to treatment at the end of therapy and at the 2-week posttreatment follow-up for the 20 patients who were evaluated for overall efficacy (complete cure or mycologic cure with minor residual clinical signs). At the end of treatment, a difference favoring terbinafine (78% vs 18%) was observed. At follow-up, the difference in overall efficacy was still remarkable (89% vs 18%) and was statistically significant (p -< 0.003, onetailed Fisher exact test). Adverse events
No significant adverse events were reported for either treatment group . Only one patient (placebo group) reported a local side effect, itching and burning, which was likely due to the vehicle. No significant changes in laboratory test results of hematologic, liver, and kidney function were observed during or after therapy. One patient in the terbinafinetreated group had a decrease in total WBC count from 8400 to 2400jmm 3 at 2 weeks of treatment,
Response oj tinea cruris to topical terbinafine 803 but this change was not accompanied by any signs or symptoms. This was not considered a drug-related effect. DISCUSSION
Our results confirm those of earlier clinical studies of topical terbinafine in a variety of superficial dermatomycoses. In another double-blind, placebo-controlledstudy, terbinafine treatment of tinea cruris or tinea corporis led to mycologic cure with improvement of signs and symptoms in 76% of patients versus only 17% in placebo-treated patients. However, by follow-up, 88% of the terbinafinetreated group was considered cured. 10 A multicenter Japanese trial of 614 patients found that terbinafine 1% cream was both effective and safe in the treatment of the followingdermatomycoses: tinea cruris, tinea corporis, tinea pedis, interdigital or intertriginous candidiasis, and pityriasis versicolor. I I Furthermore, the side effect profile oftopical terbinafine appears to be excellent; side effects were infrequent and mild. In the Japanese trial, adverse reactions consisting of local irritant contact dermatitis and pruritus were noted in only I % of the patients. I I In the other small placebo-controlled trial, no side effects were noted.'? A review of 27 clinical studies of terbinafine 1% cream noted that side effects consistingof only localburning, itching, or redness at the application site occurred in 2.2% of 1258 patients. 12 The efficacy of terbinafine as an oral treatment for more recalcitrant fungal infections, such as moccasin-type tinea pedis or onychomycosis, has recently been confirmed'
16/0/23515
800
fectiveness against nail infections.S 9 Reported herein are the results of a double-blind, placebocontrolled trial of terbinafine 1%cream in the treatment of tinea cruris. PATIENTS AND METHODS
In this randomized trial, 23 men with tinea crurisbetween 18 and 65 years of age documented clinically and by positive KOH microscopy were recruited. Patients withconcomitant yeast or bacterial infections of the skin wereexcluded, as were those treated withsystemic antifungal drugs within the preceding 4 weeks or with topical antifungal therapy within the preceding 2 weeks. Concomitant therapyforchronic diseases, suchas diabetes or hypertension, was allowed. After providing informed consent, patients who met the study entry criteriawere randomly assigned to treatmentwitheitherterbinafine 1% creamor its creamvehicle (placebo). Thesepatients wereinstructed to rub the cream twice daily for 2 weeks into the entire visibly affected area to a l-inchwide marginofhealthyskinsurrounding the lesion. Study visits were scheduled before treatmentwasstarted,after 1and2 weeks oftherapy, and again 2 weeks after the completion of therapy. At each visit, skin scrapings were takenfor microscopic examinationbyKOH preparation andforculture. If a patientwith abnormal microscopy findings before treatment failed to havecultureconfirmation after the 2-week cultureincubationperiod, he was categorized as a delayed exclusion and was not included in the evaluation of drug efficacy. In addition to mycology, sixsigns and symptoms were assessed at eachstudyvisit (erythema, pustules, desqua-
Volume 23 Number4, Part 2 October 1990
Response of tinea cruris to topical terbinafine 801
100 >.
Cl
~
90
E
80
~
Q)
.~
'iii g' c
:: 'j .!!l cQ)
TERBINAFINE
- 0 - Placebo
60 50
....10
40
*-
30
a.
--.-
70
20
10 4 (follow-up)
Treatment week
Fig. 1. Percentage of patients withnormal microscopy findings andnegative culture before, during, and after topical terbinafine or placebo treatmentfor tineacruris. mation, incrustation, vesiculation, and pruritus) and were scored on a scale of 0 to 3 (0 =absent, I =mild, 2 = moderate, 3 = severe). Blood samples were obtained for hematologic and biochemical tests at the initial examination and againat theendofthe 2-weektreatment period. These tests could be repeated the follow-up examination at the discretion of the investigator if values detected earlier were significantly outside the accepted normal range. At each visit, local irritation or redness, burningor stinging on application of themedication, and dryness were rated on a scale of 1 to 3 (1 =mild, 2 = moderate, 3 = severe). Other adverse events that may haveoccurred during treatment were also recorded and rated according to this same scale. At the end of treatment and at the 2-week follow-up examination, therapeutic response in each patient was categorized as follows: complete cure-normal microscopyfindings and negative culture, no residual signs and symptoms; mycologic cure-normal microscopy findings and negative culture, mildresidual erythema andjor desquamation andj orpruritus(totalscore::::;2), butno other signs and symptoms; improvement-significant reduction in signs and symptoms, but residual signs and symptoms (total score>2) andjor presence of pathogen; failure-no significant response totherapyorexacerbation of signs and symptoms. If a patient achieved a complete cure or a mycologic cure with mildresidual signs or symptoms, the response
Table I. Patient population characteristics
I
Terbinafine
No. of 9 patients Mean age (yr) 38 (range) (22-64) Duration of illness 16 (wk) Infecting organism Trichophyton rubrum 8 Epidermophyton 1 floccosum T. mentagrophytes 0 Previous antifungal Rx 5
I
Placebo
11
I
Total
20
41 (25-63) (22-64) 20 10 0
18 1
I
1 8
3
to treatment was considered to be "effective." Therapy was defined as "ineffective" if any other response 0ccurred. In addition to this objective evaluation of response, the study investigator also provided a subjective assessment of the clinical response to treatment. Statistical analyses. Sign tests were used to assess changes from baseline for microscopy, culture, and each sign or symptom. Comparison oftotalscores ofsigns and symptoms at eachstudy visit, aswell as their change from baseline, was accomplished by means of WilcoxonMann-Whitney U tests. The one-tailed Fisher exacttest wasusedfor confirming the null hypothesis that terbin-
Journal of the American Academy of Dermatology
802 Greer and Jolly 10 CIl
9
~
8
l!!
•
CIl
E sac. E
7
CIl
S
>0-
-0-
TERBINAFINE Placebo
~ CIl
r::: Cl 'iii
'0
E
5
4
p
~
CIl
r::: al
s
0.025
3
Q)
::!:
2
o
L---.------=====:::=:::::::=$.-----.J o
4
2
(follow-up)
Treatment week
Fig. 2. Mean sum of scores for signsand symptoms by weekof treatment with topical terbinafineor placebo for tinea cruris infections; includes erythema,pustules, desquamation, incrustation, vesiculation, and pruritus. Total possible score, 18.
Table II. Overall evaluation of clinical and mycologic response to topical terbinafine versus placebo in treatment of tinea cruris Follow-up
End of therapy Terbinafine
Complete cure Mycotic cure with minimal signs EffectiveRx Mycologic cure with symptom improvement Mycologic failure with symptom improvement Failure Ineffective Rx
afine was equivalent in efficacy to placebo. Changes in laboratory variables from baseline were assessed individually by means of sign tests.
RESULTS One patient who began treatment with terbinafine became categorized as a delayed exclusion because of negative initial culture for dermatophytes, and two patients were considered dropouts because they failed to attend study visits (one terbinafine, one placebo). The final study group thus included 20 patients, nine treated with terbinafine and 11 treated
I
Placebo
0
5 2
2
Terbinafine
7 1
I
Placebo
1 1
"7 (78%)
:2 (18%)
8" (89%)
:2 (18%)
1
0 5 4
0 0
0 1
T (11%)
9 (82%)
0
1
:2 (22%)
9 (82%)
1
8
with placebo. Three patients (one terbinafine, two placebo) terminated the study prematurely because of lack of efficacy after I week. They are classified as failures in the overall efficacy of evaluation. The two treatment groups were demographically similar (Table I). Most of the patients were either white (35%) or black (60%). Tinea cruris infection was classified as chronic in six patients and acute in 14 and was evenly divided between the two treatment groups. Drug efficacy was evaluated by the determination of mycologic response (time to normal microscopy
Volume 23 Number 4, Part 2 October 1990
findings and negative culture), signs and symptoms, and a combination of the two. Mycologic efficacy At all study time points, terbinafine showed a higher percentage of patients with conversion to normal microscopy findings and negative culture than did placebo treatment (Fig. 1). By the end of the 2-weektreatment period and at follow-up, 100% of the terbinafine-treated patients had achieved conversion to normal microscopy findings and negative culture versus 22% (two of nine) and 29%(two of seven), respectively, in the placebo-treated group. Clinical efficacy The most frequently reported signsand symptoms before therapy were erythema (100%), desquamation (100%), and pruritus (100%). Each of these resolved at a rapid rate in the terbinafine-treated group and at only a limited rate in the placebo-treated group. Fig. 2 shows the mean sum of scores for all signs and symptoms combined before, during, and after treatment. Although a marked reduction in the mean scores was observed in both groups, a significant difference in response between the two groups was observed at the 2-week posttreatment follow-up favoring terbinafine (p < 0.025). Overall efficacy Table II shows the response to treatment at the end of therapy and at the 2-week posttreatment follow-up for the 20 patients who were evaluated for overall efficacy (complete cure or mycologic cure with minor residual clinical signs). At the end of treatment, a difference favoring terbinafine (78% vs 18%) was observed. At follow-up, the difference in overall efficacy was still remarkable (89% vs 18%) and was statistically significant (p -< 0.003, onetailed Fisher exact test). Adverse events
No significant adverse events were reported for either treatment group . Only one patient (placebo group) reported a local side effect, itching and burning, which was likely due to the vehicle. No significant changes in laboratory test results of hematologic, liver, and kidney function were observed during or after therapy. One patient in the terbinafinetreated group had a decrease in total WBC count from 8400 to 2400jmm 3 at 2 weeks of treatment,
Response oj tinea cruris to topical terbinafine 803 but this change was not accompanied by any signs or symptoms. This was not considered a drug-related effect. DISCUSSION
Our results confirm those of earlier clinical studies of topical terbinafine in a variety of superficial dermatomycoses. In another double-blind, placebo-controlledstudy, terbinafine treatment of tinea cruris or tinea corporis led to mycologic cure with improvement of signs and symptoms in 76% of patients versus only 17% in placebo-treated patients. However, by follow-up, 88% of the terbinafinetreated group was considered cured. 10 A multicenter Japanese trial of 614 patients found that terbinafine 1% cream was both effective and safe in the treatment of the followingdermatomycoses: tinea cruris, tinea corporis, tinea pedis, interdigital or intertriginous candidiasis, and pityriasis versicolor. I I Furthermore, the side effect profile oftopical terbinafine appears to be excellent; side effects were infrequent and mild. In the Japanese trial, adverse reactions consisting of local irritant contact dermatitis and pruritus were noted in only I % of the patients. I I In the other small placebo-controlled trial, no side effects were noted.'? A review of 27 clinical studies of terbinafine 1% cream noted that side effects consistingof only localburning, itching, or redness at the application site occurred in 2.2% of 1258 patients. 12 The efficacy of terbinafine as an oral treatment for more recalcitrant fungal infections, such as moccasin-type tinea pedis or onychomycosis, has recently been confirmed'
